Educating, Evaluating, and Selecting Living Kidney Donors

EDUCATING, EVALUATING, AND SELECTING LIVING KIDNEY DONORS

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EDUCATING, EVALUATING, AND SELECTING LIVING KIDNEY DONORS Edited by Robert W. Steiner University of California, UCSD Center for Transplantation, San Diego, U.S.A.

KLUWER ACADEMIC PUBLISHERS NEW YORK, BOSTON, DORDRECHT, LONDON, MOSCOW

eBook ISBN: Print ISBN:

1-4020-2276-X 1-4020-1271-3

©2004 Kluwer Academic Publishers New York, Boston, Dordrecht, London, Moscow Print ©2004 Kluwer Academic Publishers Dordrecht All rights reserved No part of this eBook may be reproduced or transmitted in any form or by any means, electronic, mechanical, recording, or otherwise, without written consent from the Publisher Created in the United States of America Visit Kluwer Online at: and Kluwer's eBookstore at:

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Table of Contents Foreword

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Chapter One Ethical Approaches to Living Kidney Donor Education and Acceptance Robert W. Steiner, M.D., William M. Bennett, M.D. and Bernard Gert, Ph.D.

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Chapter Two Quality of Life and Survival on Dialysis and after Renal Transplantation Paul A. Keown, M.D., DSc., M.B.A.

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Chapter Three Outcomes for Living Donor and Cadaver Donor Kidney Transplantation Pablo Ruiz-Ramón, M.D. and Lawrence Hunsicker, M.D.

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Chapter Four The Medical Evaluation and Risk Estimation of End Stage Renal Disease for Living Kidney Donors Robert W. Steiner, M.D. and Gabriel Danovitch, M.D.

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Chapter Five The Risk of End Stage Renal Disease for Hypertensive Kidney Donors Scott R. Mullaney, M.D. and Michael G. Ziegler, M.D.

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Chapter Six Risk of Diabetes and Diabetic Nephropathy David M. Ward, M.D.

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Chapter Seven The Education and Counseling Process for Potential Donors and Donor Attitudes after Living Kidney Donation Robert W. Steiner, M.D. and Christine A. Frederici, L.C.S.W.

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Chapter Eight Attitudes, Practices, and Ethical Positions among Transplant Centers Concerning Living Kidney Donor Selection Aaron Spital, M.D.

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Index

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Foreword This book is intended to provide information and policy and procedure suggestions for centers that perform living donor kidney transplantation. Its purpose is not to argue either for kidney donation for any candidate or against donation for most candidates, but rather to help make the donation process well considered regardless of individual decisions. We look forward to an ongoing effort that will improve and expand the offerings in this volume, to promote defensible kidney donor education, evaluation, and selection. The Authors

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Chapter One Ethical Approaches to Living Kidney Donor Education and Acceptance Robert W. Steiner, M.D., William M. Bennett, M.D. and Bernard Gert, Ph.D. Summary Points • The center’s desire to perform transplants creates a conflict of interest that it must explicitly address. • In evaluating a donor, ethical issues should be distinguished from factual ones and approached accordingly. • The medical question is always the degree of risk, not whether donation is (safe) for the donor. • To accept living kidney donors, centers must have good reason to believe that they are: (1) informed, (2) acting freely, and (3) acting rationally. • Willing, informed, and rational donors at increased risk can only be rejected if acceptance would unavoidably erode the standards of the center or engender public suspicion of the selection process. • Centers must distinguish rejecting a donor due to increased medical risk from rejecting a donor who is inadequately informed or for whom the risk is truly unknown. • The donor’s decision must be reasonable (rational) for him, but it does not have to be the decision that the donor counselor or many others would make in the same situation. • Transplant centers are held to a higher standard for determining donor suitability, compared to self interested supporters of other activities involving personal risk in our society.

1 R.W. Steiner (ed.), Educating, Evaluating, and Selecting Living Kidney Donors, 1–12.  2004 Kluwer Academic Publishers. Printed in the Netherlands.

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This chapter will discuss the ethically acceptable reasons and procedures for accepting or rejecting living kidney donors. By so doing, we hope to clarify ethical debate by framing the appropriate fundamental issues. The chapter will not settle all ethical debate, as ethically sensitive and conscientious individuals may still differ in difficult cases. Our aim nevertheless is that even when individuals disagree on the acceptability of specific donors, they will still agree on the general fundamental ethical principles which must be satisfied for donor acceptance or rejection. It is essential to distinguish ethical issues from factual ones. When an individual claims that donors should be rejected if they are being pressured to donate, he is providing a valid ethical reason. The factual question is whether a donor is actually being pressured to donate. Facts can be determined by investigation. Ethical disagreements are argued by considering clear cases in which we all agree, and then applying those formulations of appropriate ethical reasoning to difficult cases. Other chapters in this book deal primarily with factual issues surrounding living donor transplantation. This chapter deals primarily with what we suggest are the appropriate ethical considerations. Living kidney transplantation has long been regarded as a difficult area ethically. In the process of living kidney donation, the center must put the donor in harm’s way both with the inevitable perioperative risks and discomfort and the long term risk incurred by having one kidney instead of two. In contrast, medical professionals are accustomed only to helping patients directly or to harming a patient in order to help the same patient – as with surgery to remove a tumor. To further complicate matters, transplant professionals have conflicts of interest since transplantation benefits a third party, the recipient, for whom they have both altruistic concern and ongoing medical responsibility before and after transplantation. The transplant center is also compensated both financially and by the increased prestige that a busy transplant program generates. Finally, that same center is charged with the responsibility of informing as many potential donors as possible about living kidney donation, so that some may then wish to come forward to be considered for donation. The center must then continue to educate those donors and test, counsel, and accept or reject them for donation. One hears a variety of reasons for accepting or rejecting a living kidney donor. One may hear that a donor should be accepted because “risk is low”, or that he should be rejected because “there is a risk”, or “he will live to regret it”, or “I have a bad feeling about this one”. These particular reasons may seem valid, but they are not by themselves the essential factors that should make us decide that it is ethical or unethical to proceed with the transplant in question. Some donors should be rejected even though their risk is low. Donors always take risk. An appropriately accepted donor may live to regret donation. One may have a bad feeling about something that is still the ethically correct thing to do. In explicitly formulating its ethical position, the center must first recognize that it has inherent conflicts of interest in the process of kidney donor selection. Conflicts of interest are common in medical practice and in life, and to have them is not unethical. Indeed the center’s desire to perform as many transplants as possible is in many ways laudable. It can be unethical however to conceal a conflict of interest or to organize a transplant program so that one is avoidably influenced by it. A center can also be so concerned about its conflicts of interest

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that it overreacts and denies acceptance to appropriate donors to avoid any possibility of criticism. As will be discussed below, full disclosure, a healthy conditional respect for the donor’s right to decide for himself and an impartial and thorough education are the basic features of the center’s only ethically justified position. The following paragraphs explain these features. All involved in living kidney donor transplantation must acknowledge that donation always involves the risk and discomfort of the operative procedure itself and the long term risk of having only one kidney. The risk may be acceptable for many centers and many individuals, but it is never nil. Risk also is often different for different classes of acceptable donors. Young donors will live longer, and will have more time to develop renal disease in later life. Black donors are at risk relative to Caucasians [1, 2]. Blood relatives of patients with many renal diseases, even though they have a benign donor evaluation, can be at increased risk [3]. Therefore, centers should not focus on whether there is “a risk”, but to try to quantify the risk, convey it to the donor, and let the donor decide [4]. There will, of course, still be cases in which the center decides it would be unethical to proceed, and these are also discussed below. Respect for the right of the patient to decide requires centers to recognize that altruism is ethically acceptable as a reason to donate – it needs no reward. Professed altruism need not suggest that a donor is irrational or uninformed. It is perfectly reasonable for an individual to want to donate a kidney simply to help another. It also wrongly makes altruism sound self interested if one speaks of “a mental benefit” or a “feeling of importance” for the donor coming from donation [4]. The center cannot guarantee these mental benefits to donors and need not ascertain whether they will occur after donation. It is reasonable for someone to act to help someone else as the sole justification for that action. Some people often act this way; others seldom do. Both choices are reasonable and must be recognized as such. However, altruism is not the only motive which should be acceptable to centers. Donors may donate because avoiding dialysis for the recipient improves the donor’s individual situation. Spousal donation may have such a self interested rationale [5], as may the donation of a kidney from a parent to a child who must otherwise undergo in-center dialysis. Of course, some donors can have both altruistic and self interested reasons, but self interested reasons are not in themselves unacceptable. Individuals who want to donate a kidney for money or for some other reward are discussed in subsequent sections. These donors differ importantly from conventional donors, either altruistic or self interested, in that they need not care at all whether the donated kidney functions. Their reward is different and usually is financial. It is often proper to sanction individuals who have a clear-cut duty that they do not fulfil. Dutiful donors are those who feel that they deserve such ethical sanction if they do not make every attempt to donate. Most of us recognize however that no one has a duty to donate a kidney, i.e., – no one deserves criticism or punishment if they do not come forward. Dutiful donors may still suffer if they do not donate, because they themselves feel guilty if they do not do so. A persistent, dutiful donor who receives the usual complete and impartial evaluation and counseling can ethically be accepted by centers. However, the center should not tacitly encourage the donor’s sense of duty, but rather should point out that there

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is not an accepted duty for anyone to donate a kidney. Donors who donate for religious reasons are also often dutiful donors. There is no consensus that acts such as kidney donation are required by any religion, but it may be easy to wrongly manipulate some potential donors with religious arguments. Nevertheless, the center may encounter individuals secure in their religion who wish to donate as a religious duty, to receive a divine reward, or to please God. As long as the center is neutral about such religious reasons, is careful that it does not overtly or tacitly encourage this rationale, and does not abridge its usual donor selection procedure, donors with religious motivation would also seem acceptable. The only four appropriate general reasons for rejecting a donor on ethical grounds are (1) that the donor is not informed, (2) that donation would not clearly be rational for that donor, i.e., the benefit is too small in relation to risk for that person and sometimes for any reasonable person, (3) that consent is not free and voluntary, and (4) that donor acceptance would significantly risk harm to future donors or recipients. Any of these four reasons justifies donor non-acceptance by itself. Many individuals already instinctively use these reasons to justify ethical decisions, although they may or may not be able to articulate and explain them systematically. Therefore in offering these formulations, we do not necessarily suggest that anyone involved in donor selection should change his or her donor selection practices. This certainly may happen in some difficult cases with discussion and reflection, as it may with any complicated intellectual process. However, we suggest that ultimately all the good reasons for rejecting a donor ultimately come down to the four we have formulated. The following paragraphs consider each of these reasons in more detail. The first good reason to reject donors is because they are not informed. Donors must be informed to be acceptable. This does not mean that donors need simply to be exposed to material regarding renal transplantation. Donor understanding is important because the donor formulates his idea of risk and benefit on the basis of it. A donor must know what he is likely to achieve, what he is risking, and the alternatives available to the recipient. These alternatives, of course, include dialysis, cadaver kidney transplantation, and transplantation from other living donors [6]. These issues are discussed elsewhere in this book. The center needs a reasonable measure of whether the donor has understood these important issues. This can be obtained with specific donor testing [7] and is discussed in Chapter Seven. Donors who cannot be adequately be informed should not be accepted. The belief that a donor could not be informed may be the underlying and sometimes vaguely formulated reason that some centers do not accept unsophisticated donors who either have complicated medical findings on their evaluation or have a recipient with unusual risk factors. However, the center is usually not justified in simply assuming that unsophisticated donors cannot be taught and tested as to their level of understanding. Rejecting a donor because he or she is not informed can only justifiably take place when reasonable efforts have been made to educate and test that donor. The center and the rejected donor should be clear that donor rejection took place because of doubts about the donor’s understanding of risk, not because donation was high risk. Conversely, even a donor with an extremely benign medical evaluation must be declined if he is not successfully educated in a standard fashion. What would not appear to be fundamentally important when deciding on donor

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acceptability is donor emotion. An emotional donor, in fact, could be one who resists being educated and makes a bad personal choice to donate. A donor who is particularly fond of the recipient still must be educated and meet the other ethical requirements before being accepted. Some caring, emotional donors certainly give evidence that they might be donors who could be appropriately educated and would still wish to proceed, but emotion is not the central issue. Relatives who wish to donate have been considered by some to be fundamentally different from unrelated donors, but they are not [8]. Blood relation is neither a substitute for donor understanding nor a guarantee against coerced donation. Personal relationships among blood relatives are often strong enough so that adequately informed donors might freely wish to donate, but this cannot be assumed. Likewise, for the reasons discussed above, the center should not feel or suggest that blood relatives have a duty to donate or need not be educated. Unrelated lifelong friends often have as strong or stronger relationships than many close blood relatives. For these reasons, the center’s ethical guidelines for selecting living unrelated donors cannot be different in kind from its guidelines for selecting living related kidney donors. Good Samaritan donors are living unrelated donors who wish undirected donation or donation to someone with whom they have a minimal prior relationship [9]. They are often particularly uninformed about many aspects of donation, and they need to be educated and their expectations ascertained. The issues involved in selecting these donors, however, are not fundamentally different from those involving other donors. The importance of ascertaining that a donor understands all of the relevant information about kidney donation is suggested by a recurring scenario in which a problematic donor is refused at one center and then applies to a second center and is accepted. This is not a rare occurrence and certainly could simply reflect a difference in ethical judgment at the two centers. However, the second center may be more confident that a donor who is rejected by one center understands that he is at relatively high risk. By seeking out a second center for reconsideration the donor also suggests that he is motivated. Therefore, it may be easier for a center to accept a donor who has been refused by another program than to accept a complicated donor with the same problems on his initial presentation to its own program. Similarly, a persistent donor who repeatedly applies to the same center after first being declined is sometimes accepted because his awareness of risk and his willingness to proceed become more obvious. Of course, it is unethical to accept a donor simply because he is persistent, but such persistence can be relevant to legitimate acceptance criteria in these ways. Centers should be able to develop explicit, focused protocols to document the donor’s knowledge and motivation to minimize the number of such persistent or peripatetic, ultimately acceptable donors. Several other consequences follow from the above considerations. First, centers cannot by considering only blood relationship and the donor’s risk factors accept or reject a donor. To accept any donor and to reject most donors the center needs to interview to assess the donor’s degree of understanding and his level of motivation. If a center would ever accept even one donor with a certain risk factor, it should afford such consideration to all similar individuals. The center cannot suppose it already somehow knows each new donor’s level of knowledge and comfort with risk. It is also clear that no matter what the recipient’s need, even

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very low risk donors have the perfect right to decide not to donate, and these donors should not be treated more expeditiously in the selection process. They should be afforded the same education and the same right to withdraw that more complicated donors have. By the same token, donors who are closely related to recipients should not be assumed to be highly motivated, nor should unrelated donors be assumed to want to take less risk than related donors. Furthermore, the center must correctly inform donors as to why they are not accepted. That is, a donor who is rejected because he cannot be adequately informed must not be left to feel that he is rejected because of a high risk. He must be told that, try as it might, the center cannot document that he understands the risks, benefits, and alternatives. A donor who is being pressured to donate must understand that he is not acceptable because he is being pressured. The uncoerced and informed donor at high risk, e.g., the “heroic” donor must be told that no one is questioning his sanity or whether his purpose is laudable, but that accepting him would “lower the bar” and threaten the evaluation process for others, or that his acceptance would unavoidably incur the public’s suspicion that the transplant center had acted unethically, even when it had not. This reason will be discussed in more detail later. Having to explain to the donor the specific reason for rejection (1) clarifies the center’s thinking, (2) gives the donor a chance to respond, (3) may result in further justification for the center’s decision, and/or (4) may cause the center to reconsider its rejection of the donor. The second good reason to reject a donor is that donation is not free and voluntary. The center’s charge is to facilitate the donor’s well-considered decision to donate, but only if there are no threats or pressure placed upon the donor by other individuals. The mother who is donating to avoid having to take her daughter to and from dialysis is making a free and voluntary choice based on the facts of the situation. A wife who is donating because her husband is harassing her is donating because she is being pressured. The third good reason to reject a donor is that donation is not clearly rational. Irrational donors have false beliefs concerning donation, but are not simply uneducated. Such irrational beliefs are beliefs that are still held despite competence to understand and adequate exposure to the facts. Some reasons for donation are irrational for a specific donor, and some are irrational for all donors. If a donor wishes to donate to a recipient who will not take his medicines and lose the kidney in three months, there will not be enough benefit to make donation rational for any donor. A donor who wishes to donate to a recipient who has never worked so that the recipient will become employable may be acting irrationally but only in his specific situation. A person who cannot accept any risk of dialysis but wants to proceed with donation may be acting irrationally in this donor-specific sense. One reason for donor screening in psychosocial interviews is that the donor’s decision should be determined to be rational for him. That is, the donor’s reasons for donating should make sense in the context of his overall goals and needs, as discussed in Chapter 7. They do not have to be the reasons that the donor counselor or other donors might have in the same situation to be ethically acceptable. However, a donor who is willing to assume greater risk than most should not be characterized on that basis alone as “irrational”. For example, it need not be irrational for someone to accept a fifty percent risk of ESRD to help someone else. This can be appreciated by considering a situation of a father with that risk

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who wishes to donate to his twelve year old daughter who is about to begin dialysis. A different example with a 100% “risk” of ESRD might be a donor with one kidney who wishes to give to her identical twin because the donor knows she would fare better on dialysis than her sister. These are admittedly unusual situations, but if we can see the point of donation, it suggests that it is not irrational. Centers may decide that such heroic donors are not acceptable, but they should be as clear as possible as to whether they are categorizing donation as heroic or as irrational. The fourth and final good reason to reject donors is because their acceptance would significantly harm future donors or recipients. This reason was alluded to briefly above in discussing heroic donors. This seems to be the only reason that would justify the rejection of many “high risk” donors by centers. For example, in considering the heroic father – who fully understands his decision to donate – with a fifty-fifty chance of someday needing dialysis because of donation, the center might feel that accepting this individual would corrupt its usual careful selection practices and high standards. If the center got into the habit of taking these very high risk donors, it might become cavalier in its donor evaluations. Accepting such high risk heroic donors might also make the public unavoidably suspicious of the transplantation process. That is, no matter how scrupulously careful the center was, the public may feel that a high risk donor must have been coerced or have received a false presentation of risk. The above examples of heroic donation are admittedly provocative, but in excluding any high risk donors, the center must be clear as to what it is doing and also have tried to structure its donor selection practices so that some higher risk donors could be accepted with a sufficient degree of comfort. The center is required to investigate donors as regards these acceptability criteria not just to sit back and accept donors if no reason to reject them happens to surface. This higher standard is not ethically required of many individuals or institutions in society that are self interested participants in activities that offer others opportunities for risk (e.g., army recruiters, gambling casinos). Both transplant centers and the public however accept that this higher standard is appropriate for the medical profession. “Adequate” reason to believe that a cause for donor rejection does not exist, however, does not mean “certain knowledge” that the donor is ethically acceptable. If centers were required to be absolutely certain, they would deny the legitimate wishes of many donors and recipients and would often be charged with patronizing their donors. Altruistic deeds and risk taking are prima facie not unreasonable and not uncommon in life, so why should the center have any special responsibility to protect their donors from taking uninformed risks? Indeed, examples have been cited of “bystanders” who do not intervene when parents rush into burning buildings – or dart into traffic – to save a child [9, 10]. Of course, the center’s relationship to the act of kidney donation is much different. Unlike a bystander, the center itself will do harm to the donor and must have justification to do so. The center is also self interested in the process of transplantation and is trusted to educate and select the potential donor. For these reasons, the center cannot claim the lower ethical requirements appropriate to bystanders. In fact, as previously mentioned, the center must actively attempt to determine that the four reasons for donor rejection do not apply, e.g., the center must justifi-

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ably believe that donation is rational for that specific donor before proceeding. In society, this higher standard is often not required of self-interested parties who participate in activities involving risk to other participants. It would seem appropriate that centers are held to the higher standard in applying all four reasons, given that they must preserve the public trust. In fact, concerns as to whether donors are informed and acting freely and rationally are the fundamental reasons – albeit at times unstated – for the rejection of many donors by many centers. Compensation for donors takes many forms and is a complex issue. An organ exchange arrangement between two donor-recipient pairs is a form of compensated donation. When someone donates to a stranger in return for advancing a loved one on the cadaver kidney waiting list, that is also compensated donation. Paid donation is another form of compensated donation and is not currently practiced in most parts of the world. It is illegal in many countries [11]. As opposed to all the clearly acceptable rationales for donation, the paid – or otherwise compensated – donor need not care whether donation helps the recipient. For some of these compensated donors, it could be all the same if their kidneys were discarded, as long as they got their donor reward. Since the benefit to the paid donor is money, the center cannot educate, evaluate, and counsel paid donors about specific benefit to the same extent that it can conventionally motivated donors. If paid donation were countenanced, the center – or the general public – would have to decide to what extent the center would be responsible for paid donors who were uninformed, irrational, or incompetent. A donor without the intelligence, judgment, or knowledge to utilize well his donor payment might be an example of such a donor. The paid donor might squander his money over time and have nothing in the end. (However, the benefit to the recipient from “conventional” donation is usually not permanent either – in fact, some donated kidneys fail quite rapidly.) Paid donors might also be more susceptible to pressure from others, because a larger number of people could potentially stand to gain from the donor getting money than if the benefit were only that the recipient avoided dialysis. If paid donation were legal, centers – and the public – would still have to decide if the ethical responsibilities to donors could be fulfilled and if it was worth the trouble. Altruistic donation would probably decline if some people were paid to do it, and this would be a major drawback of paid donor programs. However, many would agree that a restricted program of paid or otherwise compensated donation might be of benefit to recipients. The broad ethical issues relevant to paid donation are not different from those pertaining to other kinds of donors [8]. The preceding discussion suggests that a number of ethical reasons which are commonly offered by centers for accepting or rejecting donors are not necessarily wrong, but are not the fundamental ones. For example, one does not accept donors simply because they are “low risk” or because “they are emotional” or because “it would help the recipient”. One does not reject donors because “they are not blood relations”, because “there is a concern for the donor’s welfare”, or because “they are not emotional”. The above reasons for donor acceptance or rejection, however, derive their force from the more fundamental but unstated ethical rationales which are discussed in this chapter and presented in Table 1. In difficult cases, disagreements will arise from time to time even among the most well-informed and ethically sensitive individuals. When this happens, we have emphasized the need to separate issues of fact from issues of appropriate ethical

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Table 1. The Four Fundamental Ethical Reasons for Center Refusal of a Living Kidney Donor. The donor is not informed. The donor is not acting freely and voluntarily. It would be irrational for the donor to donate. Donation would harm future recipients for donors (the transplant effort). There are of course many ways to express one’s reasons for refusing a donor, but they in the final analysis should come down to one or more of these four.)

reasoning. We have identified the general reasons for donor acceptance or rejection by using cases in which virtually everyone agrees so they can be applied to these difficult cases. For example, the donor selection committee may try to discuss whether to accept a donor “with a risk” (which is true of all donors), or the committee may phrase its concern more accurately and argue about whether the donor can be adequately informed about his risk. In the latter case, correctly formulating the real problem might facilitate further education efforts for that donor or at least lead to informing the donor correctly that he was not rejected because of health concerns. As we have said, certain rational and informed donors may be willing to assume an unusually high degree of risk to help their recipients. However, the public may suspect that the center is indulging its self interest in accepting them. Even if the donor selection process has been exemplary, some centers may therefore feel that accepting heroic donors will unavoidably do more harm than good. Other centers may feel that they have made their selection process acceptable even to a suspicious public and therefore may accept some higher risk donors. Therefore, instead of debating whether donation is “too risky,” centers should debate whether the donor is informed and whether the problems associated with the heroic donor are serious enough to require that the donor be rejected. As for considering situations in which donation may be irrational, it is often helpful to ask whether a member of the transplant team might ever want to donate to a close, loved one under the same circumstances. If the answer is yes, donation is probably not irrational and probably is reasonable – but perhaps heroic – for some donors. However, when physicians imagine themselves in a donor situation, they assume for themselves a great deal of background information and medical sophistication which the donor probably does not have and may be hard to transmit via donor education. In marginal cases in which donors are rejected, the center should inform the donor that as ethical people can disagree in some cases, he or she could apply to a different center and possibly would be accepted for donation there. If after unusual internal disagreement the center decides to proceed with donation or reject it, both the donor and recipient should be informed about it. Counseling donors as to degree of risk can present another problem. As will be discussed in Chapters 4 and 7, we usually see donors with risks that can be broadly quantified. There is an important difference between the degree of risk being “unknown” and the risk being not precisely quantifiable. It is heroic – or, more often, irrational – to donate a kidney when the risk of donation is completely unknown and among the possible consequences are death or life with end

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stage renal disease. When risks are completely unknown, the counseling process must come to a stop. However, the center should be clear that having no idea of risk and not being able to clarify risk precisely are two different things. When a medical abnormality in a problem donor is identified, but its effect on donor risk cannot be determined by the donor counselor, efforts should be made to find available information so that risk may be quantified. The donor should not be rejected simply because the donor counselor is inexperienced or not familiar with the medical literature. To restate, there is a difference between a risk being truly “unknown” and a risk being “unknown to the donor counselor”. One of the purposes of this book is to help donor counselors better quantify risk and thereby increase comfort with the donor selection process. The center will rarely encounter a potential donor who is acceptable in all other respects but whose acceptance might be opposed purely on the basis of cost of donor medical care to society. While it is certainly true that acceptance of some irrational, uninformed, or heroic donors might be costly to society, cost of donor medical care alone should not be a reason for centers to exclude donors. A selection committee cannot make social policy and in fact usually will have no clear direction from “society” or any more well-defined group of payers about the financial aspects of donor selection. In the absence of such a directive, the transplant committee should not invent one. In conclusion, the transplant center is properly a neutral facilitator of the donor’s well considered and uncoerced desire to donate. It must recognize the legitimate expectations and desires of donors and recipients and should refuse a donor only for good reason. Donors should be accepted if and when the center has adequate reason to believe that (1) they are informed, (2) they are acting freely, (3) they are acting rationally, and (4) their acceptance would not sufficiently harm future transplantation efforts. When donors are rejected, the center should be as clear as possible about its reasons for donor rejection. It should also attempt to construct and apply its policies and procedures so that no donors are rejected for remediable reasons. With attention to the ethics and the factual bases for donor selection, more uniform and defensible practices are likely to emerge. This account of the ethical basis for living donor transplantation was developed independently [5] of an important recent consensus statement of the Live Organ Donor Consensus Group (LODCG) on all live donor policies and procedures [6]. In most respects, our account is very similar to the main conclusions of that statement, in that both accounts mandate unbiased and complete donor education, donor volunteerism, and the fact that unrelated donors are not in principle different than related donors. The LODCG statement appears to implicitly acknowledge the unvarying reality of donor risks, and our current account does so explicitly. The LODCG statement advises that centers’ conflicts of interest must be addressed by an independent donor advocate, yet to find such a truly independent yet adequately sophisticated donor counselor may prove too great a challenge for many centers. The approaches presented in Chapter 7 may help guard against indulging center conflicts of interest through policies and procedures other than establishing independent donor counselors. The LODCG states that “the benefits to both donor and recipient must outweigh the risks associated with the donation . . .”, whereas we hold that there need not be benefits to the donor other than the potential satisfaction of his desire to help the recipient. The LODCG con-

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cludes that “the team should never feel obliged to perform a transplant from a living donor if it believes that it will do more harm than good”. Our conclusion would perhaps be more complicated, that if the team has adequate and irremediable reason to believe that one or more of the conditions in Table 1 are present, they must refuse the donor, but if they have adequate reason to believe that none of these conditions are present, they are obligated to proceed. We agree with the LODGC that the approach to educating, evaluating and selecting living donors should be the same, regardless of non-relation or familiarity with the recipient, but this position has not been universally accepted. It has been suggested that individuals with no emotional relationship to a recipient (good Samaritan donors) be permitted to donate “only when a medical evaluation reveals absolutely no medical concerns” [12]. It has also been suggested that interfamilial donations have a degree of moral obligation and that intimates should be allowed to accept more risks to donate to each other than should strangers (12, 13). While it is true that individuals who know each other well would be more likely to be ethically acceptable donor recipient pairs, this is a matter for factual investigation by the center on a case by case basis [7, 14]. A father could still be coerced into donating to a daughter, and a good Samaritan may legitimately wish to take risks to help a stranger [15]. It is our position that these cases should not be judged by impersonal donor characteristics, although the degree of caution exercised in determining the facts of donor education, motivation, and volunteerism might change depending upon whether the donor was closely emotionally related or unrelated in all respects to the recipient. Furthermore, if the center ever allows itself to think that any donor has a duty to donate, this may well corrupt the process of fair and impartial donor education and evaluation and lose the public’s trust in the living donor selection process. We expect that further dialogue will clarify and unify the ethical approach centers take in educating, evaluating, and selecting living kidney donors.

References 01. Smith SR, Svetkey LP, Dennis VW. Racial differences in the incidence and progression of renal diseases. Kid Int. 1991; 40: 815–22. 02. Lopes AAS, Port FK. Differences in the patterns of age-specific black/white comparisons between end-stage renal disease attributed and not attributed to diabetes. Am J Kidney Dis. 1995; 25: 714–21. 03. Lei HH, Perneger TV, Klag MJ et al. Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol. 1998; 9: 1270–6. 04. Calne R. The use of living donors. In: Terasak PI, Cecka JM (eds), Clinical Transplants. Los Angeles, CA, UCLA Tissue Typing Laboratory, 1994; 2995: 358–9. 05. Steiner R, Gert B. Ethical selection of living kidney donors. Am J Kidney Dis. 2000; 36(4): 677–86. 06. The Authors for the Live Organ Donor Consensus Group. Consensus statement on the live organ donor. JAMA. 2000; 284(22): 2919–26. 07. Steiner R, Gert B. A technique for presenting risk and outcome data to potential living renal transplant donors. Transplantation. 2002; 71(8): 1056–7. 08. Principal discussant: Hou S. Expanding the kidney donor pool: ethical and medical considerations. Kid Int. 2000; 58: 1820–35.

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09. Spital A. Public attitudes toward kidney donation by friends and altruistic strangers in the United States. Transplantation. 2001; 71(8): 1061–4. 10. Stiller CR, Robinette MA. Emotionally related donors and renal transplantation. Transplant Proc. 1985; 17: 123–7. 11. Levine DZ. Nephrology ethics forum: exploring ethical, moral, and legal issues related to kidney diseases. Am J Kidney Dis. 2000; 35(5): 1002–18. 12. Ross LF, Glannon W, Josephson MA, Thistlethwaite JR Jr. Should all living donors be treated equally? Transplantation. 2002 Aug 15; 74(3): 418–21; discussion 421–2. 13. Spital A. Justification of living-organ donation requires benefit for the donor that balances the risk: Commentary on Ross et al. Transplantation. 2002 Aug 15; 74(3): 423–4. 14. Kahn J, Matas AJ. What’s Special About the Ethics of Living Donors? Reply to Ross et al. Transplantation. 2002 Aug 15; 74(3): 418–21; discussion 421–2. 15. Daar AS. Strangers, intimates, and altruism in organ donation. Transplantation. 2002 Aug 15; 74(3): 424–6.

Chapter Two Quality of Life and Survival on Dialysis and after Renal Transplantation Paul A. Keown, M.D., D.Sc., M.B.A. Summary Points • Transplantation usually replaces 40–80% of normal kidney function. Dialysis provides less than 10%. • Major improvements have been made over the years in both dialysis and transplantation, but patients receiving either treatment can still have problems. • Numerous studies have been done on medical and emotional health and functioning in society (quality of life) for dialysis patients and transplant patients. • Transplantation gets most dialysis patients at least partially “back to normal”. • There is overlap in quality of life measurements and in the severity of medical problems between healthier transplant patients and dialysis patients. • Transplantation seems to benefit older recipients less than it does younger ones. • Transplant recipients themselves strongly prefer transplantation to dialysis. • The most predictable and concrete benefit of transplantation is day-to-day freedom from dialysis.

13 R.W. Steiner (ed.), Educating, Evaluating, and Selecting Living Kidney Donors, 13–33.  2004 Kluwer Academic Publishers. Printed in the Netherlands.

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Introduction End-stage renal disease is a debilitating chronic disorder resulting in multi-system dysfunction with profound mental, physical and social consequences. The incidence and prevalence of ESRD have increased at a compound rate of up to 10% per annum during the last decade. Recent demographic surveys show that growth has occurred particularly in patients greater than 65 years of age, and that the degree of co-morbidity is continuously increasing resulting in an older and sicker population for care [1–4]. The direct annual costs of renal disease care at a national level are estimated to approach $700 million in Canada and exceed $17.9 billion in the United States [2]. When indirect medical and non-medical costs, patientborne costs and the psychosocial impacts are also considered, the true economic burden of ESRD is readily apparent. The effective management of end-stage renal disease (ESRD) is a major societal challenge, with kidney dialysis and renal transplantation being the principal therapies currently available [5]. Advances in biomedical engineering, along with the availability of new drugs to prevent anemia and bone disease, and a structured approach to ESRD care have improved the success and effectiveness of dialysis over the past decade resulting in lower morbidity if not mortality [6]. During the same interval, rapid advances in the biology of the immune system have resulted in the development of powerful and effective drugs that prevent the rejection of the transplanted organ, dramatically improving the success and safety of renal transplantation [7, 8]. Renal transplantation is generally regarded as the optimal therapy for most patients with ESRD, based upon the promise of superior health, rehabilitation and quality of life compared to dialysis and the fact that treatment costs are substantially reduced with this therapy [9]. Acute rejection still occurs in an important proportion of subjects undergoing renal transplantation, however, and is tightly linked to the occurrence of subsequent chronic rejection resulting in progressive transplant dysfunction and a return to dialysis [10]. In parallel, the increased risk and accelerated progression of cardiovascular disease, skeletal demineralization, metabolic disorders, infection and malignancy constitute important risk factors that limit both the quantity and quality of life of the transplant recipient [11]. Most importantly, however, the use of this therapy is seriously limited by the lack of availability of cadaveric organs so that live donation is an increasingly important resource [12]. Selection of optimal treatment by thoughtful, evidence-based comparison of alternatives is emerging as one of the most important issues in current health care. While the decision to proceed with live donor transplantation is highly influenced by the potential for improvement in the recipient’s longevity and quality of life, the acceptance of a living donor is necessarily based on a careful and individualized comparison of the risks and benefits to both individuals. This chapter will therefore review the demands and outcomes of chronic renal failure management, and summarize the health quality consequences of renal transplantation which form the foundation for this decision. It will describe the measures used in estimating quality of life in the graft recipient, and the approach to calculation of overall health benefit calculated as incremental quality-adjusted life years gained.

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Incidence and Implications of ESRD The reported incidence of chronic renal failure has increased dramatically during the last decade. In the United States the number of new patients per year has almost doubled from 48,000 in to over 88,000 by 1999, representing an increase from 190 to 317 patients per million population (ppmp) across this decade [2]. This growth is mirrored elsewhere in Europe, Canada, Australia and Asia, although incidence rates are lower than in the US, ranging from 78 ppmp in Australia to 229 ppmp in Japan [1, 3, 4] (Figure 1). The demographic and clinical characteristics of patients presenting with ESRD have also changed importantly across this time, with increasing proportions of older patients, minorities and diabetics now being referred for care. The mean age of patients starting treatment in the US is currently over 61 years, an almost tripling in the overall incidence of subjects over 65 years of age. Adjusted incidence rates in Native North Americans and Blacks are now 652 and 953 ppmp respectively, reaching almost 2,000 ppmp among diabetic patients over 60 years reflecting the potent interaction of these risk factors. Almost 350,000 patients are now alive with ESRD in the US, a prevalence of 1,217 per million population. This is second only to Japan, and almost twice the prevalence in other developed nations. Point prevalence is low (73 ppmp) among subjects less than 19 years rising rapidly (4,163 ppmp) to peak in those age 65–74 years, and is almost 4 fold higher in Native North Americans (3,089 ppmp) and Blacks (3,096 ppmp) than in Whites (871 ppmp). Diabetes and hypertension remain the leading causes of ESRD, together exceeding all other causes combined, (Table 1).

Figure 1. Incidence and prevalence of end-stage renal disease reported by country (rate per million population). Canadian Organ Replacement Registry, 2000.

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Table 1. Incidence and prevalence of end-stage renal disease by patient characteristics and treatment modality. USRDS, 2001 (2). Patient characteristics

Incidence (per million)

Prevalence (per million)

Dialysis (total number)

Transplant (total number)

0–19 years 20–24 years 45–64 years 65–74 years 75+ years

00,15 0,119 0,603 1,317 1,434

0,073 0,745 2,534 4,163 3,449

001,857 041,233 091,646 060,214 048,206

004,337 040,409 046,193 008,898 001,105

White Black Native American Asian/Pacific Islander Other/Unknown

0,237 0,953 0,652 0,386

0,871 3,926 3,089 1,466

133,119 092,356 004,184 008,766 004,895

074,317 018,445 001,181 003,945 003,112

Male Female

0,380 0,266

1,442 1,014

128,101 115,051

059,928 041,066

Diabetes Hypertension Glomerulonephritis Cystic kidney disease Urologic disease Other known cause Unknown cause Missing cause

0,136 0,083 0,029 0,007 0,006 0,035 0,012 0,007

0,411 0,282 0,194 0,054 0,024 0,136 0,049 0,068

096,147 066,080 030,185 007,184 004,681 024,024 009,464 005,554

019,936 012,506 024,616 007,809 002,033 014,025 004,477 015,599

Total

0,315

1,217

243,320

101,000

Patients with chronic renal failure have a high burden of co-morbidity. Over three-quarters of US patients (77%) have a history of hypertension, 25% coronary artery disease, 15% peripheral vascular disease, and 23% insulin-dependent diabetes mellitus [2]. Chronic obstructive pulmonary disease or cerebrovascular disease are present in a further 7–9% respectively, and approximately 5% have a malignancy. Less than 20% of these patients are still employed. Nor is this disease burden diminishing. Among Canadian patients presenting with ESRD in 1998, 27% had angina, 21% a previous myocardial infarct, 29% pulmonary edema, 40% diabetes mellitus, 11% a cerebrovascular accident, 11% pulmonary disease, and 81% were receiving treatment for hypertension. ESRD therefore carries a significant increase in the risk of mortality that is closely linked to the age at presentation. In the US, 6% of patients less than 19 years have died 2 years after developing ESRD, while this figure escalates to 52% in those greater than 65 years [2]. ESRD causes a 20% reduction (79% vs 99%) in the 10 year probability of survival in young patients (< 35 years), comparable to the effect of Hodgkin’s disease. This impact is more serious in patients in the 4th to 7th decades (34–64 years), where 10 year survival is reduced by more than half among patients with ESRD (38% vs 87%), comparable to prostate or colon cancer [3]. ESRD is most serious in the

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elderly, however, where the expected 10 year survival is only 10% of that in the general population (4% vs 49%), a risk greater than that of either prostate or colon cancer (Figure 2). Longitudinal follow up of patients presenting with ESRD in 1983 show that more than 70% have died in the last 2 decades, while 7% remain alive on dialysis and 20% have a functioning graft [3].

Figure 2. Patient survival with ESRD compared with selected malignant disorders. Canadian Organ Replacement Registry [3].

Treatment Decisions and Outcomes Treatment patterns for chronic renal failure are influenced by location, resources, expertise, population and era. In the US, approximately 30% of ESRD patients are treated by transplantation and the vast majority (87%) of dialysis patients are maintained on in-center hemodialysis [2]. Few patients receive CAPD or CCPD (9%), and fewer still self-care or home hemodialysis (1.5%). Transplantation is generally the most prevalent modality in children and young adults, while dialysis is more common in elderly subjects. USRDS data show that 54% of patients less than 19 years of age have received a renal transplant 2 years after presentation, compared with 25% aged 20–44 years, 10% aged 45–64 years, and only 1% of those over 65 years of age [2]. In Australia and Canada, almost half of all patients with ESRD are maintained with a functioning transplant. In contrast, certain other developed countries such as Germany and Japan have very low transplantation rates (1–10% respectively), due to societal, logistical or economic factors, and the majority of patients are maintained on in-center hemodialysis [3]. The proportion of patients transplanted has declined over the last decade in many countries, reflecting the fall in cadaveric donation in the face of growing demand [3, 4]. The availability of cadaver donors has also reached a plateau in the US, and the

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UNOS registry shows over 41,000 active patients on the renal transplant in 1999, an increase of 280% over the previous decade and over 3 times the total number of transplants performed annually in the US. In response to this demand, Canada, Australia and the U.S. have experienced a marked increase in the number of live donor transplants, which now account for at least one third of all allografts performed (Figure 3). This differs dramatically from many European nations, where less than 5% of transplants are still from a live donor source.

Figure 3. Increase in proportion of live donor transplants during the last decade in the US, Canada and Australia [2–4].

International data consistently show that patients on dialysis have a higher morbidity and mortality than those who receive a renal transplant [2–4]. However, transplant recipients are highly selected and their medical and demographic characteristics differ from patients on dialysis so that meaningful comparisons cannot be made without considerable analytical sophistication. Dialysis patients are generally older (modal age: 70–74 vs 45–49 years), a higher proportion are Black, Hispanic or of other ethnic minorities (74% vs 55%), and more have diabetic (39% vs 20%) or hypertensive (27% vs 12%) disease [2]. USRDS data adjusted for age and disease show that the incidence of hospitalization is doubled (1,943 vs 771 per 1,000 patient years at risk), mean hospital time is increased three fold (17.1 vs 5.0 days per year), and the adjusted mortality rate is quadrupled (179 vs 43 per 1,000 patient years at risk) in dialysis patients. Cardiac arrest, septicemia, myocardial infarction, cerebrovascular disease and cardiac arrythmias are leading causes of death in both treatment groups, but their frequency and/or impact are dramatically lower in the graft recipient and other causes take precedence (Figure 4) [13]. The probability of patient survival, adjusted for age and original disease, declines from 79% at 1 year to 38% at 5 years and 13% at 10 years on dialysis. Corresponding survival figures for patients receiving a cadaveric renal transplant are strikingly better at 95% by 1 year, 82% at 5 years and 61% at 10 years. These survival rates are even higher for patients receiving a living donor graft, being 98% at 1 year, 90% at 5 years and 77% at 10 years. Similar results are observed in

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Figure 4. Causes of death (unadjusted) in patients with end-stage renal disease according to treatment modality. USRDS [2].

Canada, Australia and Europe and, while individual national mortality rates differ, the difference between treatment modalities remains striking [2–4]. Many experts consider these differences to be the result of considerable selection bias, plus some real benefit of transplantation. Because of the stringent selection criteria [14], transplant recipients have a lower frequency of advanced cardiovascular disease, serious multi-system disorders or malignancy than do those on dialysis. A more meaningful comparison is therefore between transplanted patients and those on the transplant waiting list. An important study in over 250,000 USRDS dialysis patients, of whom 46,000 were wait listed for cadaver kidney transplantation, has provided information on the survival benefit of transplantation. Half of this latter group was transplanted in a six year time period. The death rate in the transplanted group was 3.8 per 100 patient years (that is 3.8 deaths per year per 100 patients) versus 6.3 deaths per 100 patient years in the group still waiting for a transplant (Table 2) [15]. This study confirms the selection bias favouring low-risk patients for transplantation, and indicates some real improvement in expected outcome due to this treatment. Mortality increased with advancing age and the presence of diabetes in all patient groups, but was consistently lower across all risk categories after transplantation with 20 projected years of life remaining compared with 10 for those on the waiting list. The benefit of transplantation was greatest in renal transplant recipients between the ages of 20–39, who were projected to live 17 years longer than untransplanted patients. The projected difference in the life span of patients over 60 was only 5 years, possibly due to the effects of unappreciated comorbid conditions. Interestingly, although diabetes mellitus reduced overall survival, the projected

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PAUL A. KEOWN

Table 2. Annual death rates of patients on dialysis, on the transplant waiting list, and following transplantation according to demographic and clinical characteristics [15]. Variable

Patients on chronic dialysis

Patients on waiting list

Recipients of a cadaver transplant

All patients

16.1

84,713

06.3

4,353

3.8

2,436

0–19 years 20–39 years 40–59 years > 60 years

03.6 08.6 13.3 23.2

0,0257 07,499 30,935 46,022

02.2 04.3 06.5 10.0

0,031 0,897 2,372 1,053

0.9 2.3 4.1 7.4

0,021 0,500 1,293 0,622

Male Female

16.2 16.1

45,366 39,347

06.3 06.3

2,556 1,797

3.9 3.5

1,590 0,846

White Black Asian Native American

19.3 12.4 09.9 13.3

55,786 25,733 01,783 01,411

07.5 04.8 03.0 06.5

2,993 1,168 0,108 0,084

3.9 3.4 2.6 4.7

1,859 0,478 0,064 0,035

Diabetic ESRD Other causes

19.9 13.3

44,916 39,797

10.8 04.3

2,312 2,041

5.6 3.0

1,091 1,345

incremental life span due to transplantation was greater among diabetics than non-diabetics [15]. In addition to increasing age and diabetes mellitus, many other factors have an important influence on post-transplant survival including pre-existing cardiovascular and peripheral vascular disease, obesity, cirrhosis, smoking and substance abuse, and prior non-compliance with therapy [16]. Duration of dialysis and waiting time prior to transplantation also appear to determine both graft and patient survival [16–18]. Relative to pre-emptive transplants, patients waiting for 12 months show an increased risk of mortality of 20%, rising to 70% in those waiting for 48 months. Despite the mass of information now available on important risk factors, however, no simple algorithms yet exist for accurately predicting individual patient survival for the potential recipient. Ultimately, simple tools such as the calculation of observed/expected survival may prove most valuable in estimating the probability of success following renal transplantation and in providing objective information on patient risk at the time of recipient selection [19]. Measurement of Quality of Life Health-related quality of life, often abbreviated to “quality of life” is a global estimate of well-being which encompasses three principal domains of physical, psychological (emotional/mental/cognitive) and social health. It is based on the World Health Organization’s definition of health as “a state of complete physical, mental and social well-being and not merely absence of disease or infirmity [20]. Patients’ expectations, subjective perceptions of health, and ability to cope with disability influence the level of health-related quality of life so that patients with

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identical health status by objective measures of physical health or activity can experience dissimilar levels of mental health (e.g., happiness, satisfaction). For this reason, both subjective and objective measures are ideally combined in the evaluation of patient status. Three principal classes of measures are used to assess quality of life: utilities or health state preference measures, generic measures and disease-specific measures (Table 3) [9]. Utilities or health state preference measures summate functioning and well being into a single value expressed on a scale from 0 (equivalent to death) to 1 (equivalent to perfect health) [21]. Table 3. Principal measures currently employed for assessment of health-related quality of life in end-stage renal diseases. Health State Preference Measures 1. Standard Gamble 2. Time Trade-off 3. EuroQol 4. Health Utility Index 5. Well-being Generic Measures of Quality of Life 1. Medical Outcomes Survey Short Form 36 (SF-36) 2. Sickness Impact Profile 3. Nottingham Health Profile (NHP) Disease Specific Measures of Quality of Life 1. Kidney Dialysis Questionnaire 2. Kidney Transplant Questionnaire 3. Kidney Disease Quality of Life (KD-QOL)

While extremely useful for global health decisions, these measures may be insensitive to small changes in specific disease states. Utility or health state preferences may be measured using rating scales (EuroQOL, visual analog scale), econometric methods (standard gamble, time trade-off), and multi-attribute methods (the Health Utility Index) [22]. The EuroQOL describes a health state and patients indicate on the scale (from 0.0 to 1.0) their preference for that state [23]. The standard gamble asks the patient to choose between continuing the status quo or gambling on a given treatment with two possible outcomes: a return to full health or immediate death [24]. The “the point of indifference” is a measure of the patient’s current global quality of life. The time trade-off presents two health scenarios, normally a clearly defined but less-than-perfect health state (dialysis) for the remainder of the patient’s life, compared with perfect health for a specified, but shorter, length of time [25]. The point of indifference, i.e., the number of years in the current state that the patient would be willing to trade in return for perfect health for a shortened period of time, determines the score. The Health Utilities Index is based on multi-attribute utility theory and designates four attributes of health: physical function, role function, social-emotional function, and health problems [26]. Each of these attributes is subdivided into a number of levels, allowing the patient to be classified into one level for each attribute at each time point. By comparing the patient’s responses with responses obtained during

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development of the index, a determination can be made of the multivariate utility function. These measures form the basis for calculation of quality-adjusted life years (QALY) gained, calculated as the product of the incremental life years and the utility value. Generic measures are not limited to a specific disease process, age group, or special situation. They are useful for making comparisons across groups and studies and for comparing the effects of various diseases. Principal generic tools include the Sickness Impact Profile (SIP), the 36-item short-form of the Medical Outcomes Survey (SF-36), and the Nottingham Health Profile (NHP) [27–29]. Diseasespecific measures, in contrast, are used to assess the impact of a specific disease on quality of life (Table 4). Table 4. Items with the highest frequency-importance product scores from the Kidney Dialysis Questionnaire and Kidney Transplant Questionnaire [30, 31]. Ranking

Dialysis

Transplantation

01 02 03 04 05 06 07 08 09 10

Life satisfaction Loss of weight Weakness Reduced energy Tiredness Worn out Itchy, dry skin Sleepiness Sluggishness Inability to travel

Protective of transplant Fear of rejection Increased hair growth Reduced energy Sluggishness Overprotection by others Increased appetite Side effects of medications Excessive weight gain Weakness

While often more sensitive to small but clinically important changes in quality of life that accompany disease progression or treatment, they are rarely useful for making comparisons between different diseases. Disease-specific tools used in transplantation include the Kidney Transplant Questionnaire (KTQ), Kidney Disease Questionnaire (KDQ), and the Kidney Disease-Quality of Life (KDQOL) instrument among others [30–33]. Quality of Life of Dialysis and Transplantation A growing body of data indicates that ESRD has a serious impact on health-related quality of life [34, 35]. The phrase “quality of life” is broad and includes physical functioning (e.g., mobility and pain), mental health (stress, depression, and memory), social functioning (family and social relations, employment), and overall life satisfaction (how renal transplant recipients think they are doing). Chronic renal failure reduces both objective measures of functional performance, including the ability to work or pursue a career, and subjective measures of health, satisfaction and psychological well being. Quality of life is substantially impaired at the onset of dialysis, and often deteriorates further over time depending upon the treatment selected and the individual clinical course. Quality of life outcomes are unquestionably improved in patients with a functioning graft [36–41]. Many

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studies of quality of life, however, have compared different patient populations at varying intervals of treatment, often without regard to co-morbidity or mortality. To provide accurate information to the potential donor and recipient it is essential to compare treatment modalities in patient subgroups at comparable risk, to define the longitudinal response before and after transplant, and consider the influence of different immunosuppressive regimens when evaluating quality of life. Landmark cross-sectional studies by Evans and others demonstrated that life satisfaction, well-being and psychosocial affect were seriously reduced in patients on dialysis, less than half of whom were able to function at nearly normal levels [42–44]. The magnitude of incapacity was striking, with mean TTO scores of 0.43 for in hospital and 0.56 for home/self care dialysis patients indicating that patients would trade half their remaining life years to regain normal health! Confirmatory studies over the last decade have shown health preference values in dialysis patients approximately half those of the normal population, while generic measures indicate a serious erosion in physical, emotional and social functioning [45–47]. Quality of life may be influenced by gender, race and risk, and has been reported to be diminished in females, certain ethnic groups including Indo-Asians, and patients with important co-morbidity [48–52]. Elderly or malnourished patients demonstrate particularly reduced physical functioning, as do diabetics who also have the lowest mean utilities and greatest health quality burden on dialysis. Case-mix studies show little difference between hemodialysis and peritoneal dialysis in terms of quality of life restored. Improved dialysis efficiency, particularly through the increased use of daily, nocturnal or home dialysis, may help to mitigate this serious burden but the importance of this effect remains to be explored [53, 54]. Several studies, though not all, have shown that the introduction of recombinant erythropoietin has reduced cardiovascular dysfunction and led to measurable quality of life benefits particularly in the domains of fatigue, depression and relationships with others (p < 0.02–004) [55–57]. The optimal hematocrit remains a controversial topic, but current evidence suggests a range of 34–37% is reasonable; however, particular caution is required in patients with advanced cardiovascular disease. Other advances in renal failure care, including management of cardiovascular risk, intensive nutritional support, the use of recombinant growth hormone in pediatric patients, and aggressive management of dialysis osteodystrophy have improved health in patients with ESRD, though they have not overcome the profound consequences of chronic dialysis [58]. In contrast to quality of life on dialysis, cross-sectional studies showed significantly superior quality of life in renal transplant recipients even prior to the use of cyclosporine. In all over three-quarters of transplant recipients were able to work or function almost normally [42]. These differences persisted after adjustment for case-mix, suggesting that the findings could not be attributed primarily to selection bias but were due to transplantation itself. Studies in the mid 1980s using the TTO showed a mean score of 0.84, significantly superior to all forms of dialysis (p < 0.001). The RAND questionnaire, a generic measure of health quality, showed that improvement occurred particularly in the physical function domain, and to a lesser extent in mental or social functioning [43]. A comprehensive quantitative analysis by Dew et al. examining over 6,000 patients over

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PAUL A. KEOWN

the past 20 years has lent powerful support to these early studies regarding quality of life [59]. This detailed review of over 60 well-designed cross-sectional and prospective renal studies concluded that renal transplantation is beneficial to the majority of recipients, but improvements in some categories is greater than in others, and some patients do not benefit from this procedure. Approximately 80% of these independent studies documented an improvement in physical functioning and in mental health by comparison with the pre-transplant state, while 60% documented improvement in social functioning. Virtually all studies on transplant recipients found improvements in overall life satisfaction, even though improvements in specific quality of life categories could not always be documented. Despite this improvement, it is clear that kidney transplant recipients often do not “get back to normal” after transplantation. When the quality of life of kidney transplant recipients was compared to that of normal, healthy subjects, only 10% of studies found equivalent physical functioning, 70% found equivalent performance in mental health, and 40% in social functioning. However, with respect to life satisfaction, kidney transplant recipients were approximately equal to normal in almost all studies. In summary, these data showed that virtually all transplant recipients felt that they were doing better and perceived themselves to be better off compared to their time on dialysis. Studies in the cyclosporine era have confirmed these findings [60]. Almost all patients showed a rapid improvement in quality of life after transplantation as reflected in both health preference scores and disease specific measures. The mean TTO score rose from 0.57 prior to 0.68 by the first post-transplant month, reaching a maximum of 0.75 by 6 months post-transplant then stabilizing at 0.70 at 2 years post-transplant (p < 0.005). Not all measures improve immediately, however. Many items of the Sickness Impact Profile (sleep and rest, body care and movement, home management, mobility, work, recreation and pastimes, and the total physical score) worsened transiently during the first month consistent with the effects of surgery and immunosuppression, before subsequently showing a significant improvement [60]. Disease-specific measurement using the Kidney Transplant Questionnaire showed a highly significant improvement in emotional, uncertainty and physical domains (p < 0.05–0.001). Interestingly there was a significant deterioration in the appearance domain, probably reflecting the combined effects of steroids and cyclosporine in this era of high-dose treatment. Other than fatigue, the 10 physical symptoms identified most frequently pretransplant were muscle, bone and joint aches; sleep disturbances; itchy, dry skin; gastroinestinal complaints; trouble concentrating; cough and shortness of breath; headaches; decreased sexual function; cramps; and dizziness. These all improved markedly after transplantation, except for sexual dysfunction. Three months posttransplant, patients indicated new problems with acne and rashes, excessive hair growth, increased appetite, tremors, and weight gain, all of which could be related to the immunosuppression [60]. When analyzed according to patient characteristics (age, diabetes, donor type, pre-emptive transplantation), all patients exhibit a marked improvement in quality of life (Table 5), except for those whose grafts have failed who return towards the pre-transplant norm, with little difference between patients less than or greater than 60 years of age. It is particularly striking that health-related quality of life

25

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Table 5. Employment outcomes before and following renal transplantation (all subjects, irrespective of graft function) [60]. Employment status

Employed full or part time All patients Successful grafts Failed grafts Unemployed Main reason for not working Unable due to ill health Personal choice Retired – early due to health – at usual time Looking for work Student Temporarily laid off

Prior to transplantation (N = 168)

1 year post-transplant (N = 134)

2 years post-transplant (N = 77)

050 (30%) 118 (70%)

50 46 04 84

35 32 03 42

068 (51%) 020 (15%)

38 (40%) 19 (20%

23 (47%) 10 (20%)

021 009 003 008 004

18 03 09 08 00

07 02 04 02 01

(16%) (7%) (2%) (6%) (3%)

(37%) (43%) (15%) (63%)

(19%) (3%) (9%) (8%) (0%)

(45%) (51%) (21%) (55%)

(14%) (4%) (8%) (4%) (2%)

for diabetics, among the lowest of all patients pre-transplant, showed the greatest improvement after transplantation. Patients receiving a live donor graft or preemptive transplant appear to have marginally superior TTO scores and KTQ fatigue measures pre-transplant, perhaps reflecting selection bias. Life quality is comparable in both live donor and cadaveric graft recipients post-transplant assuming the graft functions normally, although patients receiving pre-emptive transplantation maintain superior quality. While many new immunosuppressive drugs have recently become available, the effect on quality of life still appears to be most closely related to the success of transplantation and freedom from complications, rather than to the specific immunosuppressive medications employed. Overall quality of life appears to be identical in patients treated with cyclosporine, tacrolimus, azathioprine, mycophenolate or sirolimus (Keown, manuscripts in preparation), although individual measures may demonstrate differences in specific drug-related adverse effects or following withdrawal of a specific agent [61–62]. For example, in international studies comparing azathioprine and mycophenolate mofetil the overall Visual Rating Scale improved from 0.73 at three months to 0.77 at six months and 0.80 at twelve months, while the Time Trade Off improved from 0.80 at three months to 0.84 at six months and 0.85 at twelve months, equivalent to the patients expectation of a “good” outcome. The TTO values were similar to those reported by Churchill et al. [43] in the “pre-cyclosporine” era, and higher than the values reported in later studies by Russell et al. [64] and Laupacis et al. [60]. With the SF-36, the greatest improvement in all three treatment groups was in the rolephysical domain (the ability of the individual to be involved in work related activities), which rose from 54.4 at 3 months to 67.5 at 6 months and 72.0 at 12 months. KTQ results showed improvement across visits especially in the physical

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PAUL A. KEOWN

symptom domain. Other than fatigue (a separate domain), the ten physical symptoms identified most frequently and creating the most distress at three months post-transplant were sleep disturbances, aching tired legs, blood pressure problems, excessive weight gain, very little strength, acne, increased appetite, decreased sexual function, shortness of breath in daily activities and forgetfulness, exactly as reported with previous immune suppression [60]. Simultaneous evaluation in Canada and Australia show little international difference in expectations or outcomes of transplantation, with over 60% of patients in both countries being essentially unrestricted by health concerns at 1 year posttransplant (Keown et al, unpublished data). Subjects with no rejection scored higher on the TTO at the three month interval, but by twelve months post transplant the “rejection” group had improved and surpassed the “no rejection” group. As might be expected, the SF-36 scores in patients who did not experience acute rejection were higher for physical functioning, role-emotional and social functioning domains. The KTQ results for the “no rejection” group showed slightly higher scores in the physical, fatigue and fear domains but very little difference in the other scores. None was clinically significant. Analysis by gender or age (under 35 years, 35–50 years, 50–65 years, and 65+ years) showed no influence of these factors on quality. Functional and Vocational Rehabilitation Post-Transplant Comparison of subjective quality of life between transplant recipients and normal subjects is often difficult and is highly influenced by prior clinical history. Dew et al analyzed 13 studies that addressed this question in renal transplantation, showing similarities in mental and overall functioning but limitations in physical and social functioning by comparison with normal controls [59]. Our own longitudinal studies confirm these observations, and suggest that while transplant recipients regain an excellent quality of life, returning to a value of 0.85 where 1 indicates normal health, it does not generally equal that of normal subjects. By 1 year post-transplant, patients have a lower quality of life in terms of physical functioning and role performance and they rate their overall health lower than that of the general population. Nonetheless, their quality of life is similar in other dimensions such as bodily pain, vitality, and social functioning, and may even be superior in terms of mental health. Loss of employment is one of the most important social consequences of chronic renal failure. The negative effects are most evident at the level of the individual, where they are manifest by a deterioration of physical health, well being, and family environment [65]. Paid employment is therefore an important objective for many transplant recipients, with the potential benefits of higher income, better social support networks, and greater levels of personal satisfaction, self-esteem and general well-being [65, 66]. Despite improvement in functional health and well being, however, renal transplant recipients do not return to productive activity in the workforce at the expected rate and employment rates generally range between 30% and 71% [67, 68]. Ferguson et al. have explored the prevalence of employment following renal transplantation, whether patients choose to pursue employment following trans-

CHAPTER TWO

27

plantation, whether they encounter specific barriers to employment, and the main factors associated with employment during the last decade in Canada (P. Keown, personal report). Of the almost 400 transplant patients studied, 53.4% were working for pay compared with 71.7% in the normal population. 24% reported that their health kept them from working at a job, doing work around the house or going to school, and 30% were unable to do certain kinds or amounts of work, housework or schoolwork because of their health. Among those not active in the labor force, 27% cited family responsibilities as their main reason for not working, 19% were in school, 18% did not want to lose their disability benefits, 12% said they lacked suitable training and 11% could not find suitable work. Only 14% said they were not working out of personal choice. Approximately 10% were receiving financial assistance from the Ministry of Social Service and Housing. When asked, 69% were satisfied with the amount of work they did while 31% were not. There were no statistically significant differences in race, marital status, months on dialysis or presence of diabetes between patients who were or were not employed. Sociodemographic variables strongly associated with employment status were younger age, male gender, higher education, previous work experience and having worked in the year before transplant (in most cases working in the year before transplant means the person worked while receiving dialysis treatments), superior quality of life and time since transplant. Multiple logistic regression showed that the five statistically significant predictors of employment status were employment activity during the year prior to transplantation (p < 0.001, odds ratio = 5.93); physical functioning scores in the normal range (p < 0.001, odds ratio = 5.00); age less than 50 years (p < 0.003, odds ratio = 2.88); social functioning scores in the normal range (p < 0.05, odds ratio = 3.54); and previous work experience (p < 0.01, odds ratio = 14.27). When examined according to the Precede-Proceed model for health promotion planning and evaluation (Green and Kreuter 1991, pp. 150–187), the major predisposing factors to employment were a strong belief in the work ethic or the perceived obligation to seek employment as a way of repaying society for the gift of life. The enabling factors were good functional and mental health, the support of family and friends, successful networking, access to vocational rehabilitation programs, availability of jobs matched to the skills of the applicant, and employer flexibility around granting time off for medical appointments. The reinforcing factors were monetary and non-monetary rewards, such as feelings of personal achievement and a sense of social affiliation. The barriers to employment included ongoing health problems, role conflict for women who tried to balance home and parenting responsibilities with work outside of the home, inflexible employers that did not allow time off for medical appointments, discrimination in the hiring practices of employers, the lack of jobs, and structural disincentives of welfare and disability programs. Synopsis Renal transplantation is considered the optimal therapy for ESRD in terms of both quality and costs of care [69–71]. When adjusted for patient demographic and risk factors, transplantation prolongs patient survival, improves health status and

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PAUL A. KEOWN

functional mobility, and ensures a measurably greater quality of life compared to dialysis. Because the cost of transplantation is substantially lower than that of dialysis after the first year of therapy [60], the incremental cost-utility achieved (measured as incremental cost per change in quality-adjusted life year gained) places renal transplantation in the most valuable category of health technology advances [72]. It is difficult to say exactly how transplantation produces objective health benefits compared to dialytic therapies, although virtually all in the field believe that it does. Transplant recipients still have hypertension, bone disease, hyperlipidemia, infection and, absent a pancreas transplant, they still have – or may develop – diabetes. As well, they must still take multiple medications and see physicians regularly. Perhaps the medical benefits of transplantation are best understood as stemming from better control of the uremic state. The most effective dialysis replaces less than 10% of normal renal function, whereas transplantation usually returns over 50%, at least in the first few years. Data from large populations of dialysis patients indicate that benefit may be associated with changes in the dialysis prescription, even though these changes result in the gain of only a small fraction of the renal function associated with transplantation. Well-documented benefits of changing the dialysis prescription include improvements in nutrition, anemia, and overall morbidity and mortality. On a scale where 0 represents death and 1 represents perfect health, mean preference scores for patients with a successful transplant range from 0.75 to 0.85, compared with 0.35 to 0.65 for patients receiving dialysis therapy [43, 60, 64]. Combination of these data permit estimation of the benefit of transplantation, calculated in quality-adjusted life years (QALY). As shown in Table 6, the benefit of transplantation decreases remorselessly with advancing recipient age from a total incremental gain of 20 QALYs for patients below 20 years to only 5 QALYs for those above 60 years. For recipients older than 70 years, the predicted benefit of transplantation may approximate a single QALYs, raising important societal questions regarding the optimal use of limited cadaver organs. Quality adjusted incremental survival is highly influenced by the clinical disease burden and co-morbid disorders at the time of transplantation. Because of the rapid clinical deterioration and high mortality of young diabetics on dialysis, the incremental benefit of renal transplantation is marginally higher than in non-diabetic recipients of a similar age (approximately 16 vs 15 QALYs in patients aged 20–39 years). In older recipients this advantage is reversed, however, with the expected incremental gain being only 4 QALYs in diabetic subjects 60–74 years of age as compared to 6 QALYs in similar patients without diabetes. While accurate data are not currently available for all possible combinations, it is evident that demographic or comorbid factors such as cardiovascular disease, cardiopulmonary disease, liver disease or malignancies which reduce patient survival probability on both treatment modalities quickly reduce the incremental benefit of transplantation. Return to work has been used as a clinically relevant index of improved quality of life and a measure of successful transplantation [42, 63]. In addition, from a broader societal perspective, unemployment represents a decrease in the purchasing power of the community, a threat to its tax base, and a potential strain on social support programs. In sum, job loss takes its toll on both the individual and the

29

CHAPTER TWO

Table 6. Incremental benefit of renal transplantation measured in terms of life years and quality-adjusted life years gained. Adapted from Wolfe et al. [15] using a utility score of 0.55 for dialysis and 0.85 for transplantation. Variable

Projected survival on dialysis

Projected survival with a transplant

Incremental benefit of renal transplantation

Life years

QALYs

Life years

QALYs

Life years

QALYs

All Patients

10

05.5

20

17.0

10

07.0

0–19 years 20–39 years 40–59 years > 60 years

26 14 11 06

13.1 07.7 06.0 03.3

39 31 22 10

33.1 26.3 18.7 08.5

13 17 11 04

20.0 18.6 12.7 05.2

Male Female

10 11

05.5 06.0

19 23

16.1 19.5

09 12

10.6 13.5

White Black Asian Native American

09 13 15

04.9 07.1 08.2

19 19 23

16.1 16.1 19.5

10 06 08

11.2 09.0 11.3

09

04.9

14

11.9

05

07.0

Diabetic ESRD 08 Other causes 11

04.4 06.0

19 19

16.1 16.1

11 08

11.7 10.1

community. Although transplantation offers patients with ESRD improved functional health and well-bring as compared to people on dialysis it is unrealistic to expect that transplant recipients will be represented in the workforce at the same rate as people with no chronic health problems [73]. There are two principal reasons for this. First, although individual patients may regain excellent physical fitness [74], many subjects with a functioning transplant in general enjoy a lower level of functional health than people with no chronic health problems, despite being psychologically well. The health domains most affected are physical wellbeing and role functioning (walking uphill, carrying groceries, running, participating in sports, doing housework, working outside of the home). About three times as many renal transplant recipients have poor physical functioning compared to the general population. The area of health least affected is mental health. These finding are consistent with the findings of other investigators [67, 42]. Second, specific health and environmental barriers persist for many people with ESRD which are not corrected by transplantation alone. Transplant recipients, compared to the general population, are in a disadvantaged position when seeking to enter, reenter, or retain their position in the workforce. A strong desire to work is not enough. To be successful in securing a job, the unemployed patient may require assistance to make appropriate occupational choices, to learn specific job search skills, or to access training programs or financial services. If discrimination by employers is viewed as a barrier to employment, the health care worker may need to become a vociferous patient advocate. Finally, in responding to the increasing unemployment and underemployment of transplant recipients, government agencies may need to

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PAUL A. KEOWN

re-examine policies that create disincentives. The loss of medical benefits when a person moves off social assistance to enter the workforce is an example of one such issue. For just these reasons, an increasing number of transplant programs have begun to develop active vocational rehabilitation programs and to include employment specialists within the transplant team [75, 76]. Finally, if productive activity is to be used as an indicator of successful transplantation, it is important to broaden the definition to include various forms of unpaid work in the home and the community. The most unarguable benefit of transplantation, however, is that it results in freedom from dialysis. This is the benefit that donors and recipients always expect from successful transplantation, and it largely defines what we mean by a successful transplant procedure. Freedom from the lifestyle of trips to the dialysis unit and needles, or peritoneal dialysis catheters and equipment remains the most clear cut, tangible benefit of renal transplantation, the benefit most often sought by kidney donors and highly valued by their recipients. References 01. Van Dijk P. Renal replacement therapy in Europe. The results of a collaborative effort by the ERA-EDTA and six national or regional registries. Nephrol Dial Transplant. 2001; 16: 1120–9. 02. US Renal Data System, USRDS 2001 Annual Data Report: Atlas of End-Stage Renal Disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, 2001. 03. C.O.R.R. 2000 Report, Volumes 1 and 2: Dialysis and Renal Transplantation, Canadian Organ Replacement Register. Canadian Institute for Health Information. Ottawa, Ontario, June 2000. 04. ANZDATA Registry Report 2000, Australia and New Zealand Dialysis and Transplant Registry, Adelaide, South Australia. 05. Keown PA, Stiller CR. “Renal transplantation: wherefore so slight an impact?” In: Gurland HJ (ed), Uremia Therapy: Perspectives for the Next Quarter Century. Berlin: Springer-Verlag, 1986: 90–98. 06. Eknoyan G, Levin N. NKF-K/DOQI clinical practice guidelines: Update 2000. Foreword. Am J Kidney Dis. 2001 Jan; 37 (Suppl 1): S5–6. 07. Keown PA. New immunosuppressive strategies. Curr Opin Nephrol and Hypertens. 1998; 7: 659–63. 08. Halloran PF. New trends in immunosuppression for renal transplantation. Curr Opin Nephrol Hypertens. 1994; 3: 575–7. 09. Keown PA. Improving quality of life: the new target for transplantation. Transplantation (in press). 10. Ishikawa A, Flechner SM, Goldfarb DA, Myles JL, Modlin CS, Boparai N, Papajcik D, Mastroianni B, Novick AC. Quantitative assessment of the first acute rejection as a predictor of renal transplant outcome. Transplantation. 1999; 68: 1318–24. 11. Keown PA, Shackleton CR, Ferguson BM. The influence of long-term morbidity on health status and rehabilitation following paediatric organ transplantation. Eur J Pediatr. 1992; 151: S70–5. 12. First MR. Expanding the donor pool. Semin Nephrol. 1997 Jul; 17(4): 373–80. 13. Herzog CA, Ma JZ, Collins AJ. Poor long-term survival after acute myocardial infarction among patients on long-term dialysis. N Engl J Med. 1998; 339: 799–805. 14. Steinman TI, Becker BN, Frost AE, Olthoff KM, Smart FW, Suki WN, Wilkinson AH;

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16. 17. 18. 19.

20. 21. 22.

23. 24. 25. 26. 27. 28. 29. 30. 31. 32. 33. 34.

31

the Clinical Practice Committee, American Society of Transplantation. Guidelines for the referral and management of patients eligible for solid organ transplantation. Transplantation. 2001; 71: 1189–204. Wolfe RA, Ashby VB, Milford EL, Ojo AO, Ettenger RE, Agodoa LY, Held PJ, Port FK. Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med. 1999; 341: 1725–30. Matas AJ, Payne WD, Sutherland DE, Humar A, Gruessner RW, Kandaswamy R, Dunn DL, Gillingham KJ, Najarian JS. 2,500 living donor kidney transplants: a singlecenter experience. Ann Surg. 2001; 234: 149–64. Meier-Kriesche HU, Port FK, Ojo AO, Rudich SM, Hanson JA, Cibrik DM, Leichtman AB, Kaplan B. Effect of waiting time on renal transplant outcome. Kidney Int. 2000; 58: 1311–7. Mange KC, Joffe MM, Feldman HI. Effect of the use or nonuse of long-term dialysis on the subsequent survival of renal transplants from living donors. N Engl J Med. 2001; 344: 726–31. Becker BN, Becker YT, Pintar TJ, Collins BH, Pirsch JD, Friedman A, Sollinger HW, Brazy PC. Using renal transplantation to evaluate a simple approach for predicting the impact of end-stage renal disease therapies on patient survival: observed/expected life span. Am J Kidney Dis. 2000; 35: 653–9. World Health Organization: Constitution in Basic Documents. Geneva: World Health Organization, 1948. Ferguson BM, Keown PA. An introduction to utility measurement in health care. Infection Control and Hospital Epidemiology. 1995; 16: 240–7. Bennett KJ, Torrance GW. Measuring health state preferences and utilities: rating scales, time trade-off, and standard gamble techniques. In: Spilker B (ed), Quality of Life and Pharmacoeconomics in Clinical Trials, Second Edition. Philadelphia: Lippincott-Raven, 1996. Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 2001; 33: 337–43. Torrance GW. Measurement of health state utilities for economic appraisal. J Health Econ. 1986 Mar; 5(1): 130. Torrance GW. Utility approach to measuring health-related quality of life. J Chronic Dis. 1987; 40(6): 593–603. Feeny DH, Torrance GW, Furlong W. Health Utilities Index (HUI). In: Spilker B (ed), Quality of Life and Pharmacoeconomics in Clinical Trials, Second Edition. Philadelphia: Lippincott-Raven, 1996. Bergner M, Bobbitt RA, Carter WB, Gilson BS. The sickness impact profile: development and final revision of a health status measure. Med Care. 1981; 19: 787–805. The MOS short form health survey (SF-36). 1. Conceptual framework and item selection. Med Care. 1992; 30: 473–81. Manninen DL, Evans RW. A longitudinal assessment of the health status of diabetic and nondiabetic renal transplant recipients. Clin Transpl. 1988: 203–9. Laupacis A, Pus N, Muirhead N, Wong C, Ferguson B, Keown P. Disease-specific questionnaire for patients with a renal transplant. Nephron. 1993; 64: 226–31. Laupacis A, Muirhead N, Keown P, Wong C. A Disease-specific questionnaire for assessing quality of life in patients on hemodialysis. Nephron. 1992; 60: 302–6. Hays RD, Kallich JD, Mapes DS. Development of the kidney disease quality of life (KDQOL) instrument. Qual Life Res. 1994; 3: 329. Parfrey PS, Vavasour H, Bullock M, Henry S, Harnett JD et al. Development of a health questionnaire specific for end-stage renal disease. Nephron. 1989; 52: 20–8. Deniston OL, Carpentier-Alting P, Kneisley J. Assessment of quality of life in endstage renal disease. Health Serv Res. 1989: 24; 555.

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35. Evans RW. Quality of life assessment and the treatment of end-stage renal disease. Transplant Rev. 1990; 4: 1. 36. Simmons RG, Anderson C, Kamstra L. Comparison of quality of life of patients on continuous ambulatory peritoneal dialysis, hemodialysis and after transplantation. Am J Kidney Dis. 1984; 4: 253–5. 37. Simmons RG, Abress L, Anderson CR. Quality of life after kidney transplantation. Transplantation. 1988; 45: 415. 38. Kutner NG, Brogan D, Kutner MH. End-stage renal disease treatment modality and patients’ quality of life. Am J Nephrol. 1986; 6: 396–402. 39. Christensen AJ, Holman JM, Turner CW, Slaighter JR. Quality of life in end-stage renal disease: influence of renal transplantation. Clin Transplantation. 1989; 3: 46–53. 40. Matas AJ, McHugh L, Payne WD, Wrenshall LE, Dunn DL et al. Long-term quality of life after kidney and simultaneous pancreas-kidney transplantation. Clin Transplantation. 1998; 12: 233–42. 41. Waiser J, Budde K, Schreiber M, Peibst O, Koch U et al. The quality of life in endstage renal disease care. Transplant Int. 1998; 11 (suppl 1): S42–5. 42. Evans RW, Manninen DL, Garrison LP, Hart LG, Blagg CR, Gutman RA et al. The quality of life of patients with end-stage renal disease. N Eng J Med. 1985; 312: 553–9. 43. Churchill DN, Torrance GW, Taylor DW, Barnes CC, Ludwin D et al. Measurement of quality of life in end-stage renal disease: the time trade-off approach. Clin Invest Med. 1987; 10: 14–20. 44. Simmons RG, Anderson CR, Abress LK. Quality of life and rehabilitation differences among four end-stage renal disease therapy groups. Scand J Urol Nephrol Suppl. 1990; 131: 7–22. 45. Neto JF, Ferraz MB, Cendoroglo M, Draibe S, Yu L, Sesso R. Quality of life at the initiation of maintenance dialysis treatment--a comparison between the SF-36 and the KDQ questionnaires. Qual Life Res. 2000 Feb; 9(1): 101–7. 46. Valderrabano F, Jofre R, Lopez-Gomez JM. Quality of life in end-stage renal disease patients. Am J Kidney Dis. 2001 Sep; 38(3): 443–64. 47. Cameron JI, Whiteside C, Katz J, Devins GM. Differences in quality of life across renal replacement therapies: a meta-analytic comparison. Am J Kidney Dis. 2000 Apr; 35(4): 629–37. 48. Bakewell AB, Higgins RM, Edmunds ME. Does ethnicity influence perceived quality of life of patients on dialysis and following renal transplant? Nephrol Dial Transplant. 2001 Jul; 16(7): 1395–401. 49. Mittal SK, Ahern L, Flaster E, Mittal VS, Maesaka JK, Fishbane S. Self-assessed quality of life in peritoneal dialysis patients. Am J Nephrol. 2001 May; 21(3): 215–20. 50. Ohri-Vachaspati P, Sehgal AR. Quality of life implications of inadequate protein nutrition among hemodialysis patients. J Ren Nutr. 1999; 9: 9–13. 51. Parsons DS, Harris DC. A review of quality of life in chronic renal failure. Pharmacoeconomics. 1997; 12: 140–60. 52. Mozes B, Shabtai E, Zucker D. Differences in quality of life among patients receiving dialysis replacement therapy at seven medical centers. J Clin Epidemiol. 1997 Sep; 50(9): 1035–43. 53. Lacson E Jr, Diaz-Buxo JA. Daily and nocturnal hemodialysis: how do they stack up? Am J Kidney Dis. 2001 Aug; 38(2): 225–39. 54. Mohr PE, Neumann PJ, Franco SJ, Marainen J, Lockridge R, Ting G. The case for daily dialysis: its impact on costs and quality of life. Am J Kidney Dis. 2001; 37: 862–5. 55. Canadian Erythropoietin Study Group. Association between recombinant erythropoietin and quality of life and exercise capacity of patients receiving hemodialysis. Br Med J. 1990; 300: 573–8. 56. Canadian Erythropoietin Study Group. Use of erythropoietin before the initiation of dialysis and its impact on mortality. Am J Kidney Dis. 2001 Feb; 37(2): 348–55.

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57. Eckardt KU. Target hemoglobin in patients with renal failure. Nephron. 2001 Oct; 89(2): 135–44. 58. Locatelli F, Bommer J, London GM, Martin-Malo A, Wanner C, Yaqoob M, Zoccali C. Cardiovascular disease determinants in chronic renal failure: clinical approach and treatment. Nephrol Dial Transplant. 2001 Mar; 16(3): 459–68. 59. Dew MA, Switzer GE, Goycoolea JM, Allen AS, DiMartini A et al. Does transplantation produce quality of life benefits? A quantitative analysis of the literature. Transplantation. 1997; 64: 1261–73. 60. Laupacis A, Keown P, Pus N, Krueger H, Ferguson B, Wong C, Muirhead N. A study of the quality of life and cost-utility of renal transplantation. Kidney Int. 1996; 50: 235–42. 61. Simmons RG, Abress L. Quality-of-life issues for end-stage renal disease patients. Am J Kidney Dis. 1990 Mar; 15(3): 201–8. 62. Shield CF, McGrath MM, Gross TF. Assessment of health-related quality of life in kidney transplant patients receiving tacrolimus (FK5006)-based versus cyclosporinebased immunosuppression. Transplantation. 1997; 64: 1738–43. 63. Kreis H, Oberauer R, Claesson K, Mota A, Arias M et al. for the Sirolimus TriContinental Renal Transplant Study Group. Quality of Life Assessment in Sirolimus-Treated Renal Transplant Patients After Cyclosporine Elimination. European Society of Dialysis and Transplantation, Vienna, July 2001. 64. Russell JD, Beecroft ML, Ludwin D, Churchill DN. The quality of life in renal transplantation – a prospective study. Transplantation. 1992; 54: 656–60. 65. Adelmann PK, Antonucci TC, Crohan SE, Coleman LM. A causal analysis of employment and health in midlife women. Women Health. 1990; 16: 5–20. 66. Kessler RC, House JS, Turner JB. Unemployment and health in a community sample. J Health Soc Behav. 1987 Mar; 28(1): 51–9. 67. Bremer BA, McCauley CR, Wrona RM, Johnson JP. Quality of life in end-stage renal disease: a reexamination. Am J Kidney Dis. 1989 Mar; 13(3): 200–9. 68. Hauser ML, Williams J, Strong M, Ganza M, Hathaway D. Predicted and actual quality of life changes following renal transplantation. ANNA J. 1991 Jun; 18(3): 295–6. 69. Evans RW, Kitzmann DJ. An economic analysis of renal transplantation. Surg Clin North Am. 1998; 78: 149–74. 70. Hariharan S, Johnson CP, Bresnahan BA, Taranto SE, McIntosh MJ, Stablein D. Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med. 2000; 342: 605–12. 71. Feld LG, Stablein D, Fivush B, Harmon W, Tejani A. Renal transplantation in children from 1987–1996: the 1996 Annual Report of the North American Pediatric Renal Transplant Cooperative Study. Pediatr Transplant. 1997; 1: 146–62. 72. Laupacis A, Feeny D, Detsky AS, Tugwell PX. How attractive does a new technology have to be to warrant adoption and utilization? Tentative guidelines for using clinical and economic evaluation. Can Med Assoc J. 1992; 146: 473–81. 73. Newton SE. Renal transplant recipients’ and their physicians’ expectations regarding return to work posttransplant. ANNA J. 1999 Apr; 26(2): 227–32. 74. Painter PL, Luetkemeier MJ, Moore GE, Dibble SL, Green GA, Myll JO, Carlson LL. Health-related fitness and quality of life in organ transplant recipients. Transplantation. 1997; 64: 1795–800. 75. Carter JM, Winsett RP, Rager D, Hathaway DK. A center-based approach to a transplant employment program. Prog Transplant. 2000 Dec; 10(4): 204–8. 76. Wlodarczyk Z, Badylak E, Glyda M, Turkiewicz W, Karczewski M. Vocational rehabilitation following kidney transplantation. Ann Transplant 1999; 4(2): 40–2.

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Chapter Three Outcomes for Living Donor and Cadaver Donor Kidney Transplantation Pablo Ruiz-Ramón, M.D. and Lawrence Hunsicker, M.D. Summary Points • Long term patient survival and living donor and cadaver kidney transplant function have improved substantially over the past few decades. • Even so, the cadaver kidney waiting list is growing and the average cadaver kidney quality is worsening. • The supply of cadaver kidneys has plateaued. • Highly sensitized patients wait four times as long as others. • Among different organ procurement regions of the country, cadaver organs are distributed using the same simple formulas. • In the mid 1990’s waiting times for cadaver kidneys in various patient subgroups varied from 2–3 years to 4–5 years. • The projected half life of a cadaver donor kidney is 10–11 years and is 17–18 years for a living donor kidney. • Much “graft loss” occurs as a result of recipient death – over one third of cadaver kidney recipients over age 50 – with the graft still functioning. • Current, detailed waitlist and living and cadaver donor kidney survival data can be found at www.unos.org.

35 R.W. Steiner (ed.), Educating, Evaluating, and Selecting Living Kidney Donors, 35–49.  2004 Kluwer Academic Publishers. Printed in the Netherlands.

36

PABLO RUIZ-RAMÓN AND LAWRENCE HUNSICKER

Introduction In the field of transplantation, the past two decades have brought dramatic developments in the understanding of cellular and molecular mechanisms, which have translated into improvements in tissue typing, immunosuppression, and management of complications. The result has been an improvement in one-year kidney allograft survival rates from approximately 50% in the pre-1980 era, to 75–85% in the 1980’s, and to 85–90% in the 1990’s. Trends in one-year patient survival rates have likewise improved, reaching 95% in 1999. It has become clear that for a substantial number of ESRD patients, renal transplantation confers a survival advantage over dialysis [1]. It is not surprising that the combined effects of the dramatic ESRD population growth and the increasing acceptance of renal transplantation as a preferred modality of renal replacement have resulted in increased numbers of potential recipients. In fact, the demand for kidney allografts has far outstripped the supply, leading to continued lengthening of waiting times for cadaver kidney transplant candidates. This trend, along with public concerns regarding equitable organ allocation, led the US Congress to pass the National Organ Transplant Act in 1984. One of the Act’s provisions was the creation of an Organ Procurement and Transplantation Network (OPTN), which has been managed by the governmentcontracted United Network for Organ Sharing (UNOS) since 1986. It is the responsibility of UNOS to ensure an equitable system of access and sharing of renal and extrarenal organs and to improve cadaveric organ procurement and distribution. Current detailed data can be obtained that are to the point and extremely helpful in many ways in counseling transplant donors at the UNOS website http://www.unos.org [2]. Some of those data will be presented in sections to follow as current near year-end 2002. Cadaver organ procurement in the US is managed by regional Organ Procurement Organizations (OPO’s), each designated by the Health Care Financing Administration (HCFA) and mandated to allocate organs equitably within their region. Waiting times for cadaver kidneys can vary substantially between regions, due to regional variability in population characteristics, numbers of ESRD patients, and organ procurement rates. In 1996, an average unsensitized patient with blood type O could wait as little as 6 months in one region and as long as four years in another [2]. Average waiting times in all OPO’s have increased in rough proportion to the yearly increase in the waiting list since then. Waiting Times As of August 2001 there were 49,546 individuals awaiting kidney transplantation in the US. In the previous year 13,290 kidney transplants were performed, 5,227 of these with a living donor kidney. The modest growth in kidney transplant numbers over the past decade has largely been due to increases in living donor procedures and has been insufficient to keep up with the growth in the waiting list (Figure 1). Between 1995 and 2000, the waiting list grew by about 10% per year, and the number of cadaver kidney donors grew by 1–2% per year; these trends continue to the present. Improvements in transportation safety measures and

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37

Figure 1. The growth of the waiting list for cadaver kidneys in the past decade, compared to the supply of cadaver kidneys. The disparity continues to increase at the same geometric rate each year (from reference 3).

national educational campaigns regarding driver safety have diminished the number of cadaver organ donors dying of traumatic brain injury. As the balance of donors occurs in the non-trauma death category (primarily cerebrovascular accidents), the associated trend is one of increasing donor age [3]. For a patient to be placed on a cadaver kidney waiting list in any OPO in the United States today, the glomerular filtration rate (GFR) must be documented to be less than or equal to 20 ml/min, unless the patient is under the age of 18, in which case “established renal disease” constitutes an acceptable criterion. There are no rules regarding the placement of a potential recipient on multiple lists from different OPO’s, and this is not an uncommon practice in some areas. All OPO’s are mandated to share kidneys first with respect to blood type compatibility. Although the same principles that govern blood transfusion apply in solid organ transplantation, with group O being the universal donor and group AB the universal recipient, the disproportionate number of group O patients awaiting kidney transplantation mandates distribution of cadaver organs solely within each specific blood group. For a blood group O patient, the widening discrepancy between the kidney supply and the waiting list has meant an increase in wait time from 477 days in 1990 to 1,213 days in 1996, or about a 10% per year increase in waiting time [4]. Possibly because medical management of dialysis patients has improved along with transplantation medicine, this trend has not had a substantial effect on the death rates of people on the waiting list [5]. Other than regional differences, various other factors affect waiting time (Table 1). In 1996 waiting times for all kidney recipients as a whole – with blood groups O, A, B, or AB – were 1,213 days, 641 days, 1,426 days, and 379 days, respectively. These waiting times are longer for candidates for repeat kidney transplants. White registrants with low PRA’s waited 653 days in comparison with similar

38

PABLO RUIZ-RAMÓN AND LAWRENCE HUNSICKER

Table 1. Factors that affect cadaver kidney median waiting times. 1. 2. 3. 4.

Blood group Race/ Ethnicity Sensitization (peak PRA %) Previous transplant(s)

unsensitized Hispanics, Blacks, and Asians who waited 1,012 days, 1,178 days, and 1,186 days, respectively [5]. As the race and ethnicity of potential recipients are not part of the allocation formula, other factors discussed in this chapter have to be in part responsible for these disparities. The racial and blood group composition of the waiting list has not changed appreciably in the past few years [2], so the across-the-board increases in the disparity between the supply and demand for cadaver kidneys would increase the waiting times proportionately. All candidates for kidney transplantation undergo testing for the presence of pre-existing antibodies that may react against a panel of known donor tissue markers (HLA antigens). Even though to be transplanted each recipient must be crossmatch negative with respect to their particular cadaver kidney, the very existence of these antibodies, referred to as panel reactive antibodies (PRA), predisposes to the development of rejection and shortened graft survival in recipients who have them. Panel reactive antibodies are found quantitatively and qualitatively more commonly in patients who have previously failed transplants, patients who have received multiple blood transfusions, and women who have given birth. The “PRA” is reported as the percentage of all human tissue markers that produce an antibody reaction with a particular candidate’s blood sample. A previous transplant and a high panel reactive antibody titer each separately increases the probability of incompatible matches and thus increases waiting time. A patient who is “highly sensitized”, defined as a PRA of greater than 80%, can expect to wait four times longer than an unsensitized (PRA < 20%) counterpart. Even when unsensitized, a repeat transplant recipient waits twice as long. Numerous variations in “standard” protocols are being explored in hopes of reducing waiting times. The greater acceptance of laparoscopic organ recovery has begun to increase the numbers of living donors, many who were previously unwilling to accept an open surgical procedure, and thereby “unburden” the cadaver kidney waiting list in some regions. Other regions have advocated using kidneys from donors with compatible blood group A subtypes A2 and A2B in blood group B candidates in order to equalize waiting time between these two blood groups [6]. Newer protocols have achieved some promising short-term success in transplantation across incompatible blood groups and in sensitized donorrecipient pairs [7]. Newer procedures – often using IVIG with or without plasmapheresis – are currently being performed only in certain centers with living donors. Selection and Distribution Procedures for Cadaver Kidneys The clear historical survival advantage of a HLA phenotypically identical kidney (one having exactly the same antigens as found in the recipient) led to the

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development of a national sharing system in 1987. Under this system, all cadaver kidneys that are procured are first offered to the national waiting list for confirmation of a “phenotypically identical match.” If such a match exists within any compatible blood group, as it does in approximately 5% of cases, the “perfectly matched” recipient, regardless of OPO region, is offered the organ. This system has been extended to require the same national sharing of kidneys for which a “zero-mismatched” recipient can be found, that is, a recipient that shares all of the detectable antigens present in the cadaver kidney (though the recipient might have other antigens not found in the kidney). This has raised the percentage of nationally shared cadaver kidneys to about 15%. If no such matches exist, the organ remains to be offered within the procuring OPO. Although debated by some, the benefits of implementing such a program have recently been confirmed [8]. Although there are exceptions, most OPO’s follow a UNOS-developed point system to guide in the distribution of procured cadaver kidneys (Table 2). This system aims to allocate points so as to optimize graft survival and reduce waiting times within certain subsets of recipients. The waiting list candidate with the highest point value is offered the incoming cadaver kidney. The discrepancy between supply and demand has increased scrutiny of organs from some cadaver donors that were previously felt to be unsuitable, the socalled “extended donors.” This urgency has both energized efforts at improving organ preservation and brought attention to the need for OPOs to justify turning down any donor organs. Careful selection and individualized placement are now allowing for successful results with kidneys procured from older donors and donors with hepatitis C (used by some for hepatitis C positive recipients), as well as with pediatric en-bloc kidneys and adult dual kidneys. There are general acceptance criteria for cadaver kidneys that are usually closely followed by OPOs. Donor HIV infection carries a significant risk of transmission and represents an exclusion criterion. Increased risk of transmitting malignancies rules out many donors with a history of malignancy, with certain notable exceptions. Most programs also reject kidneys from donors with HTLV1, hepatitis B, hepatitis C, and a host of bacterial and fungal infections. Adequate urine output (1–3 ml/kg/hour) and a pre-procurement creatinine of less than 2.0 mg/dl usually constitute evidence of acceptable renal function. Finally, an organ may be deemed to be unsuitable for use due to anatomic abnormalities that are discovered at the time of procurement. In extenuating circumstances, where a potential recipient may be facing imminent death, the risk of receiving an organ from such “unsuitable” donors may in the end be acceptable, as is sometimes Table 2. The UNOS point system. Criterion

Points

Criterion

Points

Longest waiting patient Each year of waiting No B or DR mismatches One B or DR mismatch Two B or DR mismatches

1 1 7 5 2

PRA > 80% Patient age < 11 Patient age 11–18 Previous organ donor

4 4 3 4

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PABLO RUIZ-RAMÓN AND LAWRENCE HUNSICKER

the case with heart and liver transplant candidates where no other life-saving measures are available. Risks of Cadaver Kidney Transplantation In the first three months after renal transplantation 2.5% of cadaver kidney recipients die, and 1.1% of living donor kidney recipients die. Table 3. Patient survival rates for recipients of renal allografts, %.

All Cadaver Donor Transplants All Living Donor Transplants Patients with Acute Tubular Necrosis Cadaver Kidney Recipients Aged 18–50 Cadaver Kidney Recipients Aged > 50

3 month

1 year

3 year

5 year

97.5 98.9 96.4 98.8 95.7

94.8 97.6 92.9 97.5 90.6

88.9 94.6 85.0 92.9 80.1

81.8 91.0 76.0 88.2 67.8

While the majority of these deaths are due to pre-existing recipient factors, such as age and cardiovascular disease, donor-associated factors must also be considered. Transmission of disease from donor to recipient can occur within the broad categories of malignancy and infection. There have been scattered case reports of malignancy transmission including lung, breast, melanoma, thyroid, colon, and adenocarcinomas of unknown primary. Donors with a primary brain tumor, carcinoma in situ of the cervix and non-melanoma skin cancer are not always excluded from donation except under very specific circumstances. A recent UNOS study tried to quantitate the absolute risk and found 650 solid organ recipients transplanted between 4/1/1994 and 12/31/1996 who received an organ from a donor with a history of malignancy [9]. During 45 months of follow-up, not an unreasonable period of time to wait for tumors to appear, none of these recipients developed a donor-derived cancer. The Penn cancer registry, which has recorded the development of voluntarily reported malignancies in transplant recipients over many decades, found 117 patients who had developed a donor derived cancer [10]. Although these studies are by no means conclusive, one could derive from these observations that the risk of malignancy transmission is likely to be < 1%, using current selection practices. The transmissibility of HIV-1 infection is also < 1%, especially since OPOs follow published CDC guidelines and test potential donors for the sensitive, early appearing p24 antibody. Although successfully used in some hepatitis B surface antigen (HepBSAg) negative recipients, kidneys from HepBSAg positive donors carry a significant risk of transmission, and use of these kidneys has generally not been recommended. There appears to be acceptable short-term risk for many centers to use kidneys from HbsAg negative, anti-HepB core-positive donors [11]. Uninfected recipients of kidneys from hepatitis C positive donors have a 13-fold increased risk of developing hepatitis C within the first year of transplantation [12], and most centers do not transplant these kidneys into recipients who are not already infected with hepatitis C. Short-term analysis of mortality at

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1 and 3 years shows no increase when it comes to hepatitis B or hepatitis C transmission alone. Combined infection increases mortality by 170%. Cadaver Donor Kidney Results Between 1988 and 1999 the overall one-year survival rates for cadaver kidney grafts increased from 75.7% to 89.4% [13]. Another meaningful way of looking at these results is to calculate the half-life of the kidney, or the time period at which half of transplanted kidneys are functioning and half have failed (Figure 2). The most current UNOS data document a five year survival for cadaver kidneys of 61.3%. These are actual results, and survival projections from cohorts of patients transplanted in the past two or three years suggest even better results. Considering the potential negative influence of using more “extended donor” kidneys, this remarkable trend of improvement is a testament to the improvements in immunosuppresion, organ preservation, HLA matching, and the treatment of complications such as infection. The large American and European transplant registries identify similar factors that may influence outcomes in cadaveric renal transplantation (Table 4). Some of these factors will now be discussed. Donor Age (Figure 3). From 1995 to 2000, the number of cadaver kidney donors aged 50–64 increased from 19.9% to 23.3%, and the number of donors over age 65 increased from 4.6% to 6.9% (UNOS website data). Both extremes of age are associated with reduced graft survival rates. The average older kidney has reduced function, and the challenge is to select the better kidneys from the older donor population. Very young kidneys have a greater propensity for developing vascular thromboses. In both cases special techniques of using both kidneys from the same donor have proven to be successful [16, 17].

Figure 2. Steady improvement in actual cadaver donor and living donor kidney transplant survival over three decades, 1970–1999. Projected graft survival (half life) continues to improve by over 10% in the most recent 5 year cohorts (from reference 3).

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PABLO RUIZ-RAMÓN AND LAWRENCE HUNSICKER

Table 4. Factors that affect cadaver kidney survival. Donor Factors 1. Age/Sex 2. Ischemic time 3. Cause of death (14) 4. Pre-existing disease 5. Multiorgan vs. kidney alone donor (15) Recipient Factors 1. Age 2. Race 3. HLA matching 4. Bilateral nephrectomy 5. Original cause of ESRD 6. Degree of sensitization 7. Cardiovascular disease 8. Time on dialysis Post Transplant Factors 1. Rejection 2. Immunosuppressive protocol 3. Delayed graft function 4. Adherence to recommended regimen 5. New onset diabetes, hypertension 6. Center effect

HLA Matching (Figure 4). The national sharing system for 6-antigen-matched (or zero-mismatched) kidneys and the UNOS point system were both created on the basis of observations showing improved kidney survival with improved degrees of HLA matching. The results obtained with a zero mismatched cadaver kidney approach those of an average living donor kidney (91.8% vs. 94.5% one year graft survival; 71.6% vs. 78.4 % 5-year graft survival). Of the three commonly determined HLA loci, the DR locus plays a more important role when there are lesser degrees of matches [18]. However, the benefits of even a poorly matched cadaver kidney transplant may outweigh the mortality risk of remaining on the waiting list more than 6 months [19]. Recipient Age. The reduction in graft survival in older recipients is primarily a function of an increased proportion of deaths with a functioning graft. Most studies report a lower incidence of acute rejection in older recipients [20]. The current post transplant mortality from UNOS data for older recipients is not insubstantial – the five-year mortality for cadaver kidney recipients aged 35–49 is 15%. For patients 50–64, the mortality is 25.3% at five years post transplant. Patients with risk factors such as diabetes are not considered separately in this analysis. Delayed graft function (DGF). Delayed graft function, defined as the need for dialysis within the first week of transplantation, occurs in 20–25% of all cadaver kidney transplant procedures. The incidence of acute rejection increases in association with delayed graft function, and the concurrence of these two factors

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Figure 3. The effect of cadaver donor age on transplant survival. Donor age has a similar influence on living donor kidneys (from reference 18, with permission from Elsevier Science).

leads to a particularly poor result. Although the cold ischemia time, or cold storage time of the kidney, has an impact on the development of DGF, other factors affecting the quality of the organ and thus predisposing to DGF appear to be more predictive of long-term organ function [21]. Sensitization and Multiple Transplants. Higher degrees of immunologic reactivity, as measured by panel reactive antibodies, resulted in increased rates of acute rejection and thus lower graft survival in the pre-cyclosporine era. However this effect has now essentially disappeared. After a failed transplant procedure, subsequent transplants still reduce graft survival by about 10% at 5 years. Sex of Donor and Recipient. A small effect of “nephron dosing” appears to be observed in the differences in graft survival rates between different individuals. Thus, a kidney from a small female is more likely to survive longer in an equally sized recipient as opposed to a large muscular male in whom the critical nephron number may not be met. This effect has not been thought strong enough to warrant a separate size criterion for organ sharing.

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PABLO RUIZ-RAMÓN AND LAWRENCE HUNSICKER

Figure 4. The effect of HLA mismatch on transplant survival in the modern era. “Zero mismatched” kidneys do significantly better than the other groups (from reference 3).

Race (Figure 5). Although differences in one year graft survival among races have diminished, there remain significant differences in the five-year data. UNOS data document a 78.1% graft survival at 5 years in white recipients of a living donor kidney and a 61.8% 5 year graft survival in black recipients. Reasons for this are not entirely clear but may include an increased rate of rejection, an increase in delayed graft function, a lower percentage of HLA-matched cadaver kidneys, and a higher prevalence of post-transplant hypertension in blacks [22].

Figure 5. The effect of race on cadaver kidney survival in sensitized and non-sensitized recipients. Racial differences also influence transplant survival in many other categories of recipients. See text for details (from reference 3).

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Rejection. Newer immunosuppressive protocols have diminished acute postoperative rejection episodes from approximately 50% in the late 1980’s to 10–15% currently. Five-year graft survival declines by about 20% when an early rejection occurs, a decline roughly equivalent to that seen with delayed graft function. Cause of Donor Death. Kidneys from donors who die of trauma (motor vehicle accidents, gun shot wounds, head injury, etc.) have a significantly higher oneyear graft survival than kidneys from donors who die of non-traumatic causes, even when one corrects for donor age [14]. Kidneys from donors with hypertension and diabetes also fare slightly worse [23]. Adherence to Medication Regimen. Discontinuation or patient self-adjustment of immunosuppressive medications is an important and potentially preventable cause of graft loss. Factors that have been cited as contributing include a pre-transplant history of substance abuse, previous non-compliance with dialysis, socioeconomic status, and pre-existing belief structures. Center Effect. Numerous variables have been purported to explain differences in the results of renal transplantation between transplant centers. The effect to which each center encourages and monitors patient compliance may play a role. Differences in patient selection criteria, organ acceptance criteria, recipient population characteristics such as age and race, and affiliated OPO practices probably play a role [24]. Living Donor Kidney Results Graft survival with living donor kidneys surpasses that seen with cadaver kidneys at all time points. In the most current era, the projected average half-life of a living donor kidney was 17.7 years compared to 10.9 years with a cadaver kidney. The significant 20–25% incidence of delayed graft function observed in cadaver kidneys plays a large role in this discrepancy. Underscoring this is the 23% drop in 5 year graft survival seen in the few (4.5%) living donor kidneys that do develop delayed graft function, an outcome which is worse than that for the average cadaver kidney graft survival (Table 5). Whereas prior to the 1990’s, the majority of living donors were genetically related family members, unrelated donors such as spouses and “emotionally related” friends have become a growing donor source. In 1999 20% of all living donors Table 5. Kidney graft survival (UNOS 2000 data, in %).

All cadaver kidney transplants All living donor kidney transplants Cadaver kidney transplants with DGF Living donor kidney transplants with DGF

3 month

1 year

5 year

93.7 96.7 91.3 87.7

89.4 94.5 85.4 81.3

64.7 78.4 54.7 57.2

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were unrelated, 12% of these being spouses. Even with the lesser degree of HLA matching, graft survival is the same for a spouse-donated kidney as it is for a parentdonated kidney [25]. Overall however, the effect of HLA matching remains an important one in both categories of living donor kidneys [26], as evidenced by the superior results obtained with kidneys from an HLA-identical matched living donor . While such predictors of graft survival as donor age, donor and recipient sex, and recipient race are important in cadaver kidneys, they do not appear to have a significant impact in living donor kidneys [27]. Rejection remains the most important factor influencing graft survival in living donor kidneys. Long Term Outcomes Despite the apparent survival advantage over patients staying on dialysis that is offered by renal transplantation, mortality rates in kidney transplant recipients remain above those of age-matched controls in the general population. The marked improvements in the early management of kidney transplant recipients has made “death with graft function” the most important cause of kidney graft loss, now accounting for 43% of all losses [28]. Cardiovascular disease is the leading cause in this category, especially in diabetic and older recipients (Table 6). Fortunately, the great attention now placed on controlling hypertension, cholesterol, and other cardiovascular risk factors, has likely had a great impact in delaying “death with graft function” over the past decade. The increase in longevity associated with transplantation is still less marked in the older age group, as discussed in Chapter 2. Death with a functioning graft limits the unadjusted graft survival in older age groups (Figure 6). For transplant candidates with certain underlying causes of renal failure there is risk of recurrent disease within the renal transplant. Recurrent disease has been observed to occur in 6–19.4% of renal transplant recipients, and accounts for up to 4.4% of all graft loss. A registry has been created to more accurately gauge this problem [29]. It is important to note that although a disease may recur, the resultant risk and rapidity of loosing the allograft varies depending on the underTable 6. Cause of death with graft function among renal transplant recipients, 1988–1997 (from reference 28). Cause of death

DWGF (N = 7040) N (%)

Cardiovascular Stroke Infection/sepsis Malignancy Gastrointestinal tract disorder Accident/suicide Other Unknown Missing

2,538 0,438 1,240 0,648 0,145 0,129 0,683 1,180 0,039

(36.1) 0(6.2) (17.6) 0(9.2) 0(2.1) 0(1.8) 0(9.7) (16.8) 0(0.6)

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Figure 6. Death with a functioning graft is the principle reason for poor unadjusted transplant survival in recipients over 60 (from reference 18, with permission from Elsevier Science).

lying disease process. For example, recurrence of Focal segmental glomerulosclerosis is associated with a worse prognosis than recurrence of IgA Nephropathy (Table 7). Table 7. Recurrent diseases after renal transplantation (from USRDS and Reference 29). Disease

% of ESRD

% with recurrent

% with graft loss

Kidney T1/2

Focal segmental glomerulosclerosis Diabetic Nephropathy IgA Nephropathy Membranous nephropathy MPGN (type I and II) HUS and TTP

02.2 43 00.6 00.5 00.4 00.2

34.1 11.4 38.8 10.8 36.3 04.8

65 53 09 44 66 63

42 79 55 40 45 07

Abbr.: Membranoproliferative glomerulonephritis (MPGN), Hemolytic Uremic Syndrome (HUS), Thrombotic Thrombocytopenic Purpura (TTP). T1/2 = half life, in months, with recurrent disease.

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Conclusion Renal transplantation has become a widely accepted form of renal replacement therapy. However waiting times for potential candidates have increased dramatically and continue to increase. Patients with blood groups O and B, non-white race, a previous transplant, or a high PRA wait the longest. Despite growing numbers of older living and cadaver donors, patient and graft survival rates continue to improve. Donor age, recipient age and race, HLA matching, PRA, delayed graft function, rejection, and compliance with medical regimens remain important predictors of cadaver kidney graft survival. Living donor kidneys manifest better graft survival, and such factors as donor age and recipient race do not appear to affect results. Although long term results are improving, premature “death with graft function” especially in the form of cardiovascular events, remains an important factor in the analysis of post transplant outcomes. References 01. Port FK, Wolfe RA, Mauger EA, Berling DP, Jiang K, Comparison of survival prob02. 03. 04. 05. 06. 07. 08. 09. 10. 11. 12. 13. 14.

abilities for dialysis patients vs. cadaveric renal transplant recipients. JAMA. 1993; 270: 1339–43. UNOS WEBSITE (www.unos.org). 1997 Report of the OPTN, p. 55. Rosendale JD, McBride MA. Organ donation in the United States: 1990–1999. In: Cecka JM, Terasaki PI (eds), Clinical Transplants 2000. Los Angeles: UCLA Immunogenetics Center, 2001: 5. UNOS 2000 Annual Report, Transplant data 1990–1999, US Department of Health and Human Services Administration. Harper AM. The OPTN waiting list, 1988–1999. In: Cecka JM, Terasaki PI (eds), Clinical Transplants 2000. Los Angeles: UCLA Immunogenetics Center, 2001: 5. Bryan CF, Shield CF, Nelson PW et al. Transplantation rate of blood group B waiting list is increased by using A2 and A2B kidneys. Transplantation. 1998; 66: 1714–7. Tanabe K, Takahashi K, Sonda K, et al. Long-term results of ABO-incompatible living kidney transplantation: a single center experience. Transplantation. 1998; 65: 224–8. Takemoto SK, Terasaki PI, Gjertson DW, Cecka JM. Twelve years’ experience with national sharing of HLA-matched cadaveric kidneys for transplantation. NEJM. 2000; 343: 1078–84. Kauffman HM, McBride MA, Delmonico FL. First report of the United Network for Organ Sharing transplant tumor registry: donors with a history of cancer. Transplantation. 2000. Penn I. Transmission of cancer from organ donors. 1997; Ann Transplant. 2: 7–12. Satterthwaite R, Ozgu I, Shidban H et al. Risks of transplanting kidneys from hapatitis B surface antigen negative, hepatitis B core antibody-positive donors. Transplantation. 1997; 64: 432–5. Delmonico FL, Cherikh WS, Kauffman HM et al. Impact of positive hapatitis B and C virus donor serology on heart and kidney allograft recipients. Abstracts of the American Society of Transplantation. 2000. Cecka JM. The UNOS Scientific Renal Transplant Registry – 2000. In: Cecka JM, Terasaki PI (eds), Clinical Transplants 2000. Los Angeles: UCLA Immunogenetics Center, 2001: 5. Feduska NJ. Donor factors in cadaveric renal transplantation. Clin Trnspl. 1993: 351–7.

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15. Smits JM, DeMeester J, Persijn GG et al. The outcome of kidney grafts from multiorgan donors and kidney only donors. Transplantation. 1996; 62: 767–71. 16. Lu AD, Carter JT, Weinstein RJ et al. Outcome in recipients of dual kidney transplants: an analysis of the dual registry patients. Transplantation. 2000; 69: 281–5. 17. Bretan PN, Friese C, Goldstein RB et al. Immunologic and patient selection strategies for successful utilization of less than 15 kg pediatric donor kidneys – long term experiences with 40 transplants. Transplantation. 1997; 63: 233–7. 18. Morris JM, Johnson RJ, Fuggle SV et al. Analysis of factors that affect outcome of primary cadaveric renal transplantation in the UK. The Lancet. 1999 454: 1147–52. 19. Edwards EB, Bennett LE, Cecka JM. Effect of HLA matching on the relative risk of mortality for kidney recipients: a comparison of the mortality risk after transplant to the mortality risk of remaining on the waiting list. Transplantation. 1997; 64: 1274–7. 20. Cameron JS. Renal Transplantation in the elderly. Int Urol Nephrol. 2000; 32: 193–201. 21. Shoskes DA, Cecka JM. Effect of delayed graft function on short- and long-term kidney graft survival. Clin Transpl. 1997: 297–303. 22. Young JY, Gaston RS. Renal transplantation in black americans. NEJM. 2000; 343: 1545. 23. Ojo AO, Leichtman AB, Punch JD et al. Impact of pre-existing donor hypertension and diabetes on cadaveric renal transplant outcomes. Am J Kidney Dis. 2000; 36: 153–9. 24. Cho YW, Cecka JM. Organ Procurement Organization and transplant center effects on cadaver renal transplant outcomes. Clin Transpl. 1996: 427–41. 25. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates for kidney transplants from spousal and living unrelated donors. NEJM. 1995; 333: 333–6. 26. Opelz G. Impact of HLA compatibility on survival of kidney transplants from unrelated live donors. Transplantation. 1997; 64: 1473–5. 27. Matas AJ, Gillingham KJ, Dunn DL, Sutherland DE, Najarian JS. Immunologic and nonimmunologic factors: different risks for cadaver and living donor transplantation. Transplantation. 2000; 69: 54–8. 28. Ojo AO, Hanson JA, Wolfe RA et al. Long-term survival in renal transplant recipients with graft function. Kidney International. 2000; 57: 307–13. 29. Harihan S, Adams MB, Brennen DC et al. Recurrent and de novo glomerular disease after real transplantation: a report from Renal Allograft Disease Registry (RADR). Transplantation. 1999; 68: 635–41.

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Chapter Four The Medical Evaluation and Risk Estimation of End Stage Renal Disease for Living Kidney Donors Robert W. Steiner, M.D. and Gabriel Danovitch, M.D. Summary Points • USRDS data and other medical literature provide a basis for risk estimation and semiquantitative counseling of potential kidney donors, although counselor interpretations and donor decisions based on these data may vary. • Even “normal” donors do not all have the same risk for ESRD, as they vary in age, race, normal range blood pressure, diabetic risk, and other factors. • Centers and their donor counselors should always attempt to quantify donor risk, as the implications of literally not knowing the risk make donor counseling and living donor transplantation largely impossible. • Centers and their donor counselors should formulate the baseline risk of ESRD separately from the incremental risk that donation would bring about ESRD, particularly for donors with common minor medical abnormalities. • The baseline lifetime risk of ESRD for unselected individuals who do not donate may be 2–3% for whites and about 7% for blacks, with almost half of ESRD in the United States occurring after age 64, and almost half of this number from diabetic nephropathy. • In the past decade, 30–50% of centers have excluded from donation individuals with hematuria, low grade proteinuria, nephrolithiasis, and hypertension. For many of these donors, the baseline predonation risk of ESRD may well be less than one in one hundred. • Nephrectomy in a healthy donor reduces overall renal function immediately by almost 20%. Five cc/minute additional GFR is lost per decade, a rate similar to the nondonating population. End stage renal disease acquired after donation would therefore develop at least 20% sooner because of donation, and long term predictions of renal function can also be made for donor candidates with borderline low predonation GFR’s. • Fewer data are available to calculate the effects of nephrectomy on the progression and complications of ESRD. • Long term follow up of donors from past decades suggests a one in several hundred risk of ESRD based purely on blood relationship for most evaluated, normal donors. 51 R.W. Steiner (ed.), Educating, Evaluating, and Selecting Living Kidney Donors, 51–70.  2004 Kluwer Academic Publishers. Printed in the Netherlands.

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The primary purpose of the donor medical evaluation is to estimate the risks of kidney donation for the prospective donor. The risks to the donor primarily involve perioperative morbidity and mortality and the long term risk of end stage renal disease (ESRD). After the evaluation and with the counseling of the center, the donor then decides if he or she wishes to proceed. It is hoped that the center’s own subsequent decision as to whether to participate will be based on the policies, practices, and criteria set out in this book. This chapter will not discuss in any detail the methods of medically testing or examining donors, as these are fairly standard at the present time. This chapter will however discuss the estimation of baseline risk for ESRD that is associated with the common isolated medical abnormalities (IMA’s) that are found during medical testing in potential kidney donors. Methods for estimating risk will be presented and illustrated, and data from prospective population studies that follow individuals with IMA’s will also be presented. As we discuss these risks, we do not intend to advocate to any center or to any donor that donation is advisable or inadvisable. In many cases, reasonable donor counselors may well disagree among themselves as to the estimate of risk, and many donors may of course disagree as to whether to donate, based upon their personal values and goals, as discussed in Chapter 1. Another important feature of the donor medical evaluation is also to help estimate the donor-related risks for the recipient, which are chiefly those of transmission of disease with the kidney and of poor donor allograft quality. These general issues are discussed to some extent in Chapter 2. The short term perioperative risk for the donor is usually not at issue. The long term risks of nephrectomy per se are discussed later in this chapter and in Chapter 5. The perioperative mortality for kidney donation is less than one in a thousand [1, 2]. Perhaps 5% of donors have wound discomfort beyond a few months, and 1–2% develop a wound hernia. Laparoscopic nephrectomy is associated with less donor pain and a quicker recovery [3], but there is a lengthening of warm ischemic time and slower return of GFR in the recipient in 10–20% of patients [4]. The long term results of laparoscopic donor nephrectomy versus open nephrectomy are not known, but available data suggest they are very similar [5]. The experience and expertise of the particular center is essential for the successful practice of laparoscopic nephrectomy and must be considered carefully by donors and their counselors. The long term reduction in renal function that is associated with unilateral nephrectomy in healthy individuals is relatively well-documented. A meta-analysis of 48 studies in 3,124 nephrectomized or other single-native-kidney patients and 1,703 controls documented a 17 cc/minute decrement in glomerular filtration rate (GFR), with a confidence interval (CI) of –20.2 to –14 cc/minute [6]. The difference between nephrectomized patients and controls narrowed by 1.4 cc/minute per decade post nephrectomy (CI 0.3 to 2.4 ml/minute). As baseline GFR in these subjects appeared to be about 103 cc/minute, nephrectomy resulted in about a 17% reduction in GFR that improved slightly over time. This group lost renal function after nephrectomy at about 5 cc/decade, i.e., a rate of loss of GFR with ageing of about 0.5 cc/year that is consistent with – but may be slightly better than – data for the general population as a whole [7]. Predicting the gradual loss of renal function after donation in donors with borderline low predonation GFR’s is discussed in a later section of this chapter.

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Data bearing on the loss of GFR that are specifically associated with donation are important because they provide a minimum estimate of the additional risk associated with donation in donors who develop renal disease in later life. That is, this is the baseline post donation physiologic disadvantage for all donors, even if (1) there is no additional risk of glomerular hyperfiltration in large mammals, (2) any deleterious effect of hyperfiltration can be controlled by medication, and/or (3) hyperfiltration occurs early on in the progression of two-kidney renal disease, so that it affects two and one-kidney individuals approximately equally. In the following sections of this chapter, we will be considering the risk of end stage renal disease for isolated medical abnormalities such as microscopic hematuria. As will be pointed out in several sections, counseling these donors should focus on two separate areas – first, the donor’s baseline predonation risk for ESRD, and second, the additional risk for ESRD that is specifically associated with donation. It is this second topic to which the data on the predicable loss of GFR post donation are most relevant. The donor should always be told that if he does develop ESRD at any point in later life, he can count on at least a 17% shorter time span until dialysis is needed, because he will have 17% less renal function after donation. Because the figure of 17% loss of renal function from donation is not exact, it may be best to think of the donor’s loss as 20% of predonation renal function. This figure is easier to convey, as one out of every 5 dialysis-free years that is unavoidably given up should end stage renal disease be contracted after donation. The possibility that hyperfiltration in the remaining kidney will also accelerate the progression of chronic renal disease that arises after donation, however, does not apply only to donors with IMA’s. As discussed in later sections of this chapter, even “normal” donors are at risk for chronic progressive renal diseases in later life, especially type II diabetes. Therefore all donors need to know that donation will predictably reduce overall renal function by almost 20% and may accelerate the progression of chronic renal disease should they acquire it in later life. The remainder of this chapter will address the estimation of baseline long term risk for end stage renal disease, particularly for individuals with common, isolated medical abnormalities. The spectrum of standard practices at centers in the United States for donor medical testing are presented in Figure 1. Specific recommendations for center donor medical evaluations and donor exclusion policies have been promulgated (8–10). Surveys of the policies of transplant programs show that in the past decade, centers have not uniformly agreed on donor testing (Figure 1) and acceptance policies (Table 1). The stated policy of some centers may be that identification of any donor risk factor justifies refusal of that donor. As is discussed in Chapter 1, since there is always donor risk, it is difficult to take this formulation literally. Donor exclusion policies emanating from “no risk” centers therefore may not be helpful to centers that recognize the possibility of acceptable donor risk. At present, some centers also may not be aware of reasonable estimates of the baseline risk of ESRD for donor candidates and how donor medical abnormalities might affect that risk. Therefore, the current practices of centers in accepting or rejecting living kidney donors must be respected, but they must still be regarded as open to rational modification. In the following sections, data will be provided which will help the donor counselor estimate risk for several common abnormal medical findings that can

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Figure 1. Living kidney donor testing protocols from different transplant programs in the past decade. Used with permission from reference 9.

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Table 1. Kidney donor exclusion criteria of US transplant centers in the past decade (from reference 9). Proteinuria 300–1,000 mg/day Persistent hematuria Nephrolithiasis Hypertension Diabetes Normalized creatinine clearance < 80 cc/minute

58% 31% 34% 54–64% 46–61% 59%

be found in donor candidates. As a first approximation, the risk associated with an isolated medical abnormality that is found on donor testing can be roughly determined from (1) the number of individuals in the United States putatively at risk for a certain type of ESRD by virtue of having a certain IMA, i.e., the prevalence of the disease-associated condition, and (2) the number of cases of that kind of ESRD actually reported per year. In other words, using population prevalence data, we define a cohort of at-risk individuals with an IMA, then assume that all yearly incident ESRD that the IMA might presage arises from that cohort. This is often an unrealistically conservative assumption but will tend to provide an upper limit to the risk of that IMA for its associated type of ESRD. The following example illustrates such yearly risk estimation using the prevalence of hypertension and the number of new cases of ESRD attributed to hypertension each year. This topic is discussed extensively in Chapter 5. USRDS statistics for the year 2000 will be used, since the US population then was known to be approximately 275 million (11). We will also use round numbers to avoid the impression of greater precision than is actually achieved in this calculation. Approximately 30% (27–43%) of the general population of the United States is hypertensive [12, 13], which equals a prevalence of 82.5 million individuals. The number of new cases of hypertensive ESRD is reported to be about 20,000 per year. This would put the yearly risk of ESRD that is specifically associated with hypertension at just over 0.0002, or one in 5,000. Using these data, the risk estimate for the next twenty years in the hypertensive donor’s life would be one in 200. Many investigators have also attempted to quantify on the basis of prospective studies the risk of essential hypertension for ESRD, and these studies indicate that the long term risk is substantially less than one in 200 [14], as discussed in depth in Chapter 5. In the past decade, over half of all centers rejected donors with mild to moderate hypertension [9]. However, many centers and many donors might find that a long term risk of ESRD of less than one in 200 is acceptable. Thus, the donor selection practices of some centers may become more satisfactory by attempting to identify risk factors qualitatively, which at the very least may bring more focus to a debate about donor acceptability. Donors with a risk of the eventual development of diabetes form another special group, where the risk is of a somewhat different nature and seems to be best presented by means of a rather detailed formulation. If one accepts that some donors are destined to develop diabetic nephropathy later in life and that uninephrectomy may only accelerate – but not cause – diabetic nephropathy, the important question for these donors regarding ESRD is “not if, but when?” Some centers may find it acceptable to formulate a

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quantitative risk estimate from the abundant data on diabetic nephropathy and present it to donors instead of rejecting all donors with diabetic risk [9] (Table 1). The findings of donor hypertension and donor diabetic risk are two common donor problems that will be discussed in detail in Chapters 5 and 6. Using the prevalence of a donor medical condition such as hypertension or hematuria to define the yearly risk for a certain kind of ESRD does not mean we have to make any assumptions about the course of the disease, as long as the prevalence of the medical abnormality, the population, and the natural history of the disease do not change. If the general population is growing over time, using current population data overestimates the number at risk and underestimates the calculated risk, especially when the disease in question progresses slowly. This will change the risk estimates, as will a recent change in the rate of disease progression to ESRD in the population. If the renal disease progresses more slowly over time as medical treatment improves, then the risk of eventual ESRD will be underestimated, but if people die of other causes without reaching ESRD, the lifetime risk will decrease. Even with these caveats, for many of the medical conditions commonly encountered during the donor evaluation, there is reasonable stability of data, we know roughly the percent of the general population that is affected by that condition, and we know how many cases of ESRD from various causes are reported each year. We therefore have the means to help asses risk and counsel donors semi-quantitatively (Table 2). In the ensuing sections, relevant data of this type will be presented on common conditions encountered in the donor evaluation, which can aid the donor counselor in estimating risk. As is discussed in other sections, when the donor counselor literally cannot estimate risk at all, the counseling process is unsatisfactory and donation should probably not be considered. There is a difference however, between a given well intentioned but uninformed donor counselor being unable to estimate risk and a particular donor’s risk – after all reasonable efforts at discovery – being incalculable by any medical professional because of lack of epidemiologic data. For many donors, there are medical data that can help the donor counselor in formulating a reasonable although admittedly imprecise estimate of risk.

Table 2. USRDS 2000 Data: The reported incidence of ESRD by general diagnostic category in 1998 (adapted from reference 16). Diabetes Hypertension Glomerulonephritis Cystic Disease Urologic Disease Other Known Cause Unknown Cause Missing Cause

36,904 19,659 10,528 02,507 04,188 03,408 06,734 01,662

Total

85,520

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Epidemiology of End Stage Renal Disease The current lifetime baseline risk for ESRD has been estimated to be 2.5% for white men, 1.8% for white women, and as high as 7.3% and 7.8% for black men and women respectively (15). About half (47.5%) of new cases of ESRD occur after age 64 (Table 3). These data are for unselected individuals, many of whom would have obvious medical abnormalities early in the course of their renal disease and would not be considered for kidney donation. The risks for most potential kidney donors would be lower. In the United States, the incidence of ESRD increases every year, chiefly because of the increase in ESRD in patients over sixty-five who have diabetic nephropathy [16]. Patients with diabetic nephropathy comprise about 40% of incident cases of ESRD [16] (Table 2). As diabetic nephropathy will progress to ESRD anyway – regardless of kidney donation – it is also useful to consider the specific effect of end stage diabetic nephropathy on general ESRD risk statistics when counseling donors. As was illustrated in previous sections, when estimating donor risk, one must consider the yearly incidence of the kind of ESRD for which the donor is thought to be at risk as well as the prevalence in the general population of the donor abnormality in question. There are four major causes of ESRD in the United States today (Tables 2 and 3). Overall, using statistics from the last half of the last decade, diabetes causes about 40% of all new cases of ESRD in the United States [16]. The other principle causes are “hypertension/large vessel disease” (25%), “glomerulonephritis” (9%) and “secondary GN/vasculitis” (2.2%) [15]. The relationship between primary (“essential”) hypertension and ESRD is discussed in detail in Chapter 5. The exact incidence of hypertensive ESRD is uncertain because of possible misclassifications as patients begin dialysis. It is likely that many patients who are reported as having “hypertensive ESRD” have hypertension as a result of primary glomerular disease, not as the primary cause of ESRD. Because of misdiagnosing ESRD due to glomerulonephritis as due to hypertension [14, 17, 18], it is plausible that “glomerulonephritis/vasculitis” may be the Table 3. Primary disease demographics, 4 year totals (1994–1998) (adapted from reference 16). Dialysis

Total Patients

% of Total

Median Age

% Age 20–64

% Age > 64

All ESRD (reference) Diabetes Glomerulonephritis Secondary GN/Vasculitis Interstitial Neph/Pyelonephritis HTN/Large Vessel Disease Cystic/Hereditary/Congenital Neoplasms/Tumors Miscellaneous Conditions Etiology Uncertain Missing

382,490 150,978 034,997 008,490 014,429 096,268 010,801 006,498 012,299 013,712 034,018

100.0 039.5 009.1 002.2 003.8 025.2 002.8 001.7 003.2 003.6 008.9

63 64 57 47 66 70 52 69 56 68 51

51.3 53.1 57.4 68.3 43.9 34.6 62.2 34.9 59.6 39.5 84.2

47.5 46.9 38.4 26.1 53.9 65.1 26.5 64.6 38.6 58.0 14.5

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cause of ESRD in significantly more than 11% of patients nationwide. The risk of eventual development of glomerulonephritis in potential donors is considered in the discussions of donor hematuria and proteinuria below. The following sections will consider several common abnormal findings which may arise during the kidney donor evaluation process. Interpreting abnormal clinical and laboratory findings in an unselected healthy population is not the usual task of the physicians who are called upon to evaluate potential kidney donors. Physicians who evaluate these donors see other patients each day who have serious medical problems, and these physicians may be predisposed to overestimate the incidence – and the risk – of a disease in the general population. Potential transplant donors are by and large healthy individuals, who are not seeking medical attention for medical problems. Therefore, medical literature and clinical experience that deal with isolated medical abnormalities and their associated disease outcomes only in hospital and clinic populations is not best suited for accurate kidney donor risk estimation. The spectrum of practice for donor laboratory evaluation is presented in Figure 1. Centers that do not perform certain donor testing may feel it has little chance of being abnormal, will not affect the selection process if abnormal, or poses greater risk than benefit. During this testing, the most frequently encountered donor conditions which may increase risk of ESRD are hypertension, diabetes, microscopic hematuria, familial renal disease, low grade proteinuria, low creatinine clearance or glomerular filtration rate, and stone disease. Most of these conditions are addressed in the following sections, and the problems of donor hypertension and donor diabetes are addressed respectively in Chapters 5 and 6. In the following sections, we will consider many population surveys or clinical series that report on individuals with more than one risk factor for ESRD, such as hematuria and proteinuria in the same person. A risk estimate for ESRD based on these data would exceed the risk associated with a single abnormality. Thus, a risk of ESRD that is derived from a series of patients with hematuria and proteinuria would be greater than that risk associated with either hematuria or proteinuria alone. Furthermore, when we calculate the yearly risk for ESRD based on the prevalence of a risk factor and the incidence of ESRD that might be associated with that risk factor, we are in many cases overestimating risks. This is because there are other populations “competing” for the same kind of ESRD that we are considering when performing this exercise, and we do not allow for these populations to achieve their “fair share” of ESRD when calculating risk for the subpopulation with which we are concerned. For example, when we estimate the yearly risk of ESRD for patients with isolated hematuria, we leave out the prevalence of patients with both hematuria and proteinuria, proteinuria alone, proteinuria and hypertension, and hematuria and hypertension, all of whom would in reality be at risk for the same kind of ESRD (the broad category of glomerulonephritis). Therefore in this respect most of the calculations in the following sections overestimate risk. It is not the purpose of this chapter to try to estimate risks for donors with combined abnormalities, especially combined abnormalities of varying severity, but such a topic is ultimately appropriate for consideration for transplant professionals. The transplant counselor would have to decide when counseling such complicated potential donors whether risks could be approximated from existing data or whether risks with these donors fell into the “truly unknown”

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category.” The ethical problems that arise when donor risk is “truly unknown” are discussed below and in Chapter 1. Microscopic Hematuria About one-third of centers categorically exclude donors with persistent hematuria (10–15 RBC/HPF); 19% accept these donors if additional urologic evaluation (e.g., cystoscopy) is normal, and 37% accept donors if kidney biopsy is normal [9]. Microscopic hematuria is not an uncommon finding in the adult population. It is often defined as greater than 2–3 red blood cells per high power microscopic field (RBC’s/HPF), which is at the level of urine dipstick positivity for blood [19]. Microscopic analysis is sensitive to how the urine is prepared for analysis, and dipstick screening is less sensitive when urine is dilute [20]. The utility of urine dipstick testing for occult disease has been questioned because it is so sensitive [21]. There is also some disagreement as to what is an abnormal number of red blood cells in the urine, and values from a significant number of subjects could be expected to fall just outside the “normal range.” Some define hematuria as greater than 3–5 RBC’s/HPF [22]. There is debate as to how extensive the evaluation of asymptomatic microscopic hematuria (AMH) should be [21]. One population screening series excluded evaluation of AMH in young women because of the likelihood of benignity [23]. The severity of the hematuria of AMH does not correlate with the gravity of the eventual diagnosis [23, 24]. Cystoscopy and IVP are performed in most urologic series from past decades, as are urinalysis and urine cytologic studies. Microscopic inspection of the urine for deformed red cells that are said to be associated with glomerulonephritis might be valuable in skilled hands but is not generally performed, and its value has been questioned [21]. In most series, systematic serological testing for glomerular disease (ANA, DNA binding antibody, complement levels, ANCA, etc.) and/or renal biopsies [21] are not performed in individuals who screen positive for hematuria. Even urologic series find no diagnosis or only questionable lesions associated with AMH in over half the patients studied [24, 25], and the true incidence of idiopathic microscopic hematuria (IMH) may be over 90%, as discussed below. Principle concerns in the patient with AMH are the presence of infection, neoplasm, glomerular disease, and nephrolithiasis. AMH due to infection [24] is easily identifiable, usually in women, and usually curable. The most serious cause of hematuria is neoplasm, the incidence of which depends on patient age and whether the study in question emanates from a urologic clinic. In one population-based study thirty of 1,034 patients (3%) with AMH had urologic malignancies [26]. Even this study included patients referred from other localities, so selection bias may have been present. Another screening study of men over 50 found malignancies in 2% of patients studied [27]. None of 177 women with an average age of 57 had malignancies in a urologic series [25]. In the population at large, the incidence of uroepithelial tumors increases from 10 per 100,000 at age forty to 40 per 100,000 at age sixty in men, with one half to one-third this incidence in women [25]. Renal parenchymal tumors are a third as common [24]. These statistics must be kept in mind when evaluating these data. Nephrolithiasis is a

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common cause of AMH [28], and AMH can be seen in hypercalciuric patients without stones [29]. Nephrolithiasis is discussed later in this chapter. Overt renal disease of all types is found in 0–14% of populations studied, with 4 of 5 studies averaging about 2% [23]. Some series of patients with AMH include patients with 1+ proteinuria, which would tend to increase the prevalence of glomerular disease. Studies of large numbers of patients with hematuria often are generated from urologic or nephrologic clinical populations, and results have been strongly influenced by the population that is studied [30]. The usual problem kidney donor has microscopic hematuria and no identifiable cause (termed here idiopathic microscopic hematuria, or IMH). The kidney transplant donor counselor principally needs to know (1) when hematuria is likely to be associated with other serious diseases such as malignancy, and (2) the risk of ESRD from IMH, in which the medical and urologic evaluation is by defnition negative. Population screening studies that report the percent of unselected individuals with AMH and IMH are the most helpful to the donor counselor. As summarized in a recent review [20] multiple surveys suggest an overall incidence of AMH of over 4% and up to 13% when largely unselected populations are studied – often with a with a single urine dipstick test [20, 23]. Another review of multiple such population surveys concluded that – when tested once – between 9% and 18% of apparently normal individuals have AMH [17]. One study reported that hematuria was present in 3.5 to 4.9% of subjects in the third decade and 11.7 to 14.2% a decade later [31]. Other studies confirm that hematuria is over twice as frequent in older individuals, and up to three times as frequent in women as compared to men [20]. AMH is often only intermittently present in population studies when individuals who initially test positive are retested within weeks to months. In 1,000 patients examined yearly for fifteen years, 38.7% had intermittent AMH, which was present on one or more examinations. Sixteen percent had hematuria on two of five examinations [32]. Urologic investigation was not systematically performed, but during long term follow up, one subject developed a bladder carcinoma, and one developed trace proteinuria [32]. Fewer studies systematically follow patients with AMH or IMH to assess outcome. One population study followed 600 such patients with IMH over three years, and no renal disease was diagnosed [23]. A Japanese study using a more restrictive standard of greater than 5 RBC/HPF on five consecutive urinalyses found 478 subjects out of 56,269 (0.8%) adults with unremitting isolated hematuria, of whom 90% had no identifiable cause, (i.e., were IMH). Ten percent of this number developed proteinuria without renal insufficiency over five years of follow up. Such high grade, sustained IMH disappeared in 44% [33]. A later study by the same group found similar results [34]. Over 6.4 years of follow up, 0.7% of patients with sustained IMH, 23.3% of patients with hematuria and any degree of proteinuria by urine dipstick, and 14.7% of patients with isolated dipstick proteinuria developed a creatinine greater than 2.0 mg/dl. Compared to patients with IMH, subjects with proteinuria had 5 times the risk of impaired renal function, and subjects with hematuria and proteinuria had 10 times the risk. The initial quantity of proteinuria (2.3 vs 0.7 gm/day) and the development of hypertension in the follow up period were major risk factors for renal impairment [34]. Importantly, renal impairment here did not mean ESRD, and the rate of progression of disease and incidence of ESRD – if any – was not stated.

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Renal biopsy is not often recommended as part of standard medical care for patients who have only IMH [35, 36]. One biopsy study in 75 patients with only IMH found 36% with thin basement membrane nephropathy, 23% with IgA nephropathy, and 9% with mesangial proliferation; the rest had a normal biopsy or other non specific abnormalities [35]. Another biopsy study in 65 patients with hematuria and proteinuria of less than 1 gram per day found IgA nephropathy in 49% and only nonspecific glomerular changes in another 29% [37]. A careful Japanese population-based study in 168 subjects who developed more than 100 mg/dl (or about 1 to 2 grams/day) proteinuria during follow up found IgA nephropathy in 76.5% of the group who initially screened positive for IMH alone. IgA nephropathy was present in 87.5% of the group that initially screened positive for hematuria and proteinuria and in 37% of the group who screened positive for proteinuria alone. Membranous disease was found in 11.5% of this latter group (34). Similar to the study quoted above [35] biopsies in 165 young British subjects with IMH and minimal proteinuria were abnormal in 47%, with about 2/3 IgA nephropathy, over 1/5 “proliferative” glomerulonephritis, and 1/10 thin basement membrane disease. Three percent had serious urologic disease but no malignancy [38]. To estimate risk, the donor counselor must first estimate the prevalence of IMH in the general population, i.e., hematuria without obvious cause on medical evaluation. Most unselected subjects with AMH do not have an identifiable cause. Most population studies find an incidence of neoplasm or other serious, identifiable cause in less than 5% of patients [30, 33, 39–40]. Some feel that the incidence of neoplasm is so low that screening urinalysis for serious urologic disease has not been recommended [39, 40], but it will have utility in older individuals [39]. In some urologic series, only about half of all those evaluated for hematuria have no cause determined [21, 22] but results are affected by urologic bias in a group studied and the readiness of investigators to assign causality to incidental findings such as a single renal cyst [20]. The following exercise estimates the risk of IMH for ESRD in light of the glomerular disease with which it is most likely associated. We first postulate that 4% of the donor pool will have hematuria on two urinalyses, and that 90% of these individuals will have no clear-cut cause for it. Year 2000 USRDS statistics show that new end stage glomerulonephritis patients with IgA nephropathy, Heinoch-Schoenlein purpura, IgM nephropathy, and “other proliferative” glomerulonephritis comprise about 16% of all specifically diagnosed and presumably biopsied patients who began dialysis that year [41]. About one-third of the patients who develop end stage glonerulonephritis are reported only as “GN,” and most presumably have not been biopsied. Adding 16% of the unbiopsied “GN” group to the “proliferative” group total extrapolates to 1,645 new cases per year of IgA or other IMH-related nephropathy. As there are 4% of the population with IMH, the yearly risk in the year 2000 was 1,645/11 million, or 0.00015, i.e., between one and two in ten thousand. The above analysis then predicts a twenty year cumulative risk of ESRD for IMH of one in 250 to one in 500. One should probably also increase this risk estimate by about 10% to account for the 10% of new ESRD patients reported in 2000 who had “unknown” or “missing” diagnoses (Table 2) , i.e., to one in 225 to one in 450. As stated above, this analysis assumes that all end stage GN begins as IHM and therefore overestimates risk,

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Other specific clinical data on early IgA nephropathy are discussed in the following sections. The donor counselor must critically consider clinical data on subjects with idiopathic hematuria who are found to have “early” IgA nephropathy. IgA disease may be less prevalent in blacks and more prevalent in Asians, but the variability among studies suggests that the reported prevalence of IgA nephropathy may depend on antecedent screening and biopsy practices, and may be as high as 30–50% of all biopsies when they are liberally performed, e.g., for IMH alone. It is unclear whether variation in diagnostic practices rather than racial or geographic predisposition explains the difference in prevalence worldwide [42]. Many biopsy studies probably include only patients with more impaired renal function and more proteinuria than would have potential kidney donors with IMH. In one study, five of 72 patients with biopsy-proven IgA nephropathy and “minimal” proteinuria (less than 400 mg/day) developed “impaired renal function” over seven years of follow up. One-third developed over 1 gram of proteinuria. Hematuria resolved in 14% [43]. The degree of renal impairment was not stated. In a study of 253 patients (70% male) median age 30 years, median serum creatinine 97 micromoles per liter, with an average of 1.2 grams of proteinuria in 24 hours, the ten year renal survival was 83% [44]. One review also put the ten year renal survival of IgA nephropathy at 80–90% [42]. Minimal clinical and laboratory abnormalities are associated with the best prognosis in these groups [45], and this would be the situation for most potential kidney transplant donors with IMH. The center physicians should minimize their involvement when donors with hematuria need further evaluation and treatment as a part of standard medical care that should take place irrespective of their donor status. As discussed in Chapter 1, the center’s role is to assess donor risk and to minimize its conflict of interest. For this reason,donors with AMH at high risk for intercurrent pathology should probably be referred to independent nephrologists or urologists for evaluation and management. In many cases, lower risk donors – when testing might not otherwise be done – will be well-evaluated by the usual donor testing, plus cystoscopy and serologic studies as the center sees fit. In this case, testing is done primarily to help the center more accurately predict risk for the donor. Malignancy must be considered in older donors, but only some would say even in donors under forty [46]. Donors over the age of fifty with AMH should perhaps best be referred to a urologist for independent assessment regardless of donor status. As noted previously, malignancy is more common in men than in women, and bladder and collecting system tumors are more common than renal parenchymal neoplasms [32]. In populations as a whole, some authorities put the frequency of malignancy and/or serious treatable disease at 2% or less [30, 40]. How should one characterize the risk for the most frequent problem donor – the young or middle aged female with idiopathic hematuria? (1) That – if this abnormality is indeed present in 4% of the general population – she has at most a 1–2 in 10,000 yearly chance of developing ESRD, and a risk of perhaps one in 250–500 over twenty years. (2) That she has a greater chance that idiopathic hematuria will disappear than of proteinuria appearing. (3) That with unremitting hematuria, IgA nephropathy may be present in about two-thirds of the 10% who develop proteinuria over ten years. (4) That with IgA nephropathy, if or when proteinuria reaches 1 gram/day, the renal ten year survival is 90%. (5) That

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donating a kidney will not cause glomerulonephritis but may result in her needing dialysis during her lifetime, i.e., if she lives long enough, donation will cause her to require dialysis at least 20% earlier than she otherwise would. (The reduction in renal function associated with donation is considered elsewhere in this chapter.) Proteinuria In a recent survey, 58% of centers in the United States said they would exclude potential kidney donors with 300–1,000 mg/day proteinuria [9] (Table 1). Proteinuria is detected either by spot testing with urine dipsticks or by chemical techniques that produce turbidity in proportion to urine protein concentration, and which test is used is important. The most common “problem” donor with proteinuria has perhaps 200–500 mg proteinuria a day in a 24 hour urine specimen and negative or trace urine protein on dipstick testing. Dipsticks primarily detect albumin, and albumin comprises about 40% of normal urine protein [47]. Currently, 24 hour urine collections are assayed by chemical techniques, which react with all protein species and are more sensitive. Normal ranges for 24 hour protein excretion vary to some extent from one laboratory to another, but often extend to 150 mg/day [47]. “One plus” dipstick proteinuria (1+) corresponds to 30 mg/dl protein (albumin) concentration, or 300 mg/liter. The sensitivity of the dipstick to albuminuria is lessened by dilute urine. Whereas hematuria often may not have a renal source, proteinuria almost always does. A 24 hour urine protein excretion of up to 1 gram/day and/or dipstick readings of up to 2+ are typically associated with tubulointerstitial disease due to interruption of tubular reabsorption of filtered albumin and smaller proteins [47]. “Obliterative” glomerular disease – that destroys glomeruli rather than increases their permeability to protein – or early glomerular disease of any type can also produce proteinuria in the “tubular” range. Isolated proteinuria (with an otherwise normal urinalysis) in healthy young adults was surveyed in past decades. Such population surveys used spot testing with chemical techniques but often did not report proteinuria quantitatively, in mg/dl. Various reagents were used to precipitate protein, and the sensitivities of each method differed [48]. On the basis of these studies, prevalence estimates range from 0.8–8.8%. In a study of 10,000 American male college students, 6.7% had nondipstick proteinuria on at least one urinalysis. 1.9% had proteinuria on more than one specimen [48]. A similar study showed a one-time prevalence of over 5% [49]. A Finnish study found only 0.4% of subjects were dipstick positive. In this study, most of the patients who went on to have renal biopsy appeared to have more than 1 gm/day of proteinuria, and four of 37 selected from the larger group with persistent proteinuria had concurrently decreased renal function, with some having obvious nonglomerular disease [50]. More importantly, the Framingham Study found low grade proteinuria in about 4% of men 35–54 years of age, and in twice that many at ages 55–64. For most of the study, a relatively sensitive chemical turbidity technique was used to identify proteinuria, where 20 mg/dl was a “definite positive”. This would correspond to 200–400 mg/day with a daily urine volume of 1 to 2 liters respectively. The prevalence of proteinuria at least doubled with coexistent hypertension or diabetes. Proteinuria in women

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was twice as prevalent and followed the same trends as did proteinuria in men. When dipstick testing (for albumin) was substituted for the turbidity technique (sensitive to all species, including lower molecular weight proteins), proteinuria “virtually disappeared” [51]. Cigarette smokers in the general population may be at increased “risk” of slightly increased creatinine clearances and low grade proteinuria [52]. Markedly hypertensive cigarette smokers have an increased risk of a decline in renal function [53]. When protein is present in a 24 hour urine collection but is not present on dipstick, microalbuminuria could be present. Microalbuminia accompanies (is a risk factor for) generalized vascular disease. It is a marker of diabetic glomerular disease in diabetics, but the prognostic value of microalbuminuria for end stage renal disease in general is less and has not been established [54]. It is not clear how much non dipstick positive proteinuria is microalbuminuria vs. low molecular weight proteinuria. Only 300 mg per day albuminuria in a one liter daily urine volume would register as 1+ by urine dipstick, yet many more patients have “chemical/turbidity” proteinuria than do even 1+ dipstick proteinuria. In the general population, there are many individuals with lesser amounts of proteinuria that is often intermittent or orthostatic and/or is stable over time. This proteinuria is present on 24 hour urine collections in far more individuals than those with positive urine dipstick testing, i.e., it may often be non-albumin proteinuria. In these patients there is relatively less risk of developing overt renal disease [55]. In this respect “non dipstick” proteinuria as determined on 24 hour urine quantitation may have a different pathophysiology and often a more benign prognosis. The donor counselor must also consider that the normal range for urine protein excretion, as with many laboratory tests, is an arbitrary statistical subset of the entire population, usually two standard deviations from the mean of a normally distributed population, or 95% [55]. This means that 2.5% of the population can be expected to have values that exceed the upper limit of normal. A substantial fraction of this group will be “minimally” abnormal. The exclusion of all 2.5% of the population from the normal range is not necessarily based on the presumption of disease, and the closer an individual laboratory value is to the normal range, the less likely it is an indicator of disease. The is also true respectively for values for reagent-determined proteinuria, dipstick albuminuria, erythrocyturia, measurements of glomerular filtration rate, and blood pressure. The donor counselor should consider studies in which proteinuria was assessed by dipstick separately from studies in which proteinuria was assessed by chemical (turbidity) methods. The following studies used urine dipstick methods, which react with urine albumin. As discussed above, positive urine dipstick tests for protein occur less frequently and seem to have overall a stronger association with significant disease. In one study, a single dipstick of the urine was positive in 4.9% of “working” men, and 3.9% of “working” women [56]. In a study of 56,269 subjects, dipstick proteinuria or hematuria or both were found in 327 subjects, but five consecutive urinalyses had to be positive for inclusion [33]. Over seven years, hematuria and proteinuria disappeared in 16.4%, and 14.9% showed renal impairment. Isolated proteinuria disappeared in 23%, but 10% of those with isolated proteinuria developed renal insufficiency [33]. In this survey study , it was not clear how much renal impairment was present when the initial screening urinal-

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yses were performed, so risk extrapolations for the usual problem renal donors may be overestimates. A later study by the same group found that 16.8% of combined hematuria and proteinuria disappeared on follow up testing over 6.4 years, and 23.5% of proteinuria disappeared [34]. Three quarters of those with hematuria and proteinuria or proteinuria alone had persistence of urinary findings and were diagnosed as “chronic nephritic”, but renal insufficiency was less frequent. On follow up testing over six and a half years, over 20% of those with hematuria and proteinuria and almost 15% of those with proteinuria alone had a or developed a serum creatinine above 2.0 mg/dl [34]. In other words, the chances of the urinary findings normalizing were about the same as the chances of overt renal disease appearing, but one of five to six subjects with dipstick proteinuria had or subsequently developed some degree of renal insufficiency. The Japanese study in 56,269 adults which was quoted previously also provided information on the frequency of hematuria, proteinuria, and renal disease in the same unselected population [33] which is consistent with the estimates advanced elsewhere in this chapter. Hematuria was present in 2–6% of males and in 4–8% of females, with rates over twofold higher in those over forty. Dipstick proteinuria was present in 1.5% of the population, with an almost twofold increase after age fifty. Hematuria and proteinuria together were present in up to 0.5% of older patients. Only patients with persistent hematuria on five samples were reported as positive and evaluated in detail. Renal biopsy was performed in 151 subjects with “moderate proteinuria”, and about two-thirds had IgA nephropathy; over 10% more had other mesangial proliferative glomerulonephritis [33]. Another Japanese study addressed the long term risks of proteinuria and other associated factors for the development of ESRD. This study screened and followed 107,192 adults and found that 193 developed ESRD over ten years [57]. About two-thirds were over fifty. On a single urine dipstick test 4.7% of men and 3.5% of women had proteinuria, and 2.8% of men and 11% of women had hematuria. Approximately half the population had a diastolic blood pressure over eighty. About 20% had a diastolic blood pressure over ninety [57]. The cumulative incidence of ESRD over a ten year period was 180/100,000. The 75 year (lifetime) incidence would be almost 1.4%, which is lower than that calculated from USRDS data [15] but is of similar magnitude, and the difference could be explained by preselection of study participants [57]. Factors which less than doubled the risk of ESRD were gender, age per ten year increment over forty, and blood pressure. Proteinuria increased the risk of ESRD fifteenfold and hematuria increased it over twofold. Sixteen percent of the ESRD that was detected on long term follow up was attributed to diabetes and 60% was attributed to glomerulonephritis. Almost a third of the subjects were on dialysis at five years. Renal function was not initially tested, and many of the subjects with medical abnormalities probably had an elevated creatinine when follow up began, which would reduce the estimate of risk for ESRD for potential kidney donors with normal renal function. A recent follow up report of this same large cohort helps define the risk of proteinuria for ESRD [58]. ESRD developed in 420 (0.4%) of 106,177 individuals over eighteen years of follow up. The risk of proteinuria for ESRD was proportional to the degree or severity of proteinuria found at screening, consistent with many other studies on proteinuria and a point to be considered by all donor counselors. For trace and 1+ proteinuria, the cumulative incidences of ESRD per 1,000 persons were

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about 2 and 10 respectively (0.2% and 1%). Renal function, diabetic status, and other risk factors for ESRD were not screened for on study entry, so these risks represent an upper limit and may for renal donors in fact be closer to half those reported [58]. The approximate risk of isolated hematuria or proteinuria may also be estimated from “raw” demographic data. The principle concern of donor counselors is that individuals with isolated hematuria or proteinuria are at risk for end stage glomerulonephritis (ESRD – GN). The reported incidence of ESRD – GN is 10,500/year [16]. The combined prevalence of isolated microscopic hematuria or proteinuria is probably over 5%. This yields a maximum yearly “raw” risk of 10,500/13.75 million or 0.0008, less than one in a thousand. Over ten years the cumulative risk of end stage renal disease is less than one in 100. This calculation must significantly overestimate risk, because it assumes that all end stage GN begins as one of these two isolated minor urinary abnormalities, without other associated laboratory or physical findings. For example, all lupus nephritis is assumed to begin without systemic laboratory or clinical findings, and all membranoproliferative disease begins without hypertension or low serum complement. Of course, proteinuria and hematuria may well not be of equal weight as risk factors for end stage GN, and they may presage or be associated with other types of ESRD, many of which would be obvious during donor testing. However, the calculation illustrates the large number of at risk individuals – particularly when the totality of single, isolated risk factors in the general population are considered – compared with the smaller number of individuals who actually develop ESRD. Individuals who are found to have minor urinary abnormalities in population studies or on kidney donor testing are infrequently reported and/or biopsied. They are probably underrepresented when populations of patients with IgA nephropathy or other glomerular diseases are studied, thus making the prognosis of these glomerular diseases appear worse than it is. Nevertheless, a certain fraction of these subjects eventually develop overt renal disease, and some will become ESRD patients. Nephrolithiasis In the past decade, only 17% of transplant centers screened all donors with 24 hour urine collections for calcium, urate, and oxalate [9]. One-third denied a prospective kidney donor with a history of nephrolithiasis [9] (Table 1). Nephrolithiasis is a common problem in adult populations. A first stone is usually diagnosed at age 39 +/– 13 years [59]. Series from specialized centers may not be representative of the general population, but 80–90% of kidney stones are calcium containing stones, and almost all of the rest are uric acid stones [59, 60]. The magnitude of the hypercalciuria or hyperurocosuria is related to the likelihood of recurrence [59]. Half of asymptomatic calculi become symptomatic by five years [61], and about half of first stone episodes recur in ten years [62]. Thiazides reduce the risk of calcium stones by about one-third but have been questioned as appropriate therapy for a first episode due to the low morbidity associated with stone recurrence [62]. Over two-thirds of stones are passed spontaneously, and severe pain is the major problem [61, 62]. Therapy for uric acid stones particularly in the setting of gout and for cystine nephrolithiasis has been recommended [62].

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About one out of 12–14 males and one-half to one-third as many females are afflicted with kidney stones at some point in their lives [60, 63]. One study suggests a “lifetime” prevelance in men over 70 of 12% [60]. If the incidence of stones is linear with time and if the general population is on the average middle aged, this would point to a prevalence of about 3% of the general population, which individuals have either nephrolithiasis or a history of it. Nephrolithiasis is an uncommon cause of ESRD; it is not reported in a separate category in the USRDS. database [16]. “Urologic disease” causes about 4,000 new cases of ESRD each year [16]. If the risk factor is prevalent in 3% of the population, then 8.25 million people would be at risk each year for end stage renal disease from nephrolithiasis. If as much as half of yearly “urologic” ESRD is from stones, which seems unlikely, the initial estimate of yearly risk based on USRDS. incidence statistics would be 2,000 ÷ 8.25 million, or just over 2 in ten thousand. The twenty year risk would be one in 250. In actuality, USRDS only reports about 400 cases per year of ESRD from calcium or uric acid stones [41]. These more exact data suggest that the yearly risk is about 1 in 20,000, and that the 20 year risk of ESRD associated with nephrolithiasis is then 1 in 1,000. Although severe renal impairment from stone disease is often bilateral, stone disease does not have the same unvarying, similar bilateral involvement that occurs with the other causes of ESRD that we have been considering. In non-donors it would take the loss of renal function in both kidneys from stone disease to cause ESRD, and the loss of function of only one kidney could go unnoticed. After donation, having only one kidney also would increase morbidity if transient obstruction occurred during passage of a stone. Therefore the raw yearly risk for ESRD and for morbidity after donation would be higher than the value of 1 in 20,000 calculated above. However, even “normal” donors share these risks, as the lifetime incidence of stone disease is so high, and as the mean age at diagnosis is in mid-life. Even kidney donors without any suspicion of nephrolithiasis are at risk for their first stone at some point after donation. So because of its high incidence rate, nephrolithiasis – as with hypertension and type II diabetes – remains an inescapable risk even for kidney donors with completely normal pretransplant donor evaluations. Donor candidates at particularly high risk for ESRD from stones would often have overt, bilateral disease at the time of evaluation, and hypercalciuria, hyperurocosuria, etc. The usual donor candidate has no obvious disease in either kidney, but just has a history of stones or a single small stone. This donor risk estimate also does not take into account the effective treatment of various kinds of renal stones [64], and is probably an overestimate of risk for the typical donor candidate. Even if the prevalence of nephrolithiasis is lower than cited above and/or the incidence of stone associated ESRD is higher,, the incremental lifetime risk of ESRD for most donors with a history of nephrolithiasis or an isolated stone is probably well less that 1%.

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Low Glomerular Filtration Rate and the Effect of Nephrectomy on Long Term Renal Function Most centers assess glomerular filtration rate (GFR) indirectly by means of a 24 hour urine collection to determine creatinine clearance. Almost three-fifths of centers accept at least occasional donors with a normalized creatinine clearance of less then 80 ccs/min/1.73 meters2 [9], but only one-fifth accept donors with a clearance of less than 60 ccs/min/1.73 meters2 (Table 1). One major center has questioned whether the normal range for iothalamate determined glomerular filtration rate might be lower than we think – averaging about 100 ccs/minute instead of 130 ccs/minute – and whether donors might be inappropriately rejected on this basis [65]. Not normalizing GFR estimates with respect to body surface area will produce lower and possibly misleading values in smaller individuals, and BSA adjusted values may be misleadingly low in t small females [66]. Not surprisingly, lower GFR’s in donors are a risk factor for graft loss [67]. A recent survey documented the prevalence and decrease with age of creatinine clearance values in a population that was meant to be representative for the United States [7]. Serum creatinine was determined in approximately 15,000 individuals, 10% of whom were diabetic, 10% hypertensive, 30% African American, and 30% Hispanic. Thirty one percent of this group had a calculated creatinine clearance of 60–89 cc/minute/1.73 m2, and 4.3% had a value of 30–59 cc/minute/1.73 m2. Fifty four percent of the diabetics and 28% of the hypertensive individuals were in the latter two groups. The decline in creatinine clearance in the entire group was about 0.75 cc/minute/year. Almost 20% of this population had a creatinine clearance below 80 cc/min. Creatinine clearance is of course age-dependent, and only 1% of the population aged 40–59, 10% of the aged 60–69 group, and 46% of those over 70 years old had clearances in the 30–59 cc/minute range [7]. (Black patients actually had a slightly decreased risk of low creatinine clearance in this study. when the data were corrected for diabetes and hypertension. The race-associated risks for ESRD are discussed in a later section of this chapter.) As discussed earlier, the normal range for measurements of GFR are products of a statistical analysis of population data. The normal range is defined as two standard deviations above and below the mean. There will by definition always be a small percentage of individuals with measurements of GFR slightly below the lower limit of normal. Most of these individuals will not have any overt evidence of disease, nor is disease necessarily presumed by classifying them as “abnormal”. One study reported low creatinine clearances in 11% of ostensibly normal potential donors, who had average values of 74 ± 18 ml/minute/1.73 meters squared in 6 men, and 68 ± 17 ml/minute/1.73 meters squared in 16 females [67]. It is not unusual to find similar percentages of donors with creatinine clearances in this range who have been accepted by many centers in the past (68–73). What might be the approximate risks for ESRD in this “abnormal” population? These patients do not have identifiable renal disease – no cystic disease, proteinuria, or hematuria. It is hard to say what type of ESRD for which these individuals might be at risk. The most likely disease category would be interstitial nephritis, which is not a separate reporting category in the USRDS report [16]. If all “other known cause” disease begins with isolated low GFR, the inci-

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dence is 3,408 per year. One half of the third standard deviation is 2.35%, which predicts 6,462,500 at-risk individuals with low GFR, and the calculated yearly risk is then five in ten thousand. This population-based analysis is broad, nonspecific, and does not consider the risks of increasing the rate of loss of GFR by uninephrectomy, or the risk of marked versus borderline decreases in GFR. Center policy for counseling and accepting donors with reduced renal function may alternatively be formulated bythe approach outlined in the next section. Methodologic differences in measurement of renal function first deserve comment. Creatinine clearances and directly measured GFR’s are commonly used indices of renal function that are not equivalent. Creatinine clearances calculated from 24 hour urine collections can be unreliable, and clearances calculated only from serum creatinine values are fundamentally based on demographic estimates or means of creatinine production rates. Isotope measurements and other more accurate determinations of GFR are laborious and perhaps should be used consistently, not just to “help” a problem donor to a level of renal function that provides more comfort to a center. In this analysis of donor risk, creatinine clearances and other measurements of GFR will be discussed together, as the same general observations are true for both. Decreased renal function may be considered a donor risk factor, but unlike hematuria or proteinuria, it is a donor medical condition that will worsen predictably over time, and some long term predictions can be made when considering otherwise normal donors with reduced renal function. As discussed at the beginning of this chapter, after donation, GFR (and creatinine clearance) in the remaining kidney increases markedly; serum creatinine levels rise almost 40% at one month [1], and then decline to a long term level of about 15–20% above the predonation baseline at 10 years [1, 6]. The same percent improvements in GFR occur postoperatively in donors with reduced predonation renal function as discussed below. If 17% (or conservatively, approximately 20%) of renal function is lost on the average with donation [6], a donor with a “low” pre-donation creatinine clearance of 80 cc/minute would then have a post donation clearance of perhaps 64 cc/minute. If creatinine clearance is lost at a rate of 0.5cc/min/year 6, in 40 years, he would lose 20cc/minute, to be at 44 cc/minute. A variety of metabolic abnormalities occur as creatinine clearance decreases. The NHANES study defined severely reduced GFR at less than 30 cc/min/1.73 meters squared, and uremic abnormalities become more pronounced as renal function decreases to this level. Thus it would seem that some young donors with very low creatinine clearances for age would predictably develop significant chronic renal failure or ESRD in later life. As discussed elsewhere in this chapter, any future uremic complication or state would be made almost 20% worse by donation. It is not as clear, however, what diagnosis otherwise normal donors with low GFR’s would receive as renal insufficiency develops, as they – by definition – would have no other systemic or urinary abnormalities that were identified in the donor evaluation. The deleterious effect of transplanting a kidney with a low GFR that, unlike the remaining donor kidney, may undergo limited or no compensatory hypertrophy, must also be considered in accepting donors with significantly reduced renal function [67]. Most representative studies of loss of renal function in actual renal donors are consistent with the meta analysis cited above (6) and in fact comprise much of the subject matter of that analysis. One study suggested a 20% postdonation

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reduction in renal function at 12 years as compared to their nondonating siblings [68], similar to what was estimated above. Other studies in kidney donors suggest that about 20–25% of baseline (two kidney) predonation function is lost due to nephrectomy by 12–15 years [69, 70], or that 28% is lost over 25 years [71]. One study, however, found that GFR’s only increased to about two thirds of predonation values, but almost identical percent postdonation improvements occurred in young and old donors, with higher and lower predonation GFR’s respectively [72]. In most reports, donors have average predonation clearances of about 100 cc/min and – without nephrectomy – would have lost about 5 cc/min at ten years (5%) and 10 cc/min at 20 years (10%). The percent decrements in renal function that were seen in all these follow up studies in donors include both the immediate effect of nephrectomy and the subsequent deterioration of renal function with time post donation. In summary, most studies suggest that the rate of long term loss of function of the single, hypertrophied, undiseased kidney appears to be no more and possibly less than would be predicted from “two kidney” population studies, and nephrectomy itself appears to reduceoverall renal function by about 20%. A recent study from the Mayo clinic illustrated the methodologic difficulties in measuring renal function in potential donors. In this study, nonradioactive iothalamate determined GFR’s were more accurate than Cockroft-Gault formulations or MDRD estimates of renal function [73]. In this highly selected, mostly white group, body surface-normalized (two kidney) glomerular filtration rates were measured only before donation, and by cross sectional analysis were shown to decrease by 0.5 cc/minute/year in males and 0.7 cc/minute/year in females. The unlabeled iothalamate-determined GFR’s were underestimated by 29 cc/minute/1.73 m2 with the MDRD equation and by 14 cc/minute/1.73 m2 by the CockcroftGault equation. The authors also cautioned that calibration bias in serum creatinine measurements could be a source of error – which would not itself be a factor if one were using serum values and 24 hour urine creatinine collection values, which pose other methodological problems [73]. In summary, data are available to assess the effects of nephrectomy on renal function in potential kidney donors, and predictions can be made with some justification as to what to expect over the long term when donors with lower GFR’s are concerned. These data also may provide a baseline to help assess the effect of nephrectomy on the progression of new-onset renal disease after donation. In this way, they are relevant to the risk factors that are discussed in other sections of this chapter. For example, if 20% of overall renal function is lost with donation, the interval to dialysis would plausibly be shortened by at least that amount when many common chronic renal diseases (that destroy renal function at a constant rate) are contracted at some time after donation. As discussed in other sections of this chapter, it is not clear whetherthe loss of renal function under these circumstances would necessarily be accelerated beyond this amount either, and more studies are needed. Limited knowledge and variation in center practices make it difficult to be categorical about other possible abnormal findings in donors. For example, twothirds of centers exclude a donor with unilateral fibromuscular hyperplasia (FMH) [9], yet a number of these donors have been accepted as a matter of policy by some centers [74, 75], and these transplants are often successful [74, 75]. If some

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degree of FMH occurs in up to 1% of the unselected population [76], the risk for renal failure from this disease may be generally similar to the other entities we have considered in this chapter, as the incidence of ESRD from FMH is significantly lower than the incidence of ESRD from glomerulonephritis or hypertension. More information is needed about the incidence and prevalence of this disease and the full spectrum of its manifestations. Risks of Race and Blood Relationship The lifetime risk of ESRD in unselected black subjects is over three times that of whites [15], and the risks of ESRD also appear to be increased even more in relatives of black patients with ESRD. This relationship may hold for black patients with SLE, hypertension, diabetes, and HIV nephropathy [77–80]. In one study, almost half of the families of hypertensive black patients had at least one member with ESRD [78]. Many studies which suggest these familial associations are performed in small numbers of patients. Relatives of the proband with ESRD are usually adults and are found to have ESRD at the time of the study, i.e., in contradistinction to the usual problem donor, who has a normal medical evaluation and a relative with ESRD. The estimate of increased risk in these studies can be imprecise, with a confidence interval (CI) in one study of 2.6 to 31.8 for all African Americans with ESRD [81]. Most relatives of the proband appear to have been receiving treatment for ESRD or at least to have overt, diagnosed renal disease when counted in these survey studies. More importantly, no information is provided in these studies about the future risks of ESRD for adult relatives who have normal medical evaluations at the time of the study, which is the central issue for transplant donors. There are no specific guidelines for determining risk in these donor candidates, and centers often consider only such nonspecific indicators as an abnormal urinalysis, hypertension, and/or mild decreases in renal function in evaluating these donors. Racial considerations per se are not important in screening black donors for relatives with autosomal dominant adult polycystic kidney disease. The accepted practice is that a normal renal ultrasound in a donor aged thirty or older excludes the disease. Ultrasound is slightly less sensitive than CT scanning, as thelimit of detection is 1.5 vs 0.5 cm cysts. Anegative study using either modality identifies all but perhaps 1–3% of affected thirty year olds. Genetic testing is conclusive, provided that the recipient has an identifiable gene – either the PKD1 mutation, which is responsible for almost 90% of cases, or the PKD2 abnormality, which is responsible for most, but not all, of the remainder. Non-PKD-1 disease tends to progress less rapidly, so both the risks of the disease and the ability to detect it clinically are less that they are for PKD-1 [82–84]. Kidney transplant recipients are also subject to race-related risks even after they develop ESRD. Black recipients are at greater risk of not receiving living donor transplants. Cadaver donors tend to be white, and black/white immunologic differences make receiving a cadaver kidney transplant more difficult for African Americans [85, 86]. Graft survival is also reduced. These data are discussed to some extent in Chapter 2. An increased incidence of ESRD in blood relatives of patients with ESRD has

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also been demonstrated for whites [87]. Excluding patients with Mendelian inherited chronic renal disease, (e.g. PCKD or Alport’s syndrome), there was a four-fold increase in ESRD in Canadians with first degree relatives on dialysis [87]. Another large multiracial study in 689 newly diagnosed ESRD patients – omitting Mendelian inherited diseases – found a risk of 1.3 (C.I. 0.7 to 2.6) for ESRD in individuals with one relative with ESRD and a 10.4 risk (C.I. 2.7 to 40.2) for individuals with two relatives with ESRD. The risk for one relative with ESRD was 1.1 (C.I. 0.5 to 2.5) in whites and 1.7 (C.I. 0.6 to 5.2) in blacks. In this study, these increases in risk were partially but not completely explained by the co-existing presence of diabetes and hypertension [88]. Diabetes and hypertension may mediate a large portion of racial risk. As mentioned above, in the NHANES survey, black individuals actually had a lower risk of renal disease absent the considerable risks of diabetes and hypertension in this population [7]. Thus, a young, completely normal black donor may be at risk because of his increased risk of hypertension and/or diabetes in later life as much or more than because of his race per se, but the risks are still increased over comparable white donors, who also are at risk for diabetes and hypertension in later life. Race-related risks for ESRD also exist for other races. In the year 2000, the adjusted rates for the incidence of ESRD (per million) for white, black, Native American, and Asian/Pacific Islanders were 228, 962, 858, and 394 respectively [16]. As with the data on familial clustering of ESRD, these data are only one of many considerations in estimating the risk of ESRD for a potential donor of any race who hasa normal evaluation or minimal abnormalities. Most living donors in past years have been blood relatives of their recipients, so familial risks in some sense have always been present. The long term follow up data on living donors from past decades as a group are reassuring with respect to the general familial risk of ESRD for blood relatives of patients on dialysis. In all, these data suggest that the risk of ESRD in this group is one in several hundred and less than the lifetime risk for the general population [15]; kidney donors may even live longer than data from the general population would predict [89]. Accumulated data from long term follow up of kidney donors are discussed in preceeding sections of this chapter. While these data do not address the familial post donation relative risks of black versus white donors, they do address in part the overall risk for ESRD of well-evaluated relatives who donate kidneys. The long term general living donor follow up data also do not address the risks of severe familial renal disease that seems to appear more regularly in certain black kindreds. Commentary In the preceding sections we have considered primarily the risks of ESRD that are associated with minor medical abnormalities as they occur in the general population, not the incremental risk of ESRD associated with kidney donation. In most cases, it would seem that if an individual is destined to develop progressive chronic renal disease, kidney donation would only cause dialysis to be needed at at earlier point in the donor’s life. Many chronic renal diseases in donors would probably eventually have produced ESRD even if donation did not take place. As we discuss elsewhere in this book, some data also indicate that uninephrectomy

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does not hasten the rate of deterioration of renal function that is caused by intrinsic chronic renal disease [90–92]. Most donor counselors would want to convey these predictive uncertainties to the donor when discussing this point. What is clear is that donation itself results in a loss of almost 20% of predonation renal function, and therefore donors who acquire renal disease post donation would need dialysis at least 20% sooner than had they not donated. At any time point, donors would be 20% more uremic that they otherwise would have been had they not donated, and the metabolic consequences of chronic renal failure would be proportionately worsened. Most donors who eventually develop ESRD will know that donation accelerated the need for dialysis, but many will never know whether dialysis would eventually have been necessary had they not donated. Without donation, these donors may have died of something else before they reached ESRD. All potential donors must also know that if they reach ESRD, it will probably happen late in life, if they are like the rest of the population (Table 3). Donation would not necessarily result in a longer time on dialysis waiting for a transplant; it would instead bring about the transplant sooner, when the donor was younger. The donor counselor should not lose sight of the larger picture when discussing risk with “normal” or complicated donors. All donors – even very low risk donors – should be told that they could in fact develop ESRD at some point in their lives with or without donation. All donor candidates and all transplanting centers as well should be able to accept the development of ESRD as a real possibility with or without donation. The risk that donation itself will cause the donor to need dialysis at some point in later life would usually be only a fraction of the baseline pre-donation risk of ESRD for unselected individuals, which may be as high as 2 to 7 per 100 [15]. While centers are properly most concerned with the donor’s risk for ESRD, centers must also accept that occasionally some donors will eventually develop it. As discussed in Chapter 1, the center might also be justifiably be concerned that the counseling process will exaggerate the risk of ESRD and prevent a donor from taking the reasonable risk that he wants to take. We have personal knowledge of donors who required hemodialysis two decades after donation, and these donors had no regrets about their decision. Clearly not every donor would feel that way, but all donors must feel that they were well-counselled regardless of what transpires in later life. When one accepts that everyone – donor or not – has some lifetime risk of end stage renal disease it is not surprising that some donors eventually develop it. If, for example, well evaluated donors have a similar but somewhat lower overall baseline risk than nonevaluated individuals, perhaps one in 100 to 300 donors – who live long enough – will develop ESRD, usually in later life. As living kidney donation becomes a more compelling option for some donors because of the shortage of cadaver kidneys, we may see over time more donors who develop ESRD. This does not necessarily imply a cavalier or otherwise defective approach to living kidney donor selection, but may be unavoidable in a world in which not everything is predictable and in which people want to take reasonable risks to help one another. It will usually be impossible to estimate risk precisely when an abnormal donor finding comes to light, but it will often be possible to present a range of risks. Donor counselors can also formulate a clearly defensible maximum risk, i.e., if the risk may be one in several hundred, the counselor can present it as “clearly less

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than one in one hundred” and counsel on that basis. Such risk estimates can be presented to donors by techniques presented in Chapter 7. Donor counselors will to some extent differ in their estimates of how the data presented in the above sections bear on the calculation of risk, but attempting to present risk quantitatively encourages neutral, factual counseling. Formulating a risk estimate also never answers the question for the donor or for the center as to whether to proceed with the transplant. That decision must be made on the basis of the qualitative criteria set out in Chapter 1. Donor counselors must also think carefully about what it means to have “no idea” of a given donor’s risk. Taken literally, this means that the risk of ESRD could equally as well be 1 out of 1 (100%) or 1 out of 100,000. As discussed in Chapter 1, when risk is truly unknown, donation becomes heroic or irrational, depending on the donor. If the donor accepts this amount of uncertainty to benefit another, he is heroic, but if he would not accept a risk of ESRD of 50% and accepts truly incalculable (unknown) risk, he is irrational. The center cannot ethically accept irrational donors and may decide not to accept most heroic donors because of possible public suspicions of flawed, self interested donor counseling. Thus we cannot accept the proposition that most of the time donor counselors have “no idea” of donor risk and still continue to conduct living kidney donor counseling and transplantation. Saying that one cannot usually calculate precisely the risk of ESRD is of course far different than saying the risk is altogether unknown. A primary purpose of the donor medical evaluation and subsequent counseling as discussed in this chapter is to estimate that risk on the basis of available data. Long term registries in which donors are followed for the development of renal disease have been proposed and will clearly be helpful. However, the results of donor registries may not provide an entirely clear answer to donor counselors either. The same general methodology as that suggested earlier in this chapter – following cohorts of individuals to see how many cases of ESRD develop each year – will be employed in donor registries. The data will be subject to uncertainties and admit of varying interpretations. Prospective donor registries will be the most reliable, and they may take 10 to 20 years to be meaningful. For the present, we only have “available data” to help us counsel donor candidates, but in some areas those data are reasonably substantial. In any event, these available data – for better or worse – should be known by all donor counselors. In one important paper on living kidney donation, a donor risk of ESRD of 1/100 was described as “small” [9]. Would it be socially irresponsible for centers to accept donors for whom donation involved an incremental 1/100 risk for ESRD? Under these conditions, for every 100 donors, there will be one who develops ESRD because of donation, perhaps in 10–30 years, if he lives that long. This donor might stay on dialysis 3–6 years, until he died or was transplanted. Those same 100 donors would have achieved 1,500 years of dialysis-free survival for their recipients if the recipients lived that long, given a half life of 15 years for living donor kidneys. These considerations do not make it justifiable for centers to coerce or manipulate donors in any way to serve the “greater good”. However, this analysis is relevant to a center that seeks to avoid criticism for socially or economically irresponsible policies. As we indicate above, currently there are significant differences among center practices in accepting donors. These practices are undoubtedly influenced by

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variations in interpretation of published medical data and variations in personal donor counselor experience. They also may reflect varying opinions about the ethical responsibilities of centers concerning acceptable donor risk. Some centers also may not have formulated an estimate of baseline donor risk or how any number of risk factors might bear on this risk. Therefore the wisdom of current standards across the country for evaluation and acceptance of donors must not be dismissed but must not be held to be above rational modification either. Even after careful consideration, some donor counselors may disagree with the approach to donor counseling presented in this chapter. They may feel that the estimates of risk are too imprecise or that they are miscalculated. However, a greater degree of precision is not attained in much other “standard” medical counseling, e.g., regarding individualized risk for various interventions for coronary artery disease. The prevalence estimates of common donor abnormalities used here appear to be supported by the medical literature, the statistical nature of the normal range, and the experience of transplant centers that frequently encounter these donor abnormalities. The reason that these abnormalities were addressed in an informative survey article of transplant centers [9] was that they were so commonly seen and so commonly vexing. Furthermore, over the risk ranges we are considering, many donors would not decide differently if their risk was, e.g., 1 in 100 instead of 1 in 500 [93]. This fact – that risks over wide ranges may seem about the same in the practical calculus of many donors’ decision-making – does not relieve the donor counselor of the responsibility to try to be precise. The donor counselor is obligated to provide all information to donors that he feels is important to their decision. Therefore, donor counselors who disagree with but respect this approach to these estimates of risk should present them to donors and then present their reasons for disagreement. It is hoped that these individuals will also articulate their disagreements publicly so the donor counseling process can be improved. Transplant professionals will refine these risk estimates over time if this general approach to donor counseling becomes accepted practice. References 01. Bay WH, Hebert LA. The living donor in kidney transplantation. Ann of Int Med 1987; 106: 719–27. 02. Williams SL, Ohler J, Jorkasky DK. Long-term renal function in kidney donors: a comparison of donors and their siblings. Ann of Int Med 1986; 105: 1–8. 03. Wolf JS Jr, Merion RM, Leichtman AB, et al. Randomized controlled trial of handassisted laparoscopic versus open surgical live donor nephrectomy. Transplantation 2001; 72(2): 284–90. 04. Nogueira JM, Cangro CB, Fink JC, et al. A comparison of recipient renal outcomes with laparoscopic versus open live donor nephrectomy. Transplantation 1999; 67(5): 722–8. 05. Laparoscopic donor nephrectomy. Nephrology Forum, principal discussant: Louis R. Kavoussi. Kid Int 2000; 57: 2175–86. 06. Kasiske BL, Ma JZ, Louis TA, Swan SK. Long-term effects of reduced renal mass in humans. Kidney Int 1995 September; 48(3): 814–9. 07. Coresh J, Astor BC, Greene T, Eknoyan G, Levey AS. Prevalence of chronic kidney disease and decreased kidney function in the adult US population: Third National Health and Nutrition Examination Survey. Am J Kidney Dis. 2003 January; 41(1): 1–12.

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08. Kasiske BL, Bia MJ. The evaluation and selection of living kidney donors. Am J Kidney Dis 1995; 26: 376–98. 09. Bia MJ, Ramos EL, Danovitch GM, et al. Evaluation of living renal donors. Transplantation 1995; 60: 322–7. 10. Beasley CL, Hull AR, Resenthal JT. Living kidney donation: a survey of professional attitudes and practices. Am J Kidney Dis 1997; 30: 549–57. 11. US Census Bureau. Statistical abstract of the United States: 2001, http// www.census.gov/ 12. Vasan RS, Martin GL, Leip EP, et al. Impact of high normal blood pressure on the risk of cardiovascular disease. NEJM 2001; 345(18): 1291–7. 13. Hyman DJ, Pavlik VN. Characteristics of patients with uncontrolled hypertension in the United States. NEJM 2001; 345(7): 479–86. 14. Schlessinger SD, Tankersley MR, Curtis JJ. Clinical documentation of end-stage renal disease due to hypertension. Am J of Kid Dis 1994 May; 23L(5): 655–60. 15. Kiberd BA, Clase CM. Cumulative risk for developing end-stage renal disease in the US population. J Am Soc Nephrol 2002; 13: 1635–44. 16. US Renal Data System: Excerpts from the USRDS 2000 Annual Data Report: Atlas of End Stage Renal Disease in the United States. Am J Kidney Dis 2000 December; 3S (sup 2): S1–239. 17. Roland AS, Hildreth EA, Sellers AM. Occult primary renal disease in the hypertensive patient. Arch Int Med 1964; 113: 101–10. 18. Kapoor A, Mowbray JF, Porter KA, et al. Significance of hematuria in hypertensive patients. The Lancet 1980 February; 23–2. 19. Grossfeld GD, Litwin MS, Wolf JS, et al. Evaluation of asymptomatic microscopic hematuria in adults: the American Urological Association best practice policy – part I: definition, detection, prevalence, and etiology. Urology 2001 April; 57(4): 599–603. 20. Tomson C, Porter T. Asymptomatic microscopic or dipstick hematuria in adults: which investigations for which patients? A review of the evidence. BJU Int 2002 August; 90(3): 185. 21. Sutton JM. Evaluation of hematuria in adults. JAMA 1990 May; 263(18): 2475–9. 22. Bauer DC. Evaluation of hematuria in adults. West J Med 1990 March; 152: 305–8. 23. Mohr DN, Offord KP, Owen RA, Melton LJ. Asymptomatic Microhematuria and urologic disease. JAMA 1986 July; 256(2): 224–9. 24. Carson CC, Segura JW, Greene LF. Clinical importance of microhematuria. JAM 1979 January; 241(2): 149–56. 25. Bard RH. The significance of asymptomatic microhematuria in women and its economic implications. Arch Intern Med 1988 December; 148: 2629–32. 26. Murakami S, Igarashi T, Hara S, Shimazaki J. Strategies for asymptomatic microscopic hematuria: a prospective study of 1,034 patients. J of Urol 1990 July; 144: 99–101. 27. Messing EM, Young TB, Hunt VB, Emoto SE, Wehbie JM. The significance of asymptomatic microhematuria in men over 50 years old: findings of a home screening study using urinary dipsticks. J Urol 1987; 137: 919–21. 28. Abuelo JG. The diagnosis of hematuria. Arch Intern Med 1983 May; 143: 967–70. 29. Andres A, Praga M, Bello I, Diaz-Rolon JA, Gutierrez-Millet V, Morales JM, Rodicio JL. Hematuria due to hypercalciuria and hyperuricosuria in adult patients. Kidney Int 1989; 36: 96–9. 30. Khan MA, Shaw G, Paris AM. Is microscopic hematuria a urological emergency? BJU Int 1990 September; 90(4): 355–7. 31. Froom P, Gross M, Ribak J, et al. The effect of age on the prevalence of asymptomatic microscopic hematuria. Am J Clin Pathol 1986 November; 86(5): 656–7. 32. Froom P, Ribak J, Benbassat J. Significance of microhematuria in young adults. Brit Med J 1984 January; 288: 20–2.

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33. Yamagata K, Yamagata Y, Kobayashi M, et al. A long-term follow-up study of asymptomatic hematuria and/or proteinuria in adults. Clin Nephrol 1996 May; 45(5): 281–8. 34. Yamagata K, Takahashi H, Tomida C, et al. Prognosis of asymptomatic hematuria and/or proteinuria in men. Nephron 2002; 91: 32–4. 35 McGregor DO, Lynn KL, Bailey RR, et al. Clinical audit of the use of renal biopsy in the management of isolated microscopic hematuria. Clin Nephrol 1998 June; 49(6): 345–8. 36. Burkholder GV, Dotin LN, Thomason WB, et al. Unexplained Hematuria: How extensive should the evaluation be? JAMA 210(9): 1729–33. 37. Copley JB, Hasbargen JA. “Idiopathic” hematuria: A prospective evaluation. Arch Intern Med 1987 March; 147: 434–7. 38. Froom P, Froom J, Ribak J. Asymptomatic microscopic hematuria – is investigation necessary? J Clin Epidemiol 1997; 50(11): 1197–200. 39. Topham PS, Harper SJ, Furness PN, et al. Glomerular disease as a cause of isolated microscopic hematuria. Q J of Med 1994; 87: 329–35. 40. Woolhandler S, Pels RJ, Bor DH, et al. Dipstick urinalysis screening of asymptomatic adults for urinary tract disorders. I. Hematuria and proteinuria. JAMA 1989 September; 262(9): 1214–9. 41. Response to email inquiry, USRDS 2002 at http://www.usrds.org, November 2002. 42. Galla JH. IgA Nephropathy. Kid Int 1995; 47: 377–87. 43. Szeto CC, Lai FMM, To KF, et al. The natural history of immunoglobulin a nephropathy among patients with hematuria and minimal proteinuria. Am J Med 2001 April; 110(6): 434–7. 44. Johnston PA, Brown JS, Braumholtz DA, et al. Clinco-pathological correlations and long term follow up of 253 United Kingdom patients with IgA nephropathy. A report from the MRC Glomerulonephritis Registry. Q J of Med 1992 August; 84(304): 619–27. 45. Ibels LS, Gyory AZ. IgA nephropathy: analysis of the natural history, important factors in the progression of renal disease, and a review of the literature. Medicine 73(2): 79–102. 46. Khadra MH, Pickard RS, Charlton M, et al. A prospective analysis of 1,930 patients with hematuria to evaluate current diagnostic practice. J Urol 2000 February; 163(2): 524–7. 47. Levey AS, Madaio MP, Perrome RD. Laboratory assessment of renal disease: clearance, urinalysis, and renal biopsy (pp 919–68). In The Kidney, Brenner BM and Rector FC, Eds, W. B. Saunders Company, Philadelphia, 1991. 48. Diehl HS, McKinlay CA. Albuminuria in college men. Arch Int Med 1931; 45–55. 49. Levitt JI. The prognostic significance of proteinuria in young college students. Ann Int Med 1967 April; 66(4): 685–96. 50. Von Bonsdorff M, Koskenvuo K, Salmi HA, Pasternack A. Prevalence and causes of proteinuria in 20-year old Finnish men. Scand J Urol Nephrol 1981; 15: 285–90. 51. Kannel WB, Stampfer MJ, Castelli WP, Verter J. The prognostic significance of proteinuria: The Framingham study. Am Heart J 1984 November; 1347–52. 52. Halimi JM, Giraudeau B, Vol S, Caces E, Nivet H, Lebranchu Y, Tichet J. Effects of current smoking and smoking discontinuation on renal function and proteinuria in the general population. Kid Int 2000; 58: 1285–92. 53. Regalado M, Song Y, Wesson DE. Cigarette smoking is associated with augmented progress of renal insufficiency in severe essential hypertension. Am J Kid Dis 2000 April; 35(4): 687–94. 54. Kaplan NM. Microalbuminuria: A risk factor for vascular and renal complictions of hypertension. Am J Med 1992; 92(4B): 8S–12S. 55. Robinson RR (principal discussant), Cohen JJ, Harrington JT, Kassirer JP (editors). Isolated proteinuria in asymptomatic patients. Kid Int 1980; 18: 395–406.

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56. Carel RS, Silverberg DS, Kaminsky R, et al. Routine urinalysis (dipstick) findings in mass screening of healthy adults. Clin Chem 1987 November; 33(11): 2106–8. 57. Iseki K, Isek C, Ikemiya Y, et al. Risk of developing end-stage renal disease in a cohort of mass screening. Kid Int 1996; 49: 800–5. 58. Iseki K, Ikemiya Y, Iseki C, Takashita S, Proteinuria and the risk of developing end stage renal disease. Kidney Int 2003; 63: 1468–74. 59. Strauss AL, Coe FL, Parks JH. Formation of a single calcium stone of renal origin. Arch Int Med 1982 March; 142: 504–507. 60. Johnson CM, Wilson DM, O’Fallon WM, et al. Renal stone epidemiology: a 25 year study in Rochester, MN. Kidney Int 1979; 16: 624–9. 61. Glowacki LS, Beecroft ML, Cook RJ, et al. The natural history of asymptomatic urolithiasis. J of Urology 1992 February 147: 319–321. 62. Uribarri J, Oh MS, Carroll HJ. The first kidney stone. Annals of Int Med 1989; 111: 1006–9. 63. Saklayen MG. Medical management of nephrolithiasis. Med Clin No Am 1997 May; 81(3): 785–99. 64. Pak CYC. Etiology and treatment of urolithiasis. Am J Kidney Dis 1991; XVIII(6): 624–37. 65. Gonwa TA, Atkins C, Zjang YA, Parker TF, Hunt JM, Lu CY, White MG. Glomerular filtration rates in persons evaluated as living-related donors – Are our standards too high? Transplantation 1993 May; 55(5): 983–5. 66. Bertolatus JA, Goddard L. Evaluation of renal function in potential living kidney donors. Transplantation 2001 January; 71(2): 256–60. 67. Norden G, Lennerling A, Nyberg G. Low absolute glomerular filtration rate in the living kidney donor. Transplantation 2000 November; 70(9): 1360–2. 68. Williams SL, Oler J, Jorkasky DK. Long-term renal function in kidney donors: a comparison of donors and their siblings. Ann Intern Med 1986 July; 105(1): 1–8. 69. Vincenti F, Amend WJ Jr, Kaysen G, Feduska N, Birnbaum J, Duca R, Salvatierra O. Long-term renal function in kidney donors. Sustained compensatory hyperfiltration with no adverse effects. Transplantation. 1983 December; 36(6): 626–9. 70. Torres VE, Offord KP, Anderson CF, Velosa JA, Frohnert PP, Donadio JV Jr, Wilson DM. Blood pressure determinants in living-related renal allograft donors and their recipients. Kidney Int 1987 June; 31(6): 1383–90. 71. Goldfarb DA, Matin SF, Braun WE, Schreiber MJ, Mastroianni B, Papajcik D, Rolin HA, Flechner S, Goormastic M, Novick AC. Renal outcome 25 years after donor nephrectomy. J Urol 2001 December; 166(6): 2043–7. 72. Velosa JA, Offord KP, Schroeder DR. Effect of age, sex, and glomerular filtration rate on renal function outcome of living kidney donors. Transplantation 1995 December 27; 60(12): 1618–21. 73. Rule A, Gussak H, Pond G, Bergstralh E, Stegall M, Cosio F, Larson T. Measured and Estimated GFR in Healthy Potential Kidney Donors. In press, AJKD. 74. Linder R, Billing H, Tibell A, Tyden G, Groth CG. Transplantation of kidneys with fibromuscular dysplasia. Trans Proc 1990 April; 22(2): 398–9. 75. Flechner SM, Sankari B, Streem SB, Modlin CS, Serrano DP, Goldfarb DA, Novick AC. Kidneys from living donors with renal vascular disease may be safely used for transplantation. Trans Proc 1997; 29: 3404–5. 76. Luscher TF, Lie JT, Stanson AW, et al. Arterial fibromuscular dysplasia. Mayo Clin Proc 1987; 62: 931–52. 77. Freedman BI, Wilson CH, Spray BJ, et al. Familial Clustering of end-stage renal disease in Blacks with Lupus Nephritis. Am J Kid Diseases 1997, 29(5): 729–32. 78. Bergman S, Key BO, Kirk KA, et al. Kidney Disease in the first-dgree relatives of Afrian-Americans with hypertensive end-stage renal disease. Am J Kid Diseases 1996: 27(3): 341–6.

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79. Freedman BI, Tuttle AB, Spray BJ. Familial predisposition to nephropathy in AfricanAmericans with non-insulin-dependent diabetes mellitus. Am J Kid Diseases 1995; 25(5): 710–713. 80. Freedman BI, Soucie JM, Stone SM, et al. Familial clustering of end-stage renal Disease in Blacks with HIV-associated nephropathy. Am J Kid Diseases 1999, 34(2): 254–8. 81. Freedman BI, Spray BJ, Tuttle AB, et al. The familial risk of end-stage renal disease in African Americans. Am J Kid Diseases 1993; 21(4): 387–393. 82. Parfrey PS, Bear JC, Morgan J, Cramer BC, McManamon PJ, Gault MH, Churchill DN, Singh M, Hewitt R, Somlo S, et al. The diagnosis and prognosis of autosomal dominant polycystic kidney disease. N Engl J Med 18 1990; 323(16): 1085–90. 83. Ravine D, Gibson RN, Walker RG, Sheffield LJ, Kincaid-Smith P, Danks DM. Evaluation of ultrasonographic diagnostic criteria for autosomal dominant polycystic kidney disease. Lancet 2 1994; 343(8901) 824–7. 84. Rose BD, Bennett WM. Genetics of polycystic kidney disease and the mechanisms of cyst growth. Uptodate online 11.3, www.uptodate.com, 2003. 85. Kerman RH, Kimball PM, Van Buren CT, et al. Influence of race on crossmatch outcome and recipient eligibility for transplantation. Transplantation 1992, 53(1): 64–7. 86. Barger B, Shroyer TW, Hudson SL, et al. The impact of the UNOS mandatory sharing policy on recipients of the Black and White races – experience at a single renal transplant center. Transplantation 1992, 53(4): 770–4. 87. O’Dea DF, Murphy SW, Hefferton D, et al. Higher risk for renal failure in firstdegree relatives of White patients with end-stage renal disease: a population-based study. Am J Kid Diseases 1998; 32(5): 794–801. 88. Lei HH, Perneger TV, Klag MJ, et al. Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol 1998; 9: 1270–6. 89. Fehrman-Ekhol I, Elinder CG, Stenbeck M. Kidney donors live longer. Transplantation 1997; 64(7): 976–8. 90. Zeier M, Geberth S, Ritz E, et al. The effect of uninephrectomy on progression of renal failure in autosomal dominant polycystic kidney disease. J Am Soc Nephrol 1992; 3: 1119–23. 91. Sampson MJ, Drury PL. Development of nephropathy in diabetic patients with a single kidney. Diabetes Med 1990; 7: 258–60. 92. Whiteside C, Katz A, Cho C. Diabetic glomerulopathy following unilateral nephrectomy in the dog. Clin Invest Med 1990; 13: 260–79. 93. Bertram DD. The reality and acceptance of risk. JAMA 1980; 244(11): 1226–8.

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Chapter Five The Risk of End Stage Renal Disease for Hypertensive Kidney Donors Scott R. Mullaney, M.D. and Michael G. Ziegler, M.D. Summary Points • Hypertension may better detected by repeated measurements and/or 24 hour monitoring. • Blood pressure increases with age in the normal population. The relatives of kidney patients may also have an increased incidence of hypertension. Kidney donation may add to those increases by a few mmHg. • Subjects who have borderline high blood pressure, a positive family history of hypertension, or obesity are at greater risk of blood pressure elevation from uninephrectomy. • While an increase in blood pressure following uninephrectomy will not measurably increase the risk of renal failure, it will increase the risk of heart attack and stroke. • Treatment of hypertension following uninephrectomy should decrease the risk of cardiovascular disease, but kidney donors seem no better than the general populace at controlling their hypertension.

81 R.W. Steiner (ed.), Educating, Evaluating, and Selecting Living Kidney Donors, 81–97.  2004 Kluwer Academic Publishers. Printed in the Netherlands.

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Introduction With an increased focus on living donor transplantation (LDT), and the prevalence of hypertension in the general population, there is a strong likelihood of encountering hypertensive prospective kidney donors. A survey completed by 75% of UNOS-designated transplant centers showed that 54% of centers would refuse an otherwise healthy potential donor with a blood pressure of 130/90 and 64% would refuse a potential donor whose hypertension is controlled on a single agent [1]. To appropriately counsel such potential donors on their risk of kidney disease from donation, one must understand the relationship between hypertension, the kidney, and uninephrectomy. It is clear that hypertension causes pathologic changes in the kidney, and that hypertension plays an important role in the progression of chronic renal failure (CRF). However the renal impact of isolated hypertension in otherwise healthy individuals appears to be less dramatic. The counseling and selection of these potential donors should be based on the abundant data that is available. Hypertension Prevalence in the Population and in Donors As is discussed in Chapter Four for other conditions, the prevalence of hypertension in the general population is important in estimating the risk of hypertensive end stage renal disease from ESRD epidemiologic data. The other source for estimating risk for hypertensive donors are the many prospective studies that have been done in hypertensive patients. Both of these topics will be discussed below. The true prevalence of hypertension in the United States is difficult to determine. The environment, time of day, method, and person measuring a patient’s blood pressure all can influence the values obtained. In addition, the definition of hypertension has been rewritten numerous times. The most widely used definition today, that employed by the National High Blood Pressure Education Program (NHBPEP), is a systolic blood pressure greater than or equal to 140 mmHg, or a diastolic blood pressure greater than or equal to 90 mm Hg, or a requirement for medications for blood pressure [2]. Using this definition it is estimated that over 42 million adults in the US have hypertension [3]. This estimate grows to over 50 million if we include those patients who do not fulfill the above criteria but have on two or more occasions been told that they have hypertension by their physician or health care provider (Figure 1). The same reports also suggest that only 68% of hypertensive patients are aware of their hypertension and of those only 53% are being treated, with only 27% achieving blood pressures under 140/90 mm Hg [3]. The sizes of all three of these groups are increasing, as access to medical knowledge becomes more widespread. The prevalence of hypertension in people who may be considered as kidney donors ranges from 2.6% in those 18–24 years of age up to 43.7% in those 55–64. In black patients the rates of hypertension are greater for every age group except 18–24 [3]. The higher rate of hypertension in the black population is an area of intense study at this time, and is of particular importance in this discussion given the higher rate of ESRD in blacks. Using the 2001 United States Renal Data System

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Figure 1. Prevelance (%) of hypertension in the US.

(USRDS) the incidence of ESRD in blacks was almost 3 times that of whites [4]. More black dialysis patients mean more potential living related donors who are black, and who are more likely to have hypertension. Several studies have examined the risk of renal disease and hypertension in the families of black ESRD patients. Bergman et al. reviewed the records 40 black ESRD patients who appeared to have hypertension as their sole cause of renal failure [5]. All 40 of the patients had family members with hypertension, reinforcing the importance of understanding the risk of hypertension in regards to kidney donation. The contribution of race to donor risk is also discussed in Chapter Four. Renal Effects of Hypertension Long-standing hypertension induces pathologic changes in several organs, most significantly the heart, brain and kidneys. Clinically, a patient with hypertension, but no other kidney disease, may uncommonly exhibit proteinuria up to 1–2 grams per day but generally will have a normal serum creatinine, normal kidney function, and less that one gram per day of proteinuria. Proteinuria of more than 2 gm/d has rarely been described with hypertension alone and is usually a marker of a separate renal disease. The vast majority of hypertensive patients without other renal disease have 0 to 1+ proteinuria on urinalysis. On ultrasound or gross inspection, the kidneys of patients with hypertension are frequently reduced in size, with a pebbled or granular surface [6]. Mild to moderate hypertension also induces certain typical changes visible on biopsy, termed benign nephrosclerosis. Under light microscopy, much like arteries elsewhere in the body, the arteries and arterioles of the hypertensive kidney demonstrate sclerosis and hyaline degeneration [6]. Arterial and afferent arteriolar walls are frequently thickened with reduced lumens. These changes are usually not seen in the efferent arterioles, suggesting the sclerosis results from the higher blood pressure in the vessel. The efferent arteriole is protected from elevated blood pressures by the glomerulus. Glomerular changes are rare in early hypertension, but in long-standing cases, complete glomerulosclerosis can occur due to prolonged ischemia as afferent

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vessels are obliterated. Even in patients who have had hypertension for a relatively short period of time, pathologic changes can be seen. Relationship between Renal Failure and Hypertension The risk of ESRD from hypertension alone can be estimated, but exact formulations are probably not possible. First, in contradistinction to a stroke or myocardial infarction, initiating dialysis for ESRD is frequently elective and occurs with a much lower frequency than other hypertensive complications. From 1995–1999 almost 400,000 patients began dialysis (80,000 a year) [4]. Regardless of how it is estimated, only a minority of these patients had primary hypertensive renal disease. In contrast, an estimated 700,000 strokes and 1.5 million acute myocardial infarctions occur annually [7, 8]. Second, as most forms of renal failure progress many patients become hypertensive. Therefore to understand the risk of isolated hypertension for ESRD, patients with other forms of renal disease need to be excluded, often by biopsy, and hypertension needs to predate the onset of renal insufficiency. One would suspect from recent registry data in the US that the prevalence of ESRD from hypertension is high. The 2001 USRDS reports that hypertension is the second most common cause of ESRD (trailing only diabetes), with an incidence of 83 cases/million people [4]. The apparent increase in ESRD from hypertension occurs during a time when mortality from other hypertensive diseases (i.e. stroke, myocardial infarction) is diminishing [7–9]. However, in many cases the causal relationship between ESRD and hypertension may be, at best, guilt by association. Frequently the diagnosis of hypertensive ESRD (H-ESRD) occurs without a diagnostic biopsy, and patients are given the diagnosis if they present late in their course of renal failure without (and even sometimes with) overt signs of glomerular disease. Schessinger addressed this issue by carefully investigating the medical histories of 43 patients referred for transplant evaluations with the diagnosis of H-ESRD [10]. He reviewed all available data, including family histories, clinical records, history of nephrotoxic exposures, and biopsies. Only 2 of the patients had complete records and documented normal serum creatinine and urinalysis when diagnosed with hypertension. Sixteen patients had an elevated serum creatinine or pathologic proteinuria when diagnosed with hypertension, and in nine patients with incomplete records other potential causes of renal failure were identified. Finally, in the six patients who had undergone biopsy, none exhibited changes consistent with hypertensive nephrosclerosis, and four patients had lesions suggestive of other renal diseases. Conversely, even if the estimates of ESRD as a result of hypertension are valid, the magnitude must be compared to that of hypertension in the population. The rate of hypertension in the US adult population is roughly 25% (250,000 per million). If 80 of those patients require dialysis annually, the risk of ESRD from hypertension is 0.032% or one out of every three thousand people with hypertension. There also seems to be a significant racial difference in the rates of H-ESRD. Whittle et al. found that black race carried with it a relative risk of 5.60 (95% CI: 3.9–8.1) for the diagnosis of H-ESRD [11]. These findings are consistent

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with current USRDS data. From 1996–1999 the incident rates for H-ESRD (per 10 million people) were 2,387 in black patients and 552 in white patients [4]. However, as stated above, the diagnosis of H-ESRD is at times based on suspect information. A separate survey by Perneger et al. reported that given identical clinical vignettes except for alteration in race, nephrologists were more likely to assign the diagnosis of H-ESRD to black patients as compared to white patients (OR = 1.97) (95% CI: 1.05–3.68) [12]. Risk of Renal Insufficiency from Hypertension Several reports, knowledge of which is essential for donor counselors, have investigated prospectively the risk of renal insufficiency or ESRD from hypertension in otherwise healthy individuals. One of the first large-scale studies to address this issue was the Hypertension Detection and Follow-up Program (HDFP) [13]. Over 10,000 patients (ages 30–69, mean 50.8 years) with hypertension were enrolled and randomized to either stepped- or referred-care. Serum creatinine values were available for 8,643 patients after five years, of which only 200 (2.3%) “experienced a progressive rise in serum creatinine concentration to levels that were considered indicative of possible renal insufficiency [greater that 2.0 mg/dl and a rise of 1.25 times the baseline value].” It is difficult to know if the progression of renal insufficiency in those 200 patients can be attributed solely to hypertension, as they were not analyzed separately. Also, at enrollment, the population included over 1,000 diabetics, over 600 patients with serum creatinine values of at least 1.5 mg/dl, and over 300 patients with proteinuria of 2+ or greater. Perneger et al. performed another large-scale analysis by examining the HDFP, National Health and Nutritional Examination Survey (NHANES), and USRDS data to determine the risk and progression of renal disease in patients with hypertension [14]. They concluded that 1.8 million Americans develop hypertension annually and one in every thirteen (8%) patients with hypertension progress to develop a creatinine over 2.0 mg/dl and subsequently one in every 334 (0.3%) patients with hypertension eventually develop ESRD. This estimate is 100 times higher than the limiting estimates based on epidemiologic data, which are discussed above. These rates are for all patients and are higher in black patients with the rate of ESRD in hypertensives projected to be around 1.2 percent. Another study examining the role of hypertension as the primary cause of renal insufficiency came from Rostand et al. in 1989 [15]. By analyzing 94 patients with hypertension (mean age of 48.9 years), they found that renal function is well preserved over 5 years. Fourteen percent of patients experienced a rise in creatinine of greater that 0.4 mg/dl over the follow-up. Interestingly, in black patients the degree of blood pressure control did not affect the likelihood of progression. These findings were supported by a separate study by Walker et al. who found that over an average of six years those patients with a systolic blood pressure greater than 160 mm Hg at baseline had a mean change in serum creatinine from 1.10 mg/dl to 1.16 mg/dl [16]. Those patients with diastolic blood pressure greater than 95 mm Hg experienced a statistically significant decline in kidney function when compared to those with better control. However, those with

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better blood pressure control demonstrated an improvement in kidney function of equal magnitude, which was defined by the authors as no change from baseline. The subset of black patients with DBP greater than or equal to 90 mmHg at baseline again saw a rise in serum creatinine values over time (1.13 mg/dL to 1.17 mg/dL), which was not affected by the degree of blood pressure control. A recent study from Sweden by Siewert-Delle et al. reported on 686 hypertensive male patients (ages 47–55) followed for 20 years, one of the longest follow-up periods [17]. Only 12 patients (1.7%) had an increase in serum creatinine without development of another clear cause (i.e. diabetes, renal artery stenosis, glomerulonephritis, obstruction . . .) of renal insufficiency. The mean change in serum creatinine in these patients was from 1.14 mg/dl to 1.57 mg/dl over 20 years, with no patient developing ESRD. In all of the above studies and in the studies discussed below, screening for patients with primary renal disease at entry and for those patients who develop non-hypertensive primary disease as the study progresses is crucial. Such screening often is not reported in detail if it is done at all. The lack of effect of treatment of hypertension on the progression of renal disease in some of these studies stands in contrast to the salutary effect of treatment on other hypertensive complications. Lack of such a treatment effect could be considered evidence that a very small purely hypertensive risk for ESRD actually exists. Risk of ESRD from Hypertension Few studies have critically examined the development of ESRD in those patients with hypertension as their only renal disease. One of the earliest attempts arose from the VA Hypertension Screening and Treatment Program (HSTP) [18]. Over 11,000 patients were included in the analysis published by Perry et al. in 1995. Forty-eight percent of the patients were black, and the patients were followed for a minimum of 13.9 years, with 245 patients (2.1%) developing ESRD. The risk of developing ESRD was greatest in those who presented with SBP > 165 mm Hg, black patients, and diabetics. In non-diabetics (at baseline) the rate of ESRD was 1.9%. They also reported that treatment of blood pressure resulted in a reduction in the rate of ESRD. However, the results can only be viewed as worst case scenario and may not reflect the effect of hypertension alone. No baseline laboratory data were recorded, raising the possibility that those patients with the worst initial blood pressure who developed ESRD may have already had undiagnosed renal disease at enrollment, greatly increasing their risk of ESRD. Also, the subsequent development of diseases that may cause renal insufficiency during the study period was not documented. The ongoing Multiple Risk Factor Intervention Trial (MRFIT) provided another population for analysis. Klag reported 814 cases of ESRD developed in the over 330,000 men screened for MRFIT (0.25%). Between 173 and 204 patients (0.05%–0.06%) with ESRD had hypertension as the sole cause, yielding a crude rate of ESRD from hypertension of between 3.40 and 4.01 per 100,000 patientyears, i.e., the risk over thirty years for a patient who developed hypertension at age 40 would be about one in a thousand [19]. The rate of ESRD was higher in those with higher blood pressures, as well as black patients and diabetics. Since

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this study was of screened patients and not only those enrolled in the MRFIT, no data on the effect of blood pressure control are available. A separate report on the MRFIT participants suggested that blood pressure control had little effect on the rate of change in renal function in those with hypertension only [16]. The rate of decline in renal function was greater in black patients (serum creatinine increased from 1.13 mg/dL to 1.17 mg/dL compared to no change in the nonblack patients) even though blood pressure control was comparable between the subgroups based on race. Two other studies examining the relationship between isolated hypertension and ESRD came out of Japan, utilizing annual health screenings performed by the Okinawa General Health Maintenance Association. The first included 107,192 adults with a 10-year follow-up period, during which 193 patients (about 2 in a thousand) developed ESRD [20]. Only 19 patients (2 in ten thousand) were listed in the dialysis registry as having nephrosclerosis as the cause of their renal failure; the remaining 174 patients had other causes of their renal failure (51% chronic glomerulonephritis, 28.5% diabetes mellitus, 2% polycystic kidney disease, 1.9% systemic lupus erythematosus, and 8.4% other). Diastolic hypertension was identified as a risk factor for ESRD; however the patients who required dialysis had a myriad of other renal diseases, and hypertension alone rarely caused ESRD. Blood chemistries were not collected, and the strongest predictor of ESRD was an abnormal urinalysis (proteinuria or hematuria) at screening, suggesting preexisting renal pathology. The second study, using the same patient population but a different study period, stratified patient risk for stroke, acute myocardial infarction and ESRD based on blood pressure at screening and did not include data on other diseases [21]. Over 37,000 patients were hypertensive at screening, and the rates of hypertension were significantly higher in those with an abnormal urinalysis or elevated serum creatinine at baseline, consistent with the tendency of patients with kidney disease to develop hypertension. Over 8,000 patients had proteinuria at screening. Sixtyone cases of ESRD developed during the study period (0.16%). The cumulative percentage of ESRD increased with the level of blood pressure at screening, from a low of 0.02% in those with systolic blood pressure < 119 mmHg to a high of 0.36% in those with diastolic blood pressure > 110 mmHg. Again, these rates must be viewed as worst-case scenarios, since no information about other causes of renal insufficiency were included. Risk of Renal Disease in Relatives of those with ESRD Before discussing the role of the transplant nephrectomy on the risk of hypertension or renal insufficiency, the impact of being related to a patient on dialysis must briefly be explored. Since most living transplant donors are related to the recipient, the donors are related to an individual with ESRD. How does this impact their long-term survival? There exist several studies that have examined this issue. Two recent studies examined relatives of black hemodialysis patients in North Carolina and Alabama. In the first, 76% of patients with ESRD from any cause had a first- or second-degree relative with hypertension, compared to only 21%

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Table 1. Studies reporting ESRD rates in hypertensive cohorts. Cases of ESRD

Total patients

Rate per 100,000 pt-years

Notes

USRD compared to US hypertensive population

–20,000

50,000,000

040

Siewert-Delle [17]

0,00000

0,00,99686

000

Less than 14,000 pt-years, but no subject developed ESRD over 20 years.

MRFIT-Klag [19]

0,00204

0,0330,000

004

No comment on effect of treatment of hypertension, nor the number of patients hypertensive at baseline.

VAHSTP-Perry [18]

0,00245

0,0011,000

245

No baseline laboratory data collected.

Okinawa health screening – Iseki [21]

0,00019

0,0107,000

203

No baseline serum chemistries reported, and the strongest predictor of ESRD was an abnormal urinalysis at screening.

Okinawa health screening – Iseki [9]

0,00061

0,0037,000

71 (SBP ≥ 160 mmHg) – 364 (DBP ≥ 110)

No report of co-morbidities that may cause renal failure.

US Census, NHANES, HDFP, and USRDs – Perneger [14]

005,300

01,800,000

294

Projected numbers and rates total patients is incident cases of hypertension annually and cases is the number who will progress to ESRD.

SCOTT R. MULLANEY AND MICHAEL G. ZIEGLER

Source

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of age, race and sex matched controls [22]. The presence of a first-, second-, or third degree relative with ESRD increased one’s risk for ESRD over four-fold (OR = 4.6). The study from Alabama concentrated on first-degree relatives of patients with the diagnosis of H-ESRD [5]. Every patient had a first-degree relative with hypertension and nine had at least one first-degree relative with ESRD (11 relatives). Another ten relatives had elevated serum creatinine values. A study by O’Dea et al. focused on first-, second-, and third degree relatives of white ESRD patients in Canada [23]. Being a first-degree relative of a dialysis patient increased one’s risk of developing ESRD three-fold. The probability of having a relative in a national registry of organ failure was 3.2 times higher for patients with ESRD compared to controls. A population-based study by Lei et al. in patients of all races found similar trends [24]. These studies support the idea that differences in genetic susceptibility to hypertension and ESRD exist. However, it is still not clear if the increased risk of ESRD in relatives of patients with ESRD is due to familial clustering of primary renal disease or to an increased renal susceptibility to renal diseases or hypertension. The impact of heredity, although not yet completely understood, should be included in our counseling of potential donors. This topic is also discussed in Chapter Four. The impact of environmental influences also may be involved although they would be difficult to divine. Summary of Risk of ESRD from Hypertension Hypertension is common in the general population, and almost universal in patients with ESRD. To counsel patients with hypertension on their risk of ESRD following kidney donation, we must first try to assess their risks from hypertension alone. Based on the available information, the risk of significant renal dysfunction or ESRD from hypertension appears to be (Table 1) on the order of one in one thousand. This estimate considers that many of the studies, which may suggest a slightly higher risk, did not control for other possible causes of renal failure. This risk is probably higher, perhaps doubled to one in five hundred, in black patients and lower in whites, although some bias in defining black patients as having H-ESRD seems to exist. The risk is probably also slightly higher in first-, second-, or third degree relatives of ESRD patients, although a definite conversion factor would be hard to determine given the design and size of the studies available. Such risk estimates treat “hypertensives” as a single group. The risk of ESRD would be higher in some hypertensive donors and lower in others and would be related to the severity and treatability of the hypertension, the extent of end-organ damage, and the presence of other risk factors. Risks of Developing Hypertension After Kidney Donation Kidney donation decreases renal mass by 50% and renal function by up to 30% [25, 26]. Most conditions that diminish renal function are associated with hypertension, and with the reduction in renal mass from donation, one would suspect that kidney donation would tend to raise blood pressure. In normal, non-donor

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populations, renal function decreases with age, and the incidence of hypertension and salt sensitivity increases. Many have examined the relationship between kidney donation and the development of hypertension, with relatively consistent results. The relationship between kidney donation and increased blood pressure as discussed below should be included as part of donor counseling. There are several reasons why it is difficult to know if unilateral nephrectomy raises blood pressure. One of the most problematic is the variation in method of measurement of blood pressure in studies to date. One of the first papers to examine the occurrence of hypertension after donation by Hakim et al. published in 1984 used blood pressure measurements obtained during a single interview, usually in the subject’s home [27]. 60% of the men and 30% of the women donors in this cross-sectional study were hypertensive. Only about 22% of control subjects were comparably hypertensive. However, in another study also published in 1984 by Williams et al., blood pressure was measured 6 times towards the conclusion of a clinical evaluation in both donors and their siblings [28]. The study found no significant difference in the incidence of hypertension between donors and siblings at 12.6 years after donation. The difficultly in obtaining a representative blood pressure measurement during a single clinic visit prompted Eberhard et al. to use 24-hour blood pressure monitoring, which suggested a 29% incidence of hypertension in individuals who had donated kidneys an average of 11 years previously [29]. In that study only half of the patients found to have hypertension during 24 hour blood pressure monitoring had elevated clinic blood pressures. In contrast, 8 patients with elevated clinic blood pressures had normal 24-hour blood pressure results. The difference between 24-hour blood pressure results and clinic blood pressure results in the study by Eberhard et al. is not an uncommon finding [29]. Twentyfour hour blood pressure monitoring typically shows that 20% of patients diagnosed as hypertensive on the basis of clinic readings actually have normal blood pressures by 24-hour monitoring. On the other hand, the incidence of hypertension diagnosed by 24-hour monitoring among those who are thought to be normotensive depends greatly on the 24-hour blood pressure criteria used to define hypertension. In addressing the risk of hypertension for living kidney donors, in subsequent sections, we will first review specific studies in different groups of patients and then consider the conclusions of reviews and meta-analyses. The differences in results of various studies that investigate the incidence of hypertension following nephrectomy point out the difficulties of making an accurate diagnosis of hypertension. A reasonable approach that avoids these problems is to compare blood pressures between donors and a control group using identical methods for blood pressure measurement. Williams et al. concluded that 12.6 years following nephrectomy, 47% of donors had hypertension and 35% of their siblings had hypertension [28]. In a similar study by Najarian et al., 32% of donors responding to a questionnaire were taking antihypertensive drugs while 44% of their siblings were taking antihypertensives [25]. However, in this study, unlike the study by Williams et al., it is not known if any of the siblings were excluded from donating their kidney because of hypertension or other medical contraindications. Several other methods have been used to determine if nephrectomy raises blood pressure. A popular approach is to compare the blood pressure of uninephrec-

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tomized subjects with that of the general population. Using this method Baudoin et al. studied patients who had been uninephrectomized during childhood [30]. 27% of this group was hypertensive at an average age of 31 years, a significant increase over the expected rate of hypertension at that age. Robitaille et al. and Wikstad et al. measured blood pressure many years after subjects underwent unilateral nephrectomy in childhood, and blood pressure was slightly higher than in a control group [31, 32]. Two other studies investigated the incidence of hypertension in adults who underwent uninephrectomy for reasons other than donation. Ohishi et al. reviewed 23 patients who underwent uninephrectomy (mean follow-up of 27 years) for unilateral renal disease [33]. Narkun-Burgess et al. reviewed data on 62 US servicemen who underwent uninephrectomy as a result of trauma (mean age at nephrectomy of 25 and follow-up of 45 years) [34]. Both studies found that in those post-uninephrectomy blood pressure was slightly but not significantly higher than predicted from the normal population, with a higher prevalence of hypertension only in the Ohishi study (men: 35.7% vs. 27.7%; women: 28.6% vs. 22.5%) and no effect on mortality. In the Ohishi study the main indications for uninephrectomy were renal tuberculosis, stones or hydronephrosis. Although one kidney was damaged to a degree that required removal, bilateral involvement in any of these disorders would sometimes occur, and disease in the remaining kidney could have contributed to the development of hypertension. The above studies offer some insight into the effect of removal of one kidney on blood pressure, yet kidney donors represent a selected segment of the general population that may differ from the above studied groups. Several studies have examined blood pressure changes after donor nephrectomy. Miller et al. asked donors to have their blood pressure measured in their personal physician’s clinic [35]. With an average follow-up of 6 years, they found nine of twenty-nine kidney donors (31%) and 13% of a control population were hypertensive, a difference that did not reach statistical significance. All donors had blood pressures below 140/90 mm Hg at donation and two of the nine with hypertension post-donation were on antihypertensives. The average blood pressure of the other seven was only 134/92 mm Hg. Also, no difference between normotensive and hypertensive donors was found with regard to serum creatinine values. Torres et al. studied 99 donors with at least ten years of follow-up and reported that blood pressure increased among kidney donors less than predicted by trends in the general population, with an increase in MAP from 94 mm Hg pre-donation to 97 mm Hg at followup [36]. Fehrman-Ekholm et al. found that 35% of donors in Sweden were hypertensive over 20 years post-donation but concluded that “kidney donors live longer”, when compared to the general population [37]. Several other studies of hypertension in kidney donors should also be discussed. Tapson concluded in 1987 that most donors could expect normal blood pressure for 25 years after surgery [38]. Fotino, in a 1989 review, noted that the prevalence of hypertension in donors was reported to be similar to that in the general population [39]. Najarian reported that in 78 donors followed for a mean of 23.7 years average blood pressure increased from 118/76 mm Hg pre-donation to 134/80 mm Hg at follow-up [25]. The prevalence of hypertension was not different from age and sex-matched controls. Kasiske performed a meta-analysis of 48 studies, including many of those discussed above, of patients who underwent nephrectomies for a variety of reasons, with 3,124 total patients [40]. There were 2,080 individuals

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in whom blood pressure was assessed. He noted that uninephrectomy did not affect the prevalence of hypertension but there was small increase in systolic blood pressure of 2.4 mm Hg, which rose further at a rate of 1.1 mm Hg per decade. Diastolic pressure was higher after nephrectomy by 3.1 mm Hg but did not change with duration of follow-up. He concluded, “There is little long term risk associated with organ donation.” [40] Although there have been numerous carefully designed studies to evaluate the effect of uninephrectomy on the prevalence of hypertension, it is impossible to say with certainty whether nephrectomy raises donor blood pressure. Many factors could lead to a systematic bias in measures of the effect of kidney donation on blood pressure. First, no study has been able to use an objective measurement technique, such as 24-hour blood pressure monitoring, both before and long after nephrectomy. Second, few studies avoid the systematic bias introduced by kidney donors being healthy individuals who may be likely to pursue a healthy life style. Third, most kidney donors have a family history of kidney disease and the impact of heritable factors has rarely been studied in this context. Finally, most studies have only been able to measure blood pressure 10 to 20 years following renal donation, although most renal donors have a life expectance greater than 20 years. From the data available, there appears to be a small but measurable increase of two to five percent in both systolic and diastolic blood pressures after donation. This increase appears additive to the normal increase in blood pressure that occurs with aging. Risk Factors for Developing Hypertension After Nephrectomy Blood Pressure at Time of Donation Several investigators have found that donors with borderline or definite hypertension at the time of donation are more likely to have high blood pressure at long-term follow-up. Torres et al. found the incidence of hypertension was 15% among normotensive donors but 38% among those with borderline hypertension at time of donation (normotensive: < 140/90 mm Hg; borderline: 141–160/91–95 mm Hg) [36]. This difference was even more extreme in the study by Talseth et al. [41]. They found that five of nine hypertensive donors at long-term followup had borderline hypertension (≥ 140/90 mm Hg) at time of donation. On the other hand, Ohishi et al. found that only one of four patients who had borderline hypertension before uninephrectomy had developed definite hypertension afterward [33]. In contrast, they found that family history, rather than borderline hypertension, predicted the development of definite hypertension. All of these studies share a common methodological problem. Obviously, borderline hypertension at a younger age predicts the development of definite hypertension over the ensuing years even in subjects with two kidneys. Thus uninephrectomy may not increase blood pressure any more in borderline hypertensive people than it does in normotensive people.

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Obesity Although obesity at a young age is a strong predictor of further weight gain, development of adult onset diabetes mellitus and development of hypertension, donor weight is generally not mentioned in most studies of the medical outcome of donors. Torres et al. found that relative weight at donation was a statistically significant predictor of post-donation blood pressure, comparable in predictive value to blood pressure and age at the time of donation [36]. In the United States, both normal weight and overweight individuals tend to gain weight with advancing age. The overweight gain more, however. Since being overweight increases the risk of developing both hypertension and diabetes, body weight is a potentially important risk factor for a long-term adverse outcome following kidney donation, which has yet to be fully explored. Control of Blood Pressure after Kidney Donation As stated earlier, in the United States, nearly 68% of people with hypertension are aware that they have high blood pressure [2]. Half of those with hypertension have been prescribed antihypertensive drugs and about half of those have their blood pressure controlled. Thus, about 1 out of every 4 hypertensives in the United States has their blood pressure adequately controlled. One might suspect that kidney donors would be more medically sophisticated, more interested in their health, and more likely to control their blood pressure. Unfortunately that does not appear to be the case. Among studies of donors that recorded hypertension therapy, 71%, less than 50% and 22% of patients with high blood pressure were receiving antihypertensive drugs [33, 35, 42]. Among donors who had a diagnosis of hypertension at follow-up, only 32%, 20%, or 0% had their blood pressure controlled [30, 33, 36]. It is thus apparent that kidney donors do little better than the general population in control of blood pressure. This fact might be mentioned to potential donors so they do not overestimate the beneficial effects of blood pressure control. The prospective kidney donor will likely be interested in the risk of renal failure from hypertension. As mentioned in the first part of this chapter, among patients without kidney disease, this risk is unmeasurably small. In the large trials of blood pressure control, there has been such a low incidence of renal failure due to hypertension that no benefit of lowering blood pressure could be shown. If a kidney donor develops hypertension, antihypertensive therapy should decrease the risk of cardiovascular disease. The large trials of antihypertensive therapy lowered diastolic blood pressure an average of 5.5 mmHg, decreased stroke by about 27%, and reduced heart attacks by about 12%. More recent studies of treatment of systolic hypertension have shown a decrease of about 35% for the risk of both heart attack and stroke. Sadly, only about half of the general population (and kidney donors) receives any treatment when they develop hypertension.

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Summary Hypertension is epidemic in the US, and is usually not completely controlled. Hypertension is a very uncommon cause of renal failure by itself, but it frequently accompanies other renal diseases, and commonly contributes to stroke, heart attack and heart failure. Although it seems reasonable to suspect that uninephrectomy will raise blood pressure in a kidney donor, it is difficult to know with certainty if this is indeed the case. The numerous studies performed suggest that uninephrectomy does lead to a slow, small progressive increase in blood pressure which may be additive to the normal increase in blood pressure with age. A borderline elevated blood pressure at the time of donation may increase this risk further. The risk of heart attack and stroke would be enhanced if blood pressure were increased on top of existing hypertension, particularly in hypertensives that smoke, have elevated blood lipids, or glucose intolerance. A strong family history of hypertension may further increase the risk of high blood pressure following uninephrectomy. Obesity or a family history of diabetes predisposes to hypertension and places a donor at higher risk if hypertension does develop. Potential kidney donors will be at increased risk if they have any of these conditions, regardless of whether they donate or not, and the risk of donation would be that portion of the risk specifically attributed to the increase, if any, in post donation blood pressure. Potential kidney donors should not be classified as hypertensive because of a single high blood pressure measurement, regardless of the donor counselors’ opinion about the risk of ESRD from hypertension. Kidney donors may have their blood pressure classification changed after evaluation by 24-hour blood pressure monitoring [29]. There are many ways to measure blood pressure more accurately than random blood pressures taken in a clinic, such as self-measurement at home, measurement on repeated clinic visits, or 24-hour blood pressure monitoring. These techniques seem worthwhile to clarify risk in potential kidney donors who have slightly elevated blood pressures in the clinic. Blood pressures that are not entirely normal are best viewed in the context of overall cardiovascular risk. A slightly elevated blood pressure will not lead to renal failure following uninephrectomy. However, a slightly elevated blood pressure combined with obesity, smoking, glucose intolerance, or lipid abnormalities puts the potential donor at increased risk of cardiovascular disease regardless of donation. Some of these conditions are modifiable, and behavioral changes may play a large role in modifying risk. If uninephrectomy raises blood pressure and blood pressure remains elevated, the donor may be at a proportionately increased risk of stroke or heart attack. On the other hand, a potential donor with no cardiovascular risk factors is much less likely to suffer an adverse consequence of hypertension, even if uninephrectomy increases blood pressure. The increased risk is likely equivalent to the decrease in risk from successful therapy of hypertension. In discussing these issues, the donor counselor must present baseline risk as well as relative risk. That is, if a medical condition doubles the risk of a hypertensive complication, and the baseline risk is one in one thousand, the incremental risk is also one in a thousand. Something that doubles risk for a complication should be clearly distinguished from something that results in a 50% risk of that complication.

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Numerous studies suggest that a normotensive donor with a negative family history of hypertension and of normal weight will increase blood pressure from zero to a few mmHg after nephrectomy. This would translate into an incremental increase in cardiovascular risk of from zero to less than 10%. On the other hand, a donor with borderline blood pressures and a positive family history of hypertension may increase diastolic blood pressure by 5 mmHg from uninephrectomy. This might be expected to increase cardiovascular risk from 12 to 25%. Successful therapy of hypertension decreases cardiovascular risk, but only about 25% of hypertensives have their blood pressure adequately treated. The risk of developing renal failure from usual increases in blood pressure of 10–20% is unmeasurably small among subjects with normal kidneys, but uncontrolled hypertension will likely accelerate progression of many renal diseases as well as systemic vascular disease. References 01. Bia MJ et al. Evaluation of living renal donors. The current practice of US transplant centers. PG – 322-7. Transplantation. 1995; 60(4). 02. Wolz M et al. Statement from the national high blood pressure education program: prevalence of hypertension. Am J Hypertens. 2000; 13(1 Pt 1): 103–4. 03. Burt VL et al. Trends in the prevalence, awareness, treatment, and control of hypertension in the adult US population. Data from the health examination surveys, 1960 to 1991. Hypertension. 1995; 26(1): 60–9. 04. WWW.USRDS.ORG. 2002. 05. Bergman S et al. Kidney disease in the first-degree relatives of African-Americans with hypertensive end-stage renal disease. Am J Kidney Dis. 1996; 27(3): 341–6. 06. Ono H, Ono Y. Nephrosclerosis and hypertension. Med Clin North Am. 1997; 81(6): 1273–88. 07. Broderick J et al. The Greater Cincinnati/Northern Kentucky stroke study: preliminary first-ever and total incidence rates of stroke among blacks. Stroke. 1998; 29(2): 415–21. 08. McGovern PG et al. Recent trends in acute coronary heart disease – mortality, morbidity, medical care, and risk factors. The Minnesota Heart Survey Investigators. N Engl J Med. 1996; 334(14): 884–90. 09. Iseki K et al. Comparison of the effect of blood pressure on the development of stroke, acute myocardial infarction, and end-stage renal disease. Hypertens Res. 2000; 23(2): 143–9. 10. Schlessinger SD, Tankersley MR, Curtis JJ, Clinical documentation of end-stage renal disease due to hypertension. Am J Kidney Dis. 1994; 23(5): 655–60. 11. Whittle JC et al. Does racial variation in risk factors explain black-white differences in the incidence of hypertensive end-stage renal disease? Arch Intern Med. 1991; 151(7): 1359–64. 12. Perneger TV et al. Diagnosis of hypertensive end-stage renal disease: effect of patient’s race. Am J Epidemiol. 1995; 141(1): 10–5. 13. Shulman NB et al. Prognostic value of serum creatinine and effect of treatment of hypertension on renal function. Results from the hypertension detection and followup program. The Hypertension Detection and Follow-up Program Cooperative Group. Hypertension. 1989; 13(5 Suppl): I80–93. 14. Perneger TV et al. Projections of hypertension-related renal disease in middle-aged residents of the United States. JAMA 1993; 269(10): 1272–7.

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15. Rostand SG et al. Renal insufficiency in treated essential hypertension. N Engl J Med. 1989; 320(11): 684–8. 16. Walker WG et al. Renal function change in hypertensive members of the Multiple Risk Factor Intervention Trial. Racial and treatment effects. The MRFIT Research Group. JAMA 1992; 268(21): 3085–91. 17. Siewert-Delle A et al. Does treated primary hypertension lead to end-stage renal disease? A 20-year follow-up of the Primary Prevention Study in Goteborg, Sweden. Nephrol Dial Transplant. 1998; 13(12): 3084–90. 18. Perry HM Jr et al. Early predictors of 15-year end-stage renal disease in hypertensive patients. Hypertension. 1995; 25(4 Pt 1): 587–94. 19. Klag MJ et al. Blood pressure and end-stage renal disease in men. N Engl J Med. 1996; 334(1): 13–8. 20. Iseki K et al. Risk of developing end-stage renal disease in a cohort of mass screening. Kidney Int. 1996; 49(3): 800–5. 21. Iseki K, Ikemiya Y, Fukiyama K. Blood pressure and risk of end-stage renal disease in a screened cohort. Kidney Int Suppl. 1996; 55: S69–71. 22. Freedman BI et al. The familial risk of end-stage renal disease in African Americans. Am J Kidney Dis. 1993; 21(4): 387–93. 23. O’Dea DF et al. Higher risk for renal failure in first-degree relatives of white patients with end-stage renal disease: a population-based study. Am J Kidney Dis. 1998; 32(5): 794–801. 24. Lei HH et al. Familial aggregation of renal disease in a population-based case-control study. J Am Soc Nephrol. 1998; 9(7): 1270–6. 25. Najarian JS et al. 20 years or more of follow-up of living kidney donors. Lancet. 1992; 340(8823): 807–10. 26. Velosa JA, Offord KP, Schroeder DR. Effect of age, sex, and glomerular filtration rate on renal function outcome of living kidney donors. Transplantation. 1995; 60(12): 1618–21. 27. Hakim RM, Goldszer RC, Brenner BM. Hypertension and proteinuria: long-term sequelae of uninephrectomy in humans. Kidney Int. 1984; 25(6): 930–6. 28. Williams SL, Oler J, Jorkasky DK. Long-term renal function in kidney donors: a comparison of donors and their siblings. Ann Intern Med. 1986; 105(1): 1–8. 29. Eberhard OK et al. Assessment of long-term risks for living related kidney donors by 24-h blood pressure monitoring and testing for microalbuminuria. Clin Transplant. 1997; 11(5 Pt 1): 415–9. 30. Baudoin P, Provoost AP, Molenaar JC. Renal function up to 50 years after unilateral nephrectomy in childhood. Am J Kidney Dis. 1993; 21(6): 603–11. 31. Robitaille P et al. Long-term follow-up of patients who underwent unilateral nephrectomy in childhood. Lancet. 1985; 1(8441): 1297–9. 32. Wikstad I et al. Kidney function in adults born with unilateral renal agenesis or nephrectomized in childhood. Pediatr Nephrol. 1988; 2(2): 177–82. 33. Ohishi A et al. Status of patients who underwent uninephrectomy in adulthood more than 20 years ago. Am J Kidney Dis. 1995; 26(6): 889–97. 34. Narkun-Burgess DM et al. Forty-five year follow-up after uninephrectomy. Kidney Int. 1993; 43(5): 1110–5. 35. Miller IJ et al. Impact of renal donation. Long-term clinical and biochemical followup of living donors in a single center. Am J Med. 1985; 79(2): 201–8. 36. Torres VE et al. Blood pressure determinants in living-related renal allograft donors and their recipients. Kidney Int. 1987; 31(6): 1383–90. 37. Fehrman-Ekholm I et al. Kidney donors live longer. Transplantation. 1997; 64(7): 976–8. 38. Tapson JS. Prognosis after donor nephrectomy: an update. Int J Artif Organs. 1987; 10(6): 341–5.

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39. Fotino S. The solitary kidney: a model of chronic hyperfiltration in humans. Am J Kidney Dis. 1989; 13(2): 88–98. 40. Kasiske BL et al. Long-term effects of reduced renal mass in humans. Kidney Int. 1995; 48(3): 814–9. 41. Talseth T et al. Long-term blood pressure and renal function in kidney donors. Kidney Int. 1986; 29(5): 1072–6. 42. Saran R et al. Long-term follow-up of kidney donors: a longitudinal study. Nephrol Dial Transplant. 1997; 12(8): 1615–21.

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Chapter Six Risk of Diabetes and Diabetic Nephropathy David M. Ward, M.D. Summary Points • Diabetes causes one-third of all end stage renal disease in the United States, often late in life, so that most of us – donors or not – are at some risk for this outcome. A subset of diabetics are at genetic risk of developing nephropathy. • Counseling kidney donors who are at increased risk of diabetes is aided by the abundance of data on the incidence and progression of renal disease, and the benefit of transplantation to the recipient. • A fasting blood sugar above 126 mg/dl now defines diabetes. • Most diabetic recipients have a clear-cut survival benefit that is associated with renal transplantation. • Most siblings who develop Type I diabetes will have been diagnosed before the question of transplantation for the proband arises. • The risk for Type I diabetes is increased by anti islet cell antibodies and specific family genetics. Over 50% of type I diabetics will never develop renal disease. • Hyperinsulinemia and borderline abnormalities in fasting blood glucose and glucose tolerance testing increases risk for Type II diabetes. Over 70% of Type II diabetics will never develop renal disease. • With current therapy of Type II diabetes, it takes 15–20 years of diabetes to develop macroalbuminuria, and the progression of renal disease from that point on may be decreased with treatment. • Nephrectomy will not cause diabetic nephropathy, but it may hasten its progression, at the least by the 20% initial loss of overall renal function that is associated with nephrectomy. • Pancreas transplantation restores euglucemia. It is a complex operation with a higher risk than kidney transplantation. It takes several years for any improvement of previous diabetic complications to occur. 99 R.W. Steiner (ed.), Educating, Evaluating, and Selecting Living Kidney Donors, 99–117.  2004 Kluwer Academic Publishers. Printed in the Netherlands.

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Introduction Diabetes in the most common cause of end stage renal failure in older people, and therefore most potential kidney donors are at some risk for diabetic nephropathy and should perhaps be counseled about this disease. The risk of developing diabetes at some time after donating a kidney is a particular concern for many potential donors when the intended recipient is a close relative who has diabetic kidney failure or when the donor family history is very strong. When the donor is genetically unrelated to the recipient, or when the recipient is non-diabetic, the question may still arise if the donor has a family history of diabetes or another risk factor for diabetes. Evaluation of the risk for future development of diabetes or diabetic nephropathy has always been considered a necessary part of the evaluation of live kidney donors [1, 2]. Because of the prevalence of diabetic nephropathy, no center – no matter how it views accepting kidney donors at increased risk of diabetic nephropathy – can avoid this area when it evaluates and counsels donors. If the prospective donor has any family history of diabetes, is significantly obese, or has an abnormal blood glucose on a simple screening test (such as a 2-hour post-prandial blood glucose), most transplant centers will pursue more detailed assessment of diabetic risk. Whatever transpires from such investigation should be the basis for individualized donor counseling. If a donor develops diabetes later in life, it would have happened regardless of whether kidney donation had occurred. The more important and central question is, in the event that diabetes does develop, to what extent does having only one kidney increase the rate of progression and/or the severity of diabetic complications such as nephropathy, hypertension and cardiovascular risk? Understanding and quantifying such risk is necessary if the donor – and the center – are to make informed decisions about the appropriateness of donation. This chapter starts with a review of the magnitude of the problem of diabetic nephropathy as the most common reason for dialysis and kidney transplantation in the world today. Thereafter several sections (1) address the possibility that the donor could subsequently develop diabetes or diabetic nephropathy, (2) outline current understanding of the biological phenomena involved, (3) review what is known with regard to quantifying the risks, and (4) explore their implications and mitigation. Finally, the last two sections examine the “benefit side” of the risk/benefit equation: the advantage to a diabetic recipient of having a living-donor kidney transplant, compared to other options including combined pancreas-kidney transplantation, and how these choices affect diabetic complications as well as other issues specific to diabetic recipients. Incidence and Prevalence of Diabetic Nephropathy in the ESRD Population Diabetes is the most common cause of renal failure in the world today, accounting for at least one third of individuals sustained by hemodialysis, and perhaps one quarter of kidney transplant recipients. End stage renal failure in diabetics has increased by epidemic proportions over the last 20 years, first in the USA, then in Europe, and now almost globally [3, 5]. Some of the increased prevalence is due to success in sustaining life by the availability of dialysis and transplanta-

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tion [5] and the application of these treatments to the diabetic population. More of the increase is due to a burgeoning incidence of Type II diabetes [6]. In the USA at the end of 1998, over 90,000 people were being maintained on dialysis because of diabetic kidney disease, this point prevalence representing 38.9% of the total dialysis population. At the same time, more than 18,000 people with diabetic renal failure were being maintained by kidney transplants [7]. The number of new cases is proportionately larger, representing 43% of new cases of end stage renal disease (ESRD) in the USA in 1998. This incidence rate is larger than the prevalence rate because the incidence is rising, and because the survival of diabetics on dialysis is less than the rest of the dialysis population. During 1998, the number of kidney transplants for diabetic recipients in the USA was 3,322, representing 25.6% of all kidney transplants performed; 19.2% of the total were diabetics receiving a cadaver kidney, and 6.4% were diabetics receiving a live donor kidney. Of the 305,876 new patients commencing ESRD treatment in the USA between 1991 and 1995, 37.4% were diabetic, 15.4% being recorded as Type I diabetics and 22.0% as Type II diabetics [6]. Risk Factors for Development of Type I Diabetes Type I diabetes is due to a deficiency of insulin consequent to the permanent destruction of the beta-cells of the islets of Langerhans of the pancreas. This form of insulin-dependent diabetes mellitus (IDDM) is common in juveniles, is of presumed autoimmune etiology, and is a strongly familial disorder. The cumulative incidence in the general US population of European descent is 0.4 or 0.5%. The first-degree relatives of patients with Type I diabetes have about a 5%–6% risk of developing the disease (other estimates range up to 10%). However, even identical twins have on average only about a 50% concordance rate for Type I diabetes, indicating that environmental factors are also important. Various lines of evidence suggest that the most likely trigger for autoimmune beta-cell destruction in genetically susceptible individuals is virus infection [8]. Studies of children implicate acute coxsackie B virus and congenital rubella infection. The detection of cytomegalovirus (CMV) genome in lymphocytes correlates less convincingly. Strong evidence comes also from a variety of animal studies, including the induction of Type I diabetes in mice infected with a strain of encephalomyocarditis virus, and similar effects with a coxsackie B4 virus. Also viruses isolated from children with acute diabetes can cause diabetes when transferred into mice. Nevertheless, the pancreatic damage may not be due directly to viral attack, but rather by inducing autoimmunity after expression of viral proteins on beta-cells or through molecular mimicry. The autoimmune hypothesis is supported by the high incidence of islet cell auto-antibodies (ICA) in patients with Type I diabetes. ICA are often present in serum samples before the onset of diabetes, often for years, suggesting that the disease usually results after a period of active but subclinical beta-cell destruction. When testing reveals high titer ICA in a family member, that person is at higher risk of developing diabetes [9]. Additional autoantibodies also occur, and are sometimes of predictive value (see section on testing for diabetic risk). The autoimmune pathogenesis of Type I diabetes is consistent also with the observa-

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tion in humans of a strong association between certain class II histocompatibility antigens (“immune response genes”) and the risk of developing the disease. HLADR3 and HLA-DR4 are two such high risk alleles. The presence of either allele increases the risk of developing Type I diabetes. When both alleles are present in a fraternal sibling who is a 2-haplotype (“full-house”) match for a diabetic recipient, his or her risk of developing diabetes is four times the average rate for siblings of Type I diabetics. (Detailed data on this topic are provided later in this section.) When both these alleles are present in identical twins, the concordance rate for Type I diabetes rises to 70%, but when neither allele is present the concordance rate is only 25% [10]. The effect of these alleles may be due to their linkage to other genes in the major histocompatibilty complex. Numerous studies have explored this subject in intricate detail. For instance, analysis of HLA-DQ genotypes suggests that much of their diabetogenic effect can be ascribed to the beta-chain of the DQ molecule, specifically at amino acid 57, where the substitution of alanine instead of aspartic acid appears to confer major increased risk for Type I diabetes [11]. This DQ-beta chain polymorphism may also explain an apparent protective effect associated with HLA-DR2 [8]. Class II HLA testing increasingly can identify individuals at higher risk for Type I diabetes. For instance, homozygous DQw8 and heterozygous DQw8/DQw2 individuals constitute only 3% of the population, but account for 40% of Type I diabetics of European descent. These genes are in linkage disequilibrium with DR3 and DR4. The reasons for huge differences in the incidence of Type I diabetes among different races and in different countries may be partly genetic and partly environmental, but data and correlation with HLA and other genetic testing is not yet sufficient to answer this question. The approximate incidence of IDDM in children less than 15 years of age ranges from 2 per 100,000 per annum in Japan, to 18 in the USA, and to 28 in Finland [12]. Within Europe, the incidence is higher at more northern latitudes. Within the USA the incidence is higher in whites than in any other racial group, but with unexplained regional variations. Though the associations with class II HLA antigens appear to extend beyond the white racial group, data are as yet insufficient to extrapolate the implications reliably to other racial types. Ironically, the best kidney for a Type I diabetic recipient may belong to a family member who is at highest risk of developing diabetes. This is because inheritance of the same major histocompatibility complexes (from the short arms of the same parental sixth chromosomes) increases not only the likelihood of prolonged graft survival in the kidney recipient, but also the donor’s risk for subsequent diabetes. This “matching effect” reflects the degree of similarity of the immune systems of the two individuals; the risk of diabetes is strongest in a sibling who shares 2 haplotypes with the diabetic proband, intermediate when there is a 1-haplotype match, and least for a 0-haplotype match. This effect is a separate phenomenon from the specific HLA-DR3, HLA-DR4, etc., risks already described, but the two phenomena are unavoidably intertwined. If we take the example of a prospective kidney donor who is the sibling of a white Type I diabetic recipient, and they are a 2-haplotype match (“6-antigen HLA match”), then the fact of their HLA identity ensures they will be concordant for the presence or absence of HLA-DR3 and HLA-DR4. If neither HLA-DR3 nor HLA-DR4 is present, the sibling has a 5.7% chance of being diabetic, which is similar to the unmodified risk for all siblings of a Type I diabetic proband. The increased risk of being a

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2-haplotype match is offset by the absence of HLA-DR3 and HLA-DR4. If either one of these alleles is present (either homozygously or heterozygously) the risk increases to about 11%. And if HLA-DR3 and HLA-DR4 are both present the risk is 19.2%, which as mentioned earlier is a 4-fold increase in risk. At the other extreme, individuals who share no haplotypes with their diabetic sibling, and who have neither HLA-DR3 nor HLA-DR4, have only an approximately 1.5% risk of being diabetic (one quarter of the average risk for siblings of Type I diabetics, and only four times the risk in the general population). It is important to emphasize that these percentage risks describe the cumulative risk of diabetes in siblings, and most siblings who are destined to become diabetic will have been diagnosed before the question of transplantation for the proband arises. Logically, as time passes, those who remain non-diabetic have a steadily diminishing risk. However, the quantification of the rate of decline in this residual incidence is supported by relatively meager information. In one data set, the age of onset of diabetes in 55 sibling pairs (no twins) was within 10 years of each other in 85% of cases. Because 10 years is much shorter than the average duration of diabetes in patients with advanced diabetic nephropathy, most siblings will be beyond the period of highest risk when the call to consider donation arises, though a much younger sibling may not be. For siblings who are still not diabetic when they reach an age that is 10 years older than the proband’s age at diagnosis of diabetes, 85% of their risk has already dissipated. Only 15% of their original 5% risk remains, yielding an overall residual risk of 0.75% of ever developing Type I diabetes. This is the number to start from; it should then be modified to take account of the results of HLA testing and islet cell antibody (ICA) testing, as described above. In summary, though much quantitative information is available, it is a complex issue to assess the likelihood of future diabetes for a prospective donor from a family with Type I diabetes. Risk Factors for Development of Type II Diabetes Type II diabetes, or non-insulin dependent diabetes mellitus (NIDDM), is much more common than Type I. The prevalence has soared in industrialized countries and wherever new affluence has led to dietary changes, sedentary habits and obesity. About 20% of cases occur by age 40, 40% more by age 60, and the remaining 40% thereafter. It is also estimated that almost half of prevalent cases are undiagnosed, and that this is true for all age groups. Although behavioral, dietary and environmental factors are major, there are also strong genetic influences. When both parents have NIDDM, 45% of their children have diabetes by age 65, compared to 9% in the general population; in the same study, onset of diabetes before age 50 in the parents correlated strongly with a similarly young age of onset in their offspring [13]. Other data accumulated over several decades also show that the familial effect is strongest in cases with onset at a younger age, suggesting the combined effects of multiple predisposing genes. Patients diagnosed with Type II diabetes before age 45, compared to those diagnosed later, are twice as likely to have a diabetic parent [14], and their siblings become diabetic at a higher rate and at a younger age (20% by age 50, compared to 17% by age 65) [15]. More recent studies have suggested that certain metabolic abnor-

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malities associated with diabetes may show predominantly maternal or paternal inheritance [16]. These data come from predominantly white populations in Europe and the USA. Other races in the USA have higher rates of NIDDM: the prevalence in men age 50 is 8% for whites, 11% for African-Americans, 14% for Mexican-Americans and highest in native Americans (55% for Pima Indians); in most European and east Asian countries the comparable rates are less than 5% [17]. Research into the pathogenesis of Type II diabetes has created a huge body of knowledge, but as yet incomplete understanding. Although resistance to the peripheral actions of insulin appears to be primary and ubiquitous in this disease, some kind of blunting of insulin secretion or pancreatic beta-cell exhaustion also has to develop before impaired glucose tolerance or frank hyperglycemia appear. Nevertheless, insulin resistance and euglycemic hyperinsulinemia are the best predictors of Type II diabetes when evaluating risk in individuals who are not yet glucose intolerant. The genetic bases for both the insulin resistance and the islet cell dysfunction of Type II diabetes remain elusive, despite rapidly expanding understanding of numerous candidate systems. The complex pathophysiology of NIDDM, as well as its pattern of hereditability, are compatible with the view that the disease in its common form has a polygenic basis. Abnormalities discovered in the insulin receptor gene, the glucokinase gene, mitochondrial DNA, and other genes, so far appear relevant only to small subsets of cases of NIDDM. However there are many promising leads, such as the discovery of a mutant glucokinase gene in half of patients with maturity-onset diabetes of youth (MODY) [18]. Although developments in this field should be expected, at present for NIDDM, unlike Type I diabetes, there is no routine genetic testing available that is relevant to the evaluation of potential kidney donors. A family history of Type II diabetes, strong racial predisposition, obesity, or a history in women of gestational diabetes or of babies weighing more than 9 pounds, should trigger further assessment of the risk of prediabetic abnormalities, as detailed below. A body mass index > 28, in addition to being a liability for future diabetes, may also increase perioperative risk. Potential donors should also be aware of the benefits of exercise, weight loss and lifestyle change in ameliorating the severity and consequences of Type II diabetes, although only a minority of patients can effect these changes. Preliminary reports of a recent study in incipient Type II diabetics indicate that metformin use reduced diabetic risks by 31% compared to placebo control patients, whereas life style change with 30 minutes of daily exercise and weight loss reduced risks by 58%. Testing for Diabetic Risk The change adopted by the American Diabetes Association (ADA) in 1997 to define diabetes in terms of a persistently elevated fasting blood glucose, and to relegate the glucose tolerance test criteria to an optional status, has also impacted the definition of borderline diabetic states [19]. By ADA criteria, diabetic states are now defined in terms of fasting plasma glucose (FPG). FPG is numerically equivalent to fasting serum glucose (FSG), but higher than fasting blood glucose (FBG). An FPG or FSG of 110 mg/dl corresponds to a FBG of approximately 95 mg/dl.

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A person is normal if their FPG is consistently below 110 mg/dl, and is diabetic if it persistently exceeds 126 mg/dl. In between is the range of “impaired fasting glucose” (IFG). A standardized oral glucose tolerance test (oGTT) is optional to help define this categorization. The plasma glucose measured 2 hours after a standardized oral glucose load of 75 grams is influenced somewhat by gastrointestinal as well as pancreatic conditions, but the criteria are that a value < 140 mg/dl confers normal status, and > 200 mg/dl is diabetic. Again, between these two values is a borderline state best referred to as “impaired glucose tolerance” (IGT). As is emphasized in other sections of this book, there is a continuum of risk along which average and increased risk kidney donors fall. Individuals with a normal fasting plasma glucose still face a variable risk – FPG values that fall into the top 25th percentile of the normal range (86–109 mg/dl) predict a cardiovascular risk 40% greater than those in the lowest 25th percentile (20). Uncovering borderline diabetes in this risk group requires at least an oGTT, and most transplant programs obtain a 2-hour oGTT value in all prospective donors. Individuals identified as having a frankly impaired glucose tolerance have a risk of progressing to overt diabetes of 3% per year. Concerns are voiced about “false positive” oGTT results, but how that can be judged is obscure; it may be simpler to say that the rate of conversion to frank diabetes is such that perhaps 4% to 10% of individuals with IGT may not develop frank diabetes in the remainder of their lifetime. It is important to recognize that a positive or borderline oGTT may result from liver disease, hyperthyroidism, glucocorticoid excess, and other hormonal abnormalities. Also, oral contraceptives and various other medications are potentially reversible causes of mild glucose intolerance [2]. Counseling and selecting a kidney donor with diabetic risk is complicated and is also discussed in other sections of this book. Every potential kidney donor has some degree of risk for eventual diabetes and diabetic nephropathy, given the prevalence of both in the United States. For any and all degrees of risk, however, the central questions are whether the donor is truly informed and acting rationally and whether the center – no matter how much care it takes – will be perceived as misleading donors at increased risk who want to proceed. A strong family history of Type II diabetes, or other diabetic risk factors as described above, may be the basis of the decision not to proceed with donation for many donors and/or many centers. Women with a history of gestational diabetes have a risk of becoming diabetic that is of the order of 30% to 50% within 10 years [21]. Also, marked obesity is a strong risk factor, for both diabetes and other health problems. There are several other situations in which donor acceptance should proceed with caution. These include proposed child to parent transplant, where the younger age of the child means that signs of future diabetes may not yet be detectable. Unusual risk is also indicated if the recipient developed renal failure less than 10 years from the diagnosis of diabetes, which implies both a familial risk of nephropathy and rapid progression to renal failure once diabetes has occurred. In practice, counseling and donor selection are based on the above testing procedures and risk considerations [1]. Further tests to define insulin resistance or pancreatic insulin reserve are employed only occasionally. Insulin resistance is common in the general population, and tends to cluster with glucose intolerance, hyperlipidemia and hypertension. The best method of measuring insulin resis-

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tance is the euglycemic insulin clamp test [22]. An abnormal result is associated with an increased risk for Type II diabetes, and for heightened cardiovascular risk. Pancreatic insulin reserve is most useful in assessing the latent phase before overt Type I diabetes, but is also possibly useful in assessing for Type II disease, where beta-cell insufficiency may be demonstrable, as well as insulin resistance. The simplest technique is to measure the insulin surge after a standardized intravenous glucose load: a normal “first phase” of insulin secretion (at 1 minute and 3 minute after injection) has a greater than 98% negative predictive value for developing Type I diabetes within 2 years. Other sensitive biochemical tests are sometimes useful to unmask a diabetic tendency [9]. The laboratory tests most useful in helping define the risk of developing Type I diabetes consist mainly of autoantibody testing and genetic profiling. As already outlined, the presence of islet cell autoantibodies (ICA) in the first degree relative of a Type I diabetic confers a high risk of developing diabetes, with an incidence between 8 and 10% per year (R08). Low titer ICA (< 40 JDF units) is of poorer prognostic value, and testing for other autoantibodies associated with diabetes is of limited utility in most donor evaluations. A possible exception may be the ICA-positive individual in whom risk needs to be further defined. The 50% of ICA-positive individuals who remain non-diabetic after 7 years are in general the ones lacking insulin autoantibodies (IAA) and whose ICA has “restricted” activity (reacting with human and rat islets, but not mouse islets). Also important is that ICA may disappear over time, and that only persistent positivity is predictive of a heightened risk of diabetes; thus one option for an ICA-positive donor candidate is to postpone a decision and undergo repeat testing over a period of time. These autoantibodies also tend to coexist with HLA genetic markers that are predictive of Type I diabetes (see above, section on risk factors for Type I diabetes). In a recent extensive study of siblings of Type I diabetic probands, prevalences of all candidate autoantibodies correlated closely with HLA identity to the proband [23]. The presence of specific HLA-related markers in combination with positive autoantibody testing markedly increased the positive predictive value of the antibody results. However, not all siblings with autoantibodies and genetic markers developed diabetes, and some with low genetic risk and initially low autoantibody levels later did develop the disease. Risk Factors for Development of Diabetic Nephropathy The previous sections deal with the development of diabetes, and the following sections deal with the development of diabetic nephropathy. The risks for developing either of these entities is not affected by living kidney donation. As is also discussed in Chapters 1 and 4, the potentially diabetic donor risks specifically that donation will shorten the time period over which diabetic nephropathy progresses to end-stage renal failure and the need for dialysis. As is the case for the development of diabetes itself, a great deal is known about both the likelihood of developing diabetic nephropathy and the factors which affect its progression, which brings some certainty to this important area of donor counseling. Type I diabetes and Type II diabetes are diseases of radically different etiology. The genetic backgrounds and environmental factors in their pathogenesis are

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entirely different, though their biological consequences and clinical features have much in common. Both can be complicated by serious kidney disease in the form of diabetic nephropathy. However, since a majority of diabetics (at least 50% of type I, and perhaps 70% of type II) escape the development of significant nephropathy throughout their lifetime, factors other than the diabetes itself clearly have a major bearing on whether nephropathy will or will not develop. Determinants of susceptibility to nephropathy are now being discovered, including genetic factors that are distinct from those implicated in the causation of diabetes. Diabetic nephropathy is a clinical syndrome consisting of heavy proteinuria and progressive renal failure, almost always with hypertension, in a patient with longstanding diabetes who typically also has other microvascular complications such as retinopathy. The pathologic correlate of this clinical renal syndrome is diabetic glomerulosclerosis, of which the primary elements are thickening of the glomerular basement membrane, and expansion of the mesangium of the glomerulus. However, the basement membrane thickening tends to parallel the thickening of vascular basement membranes elsewhere in the body, and does not correlate well with the presence or absence of overt kidney disease. In contrast, mesangial expansion is the key element of nephropathy, the clinical severity of which is roughly proportional to the degree of this pathologic change. It consists of excessive accumulation of extracellular mesangial matrix material diffusely throughout the glomeruli, or occasionally localized accumulations within glomeruli known as Kimmelstein-Wilson lesions. Thus, the diabetic basement membrane changes are distinct from the diabetic mesangial changes. In normals too, the composition of mesangial matrix, though similar to that of basement membranes, differs in the type of proteoglycan present, and in the proportion of different types of collagen. The prime factor causing alteration of both of these types of extracellular tissue in diabetics is clearly chronic hyperglycemia. At least three principal biochemical mechanisms have now been identified by which high glucose levels can cause these pathologic changes: activation of protein kinase C, increased formation of advanced glycation end products (AGE’s), and increased activity of aldose reductase (causing polyol formation) [24]. The aldose reductase pathway may be of particular importance in the initiation of glomerular pathology [25]. Also AGE’s appear to be an independent risk factor for diabetic nephropathy [26], and there is increasing understanding of their interaction with receptors and their adverse effects on tissues such as endothelium and mesangium [27]. A fourth mechanism, a hyperglycemia-induced increase in reactive oxygen species, has been postulated as the underlying trigger for each of these other pathways [28]. All four mechanisms have been studied in diabetic animal models, and clinical trials of some inhibitors of these processes are discussed later. Although inadequately controlled hyperglycemia is a fundamental risk factor for the development of diabetic nephropathy, its expression is dependent also on hemodynamic factors that have been widely studied. The phenomenon of hyperfiltration, which is an increase in glomerular filtration rate (GFR) above the normal range, is frequently seen early after the onset of diabetes, long before evidence of structural changes. Kidney size is also increased. Associated with this is the feature that has become known as microalbuminuria (increase in the urinary excretion rate of albumin, measured by antibody-based assays, but below the

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detection threshold of simple chemical assays). In individuals where these abnormalities continue despite treatment to control hyperglycemia, the subsequent risk of developing clinically-overt nephropathy is increased [29]. Underlying these phenomena is an increase in capillary blood pressure within the glomeruli, which is probably the factor directly causing glomerular stress and the increased risk of glomerular deterioration [30]. Although increased glomerular pressure may be exacerbated by systemic hypertension, the fundamental derangement can occur in the absence of systemic hypertension, and appears to involve vasodilation at the afferent arteriole, thereby moving intraglomerular pressure closer to systemic arterial pressure. Angiotensin converting enzyme (ACE) inhibitors reduce glomerular pressure by selectively reducing constriction of the efferent arteriole; however, their beneficial effect in diabetic nephropathy may not only be by this mechanism, but also by a direct action within the glomerulus, perhaps by normalizing mesangial contractility or reducing mesangial damage [31]. Various mechanisms have been proposed to account for renal vasodilation in the diabetic kidney. Among these there has been recent interest in the possibility that one primary abnormality may be increased reabsorption of fluid at the proximal tubule, giving rise to reduced distal delivery of tubular fluid, thereby activating the tubulo-glomerular (TG) feedback reflex [32]. TG feedback regulates each nephron individually, and responds to reduced delivery of salt to the distal tubule by inducing vasodilation and so increasing GFR until distal salt delivery is restored. When growth of the proximal tubular cell mass is prevented by using an inhibitor of the enzyme ornithine decarboxylase to block polyamine synthesis, diabetic rats have less increase in proximal reabsorption, therefore preserved distal delivery of salt, thus less effect on TG feedback, so less hyperfiltration, and less renal hypertrophy [33]. The use of such enzyme inhibitors to possibly benefit human diabetic nephropathy has not yet been attempted. It is of note also that ACE inhibitors may have an additional beneficial action in this area by blocking the tubular actions of angiotensin II, which include enhancement of proximal reabsorption and up-regulation of TG feedback [34]. Renal vasodilation is also increased by a high protein intake, which is why dietary protein restriction is another element in combating diabetic nephropathy. Genetic predisposition to the development of diabetic nephropathy may reflect inheritable traits that affect the above-mentioned mechanisms, or others mechanisms, probably many as yet unknown. Loss of the proteoglycan heparan sulfate from glomerular basement membranes has been implicated in the “Steno Hypothesis” as a factor in the development of diabetic nephropathy [35], and two cohorts of diabetics have shown an association between a variant allele of the heparan sulfate core protein and nephropathy [36]. Other candidate genes have included deletion/insertion polymorphism of the ACE gene, where association of increased risk of nephropathy with certain alleles was reported twice, but not confirmed in three later studies [37]. Reports implicating other genes, including those for insulin, aldose reductase, angiotensin receptors, some HLA types, etc., have not been confirmed on follow-up studies [38]. Racial background affects the risk of developing nephropathy, with higher rates in diabetic Mexican-Americans [39] and diabetic Afro-Americans [40] compared to diabetic whites in the USA, and in Asian Indians compared to Europeans in the United Kingdom [41]. Also, a family history of diabetic

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nephropathy is statistically an independent risk factor for developing nephropathy. Clear evidence of familial clustering of nephropathy has been demonstrated in Type I diabetics: in families whose diabetic probands did not have nephropathy, only 17% of diabetic siblings had nephropathy; in families where the probands had had kidney transplants for diabetic nephropathy, 83% of diabetic siblings had nephropathy [42]. Parent-offspring aggregation of nephropathy was seen also in the DCCT trial, in Type I and Type II diabetics, mainly of European descent [38]. In Pima Indians with Type II diabetes, nephropathy occurs in 46% of diabetics if both parents have proteinuria, 23% if one parent has proteinuria, and 14% if neither parent has proteinuria [43]. Increased microalbuminuria in non-diabetic first degree relatives has been found consistently in the families of proteinuric Type II diabetics, but not in the families of normoalbuminuric Type II diabetics [44]. In contrast, for proteinuric Type I diabetics, familial clustering of microalbuminuria has not been found in nondiabetic relatives [45], though of course it does occur in diabetic relatives, as noted above. Also, evidence that persistent microalbuminuria is a strong risk factor predicting later overt nephropathy applies really only to Type I diabetes [29]. In Type II diabetes, only 30% of microalbuminuric patients have changes typical of diabetic glomerulosclerosis on renal biopsy [46], and microalbuminuria is prognostic more of cardiovascular risk than renal disease [47]. These findings are difficult to reconcile, and the differences between Type I and Type II diabetes are currently unexplained. The familial predisposition to diabetic nephropathy may be linked to the genetics of essential hypertension [48]. A family tendency to hypertension is a risk factor for nephropathy in families with Type I [49] and Type II diabetes [50]. Increased Na/Li countertransport in red cells, a marker for essential hypertension, has been found in three studies to be associated with an increased risk of nephropathy in diabetics [51]. There appears also to be an increased risk of other cardiovascular events in the parents of diabetics with nephropathy as compared to the parents of diabetics without nephropathy [52]. Similar results were found in a more recent study of Type I diabetes, where the parents of proteinuric diabetics, when compared to the parents of otherwise matched non-albuminuric diabetics, died younger and had more hypertension, hyperlipidemia and insulin resistance [53]. Insulin resistance in non-nephropathic subjects is associated with hypertension, increased cardiovascular risk and increased Na/Li countertransport; it has been suggested also as a risk factor for diabetic nephropathy [54]. Thus in advising potential kidney donors, those donating to a diabetic family member are at greater than average risk of developing nephropathy if they get diabetes; this simply is because they already have a familial history of nephropathy. However, other aspects of family history, including the prevalence of hypertension or cardiovascular disease, should also be taken into account. As noted above, many treatable factors, particularly hyperglycemia and hypertension, are also implicated as risks for the development or progression of diabetic nephropathy; the prospective donor should therefore be made aware of the treatments and interventions that can mitigate the risk of serious renal damage, as detailed later.

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Pace of Development of Diabetic Nephropathy Knowledge of the rate of progression of diabetic nephropathy is crucial for counseling living kidney donors, because that is the area of risk for donors that can be assigned to kidney donation itself. Diabetic nephropathy becomes clinically manifest only after a long latent period during which glomerular pathologic changes are silently evolving, with or without subclinical evidence of disease on careful testing. Five stages of the natural history of diabetic kidney involvement have been described by Mogensen [55]: Stage 1 is seen early in the course of diabetes, consisting of hyperfiltration, increased renal size and microalbuminuria. An increase in GFR of 20%–40% above age-matched controls is seen in both children and adults with new onset Type I diabetes [56], with GFR above the upper limit of normal in 25% of cases. Kidney size is increased by the order of 20% [57]. Those with the worst hyperfiltration (> 150 ml/min) have an increased risk of later developing overt nephropathy [58]. Hyperfiltration and microalbuminuria are seen also in newly diagnosed Type II diabetics, though less consistently [59]. Stage 2 is defined as a normoalbuminuric phase, and may persist indefinitely. Typical Stage 2 patients have had some reduction in hyperfiltration following the commencement of insulin therapy, with resolution of initial microalbuminuria, though it often takes weeks for the albumin excretion rate (AER) to fall to the normal range. AER measured by sensitive radioimmunoassay in healthy normal subjects ranges from 1.5 to 20 mcg/min. Microalbuminuria is defined as the range from 20 to 200 mcg/min. Many patients who normalize their AER with good glucose control will have temporary elevations of AER when intercurrent illnesses or other factors cause a lapse in glucose control. Those who fail to normalize their AER, or who relapse easily, or who have increased AER with exercise, appear to be at increased risk of progressing to later stages of nephropathy. Stage 3 is the stage of incipient diabetic nephropathy. These patients have microalbuminuria (AER 20 to 200 mcg/min), usually preserved GFR, but often considerable histologic evidence of diabetic nephropathy if a renal biopsy is done. About 80% of patients with persistent microalbuminuria, if not successfully treated for this feature, will progress to overt nephropathy [60]. Hyperfiltration may still be detectable, though it is less prevalent in patients at the upper end of the range of microalbuminuria, suggesting these patients have begun a decline in GFR due to structural glomerular damage. Stage 4 is overt diabetic nephropathy, of which the hallmark is fixed proteinuria of more than 500 mg/day. Since it is normal to have up to 150 mg/day of non-albumin urinary protein, 500 mg/day of total urine protein is commensurate with or exceeds the upper limit of microalbuminuria (200 mcg/min is approximately 300 mg/day). Hypertension becomes prevalent early in this stage, and proteinuria usually increases over many months into the nephrotic range (> 3,500 mg/day in a normal sized adult). A progressive loss of GFR ensues, and in the absence of intervention averages a loss of 1 ml of GFR per month in many studies. This rate can be slowed considerably by appropriate interventions, but patients with heavier proteinuria decline more quickly, in one study averaging 1.1 ml/month despite renoprotective antihypertensive therapy [61]. As renal failure

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progresses, anemia and other uremic complications appear, and there is a mounting prevalence of cardiovascular complications. Stage 5 is end-stage renal failure (ESRD), defined as the point at which dialysis or transplantation is necessary. Although the rate of cardiovascular, neuropathic, infectious and ocular complications is high at this stage, many diabetic ESRD patients cope well for many years with dialysis, or are largely rehabilitated by successful transplantation. The time course of these events has been analyzed repeatedly. Twenty five years ago, before the widespread use of rigorously intensive insulin therapy or the availability of modern antihypertensive drugs, Type I diabetics who eventually developed nephropathy took on average 14 years to reach the stage of overt nephropathy (fixed proteinuria of > 500 mg/day). Thereafter their decline was rapid, reaching ESRD in a further 4 years on average in some studies. It is important to note that the 14 year latent period was an average of a fairly tight range, the great majority being between 10 and 20 years. Those Type I diabetics who had not developed overt proteinuria by 20 years after the onset of their diabetes were likely to be in the majority who never develop clinically significant nephropathy. The effect of modern diabetic management practice has been to reduce the incidence of nephropathy, and lengthen the interval between overt proteinuria and ESRD [62–64]; with the further passage of time it will become clear whether the duration of the latent period may be longer now in some cases, or whether the increasing proportion of patients who reach 20 years of diabetes without proteinuria can assume that their lifetime risk of nephropathy has diminished [65]. A recent review concluded that macroalbuminuria (> 200 µgm/min) could be expected to occur in 20 to 40 percent of diabetics after a period of 15 to 20 years after the onset of Type II diabetes, at which point the average reduction in ceatinine clearance would be 10–12 cc/minute/year, with wide variation [66]. Type II diabetes, being of more insidious onset, may not be recognized for several years, or conversely may be mild for a long time and then worsen; consequently the latent period between the diagnosis of diabetes and the appearance of overt proteinuric nephropathy appears to be more variable, ranging from 0 to 35 years. The rapidly increasing incidence of Type II diabetes in the USA, and the persistent problem in diagnosing cases and bringing them the benefits of modern management, may account in part for the apparent lack of improvement in the prevalence or tempo of diabetic nephropathy in NIDDM. The Effect of Nephrectomy on Progression Uninephrectomy, such as occurs when one kidney is removed for organ donation, results in compensatory hypertrophy of the remaining kidney. This hypertrophy is associated with increased GFR per remaining nephron (hyperfiltration) and increased renal plasma flow (RPF). Total renal function increases to about 80% of the prenephrectomy value. Increased glomerular capillary pressure can be measured in animal models, and inferred in humans when the filtration fraction rises (GFR/RPF). These are the same hemodynamic factors, noted above, that appear to exacerbate the development of diabetic nephropathy. The question there-

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fore arises whether a person who develops diabetes will do worse if he or she has only one kidney rather than two kidneys. Much of the investigation of this question has been done in experimental animal models. Non-diabetic rats that have 5/6 of their renal mass surgically removed develop hyperfiltration, hypertrophy and progressive glomerular sclerosis with renal failure of the remnant kidney [67]. It turns out, however, that rodents are much more susceptible to remnant kidney failure and glomerulosclerosis than are other classes of mammals. Nevertheless, in rats with streptozotocin-induced diabetes, uninephrectomy accelerated the development of diabetic changes in the remaining kidney, compared to the rate of progression in rats with two kidneys [68]. The histology showed accelerated mesangial expansion, the hallmark of diabetic nephropathy, not just sclerosis; of note, glomerular basement membrane thickening, a feature of diabetes that does not correlate with the clinical severity of the renal disease, was not accelerated by nephrectomy. In diabetic dogs the same effect of nephrectomy occurs but is less marked [69, 70]. Diabetic rats with hypertension secondary to unilateral renal artery stenosis (unilateral Goldblatt model) developed diabetic nephropathy changes only in the kidney exposed to high blood pressure, demonstrating the effect of high blood pressure on the rate of diabetic damage in the rat kidney [71]. Information from experience with patients suggests that the risk from nephrectomy is less in humans. Long term follow-up studies after uninephrectomy in non-diabetics are reviewed in Chapter 5. One of these series documented marked hyperfiltration in most cases, but no microalbuminuria [72], whereas another found microalbuminuria in about one quarter of cases [73]. Increased prevalences of mild proteinuria and elevated blood pressure are suggested by some studies, but not others, and some cases of glomerulosclerosis in the remaining kidney are described. Diabetic recipients of transplanted kidneys might be considered as a model of single-kidney diabetes, and do appear to have recurrence of nephropathy frequently. However they are already a subgroup preselected as destined to develop nephropathy, and the apparently increased tempo of recurrence of diabetic changes in transplanted kidneys could possibly have more to do with the more advanced state of the diabetic milieu than with the presence of only one kidney. The deterioration in renal transplant function that invites diagnostic biopsy also almost invariably reflects chronic rejection and drug toxicity as well as diabetic nephropathy. Otherwise data on diabetics with a single native kidney are limited. The series of Schmitz et al. of patients with a single kidney includes 3 diabetics. Two had congenital unilateral agenesis, and were studied at age 30 and age 28, at which time they had been diabetic for 25 years and 8 years respectively. The third, studied at age 52, had been diabetic for 34 years and was 18 years post uninephrectomy for hydronephrosis. All three were found to have normal blood pressure, normal GFR, and no microalbuminuria [72]. Fattor et al. found three cases of uninephrectomy where the resected kidney had histologic evidence of diabetic nephropathy. The patients had had NIDDM for 16, 2 and 33 years respectively at the time of nephrectomy, and thereafter were followed for another 4, 15 and 6 years respectively. Two subsequently developed ESRD requiring dialysis, one apparently from diabetic nephropathy and one from renal artery stenosis. The rate of renal decline (plotted as the reciprocal of serum creatinine against time) in the period after

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nephrectomy was not demonstrably different to that preceding nephrectomy; however, the number of pre-nephrectomy creatinine measurements was barely sufficient for analysis in 2 of the 3 cases [74]. Sampson and Drury describe 6 patients who developed overt diabetic nephropathy in a single kidney (5 after uninephrectomy and one with congenital unilateral renal aplasia). Since they knew of no other single-kidney patient in their large diabetic clinic, and the prevalence of nephropathy is otherwise low in their diabetic clinic population, they conclude that the uninephrectomy patients appear to have developed nephropathy at a much increased rate [75]. Lastly, Silveiro et al. described 20 single-kidney Type II diabetics (SKD), and compared them to 17 single-kidney non-diabetics (SKN) and 184 two-kidney Type II diabetics. Single kidney patients were included only if they were > 5 yrs post nephrectomy. The prevalence of microalbuminuria was twice as high in the SKD group as in either of the other two groups. GFR was actually higher in SKD than SKN patients. The prevalence of overt proteinuria was about 30% in the single-kidney diabetic (SKD) group and 23% in the two-kidney diabetic group; this difference does not reach statistical significance. Based only on the higher prevalence of microalbuminuria, a marker usually associated with an increased risk of progressive nephropathy, the authors suggest that uninephrectomy may indeed cause an increased risk of renal failure [76]. In aggregate these data are inconclusive, and the numbers of patients with a solitary native kidney and diabetes is too small. To summarize, the first report found no cases of nephropathy or of markers associated with subsequent nephropathy. The second found no evidence of an increased rate of renal decline in patients with known diabetic nephropathy. Only the third paper has data supporting an unexpectedly high prevalence of diabetic nephropathy in single-kidney patients, but there the control rate for comparison is based on assumptions. The last paper finds a modestly increased rate of predictive markers, but no worsening of GFR and no data on outcomes. As discussed in Chapter 4, the central question is whether glomerular hyperfiltration injury can be controlled with medication, or if it affects two-kidney disease at such an early stage that it will affect both uninephrectomized donors and individuals with two kidneys aproximally equally. Thus, though an increased rate of progression of nephropathy after uninephrectomy cannot be excluded by these data, a more concrete concern might be simply that single-kidney status will confer a decreased renal reserve once nephropathy is initiated. Uninephrectomy would at the least place the single-kidney individual in the position of having almost 20% less renal function and therefore needing dialysis 20% sooner (see Chapter 4) than would have been the case with two kidneys. It seems far less likely that prior nephrectomy could precipitate ESRD in diabetic kidney donors who would otherwise have been destined to avoid diabetic nephropathy altogether. Available Treatments and Factors that Modify Progression of Diabetic Nephropathy Glycemic control is a major determinant of the progression of nephropathy in both Type I and Type II diabetics [77]. In Type I, the US Diabetes Control and Complications Trial (DCCT) clearly demonstrated that both microalbuminuria

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and overt nephropathy appeared at a reduced rate in patients receiving intensified glycemic therapy [78]. In Type II diabetes, the United Kingdom Prospective Diabetes Study (UKPDS) has shown a 25% risk reduction for microvascular complications with more intensive therapy (insulin or sulfonylurea), though the number of patients developing renal failure was too small to analyze [79]. In a study of Type II diabetics in Japan, improved glycemic control reduced the rate of development of nephropathy [80]. Recent studies suggest that current management of diabetes and diabetic nephropathy may reduce the risk of end stage renal disease and therefore reduced the risk of kidney donation for some donors [62–64]. One in particular suggested that even after 30 years of Type II diabetes, the risk of chronic renal failure was 9.3% [62]. These therapies chiefly involve control of blood pressure and lipids, specific inhibition of the rennin-angiotensin system, and glycemic control. Obviously potential donors who could be expected to be poorly compliant with these treatment regimens would not benefit from them. The effectiveness of intensive glycemic therapy at different stages of diabetic nephropathy, however, is not completely defined. Though the benefit for Stage 2 nephropathy was clear, neither the DCCT data nor a UK study of Type I diabetics could demonstrate renal benefit in the subset of patients in whom persistent microalbuminuria was already established (Stage 3) before intensified therapy was instituted [78, 81]. In contrast, extensive Scandinavian data indicate that progression of renal disease can be retarded by better glycemic control at this stage of nephropathy in Type I diabetics [83]. Similarly an Australian study showed that the rate of renal deterioration in patients with established microalbuminuria was worse in those with poorer glycemic control [83]. For stage 4 nephropathy, where the effectiveness of antihypertensive therapy is a dominant determinant of progression, the general opinion in the past had been that intensified glycemic control was of little value for renal prognosis. However, at least in patients where effective antihypertensive management has been achieved, good data are now available to suggest that improved glucose control confers additional benefit in the rate of progression to renal failure even at this late stage of disease [84]. The benefits of the intensified use of insulin or oral hypoglycemic medications have to be weighed against the difficulties and risks involved. The UKPDS data in Type II diabetics reveal not only an approximate doubling of the rate of major hypoglycemic episodes, but also more weight gain in the patients on intensified therapy [79]. The feasibility and desirability of attempting rigorous glucose control has to be assessed on a case by case basis; it may not be the highest priority in the advanced stages of nephropathy. For Type II diabetics, as mentioned previously, the benefits of weight loss and daily exercise include reduced diabetic complications and better glycemic control. Thus such measures might be expected also to help retard the development of nephropathy, though this has not yet been adequately studied. Antihypertensive therapy is of cardinal importance in the management of progressive diabetic nephropathy. The original Scandinavian studies in the 1970’s [85] contained lessons that were subsequently overlooked and had to be relearned. Prime among these is that the choice of antihypertensive agents is of less importance than the achievement of truly normalized blood pressure (BP). For patients with overt (Stage 4) nephropathy, a better than three-fold improvement in the time for progression to end stage renal failure was achieved in those studies using drugs that

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included hydralazine, beta-blockers and loop diuretics. Though not the preferred agents now, those medications were successful because the average BP’s were brought down to the range of 128/75. A decade later the point was still being missed, with the opinion recorded that a BP of 135/90 in a young adult with Type I diabetes would not be treated by most clinicians [86]. Happily in 1997, Joint National Committee guidelines (JNC VI) introduced a target BP of 130/85 or less for all diabetics (Type I and Type II), and 125/75 or less for those with proteinuria greater than 1 gram per day (87). This target is not always easily achieved in diabetics with advanced disease, because of their high prevalence of autonomic neuropathy, nephrotic syndrome, heart disease and drug intolerance. Though ACE inhibitors, as detailed below, are now the preferred agents in this setting, the clinician should be encouraged to use whatever antihypertensive medications work in the individual case, and to be enthusiastic about the benefit of blood pressure control even when ACE inhibitors cannot be used because of hyperkalemia or other reasons [88]. A special role for ACE inhibitors has been established in at least two areas of diabetic management. First, in patients with overt proteinuria, ACE inhibitors have been shown repeatedly to be the most renoprotective class of antihypertensive drugs. Not only is the evidence unequivocal that ACE inhibition retards progression of nephropathy and reduces the number of patients reaching end stage renal failure, but it is strongly suggested that their effectiveness is more than can be attributed solely to the reduction achieved in systemic blood pressure [89]. Nevertheless, it remains imperative also to fully control hypertension; a study comparing two dosage levels of ramipril found that the higher dose group achieved good blood pressure control and progressive reduction of proteinuria, whereas the lower dose group, whose mean arterial pressure was 7 mmHg higher, had continued worsening of proteinuria [90]. Second, ACE inhibitors have been shown in numerous studies to have value in the earlier stages of nephropathy, even when blood pressure is normal. In normotensive Type I diabetics with microalbuminuria, ACE inhibition reduces the rate of increase of microalbuminuria [91, 92], and in an 8-year trial captopril prevented or greatly postponed progression to overt nephropathy [93]. In Type II diabetics with microalbuminuria, ACE inhibition reduced albuminuria in hypertensive patients [94], and at least stabilized albuminuria in normotensive subjects [95]. In diabetic patients with a normal albumin excretion rate (AER), however, there is still no hard evidence that ACE inhibitors have a renoprotective effect; studies in Type I diabetes have so far been unable to demonstrate a difference [96], and there appear as yet to be no data in Type II diabetes. Therefore the use of ACE inhibitors for renal protection in diabetics with microalbuminuria and/or hypertension can now be recommended, but their use in normotensive normoalbuminuric diabetics must still be regarded as speculative or experimental. Calcium channel blockers (CCB’s) are also valuable drugs for blood pressure control in diabetes, and their effect on renal parameters has been widely studied. Nifedipine use in the early stages of nephropathy has yielded varying results. In Type I diabetics with microalbuminuria and normal blood pressure, the rate of progression to overt nephropathy appeared to be improved by nifedipine in one study [97], but not in another [98]. In Type II diabetics, also in Stage 3 nephropathy, comparison studies with ACE inhibitors demonstrate that nifedipine has been

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ineffective in modulating microalbuminuria [94]. Some studies in Type II diabetics comparing ACE inhibitors to some members of the dihydropyridine class of CCB’s (nisoldipine, amlodipine) have shown a significantly greater number of adverse cardiovascular events in the CCB-treated group [99]. Verapamil and diltiazem have been studied in Type II diabetics with Stage 4 nephropathy, and may have advantages over nifedipine and other dihydropyridine CCB’s. In a study that both compared and combined the use of verapamil and an ACE inhibitor, the combination group had the best results both in reducing proteinuria and in slowing decline of GFR [100]. Preliminary data on angiotensin receptor blockers (ARB’s) suggest they share many of the renoprotective effects of ACE inhibitors. Dietary and other lifestyle changes are important in minimizing the impact of diabetic nephropathy. For the achievement of good glycemic control, the necessity for adherence to a diabetic diet is fundamental. Glycemic control, glucose intolerance and microvascular risk can also be improved in the NIDDM patient by exercise and weight loss, as already discussed. Because excessive intake of protein can exacerbate glomerular hyperfiltration, dietary protein restriction has been extensively evaluated in progressive renal disease and in diabetic nephropathy in particular. Analysis of all available data suggests that a restriction of protein intake to between 0.5 and 0.85 gm/Kg/day results in significant amelioration of albuminuria [101]. However, the benefit is minor compared to some other interventions, and concerns about the feasibility of complying with the complexities of a protein-restricted diabetic diet, together with the risk of protein malnutrition, may make it more reasonable to advocate more modest goals, such as simply avoiding excessive protein intake. Hyperlipemia is also an independent risk factor promoting diabetic renal damage, and dietary fat restriction and lipid lowering drugs may benefit the kidneys as well as the vasculature in at-risk individuals [102]. There is unequivocal evidence that cigarette smoking hastens the onset and progression of nephropathy in both Type I and Type II diabetes, and there is even evidence of adverse glomerular effects in non-diabetic renal diseases; cessation of smoking lessens the rate of progression of renal damage [103], but sometimes it can be very difficult for the nicotine-addicted patient to achieve this goal. Pharmacological intervention directed at some of the biochemical pathways involved in the pathogenesis of tissue damage in diabetics has been evaluated increasingly in recent years. In tissues that can take up glucose without the action of insulin, such as retina, peripheral nerves and glomeruli, aldose reductase converts excess glucose via the polyol pathway to sorbitol, apparently contributing to the tissue damage of diabetes. Aldose reductase inhibitors oppose this effect, and can delay and reduce microalbuminuria in experimental animals, but the effects are not long-lasting. Although they can help neuropathy, they have been disappointing in their effects on renal disease in clinical trials [25]. The formation of advanced glycosylation end-products (AGE’s), which are implicated in damaging glomeruli in diabetes, can be inhibited by aminoguanidine. Clinical trials of this and other agents have not yet demonstrated a practical role in the prevention or amelioration of diabetic nephropathy [24]. Nevertheless, the mechanisms of diabetic tissue damage, as described in the previous section on risk factors for diabetic nephropathy, are being intensively studied, and clinical success with inhibitors of some of these pathways should be expected in the future [104].

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Risks and Benefits of Dialysis Versus Transplantation on Diabetics and Diabetic Complications Evaluation of the relative merits of hemodialysis, peritoneal dialysis, and kidney transplantation for diabetic patients by analysis of outcomes is severely hampered by marked selection biases. For instance, younger patients with less initial comorbidity are more likely to be transplanted than older patients with established cardiac and vascular disease. Although it is possible only to partially correct such statistical information for inequalities between treatment groups, and given that no truly randomized prospective comparison of treatment modalities has been done, it is still clear from several studies that younger diabetic patients have better survival with kidney transplantation than with any form of dialysis [105, 106]. Kidney transplantation for diabetics now has a one-year patient survival rate of 93–95% [3, 4]. Graft survival in diabetics at 5 years is 70% with a live related donor, and 60% with a cadaver donor; patient survival averages 72% at 5 years and in most analyses is up to 5% better with a live-related kidney than with a cadaver kidney [107]. The 5 year survival rate for truly matched diabetic patients of similar age maintained on dialysis is unknown, but is believed to be markedly inferior. On the basis of such data, kidney transplantation is usually advocated for diabetics up to the age of 60 unless their cardiovascular status precludes major surgery. However, principally because of donor shortages, only 10% of diabetics with ESRD receive a kidney transplant, the remainder being maintained with hemodialysis (approximately 80%) or peritoneal dialysis (approximately 10%). Though most transplant databases do not distinguish between nephropathy from Type I and Type II diabetes, it is assumed that the majority of those transplanted, especially the younger ones, are Type I diabetics. At the University of Minnesota between 1984 and 1995, 90% of kidney transplants done on diabetic recipients were on Type I patients, and 93% of these Type I patients were under the age of 50 [108]. The patient survival of Type I diabetics was 92% at 1 year and 80% at 5 years after transplantation. The best long term data comparing dialysis and kidney transplantation come from a German study, where 46 Type I diabetic kidney transplant recipients over a 20 year period were matched for age, sex, diabetes duration and dialysis duration with 46 contemporaneous Type I patients who were accepted for transplant but never received one. Patient survival at 5 years and 10 years was 80% and 74% respectively for transplanted patients, significantly better compared to 62% and 32% for dialyzed patients [109]. These data confirm why the benefit of transplantation for younger Type I recipients has not been in doubt. Type II diabetics have been considered as at higher risk for a poorer outcome from kidney transplantation than Type I diabetics. There are still life-style reasons to seek transplantation, but prospective living kidney donors would need to know whether their intended recipient is truly likely to benefit medically from the gift of their kidney. In the Minnesota report there were 90 Type II diabetics, aged 44 to 72 years (average age 56.4); they can be compared to 340 non-diabetics over age 50 transplanted in the same period. The patient survival for the Type II diabetics at 1 year and 5 years was 80% and 57% respectively, compared to 90% and 68% for the non-diabetics over age 50. These survival rates for Type II diabetics, though inferior to the rates in non-diabetics, are better than was previously

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believed. Other series that have separated out Type II recipients have reported comparable [110] or lower survival rates [111]. For Type II diabetics on hemodialysis, comparable 5 year survival rates are 35% for patients aged 55 to 65 [112], and 24% for those aged 60 to 69 [113]. Selection bias is always a problem in this area. In these comparisons, even “control” patients who are waitlisted for transplantation but have not yet been transplanted may have been bypassed when cadaver kidneys come available for health reasons. Patients selected for transplant are healthier than those not selected, so the dialysis control group should be expected to do worse on average. However the survival difference between Type II diabetic and non-diabetic kidney transplant recipients appears less than that between diabetic and non-diabetic dialysis patients in the older age groups, again suggesting a benefit from kidney transplantation for older Type II diabetics. Diabetic kidney transplant recipients have a higher mortality rate, but not a higher organ rejection rate, than non-diabetics, so they are more likely to have a functioning graft at the time of death. Myocardial infarction is highly prevalent in both the dialysis and transplant settings, and is by far the most common serious perioperative risk at the time of transplant surgery. Thorough cardiological evaluation is mandatory in all diabetics before they can be considered as transplant recipients. Cardiac and vascular disease remains the leading causes of mortality, and diabetic complications continue to worsen after transplant, just as on dialysis. It has been suggested that the rates of gangrene and amputation may be higher in transplant recipients than those maintained on dialysis, but there are no recent data to support this notion. However, the presence of coronary or peripheral vascular insufficiency or a history of stroke are major risk factors for a reduced survival after transplantation. In one series these factors reduced patient survival rates at 1 year and 5 years from 88% and 59% on average to 40% and 20% respectively in this subgroup [11]. The need for vascular access and peripheral vascular disease in a significant number of diabetic hemodialysis patients are a frequent portals of entry for septicemia. Peritoneal catheters are similarly portals for serious infectious problems in diabetics. Diabetic patients with kidney transplants, though they do not have repeatedly needled vascular access sites or peritoneal catheters as a source of infectious risk, do have infections related to anti-rejection medicines, and septicemia remains a serious problem especially in older persons. A case has been made for the less aggressive use of immunosuppression in older diabetic transplant recipients [108]. Progressive retinopathy, peripheral neuropathy, and autonomic dysfunction including orthostatic hypotension and gastroparesis, remain a problem after kidney transplantation, as before with dialysis. The problem of intraocular bleeding is believed to be worse in diabetics maintained on hemodialysis because of the platelet defect of chronic uremia and the effects of rapid fluid shifts and repeated heparinization that are needed at each treatment. As discussed in chapter 2, quality of life and degree of rehabilitation are generally superior after transplantation for patients with all ESRD diagnoses [115]. The functional status on dialysis is much worse for diabetics than for non-diabetics. Twenty years ago a US-wide study of hemodialysis patients found that 77% of diabetics were incapable of physical activity beyond caring for themselves, compared to 40% of non-diabetics [116]. A similar profile has been confirmed more recently in a multicenter study [117]. Transplant candidates were not con-

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sidered separately in these studies, which limits their value for transplant counseling. The number of diabetics on dialysis continues to grow rapidly, and the ESRD population has continued to age. However, despite an increasing prevalence of comorbid conditions in diabetic ESRD patients, their overall mortality rate is improving. The one-year survival rates for all ESRD secondary to diabetes rose from 65% in 1980 to 71% in 1993, and may be higher now. In the short run, chronic dialysis is not a “death sentence” for most diabetics. Nevertheless, despite selection biases, the data continue to suggest that unless a diabetic ESRD patient has active problems with coronary, peripheral or cerebro-vascular disease, their expectation for survival and quality of life is better with kidney transplantation than dialysis. Advantages and Disadvantages of the Alternative of Kidney-Pancreas Transplantation Pancreas transplantation is an option mainly for Type I diabetics, where the primary lesion is pancreatic beta-cell failure. Nevertheless, defective insulin secretion is a feature also of Type II diabetes, and several Type II diabetics have undergone pancreas or islet cell transplant, though with mixed results [108]. Combined kidneypancreas transplantation is a more extensive operation that should be thought of as an alternative to kidney transplantion rather than as an alternative to dialysis. The combined procedure should be considered for many diabetic candidates, as the majority of kidney transplantation in diabetics is done in Type I diabetics, while the great majority of dialyzed diabetics are now Type II. Also as individuals have to be fit for major surgery, many Type I diabetics can usually be considered for both transplant options, though patients with more cardiovascular disease may be considered fit only for kidney transplant alone. Solitary pancreas transplantion is now widely available and well established [118]. Technical surgical issues have been refined, immunosuppression methods have evolved, and surgical complication rates are acceptable. Though islet-cell transplants will probably eventually replace pancreas transplantation for a majority of diabetics who have not yet developed renal failure, most pancreas transplantation is being done simultaneously with or at some time after kidney transplantation. Over 1,000 cases recently reported from a single center (the University of Minnesota) comprised 498 simultaneous pancreas-kidney transplants (SPK), 404 pancreas-after-kidney transplants (PAK), and 291 pancreas transplants alone (PTA) [119]. Since 1994 in the Minnesota experience, SPK transplants have achieved 1-year survival rates for patient, pancreas and kidney of 92%, 79% and 88% respectively; the corresponding 5-year survival rates are 88%, 73% and 81%. Thus the patient survival is the same at one year and actually better at 5 years for SPK transplant than for kidney transplantation alone (KTA) in Type I diabetics at the same institution (108). However, in this series the KTA data may be unusual in that the 4 year patient survival was worse for living donor than cadaver donor kidneys, suggesting a cluster of unfortunate outcomes that would make the aggregate KTA results less favorable than would usually be expected. Worldwide the efficacy of SPK have been established, one year patient

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survival being better than 90%, with 80% functioning kidneys and 70% no longer requiring insulin [120]. Just as the most unassailable benefit of kidney transplantation is freedom from dialysis, the most clear cut benefit of pancreatic transplantation is freedom from insulin. However, a functioning pancreas provides not only freedom from the otherwise unrelenting need for balancing insulin injections against diet and exercise, but also the possibility of halting the progression or even reversing some diabetic complications. Unfortunately, such benefits are slow to appear [121]. Retinopathy seems to progress at the same rate for two years post transplant; after that there is an increasing benefit in patients with a functioning pancreas compared to otherwise comparable kidney transplant recipients without a functioning pancreas, and usually after 3 years there is no more evidence of progression of retinopathy. Neuropathy, which also is very prevalent at the time of SPK transplant, similarly shows improvement between 1 and 4 years after restoration of euglycemia, though patients with preexisting severe autonomic dysfunction have a higher death rate post transplant [122]. Vascular disease is the most significant cause of complications and deaths in pancreas transplant recipients. The degree of vascular disease at the time of transplant correlates strongly with the risk of a subsequent major cardiovascular event [123]. Evidence of significant cardiovascular disease may therefore preclude offering pancreas transplantation [124]. The rate of development of coronary disease after SPK versus KTA is not yet known, and data on the long term effects on microvascular disease is also scant. However, progression of carotid disease appears to be measurably delayed in the presence of euglycemia from a functioning pancreas transplant [125]. Nephropathy in the transplanted kidney is demonstrable on follow-up biopsy in nearly half of diabetics who have not also received a functioning pancreas transplant [126]. The opportunity to study PAK recipients shows that diabetic changes established in a kidney transplant by the time of subsequent successful pancreas transplantation can not only stabilize but actually regress considerably over the next 2 to 10 years. Indeed the native kidneys may also show regression of diabetic changes [127]. Similarly, successful SPK recipients are generally spared recurrence of diabetes in their kidney transplant. The negative aspects of pancreas transplantation include the more extensive surgery, the need to anastomose the pancreatic duct to the bladder or bowel with the complications thereof, more frequent loss of pancreas transplant function (through rejection or thrombosis) than of kidney function, and troublesome orthostatic hypotension that may be exacerbated by the exocrine fluid and bicarbonate losses of the transplanted pancreas. Also older recipient age confers a marked risk for poorer outcomes in SPK recipients [128]. Pancreas transplants are still nearly always from cadaver donors, so there is usually delay in getting SPK transplantation completed as compared to live-donor kidney transplant alone (KTA). However, combined organ transplants currently take precedence over single organ procedures, so the SPK candidate – as well as the pancrease-alone transplant recipient – is on a much shorter waiting list in most parts of the country. SPK organs are only procured from younger, healthier cadaver donors, so kidney quality is usually above average. Potential live kidney donors should know that the recipient may still be able to have a cadaver pancreas

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transplantation some time after a successful live-donor kidney transplant (PAK). In many centers early live-donor kidney transplantion, if such a donor is available, is still deemed preferable to waiting for simultaneous organs from a cadaver source. Kidney transplantation to a diabetic person with ESRD confers benefit with respect to the recipient’s expected survival, quality of life, and potential uremic complications. The advantages to the recipient of a live donor compared to a cadaver donor kidney, including the rapid availability of the organ, are similar for a diabetic recipient as for a non-diabetic recipient. However, there are two respects in which diabetics may differ from other candidates for kidney transplantations: (1) diabetics may benefit more than non diabetics from earlier transplantation as renal failure develops, and (2) some diabetic recipients (younger patients with Type I disease) stand to gain considerable benefit from pancreas transplantation, most often simultaneous kidney and pancreas transplant from the same cadaver donor. Anticipation of the latter option may delay a decision to undergo live donor kidney transplant, and the consequences of that delay may be potentially deleterious. Therefore the recipient’s decision with regard to these options may not be an easy one. Conclusions Type II diabetes is so common that all kidney donors are at some risk for the eventual development of diabetic nephropathy, and no center can perform living donor transplantation from younger donors if it categorically excludes donors on this basis. Diabetic nephropathy is arguably the greatest renal risk faced by all young “normal” donors, who should be appropriately counseled about this risk. When the risk of diabetes for the donor is the specific concern, the donor must weigh the risk of starting dialysis sooner in life against the benefit that is desired for the recipient – about 15 years of freedom from dialysis, and quicker transplantation than would be achieved by waiting for a cadaver kidney. The donor’s specific concern, if he or she is a relative of a diabetic recipient or otherwise has a family history of diabetes or other risk factors, is the development of diabetes, which then introduces the risk of accelerated progression of diabetic nephropathy after having donated a kidney. However, the chances of becoming diabetic are not worsened by donating a kidney, and a minority of diabetics go on to have renal disease. Many treatments are now available to slow the progression of diabetic nephropathy. Those individuals who are more likely to develop diabetes and nephropathy can be identified. If still desiring to donate, their risk factors can be further defined, and they can be specifically evaluated as to their understanding and motivation by the center. Some donors may not wish to be considered, and some may be held to be inappropriate donors by centers, based on the defensible rationales discussed in Chapter 1. The information in this chapter is intended to facilitate the making of good decisions. We have an abundance of data on the risks of diabetic nephropathy, and in some ways this makes counseling kidney donors about diabetes easier that counseling them about some other conditions. In the case of the living kidney donor, it is important to recognize that a decision made with correct information

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and careful deliberation is the proper decision, and remains so even if – for better or worse – subsequent events turn out to be not what was most likely. In this undertaking, access to the correct information is crucial for centers and their donors. Although the specific issues are different for the potentially diabetic donor, counseling these donors is in general terms no different than counseling any other donor. It is hoped that centers will feel that they are indeed acting properly in formulating policy and in in counseling donors based on the information provided herein. References 001. Bia MJ, Ramos EL, Danovitch GM, et al. Evaluation of living renal donors: the current practice of US transplant centers. Transplantation 1995; 60: 322–7. 002. Kasiske BL, Ravenscraft N, Ramos EL, et al. The evaluation of living renal transplant donors: clinical practice guidelines. J Am Soc Nephrol 1996; 7: 2288–313. 003. US Renal Data System. USRDS 1998 Annual Data Report. Bethesda, Maryland, National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, 1998. 004. Annual Report on Management of Renal Failure in Europe, Part I. European Renal Association – European Dialysis and Transplant Association Registry. London, UK, 1998. 005. Brunkhorst R, Lufft V, Dannenberg B, Kliem V, Tusch G, Pichlmayr R. Improved survival in patients with type 1 diabetes mellitus after renal transplantation compared with hemodialysis: a case-control study. Transplantation 2003 July 15; 76(1):115–9. 006. Ritz E, Rychlik I, Locatelli F, Halimi S. End stage renal failure in Type II diabetes: a medical catastrophe of worldwide dimensions. Am J Kidney Dis 1999; 34: 795–808. 007. US Renal Data System. USRDS 2000 Annual Data Report: incidence and prevalence of ESRD. Am J Kid Dis 2000; 36(6:2): S37–S54. 008. Eisenbarth GS, Ziegler AG, Colman PA. Pathogenesis of insulin-dependent (Type II) diabetes mellitus. In: Kahn CR, Weir GC, Eds. Joslin’s Diabetes Mellitus (13th edition). Philadelphia: Lea and Febiger 1994: 216–39. 009. Ziegler AG, Herskowitz RD, Jackson RA et al. Predicting Type I diabetes. Diabetes Care 1990; 13:762-775. 010. Johnston C, Pyke DA, Cudworth AG, Wolf E. HLA-DR typing in identical twins with insulin-dependent diabetes: differences between concordant and discordant pairs. Brit Med J 1983; 286: 253–5. 011. Baisch JM, Weeks T, Giles R, et al. Analysis of HLA-DQ genotypes and susceptibility in insulin-dependent diabetes mellitus. N Engl J Med 1990; 322: 1836–41. 012. Patrick SL, Moy CS, LaPorte RE. The world of insulin-dependent diabetes mellitus: what international epidemiologic studies reveal about the etiology and natural history of IDDM. Diabetes Metab Rev 1989; 5: 571–8. 013. Warram JH, Martin BC, Soelder JS, Krolewski AS. Study of glucose removal rate and first phase insulin secretion in the offspring of two parents with non-insulin-dependent diabetes. In: Canerini-Davalos RA, Cole HS, Eds. Advances in experimental medicine and biology. Vol 246: Prediabetes. New York: Plenum Press, 1998; 175–183. 014. Vague P, Lassman V, Grosset C, Vialettes B. Type II diabetes in young subjects: a study of 90 unrelated cases. Diabetes Metab 1987; 13: 92–8. 015. Gottlieb MS. Diabetes in offspring of juvenile- and maturity-onset-type diabetics. J Chronic Dis 1980; 33: 331–9. 016. Groop L, Forsblom C, Lehtovirta M, et al. Metabolic consequences of a family history

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of NIDDM (the Botnia study): evidence for sex-specific parental effects. Diabetes 1996; 45: 1585–1593. Warram JH, Rich SS, Krowelski AS. Epidemiology and genetics of diabetes mellitus. In: Kahn CR, Weir GC, Eds. Joslin’s Diabetes Mellitus (13th edition). Philadelphia: Lea and Febiger 1994: 201–15. Froguel P, Zouali H, Vionnet N, et al. Familial hyperglycemia due to mutations in glucokinase; definition of a subtype of diabetes mellitus. N Engl J Med 1993; 328: 697–702. American Diabetes Association Expert Committee. Report of the Expert Committee on the Diagnosis and Classification of Diabetes Mellitus. Diabetes Care 1997; 20: 1143–58. Bjornholt JV, Erikssen G, Aaser E, et al. Fasting blood glucose: an underestimated risk factor for cardiovascular death. Diabetes Care 1999; 22: 45–9. Oats JN, Beischer NA, Grant PT. The emergence of diabetes and impaired glucose tolerance in women who had gestational diabetes. In: Weiss PA, Coustan DR, Eds. Gestational Diabetes. New York: Springer-Verlag 1988: 199. Ferrannini MA. How to measure insulin sensitivity. J Hypertens 1998; 16: 895–906. Kulmala P, Savola K, Reijonen H, et al. Genetic markers, humoral immunity, and prediction of Type I diabetes in siblings of affected children. Diabetes 2000; 49: 48–58. Lee HB, Ha H, Kim SI, Ziyadeh F. Diabetic kidney disease research: where do we stand at the turn of the century? Kidney Int 2000; 58 (Suppl 77): S1–S2. Dunlop M. Aldose reductase and the role of polyol pathway in diabetic nephropathy. Kidney Int 2000; 58 (Suppl 77): S3–S12. Makita Z, Radoff S, Rayfield EJ, et al. Advanced glycosylation end products in patients with diabetic nephropathy. New Engl J Med 1991; 325(12): 836–42. Pricci F, Leto G, Amadio L, et al. Role of galectin-3 as a receptor for advanced glycosylation end products. Kidney Int 2000; 58 (Suppl 77): S31–S39. Nishikawa T, Edelstein D, Brownlee M. The missing link: a single unifying mechanism for diabetic complications. Kidney Int 2000; 58 (Suppl 77): S26–S30. Viberti GC, Hill RD, Jarrett RJ, et al. Microalbuminuria as a predictor of clinical nephropathy in insulin-dependent diabetes mellitus. Lancet 1982; 1: 1430–2. O’Bryan GT, Hostetter TH. The renal hemodynamic basis for diabetic nephropathy. Semin Nephrol 1997; 17: 93–100. Leehey DJ, Singh AK, Alavi N, Singh R. Role of angiotensin II in diabetic nephropathy. Kidney Int 2000; 58 (Suppl 77): S93–S98. Vallon V, Richter K, Blantz RC, et al. Glomerular hyperfiltration in experimental diabetes mellitus: potential role of tubular reabsorption. J Am Soc Nephrol 1999; 10: 2569–76. Thomson SC, Deng A, Bao D, et al. Ornithine decarboxylase, kidney size, and the tubular hypothesis of glomerular hyperfiltration in experimental diabetes. J Clin Invest 2001; 107: 217–24. Cogan MG. Angiotensin II: powerful controller of sodium transport in the early proximal tubule. Hypertension 1990; 15: 451–8. Deckert T, Feldt Rasmussen B, Borch-Johnsen K, et al. Albuminuria reflects widespread vascular damage. The Steno Hypothesis. Diabetologia 1989; 32 219–26. Hansen PM, Chowdhury T, Deckert T, et al. Genetic variation of the heparan sulfate proteoglycan gene (perlecan gene): association with urinary albumin excretion in IDDM patients. Diabetes 1997; 46: 1658–9. Chowdhury TA, Dronsfield MJ, Kumar S, et al. Examination of two genetic polymorphisms within the renin-angiotensin system: no evidence for an association with nephropathy in IDDM. Diabetologia 1996; 39: 1108–14. Chowdhury TA, Dyer PH, Kumar S, et al. Genetic determinants of diabetic nephropathy. Clin Science 1999; 96: 221–30.

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039. Haffner SM, Mitchell BD, Pugh JA, et al. Proteinuria in Mexican-Americans and nonHispanic whites with NIDDM. Diabetes Care 1986; 12: 530–6. 040. Stephens GW, Gillaspy JA, Clyne D, et al. Racial differences in the incidence of end stage renal disease in types I and II diabetes mellitus. Am J Kidney Dis 1990; 15: 562–7. 041. Burden AC, McNally PG, Feehally J, Walls J. Increased incidence of end stage renal failure secondary to diabetes mellitus in Asian ethnic groups in the United Kingdom. Diabet Med 1992; 9: 641–5. 042. Seaquist ER, Goetz FC, Rich S, et al. Familial clustering of diabetic kidney disease. Evidence for genetic susceptibility to diabetic nephropathy. N Engl J Med 1989; 320: 1161–5. 043. Pettit DJ, Saad MF, Bennet PH, et al. Familial predisposition to renal disease in two generations of Pima Indians with type 2 non-insulin-dependent diabetes mellitus. Diabetologia 1990; 33: 438–43. 044. Forsblom CM, Kanninen T, Lehtovirta M, et al. Heritability of albumin excretion rate in families of patients with type II diabetes. Diabetologia 1999; 42: 1359–66. 045. Fagerudd JA, Petterson-Fernholm KJ, Riska MK, et al. Albuminuria in nondiabetic relatives of IDDM patients with and without diabetic nephropathy. Kidney Int 2000; 58: 959–65. 046. Fioretto P, Mauer M, Brocco E, et al. Patterns of renal injury in NIDDM patients with microalbuminuria. Diabetologia 1996; 39: 1569–76. 047. Schmitz A, Vaeth M:. Microalbuminuria: a major risk factor in non-insulindependent diabetes: a 10-year follow-up study of 503 patients. Diabet Med 1988; 5: 126–34. 048. Viberti GC, Keen H, Wiseman MJ. Raised arterial pressure in parents of proteinuric insulin-dependent diabetic. Br Med J 1987; 295: 515–7. 049. Barzilay J, Warram JH, Laffel LM, et al. Predisposition to hypertension: risk factor for nephropathy and hypertension in IDDM. Kidney Int 1992; 41: 723–30. 050. Strojek K, Grzeszcak W, Ritz E. Risk factors for development of diabetic nephropathy: a review. Nephrol Dial Transplant 1997; 12(Suppl 2): 24–6. 051. Trevisan R, Viberti G. Sodium-hydrogen anitporter: its possible role in the genesis of diabetic nephropathy. Nephrol Dial Transplant 1997; 12: 643–5. 052. Earle K, Walker J, Hill C, Viberti GC. Familial clustering of cardiovascular disease in patients with insulin-dependent diabetes and nephropathy. N Engl J Med 1992; 326: 673–7. 053. De Cosmo S, Bacci S, Piras GP, et al. High prevalence of risk factors for cardiovascular disease in parents of IDDM patients with albuminuria. Diabetologia 1997; 40: 1191–6. 054. Viberti GC, Earle K. Predisposition to essential hypertension and the development of diabetic nephropathy. J Am Soc Nephrol 1992; 3: S27–S33. 055. Mogensen CE, Schmitz O. The diabetic kidney: from hyperfiltration and microalbuminuria to end stage renal failure. Med Clinics of North America 1988; 72: 1465–92. 056. Mogensen CE. Glomerular filtration rate and renal plasma flow in short-term and longterm juvenile diabetes mellitus. Scand J Clin Lab Invest 1971; 28: 91–100. 057. Wiseman M, Viberti GC. Kidney size and GFR in Type I insulin-dependent diabetes mellitus revisited. Diabetalogia 1983; 25: 530. 058. Mogensen CE. Kidney function and glomerular permeability to macromolecules in early juvenile diabetes. Scand J Clin Lab Invest 1971; 28: 79–90. 059. Vora J, Thomas DM, Dean J, et al. Renal function and albumin excretion rate in 62 newly presenting non-insulin dependent diabetics. Kidney Int 1990; 37: 245 060. Mogensen CE. Microalbuminuria as a predictor of clinical diabetic nephropathy. Kidney Int 1987; 31: 673

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061. Austin SM, Lieberman JS, Newton LD, et al. Slope of serial glomerular filtration rate and the progression of diabetic glomerular disease. J Am Soc Nephrol 1993; 3: 1358–70. 062. Bruno G, Biggeri A, Merletti F, Bargero G, Ferrero S, Pagano G, et al. Low incidence of end-stage renal disease and chronic renal failure in type 2 diabetes. Diabetes Care 2003; 26: 2353–8. 063. Hovind P, Rossing P, Tarnow L, Smidt UM, Parving HH. Remission and regression in the nephropathy of type 1 diabetes when blood pressure is controlled aggressively. Kidney Int 2001 July; 60(1): 277–83. 064. Parving HH. Diabetic nephropathy: prevention and treatment. Kidney Int 2001 November; 60(5): 2041–55. 065. Bojestig M, Arnqvist HJ, Hermansson G, et al. Declining incidence of nephropathy in insulin-dependent diabetes mellitus. N Engl J Med 1994; 330: 15–8. 066. Remuzzi G, Schieppati A, Ruggenenti P. Clinical practice. Nephropathy in patients with type 2 diabetes. N Engl J Med. 2002 April 11; 346(15): 1145–51. 067. Brenner BM. Nephron adaptation to renal injury or ablation. Am J Physiol 1985; 249: F324–37. 068. Steffes MW, Brown DM, Mauer SM. Diabetic glomerulopathy following unilateral nephrectomy in the rat. Diabetes 1978; 27: 35–40. 069. Steffes MW, Buchwald H, Wigness BD, et al. Diabetic nephropathy in the uninephrectomized dog: microscopic lesions after one year. Kidney Int 1982; 21: 721–4. 070. Whiteside C, Katz A, Cho C, Silverman M. Diabetic glomerulopathy following unilateral nephrectomy in the dog. Clin Invest Med 1990; 13: 279–86. 071. Mauer SM, Steffes MW, Azar S, et al. The effects of Goldblatt hypertension on the development of the glomerular lesions of diabetes mellitus in the rat. Diabetes 1978; 27: 738–44. 072. Schmitz A, Christensen CK, Christensen T, Solling K. No microalbuminuria or other adverse effects of long-standing hyperfiltration in humans with one kidney. Am J Kidney Dis 1989; 13: 131–6. 073. Eberhard OK, Kliem V, Offner G, et al. Assessment of long-term risks for living related kidney donors by 24-h blood pressure monitoring and testing for microalbuminuria. Clinical Transplantation 1997; 11: 415–9. 074. Fattor RA, Silva FG, Eigenbrodt EH, et al. Effect of unilateral nephrectomy on three patients with histopathologic evidence of diabetic glomerulosclerosis in the resected kidney. J Diabetic Complications 1987; 1: 107–13. 075. Sampson MJ, Drury PL. Development of nephropathy in diabetic patients with a single kidney. Diabetic Medicine 1990; 7: 258–60. 076. Silveiro SP, Beck MO, Da Costa LA, Gross JL. Urinary albumin excretion rate and glomerular filtration rate in single-kidney Type II diabetic patients. Diabetes Care 1998; 21: 1521–4. 077. Steffes MW. Glycemic control and the initiation and progression of the complications of diabetes mellitus. Kidney Int 1998; 52 (Suppl. 63): S36–9. 078. The Diabetes Control and Complications (DCCT) Research Group. Effect of intensive therapy on the development and progression of diabetic nephropathy in the Diabetes Control and Complications Trial. Kidney Int 1995; 47: 1703–20. 079. United Kingdom Diabetes Study Group. Intensive blood-glucose control with sulphonylureas or insulin compared with conventional treatment and risk of complications with type 2 diabetes (UKPDS 33). Lancet 1998; 352: 837–53. 080. Ohkubo Y, Kishikawa H, Araki E, et al. Intensive insulin therapy prevents the progression of diabetic microvascular complications in Japanese patients with non-insulin-dependent diabetes mellitus: a randomized prospective 6-year study. Diabetes Res Clin Pract 1995; 28: 103–17. 081. Microalbuminuria Collaborative Study Group, United Kingdom. Intensive therapy and

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123. Manske CL, Wilson RF, Wang Y, Thomas W. Atherosclerotic vascular complications in diabetic transplant recipients. Am J Kidney Dis 1997; 29: 601–7. 124. Manske CL. Risks and benefits of kidney and pancreas transplantation for diabetic patients. Diabetes Care 1999; 22 (Suppl. 2): B114–20. 125. La Rocca E, Minicucci F, Secchi A, et al. Evolution of carotid vascular lesions in kidney-pancreas and kidney-alone transplanted insulin-dependent diabetes patients. Transplantation Proc 1995; 27: 3072. 126. Mauer SM, Goetz FC, McHugh LE, et al. Long-term study of normal kidneys transplanted into patients with type 1 diabetes. Diabetes 1989; 38: 516–23. 127. Fioretto P, Steffes M, Sutherland DER, et al. Reversal of lesions of diabetic nephropathy after pancreas transplantation. N Engl J Med 1998; 339: 69–75. 128. Sutherland DER, Gores PF, Farney AC, et al. Evolution of kidney, pancreas and islet patients with diabetes at the University of Minnesota. Am J Surg 1993; 166: 456–90.

Chapter Seven The Education and Counseling Process for Potential Donors and Donor Attitudes after Living Kidney Donation Robert W. Steiner, M.D. and Christine A. Frederici, L.C.S.W. Summary Points • The center should inform – without coercion – as many people as possible about the spectrum of outcomes (the risks and benefits) and the alternatives to kidney donation. • The center should advertise itself neither as a donor advocate nor a recipient advocate, but as the facilitator of an individual’s desire to donate. • The fundamentals of donor evaluation and counseling apply to all donors, although emphasis may vary. • The donor should be told at the outset to expect to hear negative information about kidney donation, that his autonomy will be safeguarded, and that he will be tested as to his understanding of the important issues. • The center must present all relevant negative information about donation in the same way as it presents positive information. • Because of its conflicts of interest and to preserve the public trust, the center must have adequate reason to believe that its acceptable donors are informed, have correctly thought through the process of donation, and are acting freely. • To safeguard donor freedom of choice, confidentiality of the evaluation process should be maintained. All donor evaluation and counseling should be conducted apart from the recipient. • True-false tests, stick figure fields, attitude and belief questionnaires, and/or other written material can be used to educate and test donors objectively. • Willing donors who are not accepted should be told specifically why.

129 R.W. Steiner (ed.), Educating, Evaluating, and Selecting Living Kidney Donors, 129–140.  2004 Kluwer Academic Publishers. Printed in the Netherlands.

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Introduction The primary educational and counseling activities of the transplant center are (1) to educate all possible donors about living donation, and (2) to pursue both general and individual issues with prospective donors who come forward. These center activities are distinct from donor medical evaluations, which are discussed in chapter 4. As an initial step in donor education and counseling, centers should try to inform as many potential donors as possible about living kidney donation, whether they request it or not. Most centers begin by sending educational information to friends and relatives who might consider donation. In this effort the center should stay neutral about any individual’s decision to pursue donation. Providing unrequested information about donation is not unduly coercive as long as the center attempts only to generally educate as many potential donors as it can identify. It might well be in the individual’s interest to know more about donation. Efforts to educate as many potential donors as possible have been shown to increase the number of living donor transplants [1]. Centers do not at this time make a concerted effort to attract so called “good Samaritan” donors, i.e., those who do not already know the recipient. Most information about the risks, benefits, and alternatives to living kidney donation is presented initially in the form of mailings to possible donors. The advantage of material that is not presented personally is that there is no immediate pressure to make a decision to donate. It allows donors time to think over the process of donation and to decide if they wish to take the next step to find out more about the basic issues and the actual donation process. Initial donor information must be unbiased and address all the major issues in the living kidney donation decision. Donors should be encouraged to consider facts and medical data relevant to donation and not consider donation as a test of sentiment, or fidelity to the recipient. The center should not allude to any duty to donate, but it may say that people may be surprised at a favorable risk/benefit ratio and may find it satisfying to be a kidney donor. Areas which should be covered in initial donor education are presented in Table 1. The next step in educating a donor is often an informational meeting, usually attended by many individuals interested in donating kidneys to their various recipients. Several members of a donor family often attend, who will subsequently take part in internal preliminary donor discussions [2]. Not all people who attend these meetings have decided to donate, nor will they all eventually decide to do so. They meet to hear presentations by transplant coordinators, social workers, patients, and physicians about both the risks and benefits of donation and the education, medical evaluation, and counseling process that a living donor can expect to undergo. Verbal presentations and written material are offered. Communication is usually from the center spokespersons to the audience, and the audience response and participation will be variable. Common questions and confusions may be suggested by questions from the audience, but such questions may not occur at every meeting. Therefore, the presenters from the center must anticipate common questions and confusions and present this information whether it is requested or not. Such donor meetings are not the place to undertake individual interviews to provide and document donor understanding of the central issues

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Table 1. General education of potential kidney donors. 1. The donor evaluation and counseling policies of the center, including confidentiality and those deliberate center policies which might ligitimately discourage donation for some donors. 2. The quality of life of dialysis patients and the overlap with the quality of life of transplanted patients. 3. What transplantation does for the patient: medical problems alleviated by transplantation, likely time of transplant survival, and lifestyle changes. 4. What transplantation does not do for the recipient: increasing incidence of transplant failure with time post transplant and continuing medical and psychosocial problems of transplant recipients. 5. The transplant surgical procedure, open living kidney procurement versus laparoscopic donation. 6. The operative risk, baseline risk of ESRD, and increased risk of ESRD with donation, the period in later life in which ESRD might possibly occur. 7. The alternative of cadaver donor transplantation, likely waiting time for cadaver kidneys, and survival data for cadaver kidneys.

surrounding living kidney donor transplantation. The format of the initial general living kidney donor information meeting is presented in Table 1. The center must stay neutral as regards the donor’s decision, and this means that policies and practices that might discourage donation for some donors must be part of the donor evaluation process. These possibly “chilling” features go beyond the center’s duty to provide accurate pro and con information about dialysis and cadaver donor transplantation, which might in itself persuade some donors not to proceed. Donor evaluation policies which might be seen as having a chilling effect on donation should be disclosed early in the process of donor education to avoid misunderstandings. These chilling policies are (1) that the center stays neutral and must provide donors with information that might well be seen as unfavorable to donation, (2) that donor counseling sessions are not to be conducted with the recipient present, (3) that the donors have a right to withdraw at any time, (4) that the donors’ evaluations and personal reasons for any delay or decision to withdraw are not shared with recipients, (5) that the center will not provide donor medical care long term, and (6) donors must be successfully tested with written material to see that they understand the basics of living donor transplantation. Very early disclosure of these policies lessens the chance that the donors will interpret them as hints by the center – directed at them – that they should not donate. Some centers may also not share the specifics of tissue typing with the donor or recipient as a matter of policy because of the possibility of unappreciated biological fatherhood. When presenting information to potential donors, the center must emphasize its task is not simply to facilitate donation, but to facilitate donation only for individuals who meet the criteria discussed in chapter one. As part of this process, the center must always present itself as a neutral facilitator of the

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donor’s desire to help the recipient, not as an object of donor largesse. This must be done even if such center neutrality is seen by some donors as a “chilling” factor. The center must settle on the basic facts and statistics to be presented consistently to donors. Counselors must communicate among themselves and know what each is saying. Eventually donors must be tested as to their knowledge. Potential donors vary in the way they process information, involve others, and decide whether to donate [2]. The center must conduct individual counseling sessions with each serious potential donor. The donor counselor(s) must be accepting and comfortable with a hesitant donor or those donors who appear to be deciding not to donate. Indeed the center can point to those individuals who decide not to donate as evidence that its counseling process is fair and noncoercive. While it is not of high importance that donors attend the initial informational meetings unattended by the recipient, in these subsequent donor counseling sessions this is important and will be discussed below. Educating and assuring potential donors on the issue of confidentiality is of utmost importance. The counselor needs to specify that if the potential recipient or any other member of his family or friends contacts the center to inquire about a donor’s medical records, psychosocial evaluation or any other aspect of his pre-donation work up, no information will be given without permission from the potential donor. Donors must realize that if they try to involve recipients in their medical evaluation and education, they are eroding an important right and protection. To take that one step further, it should be explained to donors that if they decide not to donate, the transplant center will keep their reasons confidential. Without the potential donor’s permission to do otherwise, the recipient would be told only that the donor was not an appropriate donor. Donors themselves can decide what more to tell the recipient. To preserve impartiality, it is usually appropriate for the center not to participate in the further evaluation or treatment of significant donor medical abnormalities. For example, a donor with a positive skin test for tuberculosis is evaluated by an independent physician, as would be the case were donation not being considered. The center in any case must make it clear that it will not be responsible for medical care of any long term donor problem, whether it relates to donation or not – including the development of ESRD. The offer of long term care may be unsustainable and could also be seen as an inducement to donate, eroding the center’s position as a neutral facilitator of the donor’s well-considered desire to donate. Individual counseling sessions with donors should be just that – the recipient should not be present, and the donor should not be able to waive this right. In retrospect, some donors have reported pressure to donate which has not been detected by the center [3, 4]. The donor may be inhibited from asking difficult questions if the recipient is present. We prefer that the recipient not even travel with the donor to or from the counseling session and not be present in the waiting room, as this may pressure the donor to inadequately consider the option of not donating. The donor’s right to withdraw and the confidentiality of the donor evaluation cannot be adequately discussed with the recipient present, and the donor may not be receptive to these issues even if the recipient is only waiting in the next room for the counseling session to end. Such measures to isolate the donor do not improperly discourage donation; rather they increase the donor’s confidence

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that the center is in fact interested in his welfare, and they also increase the center’s confidence that it may ethically proceed in complicated donor situations. Besides ensuring donor understanding of medical risk and benefit, the center (in many cases, the social worker) must examine other aspects of the donor’s situation that might create other risks for the donor. Because it is expected that the center will only accept donors for whom it is rational to donate (i.e., makes sense in the context of that donor’s beliefs, goals, and life situation), the center must pursue a number of issues in detail. Acceptable donors should have thought through all the relevant consequences of the donation process, including the home support they will need after donation and the financial and work leave consequences. Coping skills should be assessed, as some donors may have given little thought or have limited insight into how they deal with adversity. Asking these questions will increase the donor’s understanding of what to expect and help the donor plan. Major disruption in the donor’s personal or financial affairs can make the decision to donate questionable for many donors. Counseling the donor by himself also allows a counselor an opportunity to explore other factors or situations in the donor’s life that may or may not be conducive to living donation (Table 2). Table 2. Psychosocial living kidney donor evaluation. Identifying Information Family History Marital History Education and Employment History Financial and Work Leave Issues Activities, Hobbies and Interests General Medical History Psychiatric History Substance Abuse History High Risk Behavior, e.g., for HIV Infections

Understanding of Recipient’s Illness Understanding of Risks for Donor and Recipient Understanding of Alternatives to Donation Family’s Impressions and Opinions About Donation Pre-Hospital Care Plan for Donor Motivation for Donation Freedom from Coercion

The potential donor’s psychosocial situation, the environment in which he lives, the way he copes with life’s stresses, and how he problem-solves all bear upon how donation will affect the donor. The social worker can best asses these factors by creating a setting in which the donor feels comfortable relating personal and sensitive information about himself. Building trust and rapport during this interview is essential not only to assess the donor, but also to allow the donor opportunities to express his concerns and feelings. The overall purpose of these counseling sessions is to asses the appropriateness of the donor’s decision in the context of his other goals, needs, and aversions in life. This can be facilitated by consideraton of the goals, beliefs, and preference priorities of a hypothetical typical donor and a typical nondonor, as presented in Table 3. The donor counselor can use these profiles to consider with the donor whether that individual’s goals,

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Table 3. Profile of important beliefs and attitudes for donors and non donors. You should consider not donating a kidney if: • You do not want to take any risk with your health. • You feel that waiting several years for a cadaver kidney is a reasonable alternative for the recipient. • You feel that long term dialysis is a reasonable form of treatment for the recipient. • You cannot accept the fact that – sooner or later – your donated kidney will fail. • You do not want to undergo a major operation. • A major operation would be very disruptive for your life. • You do not think that the recipient will take care of the kidney. • You do not think you understand the facts surrounding kidney donation. • You feel pressured to do something you would not really want to do. You should consider donating a kidney if: • Increasing your risk of needing dialysis someday by one in several hundred to one in a thousand is acceptable to you. • You can accept the pain and inconvenience of a major operation. • You think that kidney transplantation provides sufficient advantages over dialysis. • You think that living donor kidney transplantation provides sufficient advantages over cadaver kidney transplantation. • You can accept that – sooner or later – your donated kidney will fail. • You want to be the one who helps the recipient. (In administering this profile to donor candidates, we do not indicate which statements favor donation or non donation to make the donor’s response as genuine as possible.)

preferences, and beliefs favor donation or nondonation. Using these donor/nondonor profiles also helps review understanding of the facts and issues surrounding donation. When counseling the potential donor, the counselor must be able to pick up nonverbal as well as verbal cues to what motivates the donor. This can be done by assessing the donor’s willingness to meet with the counselor, his physical posture, emotional stability, eye contact, withdrawal, avoidance, defensiveness, and interest in written material. The counselor should also attempt to gauge the donor’s expectations for the transplant. Does the donor know that the kidney might fail right away, or might fail a year after surgery? Again, using open-ended questions to elicit candid responses is an effective tool. One must not avoid discussing in detail the possibility of medical complications for the donor or transplant failure, because including these topics helps make the center’s counseling adequate and defensible. The basic considerations in donor education and counseling always remain the same, even for friends and altruistic strangers who come forward [5], but the emphasis in individual cases will vary. Donors in a position to be coerced should be interviewed more extensively with this in mind. The same would apply to donors whose relationship to the recipient might suggest that payment was involved. While centers rightly are concerned about donors who are pressured to donate, some may be pressured not to donate [3], and this issue should receive full consideration too. The acceptable donor must be able to answer correctly every key factual question

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concerning the risks and benefits of donation. Such structured donor testing should be documented, and this makes some form of written instrument desirable. Without structured, feedback-based testing, “health-illiterate” individuals in particular may not have an adequate understanding of the issues involved in donation [6]. The environment in which testing will occur should keep the process non-stressful. In the final analysis, it is entirely to both the center’s and the donor’s benefit that donation only occur with adequate understanding of its consequences and alternatives. We have developed two instruments to test donor understanding of living kidney donation. One is a series of true/false questions, all of which must be answered correctly by the donor before donation can take place (Table 4). The true/false questions as well as the answers are sent to the donors ahead of time as part of a general information letter. Donors are early on told to expect that they must eventually answer all these questions correctly. We also present data to doors visually, with the use of fields of stick figures, which are marked to show the incidence of various outcomes (Figure 1). For instance, if we wish to convey that one out of 350 individuals will likely require dialysis at some time between ages 18 and 75, we mark out of a field of 350, or three out of a field of 1,000 stick figures. If we wish to show that five percent of living donor kidneys will fail by one year, we mark five stick figures out of a field of 100. We can illustrate half-life of living donor and cadaver kidneys by marking 50 of 100 stick figures to demonstrate quantitatively how many patients will have returned to dialysis by a certain time. We can also present quantitatively the chances of receiving a cadaver kidney by marking 50 out of 100 stick figures to show the donor how many individuals on the cadaver kidney waiting list will have received a kidney over the average waiting time period for that blood group [7]. For example, if the average waiting time for a blood type A recipient is three years, then at three years 50 out of 100 patients (stick figures) will have received a cadaver kidney. Before donation, potential living donors in our program must be able to recognize data presented by means of stick figures and answer our written questions which pertain to basic informational requirements. In these respects, our donor counseling does not present a dichotomous safe/unsafe view, but a more realistic continuum-of-risk model [8]. In addition to true/false questions and stick figure counseling, to test the overall efficacy of donor understanding, we ask donors “If you donated a kidney, how would you feel if it failed at one month or one year,” or “If you needed dialysis Table 4. True/false questions (and answers) for kidney donors. 01. Kidney transplantation is usually life saving. FALSE. Many patients can stay on dialysis for years with no major health problems. Liver and heart transplantation are life saving, because there is nothing similar to dialysis to replace these failing organs. 02. Donors have discomfort after kidney donation. TRUE. Pain from the donor operation usually goes away within a few weeks, and donors are back to a normal lifestyle at four to six weeks. As with any surgery, donors occasionally have long term wound pain or discomfort.

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Table 4. (Continued). 03. Half of all living kidney donor transplants work more than sixteen years. TRUE. About half of all living donor transplants will work more than sixteen years, and half fail before sixteen years. About one out of twenty (5%) living donor transplants will stop working by one year. 04. Cadaver donor kidney transplantation is not a good option. FALSE. Cadaver kidneys usually function only about half as long as living donor kidneys, but they are in most respects about as good as living donor kidneys. 05. If someone develops a kidney problem a year after kidney donation, the Transplant Center will take care of it at no charge. FALSE. Treatment of any donor medical problem – including kidney failure – arising in later life is the responsibility of the donor. The role of the Transplant Center is only to facilitate the gift of the kidney from the donor to the recipient. 06. The waiting time for a cadaver kidney is usually four to five years. TRUE. Waiting time depends on blood type and other factors. About one-half (50%) of all patients on the waiting list will receive kidneys by four to five years. The average waiting time is a few months longer each year because the waiting list grows faster than the number of cadaver donors. 07. Transplantation is usually a better treatment for kidney disease than dialysis. TRUE. Dialysis patients almost always feel that they have a better quality of life after transplantation and strongly desire not to return to dialysis. There are long term medical benefits for most patients also. 08. After transplantation, the recipient must take medicine and see the doctor regularly to keep the transplant working. TRUE. If a kidney transplant recipient neglects his or her medical care, the kidney will fail. 09. Results of a donor’s medical evaluation are confidential. TRUE. Unless the donor indicates otherwise, the donor's medical evaluation is kept confidential. If a donor decides not to donate any time, the recipient is only told that the donor is not an appropriate donor. The donor decides what more to tell the recipient. 10. Donating a kidney causes kidney disease. FALSE. Usually almost 20% of kidney function is lost by donation, but donation never causes kidney disease. If significant kidney disease does develop later in life, having one kidney may shorten the time until dialysis is needed by about 20%, for example, 8 years until dialysis with past donation instead of 10 years without it. 11. Without kidney donation, there is still a risk for dialysis in later life. TRUE. Because donor candidates are healthy, the lifetime risk of dialysis without donation is probably less than 1 in 100 for whites and less than 3 in 100 for blacks. 12. The Transplant Center should encourage donors and will only provide information to donors that is favorable to kidney donation. FALSE. The Transplant Center should always provide complete information about the likely benefits, the risks, and the alternatives to living kidney donation. Some donors will decide to donate, and others will decide against it. The Transplant Center should always stay neutral in the donor's decision-making process.

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Figure 1. Stick figure field marked to show a 5% (top) or a 50% (bottom) incidence of an event (from reference 7, with permission from LWW).

in later life and could never be sure whether donation brought it about, could you accept this, or would you feel mislead or poorly counseled if this happened to you?” If the donor could honestly state that he would not feel mislead or poorly counseled, then he is probably on the right path to becoming an appropriate donor. These points are also addressed in the donor/nondonor belief profiles in Table 3. Presenting “negative” information about risk and benefit to potential donors or discussing conflicts of interest may be difficult for some centers as these topics tend to discourage donation. However, the center can first emphasize to donors – beginning early in the process – that it is interested in their welfare and their need to be completely informed. The center can present itself as recipient and a donor advocate, eager to perform transplants but only so long as it knows that its donors are thoroughly and impartially educated. As mentioned earlier, this will be better understood if the need for presentation of negative or “chilling” information is emphasized very early in the process so the donor does not think that it is specifically directed at him.

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Donors should also be counseled individually when there are abnormalities in their medical evaluation. As stated in Chapters 1 and 4, abnormalities may not necessarily make donation unacceptable to the center or to the donor. The implications of abnormalities uncovered during medical testing usually cannot be precisely quantitated, and even the most uncomplicated donors must be sophisticated enough to be aware of the semi-quantitative nature of all risk estimates. Some abnormalities discovered in the course of the donor evaluation may bear more on other long term health risks for the donor than on the development of ESRD, and donors must also be made aware of the need to follow up on these findings independently of the center. Another purpose of individual donor counseling at times is to inform the donors that they are not acceptable, but it is not enough just to say this much. Donors can be unacceptable because of medical risk, lack of donor understanding, donor irrationality, or lack of free and voluntary choice. The implications of each of these reasons for donor rejection are different, both for the center and for the donor. If medical risk is great enough, the center may judge donation either to be irrational or to be heroic enough to risk public suspicion of the center’s impartiality – no matter how carefully donor evaluation and counseling are in fact conducted. As discussed in Chapters 1 and 4, when medical evaluation uncovers risk factors, the impact of which literally cannot be quantitated at all, the donor cannot be counseled and cannot be accepted. Then donation is truly heroic – or more often irrational – because one literally cannot provide any idea of the risk of ESRD associated with the particular abnormal medical finding. Far more often, however, risk can be estimated acceptably for the donor. Donors who cannot demonstrate that they are sufficiently informed about the necessary issues in living donor transplantation form a different group and should be told that this is the reason they are not acceptable, not because they medical risk is too great. The donor – and the center – should understand that the requirement for donor understanding cannot be waived [9]. At times donors rejected for ineducability are those whose medical evaluation has documented some abnormality, and the donor does not appear to understand the implications of same, despite the best efforts of the center. Donors who are not motivated enough to gain the understanding they need to donate form a subgroup of ineducable donors, and must be told that this is the reason they are being rejected. These donors then have the opportunity to demonstrate to the center that they in fact are educable and are motivated to proceed. Donors, however, cannot try to demonstrate to the center that they have this motivation or educability unless they are told that this is the reason that donation is being denied. Donors who are merely refractory to education efforts must not be left with the impression that they are unacceptable because their risk is “too great”. A donor with no abnormalities whatsoever on medical testing who could not be educated would still be unacceptable. After donation, surveys report that a very high percentage of kidney transplant donors do not regret donation, and would donate again under the same circumstances [4, 10, 11]. These facts should be carefully discussed with potential donors. The overall satisfaction of kidney donors certainly attests to the safety and good results of living kidney donation as it has been practiced, but it also may attest to those donors’ realistic expectations of outcome – that over the years some recipients will die or return to dialysis. However, results of such donor

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surveys are also subject to question. Center-driven surveys may not be objective or invite criticism or expressions of dissatisfaction. Surveys of this type are not entirely helpful to the center. All donors do not participate [11], and some donors may not be realistic or honest about their feelings – nor is there particular reason to be, as they do not have to face the decision to donate again. We have asked a number of our living donors from years past to complete our true/false questions regarding donation and have found that the principle mistake was in identifying kidney transplantation as “life saving.” We have subsequently made sure that prospective donors understanding the differences between, e.g., heart and living transplantation – which are immediately and clearly lifesaving, and kidney transplantation where the “lifesaving” effects may be present in a sense over time, but are harder to predict and quantitate [12, 13], as discussed in Chapter 2. More detailed retrospective donor questionnaires from other centers have suggested unexpected problems with pressure on donors, marital stress, financial hardship [3], and postoperative pain [10]. Centers can improve their counseling process by such periodic surveys of previous donors. We expect living kidney donor education to improves as donor educational policies and testing tools are shared among centers. This approach to donor education and counseling was developed independently of [7] an important and comprehensive statement on living organ donor policies and procedures. The live organ donor consensus group (LODCG) proposes a similar approach to donor education, evaluation, and counseling [14]. The LODCG emphasizes the need for unbiased and comprehensive donor education. It recognizes explicitly and in great detail the need to establish that donation is uncoerced and makes sense (is rational) for the donor given his circumstances, beliefs, and goals. It recognizes the need for confidentiality in the donor evaluation and the relationship of confidentiality to protecting the donor’s enduring right to withdraw. To neutralize center self-interest, the LODCG recommends donor counselors who are independent of the center, but such donor advocates may be difficult to find. In this chapter, we emphasize the need to test and document explicitly donor understanding by written instruments, and we suggest that these procedures will also help neutralize center self interest. We also give examples of “negative” information that donors should be provided, and stress the importance of providing that information early on as part of the formal donor evaluation process, so that this is not taken as an indication that the center wishes the donor not to proceed. In general, the data-based counseling approach taken by this book will help guard against indulging center self interest. We expect that further dialog will clarify and unify these approaches to donor education, counseling, and evaluation. References 01. Schweitzer EJ, Yoon S, Hart J et al. Increased living donor volunteer rates with a formal recipient family education program. AJKD. 1997; 29(5): 739–45. 02. Hilton BA, Starzomski RC. Family decision making about living related kidney donation. ANNA Journal. 1994; 2(6): 346–55. 03. Smith MD, Kappell DF, Province MA et al. Living-related kidney donors: a Multicenter study of donor education, socioeconomic adjustment, and rehabilitation. AJKD. 1986; VIII(4): 223–33.

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04. Fehrman-Ekholm I, Brink B, Ericsson C et al. Kidney donors don’t regret. Transplantation. 2000; 69(10): 2067–71. 05. Spital A. Public attitudes toward kidney donation by friends and altruistic strangers in the United States. Transplantation. 2001; 71(8): 1061–4. 06. Demott K. One in three over age 65 is “Health Illiterate”. Int Med News. 2000 Oct: 18. 07. Steiner RW, Gert B. A technique for presenting risk and outcome data to potential living renal transplant donors. Transplantation, 2001; 71(8): 1056–7. 08. Dinman BD. The reality and acceptance of risk. JAMA. 1980; 244(11): 1226–8. 09. Steiner RW. Is consent of an uninformed organ donor valid? AJKD. 2001; 38(5): 1141. 10. Karrfelt HME, Berg UB, Lindblad FIE et al. To be or not to be a living donor. Transplantation. 1998; 65(7): 915–8. 11. Johnson EM, Anderson JK, Jacobs C et al. Long-term follow-up of living kidney donors: quality of life after donation. Transplantation. 1999; 67(5): 717–21. 12. Becker BN, Becker YT, Pintar TJ et al. Using renal transplantation to evaluate a simple approach for predicting the impact of end-stage renal disease therapies on patient survival: observed/expected life span. AJKD. 2000; 35(4): 653–9. 13. Dew MA, Switzer GE, Goycoolea JM et al. Does transplantation produce quality of life benefits? Transplantation. 1997; 64(9): 1261–73. 14. Delmonico F (corresponding author), Abecassis M, Adams M, Adams P, Arnold RM, Atkins CR, et al. Live Organ Donor Consensus Group. Consensus statement on the live organ donor. JAMA. 2000 December 13; 284(22): 2919–26. Review.

Chapter Eight Attitudes, Practices, and Ethical Positions among Transplant Centers Concerning Living Kidney Donor Selection Aaron Spital, M.D. Summary Points • Historically doctors have been reluctant to take a living donor’s kidney, even though that person may have good reason to donate. • Many transplant centers now are performing more living kidney donor transplants. • Many centers now accept more living donors, primarily because of the shortage of cadaver organs, they belief that the risk for a healthy donor is low, and the excellent results achieved. • Many transplant centers now seem to believe that the general issues for evaluating genetically unrelated (but emotionally bonded) and living related donors are similar. • Surveys indicate that the public is willing to allow living donors to take more risks than are transplant centers, but surveys are hypothetical and do not assess knowledge of transplantation. • Complete strangers who desire to donate a kidney are viewed suspiciously by many centers but are widely accepted by the general public, and a few centers have begun to accept such volunteers. • Most centers will not consider children as kidney donors; a few will consider children only if donation is clearly in their best interests. • Some centers refuse donors if there is any added risk factor identified. • Surveys suggest that the public believes that such volunteers should have a greater voice in determining their own suitability.

141 R.W. Steiner (ed.), Educating, Evaluating, and Selecting Living Kidney Donors, 141–155.  2004 Kluwer Academic Publishers. Printed in the Netherlands.

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This chapter will review the evolution of attitudes toward living kidney donation and the use of living kidney donors among renal transplant centers. Relevant public attitudes will also be presented. It will be seen that while transplant centers’ attitudes toward living donors have changed greatly over time, those of the public have remained fairly constant despite dramatic advances in clinical kidney transplantation. The Early Evolution of Transplant Center Attitudes Toward Living Related Kidney Donors From its inception, the practice of living kidney donation generated difficult ethical questions, the most troubling of which was summarized by Dr. Francis Moore over 35 years ago [1]: “Thus, for the first time in the history of medicine a procedure is being adopted in which a perfectly healthy person is injured permanently in order to improve the well-being [not of herself but] of another. Some laboratories have viewed this matter with such misgivings that under no circumstances have they used tissues from volunteer human donors.” Besides the concern about physically harming the donor, there was also concern about the donor’s motivation and her ability to provide truly informed consent when the life of a relative was at stake [2–4]. Nevertheless, because of the lack of alternative therapies for ESRD patients, living related kidney donation became an accepted practice [5, 6] even though the long term risks for the donor were not well defined [7]. Since those early days of renal transplantation the situation has changed dramatically. In the 1960’s and 70’s, in developed countries, the achievement of successful cadaver transplantation and the growth of dialysis provided effective alternatives for ESRD patients. Furthermore, rare postoperative donor deaths occurred [8, 9] and a few studies suggested that uninephrectomy might pose long term risks as well [10, 11]. Not surprisingly, based on concerns about donor safety and steady improvement in the results of cadaver transplantation, some physicians began to argue that living kidney donation should be used only as a last resort or not at all [9, 12]. These negative sentiments toward living kidney donation were reflected by a steady decline in the level of support for this practice among transplant centers. In a survey of 179 US centers (47% response rate) that was completed in 1983, when asked which donor source was preferred, 75% of those responding said they preferred living related kidney donors while only 6% preferred cadaver donors [13]. In another survey performed two years later, the percentage of responding centers that preferred living related donors had dropped to 54% [14]; and by 1987 that percentage had fallen even further to only 36% [15]. Current Attitudes Toward and Use of Living Related Kidney Donors Among Transplant Centers The fall in popularity of living related donors among US transplant centers that was seen in the 1980’s reversed in the 1990’s. In a survey of US transplant centers performed in 1993, 52% of the 127 responding centers said they preferred living related donors, while only 8% preferred cadavers [16]. And in a 1999 follow-up

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study, the percentage of responding centers that preferred living related donors increased further to 60% [17]. Concomitantly with this change in attitudes there has been an increase in the number of living donor kidney transplants performed. In the United States, between 1990 and 2000, the yearly number of living donor kidney transplants grew by 150%, from 2,094 to 5,256, and living donors now provide kidneys for almost 40% of all renal transplants [18] Furthermore, nearly all US renal transplant currently accept living related donors [19]. Several factors likely account for the recent increase in popularity of living related donors among US transplant centers. These are: 1) the severe shortage of cadaver organs [20]; 2) the realization that transplantation is the optimal therapy for patients with ESRD [21]; 3) the observation that even with modern immunosuppression the outcome of renal transplantation using living donors is still superior to that of cadaver kidney transplantation [22]; 4) the recognition that the desire to saved a loved one is a powerful and admirable motivating force; 5) the fact that the risk of donor nephrectomy is very low [8, 20]; and 6) the recognition that the donor as well as the recipient may benefit from donating [23, 24]. Among other countries, attitudes toward and use of living donors varies widely. For example, living donors account for more than half of all renal transplants performed in Greece and about one-third of those performed in Sweden and Norway; at the other end of the spectrum are countries such as Poland, Finland, and the Czech Republic that perform few if any living donor transplants [25, 26]. Public Attitudes Toward Living Related Kidney Donation In contrast to the changes in attitudes that have taken place among transplant centers, attitudes among the public toward living kidney donation have been much more stable. Over the past three decades, surveys have repeatedly shown that despite remarkable developments in cadaveric transplantation, the great majority of the public would be willing to donate a kidney to a loved family member in need [3, 27–29]. The stability of public support for living related donation in the face of dramatic advances in the field could be due in part to changing but offsetting considerations relevant to transplantation over time. Thirty years ago, the outcome of renal transplantation was not nearly as good as it is today, and the long term risks of donation were not well defined. These disincentives were balanced by the lack of alternative treatments for potential recipients and the realization that a successful renal transplant would therefore be life saving. Today, the excellent outcome of living donor renal transplantation and the now well known low risk of donor nephrectomy may, for some people, outweigh the advantages of alternative therapies which, though good, are still inferior to living donor transplantation [21, 22].

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While these considerations may contribute to the stability of public attitudes, many participants in public surveys may not be informed about these issues and do not carefully consider them. It is likely that many respondents base their favorable answers primarily on a strong desire to do whatever they can to help restore the health of a person who is dear to them, even if it means taking risks and enduring pain. Consistent with this hypothesis is the observation that many donors decide to donate immediately upon learning of the need, and these decisions are not changed by the provision of information that an outside observer would consider essential for reaching an informed choice [30–32]. Not surprisingly, such instantaneous decisions are most common among parents of young children, who are the least ambivalent and most committed of all donors [32] Attitudes Toward and Use of Genetically Unrelated Living Kidney Donors The use of genetically unrelated living kidney donors dates back to the early days of renal transplantation. Because there were few alternatives, genetically unrelated donors provided nearly 10% of all kidneys for the 1,488 recipients reported to the Human Renal Transplant Registry through 1966 [33]. However, because of initially poor results, growing success with cadaveric transplantation, increasing availability of dialysis, and concern about the donor’s motivation and the risk involved, unrelated living donation soon fell into disfavor at most transplant centers [34]. By 1970 the use of genetically unrelated living donors had ceased almost entirely [33]. With a few notable exceptions, negative attitudes toward unrelated living donors prevailed at most transplant centers until the 1990s. As recently as 1991, the World Health Organization concluded [35] that “adult living persons may donate organs, but in general such donors should be genetically related to the recipients.” Important developments during the past 15 years have rekindled interest in the use of genetically unrelated living donors. These include the steadily worsening organ shortage, the improving ability to successfully transplant poorly matched donor-recipient pairs, and the realization that transplantation is the optimal therapy for many ESRD patients [20–22]. Over the past several years, many centers around the world have achieved excellent results with genetically unrelated living donors that are superior to those obtained with cadaver donors [22]. Along with reports of technical success, several authors have argued cogently that the use of unrelated living donors is ethically acceptable [34, 36–44], although not all agree [45, 46]. How have these developments affected attitudes toward and use of this donor source among transplant centers? These are important questions because people who are genetically unrelated to recipients represent a large pool of potential donors and could provide kidneys for many ESRD patients [22]. As we explore these issues, we will consider people who are emotionally (but not genetically) related to the recipient (i.e., spouses, friends, in-laws) and altruistic strangers separately.

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Emotionally Related Donors Attitudes toward emotionally related donors among transplant centers have changed markedly over the past 15 years. In 1985, 40% of 83 US centers responding to a survey said they would allow spouses to donate kidneys to each other, and only 16% actually used unrelated living donors [14]. Just two years later, the fraction of responding centers that would have considered using spouses had jumped to 76%, and 48% would have considered using friends [15]. By 1993, 88% of 127 responding centers would have accepted spouses as donors, and 63% would have accepted friends [16]. And in 1999, an overwhelming 93% of 129 responding US transplant centers said they would accept a friend of the recipient as a kidney donor [17]. A similar change in attitudes over time has taken place in Canada [29, 47]. This growing support for emotionally related donation among North American transplant centers is probably explained by the organ shortage, excellent technical results, low risk for the donor, and the recognition that the desire to save a loved one is a powerful and admirable motivating force that is not limited by genetic boundaries. The EUROTOLD Project recently explored attitudes toward unrelated living kidney donation in a survey of 190 European transplant centers [25]. Attitudes were highly variable. Among the 85 responding centers, 60% would have considered spouses as donors, but very few would have considered friends. These data suggest that attitudes toward emotionally related kidney donation are more conservative in Europe than they are in the US, and some centers are strongly opposed to this practice. In France this practice is prohibited by law [48]. Still, the majority of centers appear willing to at least consider spouses, although some countries require a formal approval process (e.g. by the Unrelated Live Transplant Authority in England [25]). Attitudes toward emotionally related kidney donation among the US public are overwhelmingly positive. As was true of attitudes toward living related donation, public attitudes in this area have remained remarkably stable over time. Surveys have shown repeatedly that the most people would be willing to donate a kidney to their spouse, and a smaller majority would be willing to donate a kidney to a friend [27–29, 49, 50]. These observations are not surprising given the low risk of kidney donation for a healthy person, the value of kidney transplantation for the recipient, and the strong emotional bonds that often exist between spouses and between close friends. Are these generally favorable professional and public attitudes toward emotionally related donors affecting transplant center practice? The answer is yes. According to the Health Care Financing Administration ESRD data, the yearly number of unrelated living donor kidney transplants performed in the United States has progressively increased from just 56 in 1988 to 1,353 in 2001 [51]; most of these transplants were performed between spouses. The situation in Europe is less clear because analogous data are not available. However, it is known that several European centers are actively using emotionally related donors [25, 52–54]. On the other hand, such transplants still account for only a small fraction of all renal transplants performed. For example, in the United States in the year 2001, living unrelated donors provided kidneys for less than 10% of renal transplant recipients [51]. Considering the estimate that spouses alone could provide

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kidneys for as many as 25% of all potential recipients [55], it appears that the great potential of emotionally related donors to mitigate the severe shortage of kidneys has yet to be realized. These data suggest that despite the recent large increase in spousal donation and widespread acceptance of emotionally related donation, at some centers acceptance of these donors is more in principle than in practice. Consistent with this hypothesis, a 1994 survey showed that while most US centers said they would accept friends and spouses, at most only about one-third of centers encouraged spousal donation, and at most about one-quarter encouraged the use of friends [56]. While these numbers may now be higher, it is likely that many centers are still less comfortable with emotionally related donors than they are with genetically related ones. Altruistic Strangers as Kidney Donors From time to time strangers step forward and offer to donate a kidney to help an ill person they do not know. A poignant example is the recent donation by a renowned German transplant surgeon of one of his own kidneys to a recipient he did not know [57]. Of all potential adult donors, these unusual volunteers have always generated the most anxiety for transplant centers. The widespread concern about accepting strangers as donors was first revealed in a 1971 survey of 54 world transplant centers by Dr. Sadler and his colleagues [58]. They concluded that the results provided “evidence which reinforced the prevailing medical opinion of distrust for the motivation and mental health of [unrelated] donors. Some centers expressed repugnance toward their use as a donor source.” A negative view of strangers who offer to donate kidneys persisted well into the 1990s. In a 1987 survey of US transplant centers, only 8% of the 99 that responded would have considered a stranger as a kidney donor [15]. By 1993, that number had increased only slightly to 15% and not a single one of the few “liberal” centers had used such a donor in the year prior to the survey [16]. In the mid 1990s, the EUROTOLD Project revealed similarly negative attitudes toward strangers serving as kidney donors among most European centers, although a 1995 British Transplantation Society report indicated that more than one-third of renal transplant centers in the United Kingdom would have considered using an altruistic stranger [25]. Although negative attitudes toward strangers donating kidneys are still prevalent today, many centers are beginning to reconsider this issue. In a recent survey of US transplant centers, 38% of the 129 responding said they would consider an altruistic stranger as a kidney donor [17]. Furthermore, a few such transplants have recently been performed [59]. Nevertheless, the practice remains rare, and it is likely that even among centers philosophically accepting of this practice, most are uncomfortable with it and are reluctant to proceed when faced with an actual volunteer [17]. The major concerns about allowing living strangers to donate kidneys are that some of these people may be motivated by psychopathology or financial gain, and that this practice would open the door to commercialism in transplantation [16, 45]. On the other hand, it has been argued that none of these concerns are

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sufficient to prohibit what otherwise might be an acceptable and valuable practice [37–44]. Among the few such donors that have been used there was little evidence of psychopathology [58, 59]; and with regard to the fear of abuse, it has been suggested [38] that the proper response is “to attack the exploitation of the act of donation, not the act itself.” Based on these and other considerations, some commentators now believe that kidney donation by altruistic strangers may be ethically acceptable [38, 44, 59]. However, others do not agree [45] and this issue is still hotly debated within the transplant community. How does the public view this question? Several studies have shown that the public has always been much more accepting and supportive of kidney donation by altruistic strangers than has the transplant community. A 1987 Gallup Poll of the US adult public found that 70% of 1,022 respondents believed that kidney donation by altruistic strangers was acceptable [28]. Twelve years later another Gallup Poll found that support for this practice had actually increased to 80% [49]. Such widespread acceptance bolsters the view that the desire to donate a kidney to a stranger may be a sign of healthy altruism rather than an indicator of psychopathology, a conclusion recently supported by a study of unrelated potential donors [59a]. Believing that kidney donation by strangers is acceptable is not the same as being willing to make such a sacrifice oneself. How many people would actually do this? Several studies have addressed this question. Once again, the results are similar over time. In 1971, Sadler et al. reported that among 450 people surveyed in San Francisco, 19% of them said they were willing to donate a kidney to a stranger who needed a transplant to survive, and 33% were unsure; most who said they would donate were motivated by altruistic reasons [58]. (The effect of transplantation on recipient survival and quality of life are discussed in Chapter Three.) At about the same time, Fellner and Schwartz surveyed 116 adults in a Midwestern city; 11% said they would definitely donate a kidney to a stranger and 43% said they probably would [3]. One year later, Gade reported that 41% of 119 people interviewed in Detroit would have considered donating a kidney to a stranger [60]. In 1985, Stiller et al. surveyed 43 Canadian kidney donors and found that 26% would have considered donating a kidney to a stranger [29]. In 1998, Toronyi et al. reported a survey of 30 Hungarian living related kidney donors; 46% said they would have donated a kidney to a stranger [50]. More recently, Spital reported the results of a Gallup Poll of 1,009 randomly chosen members of the US adult public; despite informing respondents that donation requires major surgery and that rare donor deaths have occurred, almost one quarter of the respondents said they would donate a kidney to a stranger, and a nearly equal number said they would probably do so [49]. These data demonstrate a remarkable degree of professed public altruism. Of course, opinion polls that ask about willingness to do noble deeds may not be very reliable. The knowledge and beliefs upon which responses are based may not be correct. For example, there are probably misconceptions about the benefits of and alternatives to renal transplantation for recipients as well as misunderstanding about the risk for the donor. Some respondents may give what they believe to be socially desirable answers rather than genuine ones. Others may think they would donate but in fact they would not when confronted with a real situation. Indeed, it is likely that the results of these surveys overestimate the number of

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people who would truly be willing to donate a kidney to a stranger. However, several considerations suggest that the estimates provided may not be as far from reality as one might think [49]: (1) the anonymity of the respondents reduces the social desirability factor; (2) the results of the studies are consistent; (3) there have been people who have actually donated kidneys to strangers and many more who have volunteered [58, 59]; and (4) the National Marrow Donor Program now has over three million registered volunteers who are prepared to donate bone marrow to a stranger, which demonstrates that there are in fact many people who are willing to make major sacrifices and take risks to help people they do not know [61]. But regardless of the number of people who would actually donate a kidney to a stranger, the data indicate that at least most would find it acceptable for others to do so [49]. This high level of public support for kidney donation by strangers is probably due to: (1) publicity about the severe shortage of organs and the success of kidney transplantation; (2) trust in the medical profession to minimize the danger of donating; and probably most importantly, (3) widespread respect for individual autonomy and the belief that people should be free to decide for themselves whether or not to take risks to help others. Attitudes Toward and Use of Children as Living Kidney Donors The use of children as living kidney donors dates back to the earliest days of renal transplantation [62, 63]. At that time, successful transplantation could be achieved only in those rare recipients who were fortunate enough to have a healthy identical twin willing to donate a kidney. And before the availability of dialysis, renal transplantation offered ESRD patients the only hope for long term survival. Therefore, some of the initial kidney transplants were performed between identical twins younger than 18 years of age. However, this practice generated major ethical concerns. These include [64, 65]: (1) the inability of children to balance risks and benefits and provide valid consent to a major surgical procedure; (2) the concern that children may not feel free to say no for fear of jeopardizing parental love; (3) the conflict of interest for parents when siblings are involved; and (4) the risk of living a lifetime with only one kidney. Nevertheless, because of the lack of alternatives, renal transplantation between identical twin minors became an accepted practice at some centers [63]. Since those early days, the situation has changed dramatically. The dream of successfully transplanting less well-matched donor-recipient pairs soon became a reality and along with dialysis provided alternative treatments for ESRD patients. Identical twin donors were no longer the only hope for recipient survival. Concerns about using children as kidney donors remained great and nearly universal. Therefore, it is not surprising that very few children have donated kidneys. According to the United Network for Organ Sharing, between 1995 and 2002 only 24 renal transplants were performed in the United States using kidneys from living donors less than 18 years old [66]. However, occasionally the question of kidney donation by children still arises when a highly sensitized child doing poorly on dialysis has a well-matched young sibling and no other potential living donor is available.

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Some commentators have argued that children should never serve as kidney donors [67]. In agreement with this suggestion, ten years ago the World Health Organization concluded [35]: “No organ should be removed from the body of a living minor for the purpose of transplantation.” On the other hand, others believe that under very special circumstances (which must include an extremely low risk of uninephrectomy) it may be ethically acceptable to allow children to donate kidneys [62, 65, 68]. It has been suggested that mature minors (at least 14 years old) should be considered capable of providing valid consent for kidney donation if a careful evaluation finds them to be competent and acting voluntarily [68, 69]. And according to The Council on Ethical and Judicial Affairs of the American Medical Association [68], even immature minors may rarely be acceptable sources of kidneys under unusual circumstances in which the parents, health professionals, and the court all agree that transplantation would provide a “clear benefit” to the “minor source.” The latter standard is appropriately much more stringent than is the standard applied to competent volunteers. How do transplant centers view these issues? In a 1987 survey of US centers, 64% of the 99 responding said they would consider allowing a monozygotic twin minor (< 18 years of age) to donate to her twin, and 43% would have considered using non-twin minors as donors for closely related family members [15]. The minimum acceptable donor age varied widely, ranging from 5–21 years; of the 75 centers that answered this question, 44 (59%) would have considered using willing children less than 18 years old. More recent studies have shown that attitudes toward kidney donation by minors have become more conservative. In a 1993 survey of all UNOS approved renal transplant centers which was conducted by the American Society of Transplant Physicians, only 18% of those responding would have considered volunteers less than 18 years old [19]. Three years later, another survey [65] again found that only a small number of US centers (24% of the 143 responding) would have considered children less than 18 years of age; even in the special case of monozygotic twins, only 33% would have considered accepting a minor as a kidney donor. Among the few centers that would have considered using minors, the great majority would have required consent from the child, the parents, and the courts, and many would have asked for permission from an appointed guardian. Not surprisingly, in the year prior to this survey, only two kidney transplants from minor sources were performed among all the responding centers. These results contrast sharply with the more liberal approach revealed in the 1987 survey and are probably explained by the steadily improving efficacy of alternative therapies for children with ESRD and the great concern about the propriety of removing a kidney from a child to help another person. Attitudes among European transplant centers appear to be similar. The EUROTOLD study found that very few of the surveyed centers would have considered volunteers under the age of 18 [25]. Even in the case of a 14 year old doing poorly on dialysis who had a willing monozygotic twin, only about one-third of the responding centers would have been willing to consider the healthy twin as a donor [25]. This result is almost identical to that uncovered in the 1996 US study [65]. It should also be noted that in several countries, organ donation by minors is prohibited by law [25]. There are few data regarding public attitudes toward living minors serving as

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sources of kidneys. In a 1991 national telephone survey of 1,000 members of the US public, 45% of the respondents thought it was acceptable for a child less than 18 to give a kidney to a relative, 42% thought this would be unethical, and 13% were unsure [70]. It appears that the public may be less opposed to kidney donation by minors than is the transplant community. Support among the public might have been even greater had they been asked to consider a child doing poorly on dialysis who had a willing identical twin and had they been told how successful kidney transplants between twins are. Attitudes Toward Kidney Donors at Added Risk In the early days of renal transplantation, the lack of alternative treatments for desperately ill patients with ESRD led to the acceptance of living kidney donation even though the long term risks of donor nephrectomy were unknown. In fact, some volunteers were accepted despite having medical conditions that probably increased the risk of donating [71]. Today there are other good treatments for ESRD patients, and most transplant centers require living kidney donors to be almost perfectly healthy. But what if the mother of a child doing poorly on dialysis wants to give a kidney to her child even though the mother has a medical problem that increases her risk of donating? Will transplant centers accept such a highly motivated volunteer despite added risk? Does the potential donor have any say in determining her own suitability? These questions were addressed in a survey of US transplant centers performed in 1983 [13]. The centers were asked if they would accept a volunteer with orthostatic proteinuria as a kidney donor. Fifty-eight percent of the 85 responding centers would have rejected this person and 18% would have discouraged him. Considering the benign nature of orthostatic proteinuria as discussed in Chapter Four, these results indicated that most transplant centers were unwilling to accept potential donors at added risk, even when the risk is very low. It is not known if centers would not have accepted these donors because there may have been some added risk or because the centers could not estimate the risk. (This distinction is discussed in Chapter One, and the risk to a donor with low grade proteinuria is discussed in Chapter Four.) The results also showed that the final decision regarding acceptability was usually made by the transplant center with the volunteer having little or no say. These findings were confirmed in another study of US transplant centers performed two years later [14]. How does the public view these issues? Are people who wish to donate kidneys willing to accept more risk than their physicians think they should? These issues were explored in a survey of 264 adults in Rochester, New York [28]. Not surprisingly, over 60% were willing to accept a great deal of added risk to donate to their children, and most of the remainder were willing to accept a moderate amount of added risk. Furthermore, over 70% of the participants believed that in situations of added risk, they, rather than their physicians, should have the final say about whether or not they may donate their kidneys. These local results were confirmed in a larger survey of 1,022 randomly chosen adult members of the U.S. public conducted by the Gallup Organization [28]: 76% said they would likely donate to their children even if added risk were involved, and 76% believed that the final say regarding suitability should rest with the prospective donor. The results

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of a recent study of public attitudes toward living liver donation were similar [72]. These data show that transplant centers are much more conservative than the public regarding the acceptability of volunteers at added risk. This is not surprising. When the health of a close friend or relative is at stake, many people want to do whatever they can to help the person who means so much to them, even if risk is involved [73]. However, it is also understandable that many transplant centers often do not allow volunteers to decide about donation for themselves in the face of added risk. Several factors explain this paternalistic approach [44]. Most volunteers lack medical expertise; thus, there is concern about the ability of potential donors to understand fully the risks they are undertaking and to provide valid consent. Perhaps even more important is the fact that physicians are the agents of donation – kidney donation cannot be accomplished without their help. Therefore, transplant physicians naturally feel responsible for the welfare of each volunteer and would probably be devastated should any serious harm come to the donor as a result of nephrectomy, especially because kidney donation is intended primarily to help someone else. On the other hand, it has been argued that while these concerns have merit, there are also problems with transplant center paternalism [42, 44]. Implicit in the paternalistic approach is the assumption that physicians are able to assess and prioritize the relative risks and benefits of donating better than the volunteers themselves. But such an assessment depends heavily upon personal values, which, are not universally shared [74]. Therefore, despite their medical expertise, transplant centers may not always know or be in the best position to decide what is in the best overall interests of a given well informed and willing volunteer. Based on these considerations, some people believe that competent potential donors at added risk should have a greater voice in determining their own suitability [13, 42, 44, 75]. The ethical rationale for performing living donor kidney transplants and for refusing certain living donors is considered further in Chapter One, and counseling techniques to help insure donor understanding and freedom from coercion are discussed in Chapter Seven . Summary and Conclusions Attitudes toward living kidney donors among US transplant centers are generally positive. Almost all US centers now perform kidney transplants from genetically related living donors. In general, such individuals must be in excellent health and will not be accepted if they have conditions that place them at added risk. Attitudes toward emotionally related donors have also become favorable. As a result, a steadily growing number of emotionally related donor kidney transplants are being performed, although the degree of enthusiasm for this practice still varies widely. Most transplant centers remain opposed to using altruistic strangers as donors, but even here there has been a gradual liberalization of views and practice. Attitudes about children serving as kidney sources have become more conservative and only a few centers will consider minors. While transplant center attitudes toward living kidney donors have undergone major changes over time, the views of the public have been much more constant

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and overwhelmingly positive. This is not surprising when one considers the different perspectives of each [76]. Transplant centers are appropriately concerned about the welfare of living donors and must be convinced that donation is reasonable and ethically sound. Some centers seem to believe that donation must be completely safe to be acceptable, a view that is questioned elsewhere in this book. Given the small but real dangers of donor nephrectomy and the unique status of the donor as a patient, it is understandable that transplant centers have generally taken a conservative stance when evaluating volunteers. In contrast, people who offer to donate kidneys are often not concerned with risks or ethical questions but rather with an ill person who is very dear to them. Accordingly, if there is any reasonable chance for success, many people will choose to donate almost regardless of the risks involved. This caring response is neither new nor unique to transplantation and provides an explanation for the rapid and unconsidered choices that some donors make. Such a response makes it more difficult for centers to educate these donors and obtain fully informed and considered consent. Whether the divergent attitudes towards living donation of a more permissive general public and a more conservative transplant community can be brought closer together by a systematic consideration of the ethical justification for living kidney donation and proper counseling of living donors remains to be seen.

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40. Levey AS, Hou S, Bush HL. Kidney transplantation from unrelated living donors: time to reclaim a discarded opportunity. N Engl J Med. 1986; 314: 914–6. 41. Newton WT. Who is the brother that I should keep? Arch Surg. 1979; 114: 992–3. 42. Spital A. The ethics of unconventional living organ donation. Clin Transplant. 1991; 5: 322–6. 43. Spital AL. Unrelated living donors: should they be used? Transplant Proc. 1992; 24: 2215–7. 44. Spital A. When a stranger offers a kidney: ethical issues in living organ donation. Am J Kidney Dis. 1998; 32: 676–91. 45. Broyer M, Affleck J. In defense of altruistic kidney donation by strangers: a commentary. Pediatric Nephrology. 2000; 14: 523–4. 46. Isoniemi H. Living kidney donation; a surgeon’s opinion. Nephrol Dial Transplant. 1997; 12: 1828–9. 47. Blake PG, Cardella CJ. Kidney donation by living unrelated donors. CMAJ. 1989; 141: 773–5. 48. Soulillou JP. Kidney transplantation from spousal donors. N Engl J Med. 1995; 333: 379–80. 49. Spital A. Public attitudes toward kidney donation by friends and altruistic strangers in the United States. Transplantation. 2001; 71: 1061–4. 50. Toronyi E, Alfoldy F, Jaray J et al. Attitudes of donors towards organ transplantation in living related kidney transplantations. Transplant Int. 1998; 11 (Suppl 1): S481–3. , 51. Summary report of the end stage renal disease (ESRD) Networks Annual Reports, 2001. HCFA, Baltimore, MD. www.hcfa.gov\quality\5d.htm 52. Alfani D, Pretagostini R, Rossi M, Poli L et al. Analysis of 160 consecutive living unrelated kidney transplants: 1983–1997. Transplant Proc 1997: 29: 3399–401 (Completed reference). 53. Binet I, Bock AH, Vogelbach P et al. Outcome in emotionally related living kidney donor transplantation. Nephrol Dial Transplant 1997; 12: 1940–8. 54. Foss A, Leivestad T, Brekke IB et al. Unrelated living donors in 141 kidney transplantations. Transplantation. 1998; 66: 49–52. 55. Terasaki PI, Cecka JM, Gjertson DW, Takemoto S. High survival rates of kidney transplants from spousal and living unrelated donors. N Engl J Med. 1995; 333: 333–6. 56. Spital A. Do US transplant centers encourage emotionally related kidney donation? Transplantation. 1996; 61: 374–7. 57. Karcher H. German doctor donates kidney. BMJ. 1996; 313: 443. 58. Sadler HH, Davison L, Carroll C, Kountz SL. The living, genetically unrelated, kidney donor. Seminars Psych. 1971; 3: 86–101. 59. Matas AJ, Garvey CA, Jacobs CL, Kahn JP. Nondirected donation of kidneys from living donors. N Engl J Med. 2000; 343: 433–6. 59a. Henderson AJZ, Landolt MA, McDonald MF, et al. The living anonymous kidney donor: lunatic or saint? Am J Transplantation 2003; 3: 203–13. 60. Gade DM. Attitudes toward human organ transplantations. A field study of 119 people in the greater Detroit area. Henry Ford Hospital J. 1972; 20: 41–50. 61. Walker T. The National Marrow Donor Program. Minnesota Med. 1999; 82: 26–8. 62. Fost N. Children as renal donors. N Engl J Med. 1977; 296: 363–7. 63. Tilney NL. Renal transplantation between identical twins: a review. World J Surg. 1986; 10: 381–8. 64. Hollenberg NK. Altruism and coercion: should children serve as kidney donors? N Engl J Med. 1977; 296: 390–1. 65. Spital A. Should children ever donate kidneys? Views of US transplant centers. Transplantation. 1997; 64: 232–6.

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66. www.unos.org/Newsroom/critdata_donors.htm 67. Daube D. Transplantation: acceptability of procedures and the required legal sanctions. In: Wolstenholme GEW, O’Connor M (eds), Ethics in Medical Progress: With Special Reference to Transplantation. Boston: Little Brown, 1966; 198. 68. Council on Ethical and Judicial Affairs, American Medical Association. The use of minors as organ and tissue donors. Code Med Ethics Rep. 1994; 5: 229–42. 69. Price DPT. Minors as living organ donors: ethics and law. Transplant Proc. 1996; 28: 3607–8. 70. Poll conducted by Yankelovich Clancy Shulman for Time/CNN, June 4–5,1991. 71. Bennett AH, Harrison JH. Experience with living familial renal donors. Surg Gyn Ob. 1974; 139: 894–8. 72. Cotler SJ, McNutt R, Patil R et al. Adult living donor liver transplantation: preferences about donation outside the medical community. Liver Transplantation 2001; 7: 335–40. 73. Spital A. Ethical issues in living organ donation: donor autonomy and beyond. Am J Kid Dis. 2001; 38: 189–5. 74. Childress JF. Who Should Decide? Paternalism in Health Care. New York: Oxford University Press, 1982; 48. 75. Steiner RW, Gert B. Ethical selection of living kidney donors. Am J Kidney Dis. 2000; 36: 677–86. 76. Elliott C. Doing harm: living organ donors, clinical research and The Tenth Man. J Med Ethics. 1995; 21: 91–6.

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Index autosomal dominant adult polycystic kidney disease 71 availability of cadaver donors 17 average waiting time 36, 135, 136

2 hour oral glucose tolerance test (oGTT) 105 2 hour post prandial blood glucose 100 24 hour monitoring 81, 90, 92, 94 ability of potential donors to understand 151 abnormal laboratory findings 58 acceptable donors 3, 11, 53, 75, 129, 133, 134, 149 acute postoperative rejection 45 adequate reason 7, 10, 11, 129 adherence to medication regimen 42, 45 advanced glycation end products (AGEs) 107, 116 advancing recipient age 28 age of onset of diabetes 103 agents of donation 151 albumin excretion rate (AER) 110, 115 aldose reductase 107, 108, 116 - inhibitors 116 alternative treatments for potential recipients 143 altruism 3, 147 altruistic donation 8 altruistic stranger 134, 144, 147 - as donors 151 - as kidney donors 146 American Diabetes Association (ADA) 104 angiotensin converting enzyme (ACE) inhibitors 108, 115, 116 - for renal protection 115 annual death rates 20 anti islet cell antibodies 99 antihypertensive therapy 93, 110, 114 appropriate ethical considerations 2 arteries and arterioles of the hypertensive kidney 83 assessment of health-related quality of life 21 asymptomatic microscopic hematuria (AMH) 59-62 attitude and belief questionnaires 129 attitudes toward unrelated living donors 144 autoantibody testing 106 autoimmune beta cell destruction 101

baseline pre-donation risk of ESRD 51, 73 basic consideration in donor education 134 benefit of transplantation 13, 19, 28, 30 benign nephrosclerosis 83 biopsies 59, 61-63, 65, 83, 89, 109, 110, 112, 120 black donors 3, 71, 72 black patients 71, 82, 85-87, 89 black subjects 71 blood pressure control 85-87, 93, 115 blood pressure of uninephrectomized subjects 90, 91 blood pressures by 24 hour monitoring 96 blood relatives 3, 5, 71, 72 blood type compatibility 37 bystander 7 cadaver donor kidney results 41 cadaver kidney donors 36 calcium channel blockers 115 calcium containing stones 66 captopril 115 cardiovascular disease 14, 19, 23, 28, 40, 42, 46, 81, 93, 94, 109, 119, 120 cause of donor death 45 causes of death 18, 19 causes of ESRD 15, 57, 67 cavalier in its donor evaluations 7, 73 center attitudes toward living kidney donors 151 center effect 42, 45 center neutrality 132 center practices 70, 74, 145 certain knowledge 7 chemical turbidity technique 63 children as living kidney donors 148 chilling features 131 choice of antihypertensive agents 114 chronic nephritic 65 157

158

INDEX

cigarette smokers 64 cigarette smoking 116 clarify ethical debate 2 combined hematuria and proteinuria 65 co-morbidity 14, 16, 23 compensation for donors 8 compensatory hypertrophy 69, 111 confidentiality 129, 131, 132, 139 - of the evaluation 129, 139 conflicts of interest 1, 2, 10, 62, 129, 137, 148 continuum of risk model 135 coping skills 133 correctly formulating 9 cost of donor medical care 10 costs of renal disease 14 counseling donors 57, 112 counseling donors as to degree of risk 9 coxsackie B virus 101 crossmatch negative 38 cystoscopy 59, 62 dangers of donor nephrectomy 152 DCCT 109, 113, 114 death with a functioning graft 46, 47 death with graft function 46, 48 definition of hypertension 82 deformed red cells 59 delayed graft function (DGF) 42-44, 45, 48 deterioration in the appearance domain 24 development of diabetic nephropathy 106-108, 110, 121 diabetic afro americans 108 diabetic basement membrane 107 diabetic changes established in a kidney transplant 112, 120 diabetic complications 99, 100, 114, 117, 118, 120 diabetic glomerulosclerosis 107, 109 diabetic kidney failure 100 diabetic mexican americans 108 diabetic nephropathy 47, 51, 55-57, 99, 100, 103, 105-114, 116, 121 diabetic probands 102, 106, 109 diabetic recipients of transplanted kidneys 112 diabetic risk 51, 56, 100, 101, 104, 105

diabetic sibling 103, 109 diabetics with a single native kidney 112 diastolic blood pressure over eighty 65 diastolic blood pressure over ninety 65, 82 differences among center practices 74 differences in the incidence of type I diabetes 102 dihydropyridine 116 dipstick proteinuria 60, 63-65 disagreements 2, 8, 9, 59, 75 disease demographics 57 disease-specific tools 22 donation and the development of hypertension 90 donor 1-11, 14, 17, 18, 23-25, 30, 35-46, 48, 51-75, 81-83, 85, 87, 89-95, 99, 106, 109, 110, 113, 114, 117, 119122, 129-139, 141-152 donor acceptance 105 donor age 37, 41, 43, 45, 46, 48, 65, 149 donor cannot be counseled 138 donor deaths 45, 142, 147 donor emotion 5 donor factors 42 donor information 130, 131 donor medical care 10 - long term 131 donor medical evaluation 52, 53, 74, 130 donor meetings 130 donor reward 8 donor understanding 4, 5, 130, 133, 135, 138, 139, 151 donor weight 93 donor who is being pressured 6 donor/nondonor profiles 134 donor’s expectations 10, 134, 138 donor’s medical records 132 donor’s understanding of risk 4, 133 donors can be unacceptable 138 donors rejected for ineducability 138 donors who are pressured 134 donors who develop ESRD 68 dutiful donors 3, 4 early disclosure 131 economically irresponsible policies 74 educate all possible donors 130 elderly or malnourished patients 23

INDEX

elevated fasting blood glucose 104 emotionally related donors 145, 146, 151 emotionally related friends 45 emotionally related kidney donation 145 employment following renal transplantation 25, 26 employment outcomes 25 end stage glomerulonephritis 61, 66 end stage renal disease by patient characteristics and treatment modality 16 ensuring donor understanding 133 ESRD - from hypertension 84-86, 89, 94 - baseline pre-donation risk of 51, 73 - causes of 15, 57, 67 - donors who develop 68 - genetic susceptibility to hypertension and 89 - hypertensive 55, 57, 84 - incidence of 14, 56-58, 60, 65, 66, 71, 72, 83 - lifetime baseline risk for 57 - patient survival with 17 - prevalence of 14 - - from hypertension 84 - rate of, from hypertension 86 - relative with 71, 72, 89 - relatives of patients with ESRD 71, 89 - risk of 6, 7, 51, 53, 55, 58, 60, 61, 65, 67, 71-74, 84, 86, 89, 94, 131, 138 - - from hypertension 84, 86, 89, 94 estimate of baseline donor risk 75 estimating risk 52, 56, 82 ethical requirements appropriate to bystanders 7 euglycemic hyperinsulinemia 104 euglycemic insulin clamp test 106 European transplant centers 145, 149 EUROQOL 21 EUROTOLD project 145, 146, 149 evidence-based comparison of alternatives 14 exercise 58, 61, 104, 110, 114, 116, 120 extended donor kidneys 41 extended donors 39 facilitator of an individuals desire to donate 129, 132 factual issues 2

159 factual question 2, 134 familial associations 71 familial clustering 72, 89, 109 family history of diabetes 94, 100, 104, 105, 121 family history of hypertension 81, 94, 95 family history of type II diabetes 104, 105 family tendency to hypertension 109 feedback based testing 135 female with idiopathic hematuria 62 fibromuscular hyperplasia (FMH) 70, 71 fields of stick figures 129, 135, 137 first stone 66, 67 five year survival for cadaver kidneys 41 fixed proteinuria 110, 111 focal segmental glomerulosclerosis 47 Framingham Study 63 free and voluntary 4, 6, 138 freedom from dialysis 13, 30 full disclosure 3 functional status on dialysis 118 fundamental but unstated ethical rationales 8 Gallup poll 147 general reasons for rejecting a donor 4 genetic profiling 106 genetic susceptibility to hypertension and ESRD 89 genetically unrelated donors 144 gestational diabetes 104, 105 glomerular disease 57, 59-61, 63, 64, 66, 84 glomerular sclerosis 112 glomerulonephritis 16, 47, 56-59, 61, 63, 65, 66, 71, 86, 87 glomerulosclerosis 47, 83, 107, 109, 112 glucose tolerance 99, 104, 105 glycemic control 113, 114, 116 glycemic therapy 114 good samaritan donors 5, 11, 130 graft survival in black recipients 44 graft survival in diabetics 117 greater good 74 half life of a living donor kidney 45 health care financing administration 36, 137

160

INDEX

health related quality of life 20-22, 24 health utilities index 21 Heinoch-Schoenlein purpura 61 hematuria 51, 53, 55, 56, 68-66, 68, 69, 87 heparan sulfate core protein 108 hepatitis c 39-41 hepatitis c positive donors 40 hepbsag positive donors 40 heroic donors 6, 7, 9, 10, 74 hesitant donor 132 heterozygous DQw8/DQw2 102 HIV 1 infection 40 HLA DQ genotypes 102 HLA matching 41, 42, 44, 46, 48 home support 133 homozygous DQw8 102 HSTP 86 hypercalciuria 60, 66, 67 hyperfiltration 53, 107, 108, 110-113, 116 hyperinsulinemia 94, 104 hyperlipemia 116 hypertension 15, 16, 28, 44-46, 51, 5558, 60, 63, 66-68, 71, 72, 81-95, 100, 105, 107-110, 112, 115 hypertension detection and follow up program (HDFP) 85, 88 hypertension following nephrectomy 81, 90 hypertension in donors 91 hypertension in kidney donors 91 hypertension in the black population 44, 82 hypertension/large vessel disease 57 hypertensive black patients 71 hypertensive complications 84, 86, 94 hypertensive end stage renal disease 82 hypertensive ESRD 55, 57, 84 hyperurocosuria 66, 67 identical twin donors 148 idiopathic microscopic hematuria (IMH) 59-62 - related nephropathy 61 IgA 61 - nephropathy 47, 59, 60-63, 65, 66 IgM nephropathy 61 immature minors 149

impact of isolated hypertension 82 impaired fasting glucose (IFG) 105 impaired glucose tolerance 104, 105 impartial and thorough education 3 implications of abnormalities 138 incidence and prevalence of ERSD 14 incidence of chronic renal failure 15 incidence of ESRD 56-58, 60, 65, 66, 71, 72, 83 incidence of hospitalization 18 incidence of hypertension between donors and siblings 90 incompatible matches 38 increased glomerular pressure 108 incremental benefit of renal transplantation 28, 29 incremental cost utility 28 indians with type II diabetes 109 individual counseling sessions 132 inescapable risk 67 informational meeting 130, 132 inherent conflicts of interest 2 initial donor education 130 instantaneous decisions 144 instruments to test donor understanding 135 insulin dependent diabetes mellitus (IDDM) 16, 101-103 insulin resistance 104-106, 109 intake of protein 116 interstitial nephritis 57, 58 intraocular bleeding 118 investigate donors 7 iothalamate determined glomerular filtration rate 68, 70 irrational donors 6, 74 irrational for a specific donor 6 islet cell auto antibodies (ICA) 99, 101, 103, 106 islet cell transplants 119 isolated medical abnormality 52, 53, 55, 58 isolated proteinuria 63, 64 IVIG 38 IVP 59 Joint National Committee guidelines 115 kidney biopsy 59

INDEX

kidney dialysis questionnaire and kidney transplant questionnaire 22 kidney donation and increased blood pressure 90 kidney donation by altruistic strangers 147 kidney donor exclusion criteria 55 kidney donors live longer 91 kidney for money donation 33 kidney graft survival 45, 48 kidney pancreas transplantation 119 kidney transplant questionnaire 21, 22, 24 kidney transplantation for older type II diabetics 118 kidneys of patients with hypertension 83 Kimmelstein-Wilson lesions 107 lack of alternative treatments 143, 150 laparoscopic nephrectomy 52 laparoscopic organ recovery 38 level of motivation 5 life years and quality adjusted life years gained 29 lifesaving effects 139 lifetime baseline risk for ESRD 57 lifetime risk of end stage renal disease 73 likelihood of recurrence 66 living donor procedures 36 living unrelated donors 5, 145 long term risks of donation 143 low glomerular filtration rate 68 low PRA 37 lower limit of normal 68 malignancies 14, 16, 19, 28, 39, 40, 46, 59-62 marginal cases 9 material that is not presented personally 130 mature minors 149 measures to isolate the donor 132 medical benefits of transplantation 28 medical care of any long term donor problem 132 membranous disease 61 mental benefits to donors 3 mesangial expansion 107, 112 mesangial proliferation 61

161 mesangial proliferative glomerulonephritis 65 microalbuminuria 64, 107, 109, 110, 112-116 minimal proteinuria 61, 62 minor as a kidney donor 149 misconceptions about the benefits 147 mislead or poorly counseled 137 misunderstanding about the risk 147 monzygotic twin minor 149 morbidity and mortality 18, 28 mortality of young diabetics 28 mortality rates in kidney transplant recipients 46 multiple risk factor intervention trial (MRFIT) 86-88 multiracial study 72 National health and nutritional examination survey (NHANES) 69, 72, 85, 88 national high blood pressure education program (NHBPEP) 82 national marrow donor program 148 nationally shared cadaver kidneys 39 natural history of diabetic kidney 110 negative aspects of pancreas transplantation 120 negative information about donation 139 neoplasm 57, 59, 61, 62 nephrolithiasis 51, 55, 59, 60, 66, 67 nephrology evaluation 62 nephropathy in a single kidney 113 neuropathy 115, 116, 118, 120 neutral facilitator 10, 131, 132 no idea of donor risk 74 no risk centers 53 non hypertensive primary disease 86 non trauma death 37 non verbal as well as verbal cues 134 non-albumin proteinuria 64 non-dipstick proteinuria 60, 63, 64 non-twin minors 149 normal range 51, 59, 64, 68, 75, 105, 107, 110 normal range for urine protein excretion 64 normal ranges for 24 hour protein excretion 63

162

INDEX

normalizing GFR 68 number of diabetics on dialysis 119 number of live donor transplants 18 number of living donor kidney transplants 143 obesity 20, 81, 93, 94, 103-105 offer of long term care 132 okinawa general health maintenance association 87 optimal therapy 14, 27, 143, 144 oral glucose load 105 oral glucose tolerance test (oGTT) 105 organ donation by minors 149 organ procurement and transplantation network (OPTN) 36 organ procurement organizations (OPO) 36, 37, 39, 45 organ shortage 144, 145 orthostatic proteinuria 150 other countries 143 outcome of renal transplantation 143 overall life satisfaction 22, 24 overt diabetic nephropathy 110, 113 paid donor 8, see also kidney donation for money pancreas transplantation 99, 119-121 pancreatic insulin reserve 105, 106 panel reactive antibodies (PRA) 38, 43 paternalistic approach 151 pathogenesis of type II diabetes 104 patient survival 17, 18, 20, 27, 28, 35, 36, 40, 117-119 - rates 36, 40, 117, 118 - with ESRD 17 Penn cancer registry 40 perioperative morbidity and mortality 52 perioperative risk 2, 52, 104, 118 permission from an appointed guardian 149 phenotypically identical match 39 physical functioning 22-24, 26, 27, 29 physical symptoms 24, 26 plasmapheresis 38 point of indifference 21 polyol formation 107 poor physical functioning 29

popularity of living related donors 142, 143 population screening studies 60 post transplant factors 42 post transplant mortality 42 post uninephrectomy blood pressure 91 potential donors at added risk 150, 151 potential kidney donors exclusion 63 potential of emotionally related donors 146 potential uremic complications 121 practices that might discourage donation 131 pre emptive transplantation 24, 25 predictors of employment status 27 preference measures 21 preference priorities of a hypothetical typical donor 133 prevalence of diabetic nephropathy 100, 113 prevalence of ESRD from hypertension 84 prevalence of hypertension 55, 82, 83, 91, 92, 109 probability of survival 16 progression of diabetic nephopathy 109, 110, 113, 121 progression of nephropathy 113, 115, 116 proportion of live donor transplants 18 protein intake 108, 116 proteinuria 51, 55, 58, 60-66, 68, 69, 8385, 87, 107, 109-113, 115, 116, 150 psychosocial situation 133 public altruism 147 public attitudes 142-145, 149, 151 - toward living minors 149 public support for living donation 143 public unavoidably suspicious 7 quality of life 13, 14, 20-30, 118, 119, 121, 131, 136, 147 - in renal transplant recipients 23 - on dialysis 23 - outcomes 22 race related risks 71, 72 racial difference 44, 84 Rand questionnaire 23 range of risks 73

INDEX

rapid and unconsidered choices 152 rate of ESRD from hypertension 86 rate of increase of microalbuminuria 115 rate of renal decline 112, 113 rates of NIDDM 104 realistic expectations of outcome 138 reasons for donor acceptance or rejection 2, 8, 9 reasons for donor rejection 7, 10, 138 recipient age 28, 42, 48, 120 recipient factors 40, 42 recurrent disease 46 - after renal transplantation 47 refractory to education 138 relative of a dialysis patient 89 relative of black hemodialysis patients 87 relative with ESRD 71, 72, 89 relative with hypertension 87, 89 relatives of patient with type I diabetes 101 relatives of patients with ESRD 71, 89 relatives of the proband 71 religious duty 4 religious reasons 4 renal biopsy 59, 61, 63, 65, 101, 102, 109, 110 renal disease in relatives 87 renal parenchymal tumors 59 renoprotective effect 115, 116 repeat kidney transplants 37 repeat transplant recipient 38 requirement for donor understanding 138 retrospective donor questionnaires 139 return to work 28 reversing some diabetic complications 120 right of the patient to decide 3 right to withdraw 6, 131, 132, 139 risk being unknown 9, 10 risk factors for developing hypertension 92 risk is truly unknown 1, 10, 58, 59, 74 risk of developing diabetes 100-102 risk of developing type I diabetes 102, 106 risk of diabetes 99, 101-103, 106, 121 risk of donor nephrectomy 143

163 risk of ESRD 6, 7, 51, 53, 55, 58, 60, 61, 65, 67, 71-74, 84, 86, 89, 94, 131, 138 - from hypertension 84, 86, 89, 94 risk of heart attack and stroke 81, 94 risk of mortality 16, 20 risk of nephropathy in diabetics 109 risk of renal failure from hypertension 93 risks of cadaver kidney transplantation 40 risks of kidney donation 52, 114, 145 risks of nephrectomy per se 52 safe/unsafe world view 135 satisfaction of kidney donors 138 screening for patients with primary renal disease 86 screening urinalysis 61, 65 secondary GN/vasculitis 57 selection biases 117, 119 self interested rationale 3 sensitivity of the dipstick 63 sensitization and multiple transplants 43 serologic studies 62 serological testing 59 severity of the hematuria 59 sex of donor and recipient 43 sexual dysfunction 24 sf 36 scores 26 shortage of cadaver organs 141, 143 sickness impact profile 19, 20, 22 situations of added risk 150 social functioning 22-24, 26, 27 social worker 139, 133 socially desirable answers 147 socially irresponsible 74 specific donor testing 4 specific immunosuppressive medications 25 specific reason for rejection 6 spectrum of practice 58 SPK organs 120 SPK transplantation 120 SPK transplants 119, 120 spouse donated kidney 46 spouses as donors 145 standard gamble 21 standard medical counseling 75 standard practices at centers 53

164

INDEX

standardized intravenous glucose load 106 steno hypothesis 108 stick figure fields 129, 135, 137 strangers as donors 146, 151 streptozotocin induced diabetes 112 structured donor testing 135 studies on transplant recipients 24 subjective quality of life 26 successful therapy of hypertension 94, 95 survey of U.S transplant centers 142, 146, 149, 150 survival 13, 19, 20, 27-29, 35-39, 45-48, 71, 74, 87, 101, 117-121, 131, 147, 148 - advantage 36, 38, 46 - benefit of transplantation 19 - of diabetics on dialysis 101 - of type I diabetics 117 test donors objectively 129 tested with written material 131 TG feedback 108 thiazides 66 thin basement membrane nephropathy 61 time trade off 21, 25 transmission of disease from donor to recipient 40 transmitting malignancies 39 transplant center paternalism 151 transplantation across incompatible blood groups 46 transplantation as life saving 139 transplantation for diabetics 117 treatment of hypertension 81, 86 treatment of significant donor medical abnormalities 132 treatment of systolic hypertension 93 treatment patterns or chronic renal failure 17 true/false questions 135, 139 true/false tests 129 type I diabetes 101-104, 106, 109, 110, 115-117 type II diabetes 53, 67, 99, 101, 103-106, 109, 111, 114, 116, 117, 119, 121 U.S. diabetes control and complications trial (DCCT) 109, 113

ultimately acceptable donors 5 unemployed patient 29 uninephrectomy 55, 69, 72, 81, 82, 91, 92, 94, 95, 111-113, 142, 149 United kingdom prospective diabetes study (UKPDS) 114 universal donor 37 universal recipient 37 UNOS developed point system 39 UNOS point system 39, 42 unrelated donors 5, 6, 10, 45, 144, 146 unrelated living donors 144, 145 unremitting isolated hematuria 60 unrequested information about donation 130 unsophisticated donors 4 uric acid stones 66, 67 urine dipstick 59, 60, 63-65 uroepithelial tumors 59 urologic disease 16, 56, 61, 67 urologic malignancies 59 urologic series 59, 61 USRDS statistics 17, 18, 51, 55, 56, 61, 65, 85 VA hypertension screening and treatment program 86 valid consent 148, 149, 151 vascular access 118 vascular disease 16, 20, 64, 95, 117-120 verapamil and diltiazem 116 visual rating scale 25 waiting list 8, 19, 20, 35-39, 42, 120, 135, 136 waiting times 20, 35-39, 48, 131, 135, 136 weight at donation 93 weight loss 104, 114, 116 welfare of living donors 152 world health organization definition 20 worst case scenarios 86, 87 written instrument 135, 139 young donors 3, 69 zero mismatched cadaver kidney 42 zero mismatched recipient 39