Renal Failure and Replacement Therapies (Competency-Based Critical Care)

Competency-Based Critical Care

Series Editors John Knighton, MBBS, MRCP, FRCA Consultant Intensive Care Medicine & Anaesthesia Portsmouth Hospitals NHS Trust Portsmouth UK

Paul Sadler, MBChB, FRCA Consultant Critical Care Medicine & Anaesthesia Queen Alexandra Hospital Portsmouth UK

Founding Editor John SP Lumley Emeritus Professor of Vascular Surgery University of London London UK and Honorary Consultant Surgeon Great Ormond Street Hospital for Children NHS Trust (GOSH) London UK

Other titles in this series Sepsis Simon Baudouin (Ed.)

Sara Blakeley (Ed.)

Renal Failure and Replacement Therapies

Sara Blakeley, BM, MRCP, EDIC Queen Alexandra Hospital Portsmouth Hampshire, UK

British Library Cataloguing in Publication Data Renal Failure and Replacement Therapies.—(Competency-based critical care) 1. Kidneys—Diseases 2. Kidneys—Diseases—Treatment 3. Acute renal failure 4. Acute renal failure—Treatment I. Blakeley, Sara 616.6′1 ISBN-13: 9781846289361 Library of Congress Control Number: 2007927934 Competency-Based Critical Care Series ISSN 1864-9998 ISBN: 978-1-84628-936-1

e-ISBN: 978-1-84628-937-8

© Springer-Verlag London Limited 2008 Apart from any fair dealing for the purposes of research or private study, or criticism or review, as permitted under the Copyright, Designs and Patents Act 1988, this publication may only be reproduced, stored or transmitted, in any form or by any means, with the prior permission in writing of the publishers, or in the case of reprographic reproduction in accordance with the terms of licences issued by the Copyright Licensing Agency. Enquiries concerning reproduction outside those terms should be sent to the publishers. The use of registered names, trademarks, etc. in this publication does not imply, even in the absence of a specific fi statement, that such names are exempt from the relevant laws and regulations and therefore free for general use. Product liability: The publisher can give no guarantee for information about drug dosage and application thereof contained in this book. In every individual case the respective user must check its accuracy by consulting other pharmaceutical literature. 9 8 7 6 5 4 3 2 1 springer.com

Contents

Contributors . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Chapter 1

Assessment of Renal Function . . . . . . . . . . . . . . . . . . . . . Mohan Arkanath

Chapter 2

Imaging of Acute Renal Failure—A Problem-Solving Approach for Intensive Care Unit Physicians . . . . . . . . Tom Sutherland

vii 1

7

Chapter 3

Drug-Induced Renal Injury . . . . . . . . . . . . . . . . . . . . . . . . Sara Blakeley

14

Chapter 4

Acute Kidney Injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . Sara Blakeley

19

Chapter 5

Medical Management of Acute Renal Failure . . . . . . . . Nerina Harley

26

Chapter 6

Acute Renal Failure in the Surgical Patient . . . . . . . . . . Marlies Ostermann

33

Chapter 7

Rhabdomyolysis and Compartment Syndrome . . . . . . . Laurie Tomlinson and Stephen Holt

38

Chapter 8

Multisystem Causes of Acute Renal Failure . . . . . . . . . . Tim Leach

42

Chapter 9

Therapeutic Plasma Exchange . . . . . . . . . . . . . . . . . . . . . Tim Leach

49

Chapter 10 Renal Replacement Therapy . . . . . . . . . . . . . . . . . . . . . . . John H. Reeves

51

Chapter 11 Technical Aspects of Renal Replacement Therapy . . . . Sara Blakeley

57

v

vi

Contents

Chapter 12 End-Stage Renal Disease . . . . . . . . . . . . . . . . . . . . . . . . . . Emile Mohammed

64

Chapter 13 Clinical Hyperkalemia and Hypokalemia . . . . . . . . . . . . Harn-Yih Ong

71

Chapter 14 Clinical Hyponatremia and Hypernatremia . . . . . . . . . . Himangsu Gangopadhyay

77

Chapter 15

Clinical Metabolic Acidosis and Alkalosis . . . . . . . . . . . Sara Blakeley

81

Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .

87

Contributors

Mohan Arkanath, MRCP Consultant Nephrologist Doncaster Royal Infi firmary Doncaster, UK Sara Blakeley, BM, MRCP, EDIC Queen Alexandra Hospital Portsmouth Hampshire, UK Nerina Harley, MBBS, MD, PGDIPEcho, FRACP, FJFICM Intensive Care Consultant The Royal Melbourne Hospital Victoria, Australia Stephen Holt, PhD, FRCP Consultant Nephrologist and Honorary Senior Lecturer Sussex Kidney Unit Brighton and Sussex University Hospitals Royal Sussex County Hospital Brighton, UK Himangsu Gangopadhyay, MD, MBBS, FFARCS(Ireland), FJFICM Consultant in Intensive Care Frankston Hospital Frankston, Victoria, Australia Tim Leach, BM, FRCP Consultant Nephrologist Wessex Renal and Transplant Unit Queen Alexandra Hospital Portsmouth, UK Emile Mohammed, MB, ChB, MRCP (UK) Lecturer in Medicine (University of the West Indies) and Consultant Nephrologist

School of Clinical Medicine and Research Queen Elizabeth Hospital & Cavehill Campus Bridgetown, Barbados Harn-Yih Ong Registrar Intensive Care St Vincent’s Hospital Melbourne, Victoria Australia Marlies Ostermann Consultant Nephrology and Critical Care Intensive Care Unit St Thomas’ Hospital London, UK John H. Reeves, MD, MBBS, FANZCA, FJFICM, EDIC Consultant in Intensive Care and Anaesthetics Department of Anaesthesia and Pain Management Alfred Hospital Melbourne, Victoria Australia Tom Sutherland, MBBS (Hons) Radiology Registrar St Vincent’s Hospital Melbourne, Victoria Australia Laurie Tomlinson, MRCP Specialist Registrar Nephrology Sussex Kidney Unit Brighton and Sussex University Hospitals Royal Sussex County Hospital Brighton, UK

vii

1 Assessment of Renal Function Mohan Arkanath

Normal Functions of the Kidney To be able to assess a degree of renal function or dysfunction, it is important to first fi consider the normal functions of the kidney: 1. Maintenance of body composition: The volume of fl fluid in the body, its osmolarity, electrolyte content, concentration, and acidity are all regulated by the kidney via variation in urine excretion of water and ions. Electrolytes regulated by changes in urinary excretion include sodium, potassium, chloride, calcium, magnesium, and phosphate. 2. Excretion of metabolic end products and foreign substances: The most notable are urea and a number of toxins and drugs. 3. Production and secretion of enzymes and hormones: a. Renin: See Figure 1.1. b. Erythropoietin: A glycosylated, 165-amino acid protein produced by renal cortical interstitial cells that stimulates maturation of erythrocytes in the bone marrow. c. 1, 25-Dihydroxyvitamin D3: The most active form of vitamin D3, it is formed by proximal tubule cells. This steroid hormone plays an important role in the regulation of body calcium and phosphate balance.

The Role of the Kidney in Homeostasis Maintenance of body fluid fl composition and volume are important for many functions of the body. For example, cardiac output and blood pres-

sure are dependent on optimum plasma volume, and most enzymes function best in narrow ranges of pH or ion concentration. The kidneys take up the role of correcting any alterations in the composition and volume of body fluids that occur as a consequence of food intake, fl metabolism, environmental factors, and exercise. In healthy individuals, these corrections occur in a matter of hours, and body fluid fl volume and the concentration of most ions return to normal set points. In many disease states, however, these regulatory processes are disturbed, resulting in persistent deviations in body fl fluid volume and composition.

Body Fluid Composition A large proportion of the human body is composed of water (Table 1.1). Adipose tissue is low in water content and, hence, obese individuals have a lower body water fraction than lean individuals. Because of slightly greater fat content, women generally contain less water than men.

Clinical Evaluation of Renal Function Glomerular filtration fi rate (GFR) is generally considered the best measure of renal function; it is the sum of filtration fi rates of all of the functioning nephrons. It is defined fi as the renal clearance of a particular substance from plasma, and is expressed as the volume of plasma that can be completely cleared of that substance in a unit of time. In the following sections, we will compare the advantages

1

2

M. Arkanath TABLE 1.2. Other factors altering blood urea or serum creatininea

Renin Angiotensinogen (Plasma globulin)

Angiotensin (Vasoconstrictor)

Increased level

Salt balance and blood pressure control

Urea

FIGURE 1.1. Production and secretion of enzymes and hormones for renin.

and disadvantages of the various methods available for GFR estimation or quantification. fi

Creatinine

Clearance Urine mg/dL Volume mL/min ) = (mL/min ) Plasma mg/d ) Where x is the substance being cleared. Features of an ideal marker for determination:

GFR

• Appears endogenously in the plasma at a constant rate • Is freely filtered by the glomerulus • Does not undergo reabsorption or secretion by the renal tubule • Is not eliminated by extrarenal routes

Urea

TABLE 1.1. Body fluid compartment volumesa Example for a 60-kg patient

a

Cirrhosis Protein malnutrition Water excess (e.g., SIADH, saline infusion) leads to reduced tubular reabsorption

Decreased muscle mass

a

SIADH, syndrome of inappropriate ADH secretion.

Creatinine

Urea was first isolated in 1773, and urea clearance as a surrogate marker for GFR introduced in 1929. Although urea measurement is performed frequently, it is well recognized that its many drawbacks make it a poor measure of renal function (see Table 1.2). For example, the rate of production is influenced fl by factors such as the availability of nitrogenous substrates, and the rate of reabsorption in the tubules can be affected by volume status.

TBW = 60% × body weight ICW = 2/ TBW ECW = 1/ TBW Plasma water = 1/ ECW Blood volume = Plasma water ÷ (1 − hematocrit)

Prerenal causes (e.g., congestive heart failure, volume contraction) lead to increased tubular reabsorption • Gastrointestinal bleeding • Catabolic state • Corticosteroids • Hyperalimentation • Tetracyclines Overproduction (e.g., rhabdomyolysis, vigorous sustained exercise, anabolic steroids, dietary supplements such as creatine) Blocked tubular secretion (e.g., drugs such as trimethoprim and cimetidine) Assay interference (e.g., ketosis and drugs such as cephalosporins, flucytosine, methyldopa, levodopa, and ascorbic acid)

Decreased level

60% × 60 kg = 36 L / × 36 L = 24 L 1/ × 36 L = 12 L 1/4 × 12 L = 3 L 3 L ÷ (1 − 0.40) = 6.6 L 23

TBW, total body water; ICW, intracellular water; ECW, extracellular water.

Creatinine is a metabolite of creatine and phosphocreatine found in skeletal muscle. It is a small molecule that is not protein bound and, hence, freely filtered by the glomerulus. It does, however, undergo tubular secretion which is variable (see Table 1.2). Creatinine production can vary in an individual over time with muscle mass changes or acutely with massive myocyte turnover. There are also age- and sexassociated differences in serum creatinine (Sα) concentration; it is lower in the elderly and in women. The ratio between serum urea and creatinine can be useful when assessing the patient with acute renal failure. Under normal circumstances, the ratio between urea and creatinine is 10 : 1 but this value can rise to greater than 20 : 1 when the extracellular volume is contracted. A volume-contracted state ((prerenal) is a “sodium avid” state and promotes proximal tubular and distal nephron reabsorption of urea but not creatinine. Acute

1. Assessment of Renal Function

tubular necrosis (ATN) will have a urea-to-creatinine ratio of 10 : 1 because tubular reabsorption of urea is not preferentially increased.

Assessment of GFR Sα has become a standard measure of renal function because of its convenience and low costs; however, it is crude marker of GFR. A 24-hour creatinine clearance (Cα) is often used in practice as a measure of the GFR because creatinine is freely fi filtered and not reabsorbed by the tubule. However, approximately 15% of urinary creatinine is a result of tubular secretion and, thus, this method overestimates GFR. The other problems with Cα are incomplete urine collection and increasing creatinine secretion. Inulin clearance is traditionally considered the “gold standard” for the measurement of GFR (1). It is one of the most accurate measures of renal function, but the inconvenience of administration, cost, and limited supply of inulin preclude its use in routine practice.

Estimated Ca: The Cockroft and Gault Formula (2) This formula is used to estimate Cα at the bedside using age of the patient and Sα value (both correlate inversely with GFR), and the ideal body weight (IBW) of the patient. This formula can used only when the Sα value is in a steady state and not when it is rapidly changing, as in acute renal failure. It has also been shown that Sα and estimations of GFR using various formulae are often inaccurate in critically ill patients (3). Although they may give an estimate, their limitations should be remembered when assessing renal function in patients on the intensive care unit. Other factors, such as urine output, clearance of acid and electrolytes, and rate of change of serum urea and creatinine should all be considered together. The Cockroft and Gault formula is: (140 − patient age weight in kg ) Estimated C α = (Sα in mol/L )

Multiply by 0.85 for women, 1.23 if male.

3

Urinalysis (4, 5) The microscopic examination of the urinary sediment is an indispensable part of the work-up of patients with renal insuffi ficiency, proteinuria, hematuria, urinary tract infections, or kidney stones. A careful urinalysis has been referred to as a “poor man’s renal biopsy.” The urine should be collected as a midstream catch or fresh catheter specimen, and because the urine sediment can degenerate with time, it should be examined soon after collection. Urinalysis should include a dipstick examination for specifi fic gravity, pH, protein, hemoglobin, glucose, ketones, nitrites, and leucocytes. This should be followed by microscopic examination if there are positive fi findings. Microscopic examination should check for all formed elements: crystals, cells, casts, and infecting organisms.

Appearance Normal urine is clear, with a faint yellow tinge caused by the presence of urochromes. As it becomes more concentrated, its color deepens. Bilirubin, other pathologic metabolites, and a variety of drugs may discolor the urine or change its smell.

Specific Gravity The urine specific fi gravity is a conveniently determined but inaccurate surrogate of osmolality. Specific fi gravities of 1.001 to 1.035 correspond to an osmolality range of 50 to 1000 mOsm/kg. A specific fi gravity near 1.010 connotes isosthenuria (urine osmolality matching plasma). The specific fi gravity is used to determine whether the urine is, or can be, concentrated. During a solute diuresis accompanying hyperglycemia, diuretic therapy, or relief of obstruction, the urine is isosthenuric. In contrast, with a water diuresis caused by overhydration or diabetes insipidus, the specifi fic gravity is low. It is also useful in differentiating between prerenal cause of renal failure (high) and ATN.

Volume In health, the volume of urine passed is primarily determined by diet and fluid fl intake. The minimum amount passed to stay in fluid fl balance is

4

determined by the amount of solute being excreted (mainly urea and electrolytes), and the concentrating ability of the kidneys. In disease, impairment of concentrating ability requires increased volumes of urine to be passed for the same solute output.

M. Arkanath TABLE 1.3. Causes of hematuriaa Glomerular disease

• Oliguria is defi fined as the excretion of less than 300 mL/d of urine, and is often caused by intrinsic renal disease or obstructive uropathy. • Anuria suggests urinary tract obstruction until proven otherwise. • Polyuria is a persistent, large increase in urine output, usually associated with nocturia. Polyuria is a result of excessive intake of water (e.g., compulsive water drinking), increased excretion of solute (hyperglycemia and glycosuria), a defective renal concentrating ability, or failure of production of antidiuretic hormone (ADH).

Vascular and tubulointerstitial disease

Urinary tract diseases

Chemical Testing Blood Hematuria may be macroscopic or microscopic (Table 1.3). Currently used dipstick tests for blood are very sensitive, being positive if two or more red cells are visible under the high-power fi field (HPF) of a light microscope. A disadvantage is that dipstick testing cannot distinguish between blood and free hemoglobin. A positive dipstick has to be followed by microscopy of fresh urine to confirm fi the presence of red cells and to exclude rare conditions such as hemoglobinuria and myoglobinuria. In female patients, it is essential to enquire whether the patient is menstruating. Abnormal numbers of erythrocytes in the urine may arise from anywhere from the glomerular capillaries to the tip of the distal urethra. Dysmorphic erythrocytes tend strongly to be associated with a glomerular source. Abnormal proteinuria along with dysmorphic erythrocytes is a reliable sign of glomerular disease. Urinary tract abnormalities lead to microscopic or macroscopic hematuria but the erythrocytes exhibit normal morphology.

Protein Proteinuria is one the most common signs of renal disease (Table 1.4). Most reagent strips detect a

Mesangial IgA nephropathy Thin basement membrane disease Mesangial proliferative GN Membranoproliferative GN Crescentic GN Systemic lupus erythematosus Post streptococcal GN Infective endocarditis Alport’s syndrome Acute hypersensitivity interstitial nephritis Tumors (renal cell carcinoma, Wilm’s tumor, leukemia) Polycystic kidney disease Malignant hypertension Analgesic nephropathy Diabetes mellitus Obstructive uropathy Carcinoma (renal pelvis, ureter, bladder, urethra, prostate) Calculi Retroperitoneal fibrosis Tuberculosis Cystitis Drugs (e.g., cyclophosphamide) Trauma Benign prostatic hypertrophy Urethritis Platelet defects (e.g., idiopathic or drug induced thrombocytopenic purpura)

a

GN, glomerulonephritis.

concentration of 150 mg/L or more in urine. They react primarily to albumin and are insensitive to globulin or Bence-Jones protein. False-positive results are common with iodinated contrast agents; hence, urine testing should be repeated after 24 hours. The normal rate of excretion of protein in urine is 80 ± 24 mg/24 h in healthy individuals, but protein excretion rates are somewhat higher in children, adolescents, and in pregnancy. Fever, severe exercise, and the acute infusion of hyperoncotic solutions or certain pressor agents (e.g., angiotensin II or norepinephrine) may transiently cause abnormal protein excretion in normal individuals. The protein in normal and abnormal urine is derived from three sources: 1. Plasma proteins filtered fi at the glomerulus and escaping proximal tubular reabsorption. 2. Proteins normally secreted by renal tubules.

1. Assessment of Renal Function

5

TABLE 1.4. Causes of proteinuria based on pathophysiologic mechanisma Glomerular proteinuria

Primary glomerular disease • Minimal change disease • Mesangial proliferative GN • Focal and segmental glomerulosclerosis (FSGS) • Membranous GN • Mesangiocapillary GN • Fibrillary GN • Crescentic GN

Tubular proteinuria

Endogenous toxins: light chain damage to proximal tubular, lysozyme (leukemia) Exogenous toxins and drugs: mercury, lead, cadmium, outdated tetracycline SLE Acute hypersensitivity interstitial nephritis Acute bacterial pyelonephritis Obstructive uropathy Chronic interstitial nephritis Multiple myeloma Light chain disease Amyloidosis Hemoglobinuria Myoglobinuria Certain colonic or pancreatic carcinomas Acute inflammation of urinary tract Uroepithelial tumors

Tubulointerstitial disease

Overflow proteinuria

Tissue proteinuria

Secondary glomerular disease • Drugs: e.g., mercurials, gold compounds, heroin, penicillamine, probenecid, captopril, lithium, NSAID • Allergens: bee sting, pollen, milk • Infections: bacterial, viral, protozoal, fungal, helminthic • Neoplastic: solid tumors, leukemia • Multisystem: SLE, Henoch-Schonlein purpura, amyloidosis • Heredofamilial: diabetes mellitus, congenital nephritic syndrome, Fabry’s disease, Alport’s syndrome • Others: febrile proteinuria, postexercise proteinuria, benign orthostatic proteinuria

a

GN, glomerulonephritis; NSAID, nonsteroidal anti-inflammatory drugs; SLE, systemic lupus erythematosus.

3. Proteins derived from the lower urinary tract or leaking into the urine as a result of tissue injury or inflammation. fl Most patients with persistent proteinuria should undergo a quantitative measurement of protein excretion, with a 24-hour urine measurement. A protein excretion rate greater than 3.5 g/d (nephrotic range proteinuria) should prompt further investigations to ascertain the exact cause of the proteinuria with measurements of urea, creatinine, liver function tests (most importantly, serum albumin), and a full blood count. A defi finitive diagnosis has to be achieved with a renal biopsy. Nephrotic syndrome is defined fi as a combination of proteinuria in excess of 3 g/d, hypoalbuminemia, edema, and hyperlipidemia.

Bacteriuria Dipsticks detect nitrites produced from the reduction of urinary nitrate by bacteria and also leucocyte esterase, an enzyme specific fi for neutrophils. Detection of both nitrites and leucocytes on dipstick has a high predictive value for urinary tract infection.

Urine Microscopy An unspun sample of urine may be examined under low- or high-power microscopy, however, a spun sample is a more accurate. Urine is centrifuged, the supernatant is discarded, and an aliquot of the residue is placed on a glass slide using a Pasteur pipet. All patients suspected of having renal disease should have urine microscopy.

Glucose

White Blood Cells

Renal glycosuria is uncommon and any positive test requires evaluation of diabetes mellitus.

The presence of 10 or more white blood cells per cubic millimeter is abnormal and indicates an

6

infl flammatory reaction within the urinary tract. Most commonly this represents a urinary tract infection but it may also be found with a sterile sample in patients on antibiotic therapy, or with kidney stones, tubulointerstitial nephritis, papillary necrosis, or tuberculosis.

Red Blood Cells As mentioned previously, erythrocytes can find fi their way into the urine from any source between the glomerulus to the urethral meatus. The presence of more than two to three red blood cells per HPF is usually pathological. Erythrocytes originating in the renal parenchyma are dysmorphic, whereas those originating in the collecting system retain their uniform biconcave shape.

Casts Based on their shape and origin, casts are appropriately named. Hyaline casts are found in concentrated urine, during febrile illnesses, after strenuous exercise, and with diuretic therapy. They are not indicative of renal disease. Red cell casts indicate acute glomerulonephritis. White cell casts indicate infection or infl flammation, and are seen in pyelonephritis and interstitial nephritis. Renal tubular casts are found in cases of ATN and interstitial nephritis. Coarse granular casts are nonspecific fi and represent the degeneration of a cast with a cellular element. Finally, broad waxy

M. Arkanath

casts are indicative of stasis in the collecting tubules and are seen in chronic renal failure.

References 1. Brown SC, O’Reilly PH. Iohexol clearance for the determination of glomerular filtration fi rate in clinical practice: evidence for a new gold standard. J Urol. 1991; 146(3): 675–679. 2. Cockroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron. 1976; 16: 31–41. 3. Hoste EA, Damen J, Vanholder RC, et al. Assessment of renal function in recently admitted critically ill patients with normal serum creatinine. Nephrol Dial Transplant. 2005; 20(4): 747–753. 4. Henry JB, Lauzon RB, Schaumann GB. Basic examination of the urine. Clinical Diagnosis and Management by Laboratory Methods. 19th ed. Philadelphia: Saunders. 1991. 5. Graff L. A Handbook of Routine Urinalysis. Philadelphia: Lippincott. 1983.

Suggested Reading Davison AM, Cameron S, Grunfeld J-P, et al. Oxford Textbook of Clinical Nephrology. 3rd ed. Oxford: Oxford University Press. 2005. Greenberg A, Cheung AK, Coffman TM, et al. Primer on Kidney Diseases. 3rd Ed. London: Academic Press. 2001. Guyton AC. Textbook of Physiology. 8th Ed. New York: Saunders. 1991.

2 Imaging of Acute Renal Failure—A Problem-Solving Approach for Intensive Care Unit Physicians Tom Sutherland

Acute renal failure (ARF) is a common problem in hospitalized patients. It has a variety of causes, traditionally divided into prerenal, renal, and postrenal. A further classification fi can be made into medical and surgical causes, with the later defined fi as patients who will benefi fit from mechanical intervention. Acute tubular necrosis (ATN) is the most common cause of ARF (approximately 45%) and postrenal obstruction accounts for roughly 10% of presentations (1). A variety of imaging modalities may be used to help diagnose the cause, or, if this is not possible, to differentiate medical from surgical causes. ARF in renal transplants will not be addressed.

(MRI) scans analyze renal structure and renal artery calcifi fication, and dynamic gadoliniumenhanced MRI renal studies allow functional assessment. Other functional studies, such as mercaptoacetyltriglycine (MAG3) and diethylene triamine pentaacetic acid (DTPA) show reduced renal uptake and delayed excretion of tracer. A further role of imaging is to determine the number of present and functioning kidneys. For ARF to occur in previously normal kidneys, the underlying cause must be a bilateral process, or else a single functioning kidney must be compromised (Figure 2.1).

Acute or Chronic Renal Failure?

Ultrasound will usually show enlarged kidneys with a smooth contour caused by interstitial edema, no hydronephrosis, and renal arterial and venous flow. The examination of choice in suspected ATN is a MAG3 nuclear medicine study. Scintigraphic examinations in ATN using Tc99m-MAG3 demonstrate relatively well-preserved on-time renal perfusion, and delayed tracer uptake, often with a continuing activity accumulation curve. If the activity curve does have a maximum, the time to maximum is delayed (2). Excretion of tracer into the collecting system is delayed and reduced, but there is no obstruction to drainage of the collecting systems. If excretion and drainage occur, the time from maximal activity to half-maximal activity (or another quantitative measure of tracer excretion) is prolonged. What underlies this scintigraphic pattern

This is best answered by clinical assessment rather than with imaging. Imaging findings fi in chronic renal failure are nonspecific fi and essentially characterized by small kidneys. X-rays can show the renal outline, calcifi fication, renal bone disease and effects of hyperparathyroidism. Ultrasound is an excellent modality for structural imaging because it is able to detect reduced renal parenchyma, scarring (usually secondary to previous reflux fl nephropathy), calcification, fi and polycystic kidneys. The echogenicity of the cortex can be assessed with a hyperechoic cortex (normal cortex is hypoechoic to liver), present in most causes of chronic renal failure; adult polycystic kidney disease being the notable exception. Noncontrast computed tomographic (CT) and magnetic resonance imaging

Acute Tubular Necrosis

7

8

T. Sutherland Liver

Liver

Renal cortex

Dialysis fluid

A

B FIGURE 2.1. A, ultrasound of a normal kidney. Smooth cortex, hypoechoic to liver. B, chronic renal failure with a small irregular kidney with hyperechoic cortex compared with liver (anechoic area around the liver is peritoneal dialysis fluid).

FIGURE 2.2. MAG3 study showing progressive accumulation of tracer in the renal cortex indicating normal perfusion but no excretion, consistent with ATN. A normal activity curve should initially

peak as the kidneys are perfused and then activity declines as tracer is excreted and passes into the bladder. Lt, left; Rt, right; Bkg, background.

2. Imaging of Acute Renal Failure

is parenchymal retention of MAG3 by the remaining viable tubular cells, whereas tubular obstruction prevents drainage of tracer into the collecting system. The tubular cells continue to take up tracer while they are viable and, thus, the cortical activity can be used to monitor disease progress, with progressive loss of cortical activity being a poor prognostic indicator (Figure 2.2). If a MAG3 study cannot be performed, ultrasound will demonstrate a cortex of normal echogenicity with either a normal or hypoechoic medulla. The renal arteries can also be interrogated for the renal index (RI), which is an objective measure of the resistance to renal perfusion. RI is defi fined as (systolic velocity minus diastolic velocity) divided by systolic velocity, and has been heavily investigated to determine whether elevation in RI can differentiate ATN from renal hypoperfusion not yet complicated by ATN. Unfortunately, there have been mixed results and, generally, RI has inadequate specifi ficity for routine clinical use.

Glomerulonephritis and Acute Interstitial Nephritis Clinical history and urinalysis plays a vital role in differentiating GN and acute interstitial nephritis (AIN) with the “gold standard” diagnostic test being a renal biopsy. The main role of imaging is to detect structural signs of chronic renal disease and to exclude other causes of ARF. MAG3 studies will show poorly functioning kidneys, but no accumulation pattern and also no obstruction to drainage. Edema can sometimes be demonstrated with ultrasound, manifest as hypoechoic large kidneys. If there is a clinical suspicion to direct imaging, a careful search may also find fi other signs of the underlying cause, for example, pulmonary hemorrhage in Goodpasture’s syndrome and pulmonary nodules in Wegener’s granulomatosis.

9

Ultrasound is the first-line fi test for obstruction. It is radiation free, portable, is not nephrotoxic, and can simultaneously gather other structural information. Obstructed kidneys are typically normal sized with dilated ureters, renal pelvis, and calyceal systems. These urine-filled fi structures appear as anechoic areas with posterior acoustic enhancement. Caution is required in interpretation because a ureter and renal pelvis may be dilated without being obstructed (a false positive). This can occur after previous obstruction that leaves a residual “baggy” collecting system, or as an anatomical variant (enlarged extrarenal pelvis). Differentiation can often be made by examining the bladder for ureteric jets, which are the periodic expulsion of urine from the ureter into the bladder, which can be detected by Doppler imaging. If ureteric jets are present, then there is not a complete obstruction on that side (3). False negatives can occur in the hyperacute setting if the renal collecting system has not had time to dilate, or if the system has spontaneously decompressed by forniceal or renal pelvis rupture (Figure 2.3). Noncontrast CT scan is the gold standard for detecting ureteric calculi (4). The ureters can usually be traced between the kidney and bladder, and a hyperdense stone can be seen at the distal site of hydroureter. More than 99% of renal calculi are radiopaque on CT scan, however, xanthine calculi may be radiolucent and stones associated with indinavir are radiolucent. The obstructed kidney is typically edematous (i.e., swollen) with

Cortex

Renal pelvis

Calyx

Ureteric Obstruction For obstruction to produce ARF it must be bilateral or affecting a single functioning kidney. This is the classical cause of surgical ARF.

FIGURE 2.3. Ultrasound of a hydronephrotic kidney. Size is normal with dilated renal pelvis and calyces (the anechoic central part).

10

T. Sutherland

perirenal stranding. The administration of contrast is contraindicated in ARF because of its potential nephrotoxicity. Although not as helpful as a contrast-enhanced CT scanning, a noncontrast study can usually detect many extrinsic compressing masses, such as retroperitoneal tumors, or cervical or colon carcinomas, that may produce bilateral obstruction. Complications related to trauma, such as urinoma or renal pedicle avulsions, are also visible even without contrast (Figure 2.4). Scintigraphic imaging with either Tc-99mMAG3 or Tc-99m-DTPA can detect ureteric obstruction by showing a dilated collecting system with delayed drainage of tracer. The collecting system is outlined down to the level of the obstruction with no or limited tracer draining beyond this. The negative predictive value of nuclear medicine scanning is extremely high, with a normal study virtually excluding obstruction. Of course, sufficient fi tracer must be present in the collecting system to reach the obstruction point. Reduced urine production associated with renal failure may deliver so little tracer into the collecting system that obstruction cannot be excluded. The lower the patients glomerular fi filtration rate (GFR), the higher the probability of having an indeterminate study (5). Further, an enlarged but nonobstructed collecting system may mimic delayed drainage. In this latter situation, the specifi ficity of the examination is increased by administering 20 mg (or sometimes 40 mg) of frusemide IV, and scanning for a further 20 minutes. A baggy nonobstructed system will promptly wash out, and the delay in washout after frusemide correlates with Arrow heads are fatty stranding.

Right ureteric calculus

the degree of obstruction. Once again, it must be stressed that the only way mechanical obstruction can produce ARF in previously normal kidneys is by affecting a solitary functioning kidney, or by blocking both kidneys simultaneously.

Renal Artery Dissection or Occlusion Each kidney is normally supplied by a single renal artery that arises from the aorta before dividing into an average of five segmental end-arterial branches. Arterial dissection and occlusion is another surgical cause of ARF. Renal infarction may be caused by blunt trauma with avulsion of the renal pedicle or penetrating trauma transecting the renal artery. Renal artery dissection may be iatrogenic, occurring during endovascular intervention. Bilateral dissection or exclusion from the circulation can occur secondary to an aortic dissection. Suspicion of a dissection or occlusion is virtually the only differential diagnosis that warrants the administration of intravenous CT contrast in the setting of ARF in which MRI scanning is unavailable. An arterial phase CT scan highlights the renal artery anatomy, demonstrating the intimal fl flap of dissection and can also detect signs of renal infarction and lacerations (6) (Figure 2.5). Magnetic resonance angiography (MRA) has excellent sensitivity and specifi ficity for detecting dissection and occlusion of proximal renal arteries. Segmental arteries are less well visualized, however, unilateral or isolated segmental pathology will not produce ARF. MR contrast is much Inferior pole left kidney

FIGURE 2.4. Noncontrast CT scan with complete right-sided and moderate leftsided obstruction secondary to bilateral ureteric calculi (left calculus not shown). Edematous fatty stranding around each kidney with the right calculus in the dilated ureter. Arrowheads indicate fatty stranding.

2. Imaging of Acute Renal Failure FIGURE 2.5. Contrast enhanced CT scan (magnified view of the left kidney) with no renal parenchymal enhancement or renal vascular enhancement secondary to an occlusive renal artery embolus.

11 Contrast in the aorta

left kidney

less nephrotoxic than CT contrast. MRI scanning is logistically difficult fi for most intensive care unit (ICU) patients, and has a considerably longer scan time and, therefore, CT scanning remains a more practical modality. MAG3 examinations will reveal an absence of perfusion (segmental or unilateral or bilateral, as the case may be) but not the cause.

of blood flowing around the thrombus is shown on color Doppler imaging (7). The kidney itself may have reduced corticomedullary differentiation, be enlarged, and contain focal areas of increased echogenicity related to edema and hemorrhage. Contrast-enhanced CT scanning has a similar appearance in the acute setting, with a dilated renal vein with hypodense thrombus within. Secondary findings, fi such as perirenal stranding, dilated gonadal vein, prolonged nephrogram, and complications such as retroperitoneal hemorrhage may also be present. As the chronicity increases, the thrombus contracts and multiple collateral vessels develop. Renal veins are well demonstrated by MRI scanning, with the thrombus appearing hyperintense on both T1- and T2-weighted images. The kidney appears swollen with loss of corticomedullary differentiation on T1-weighted images, with both cortex and medulla having low signal secondary to prolonged T1 and T2 relaxation times. Venography is the gold standard and can accurately determine the presence of thrombus and its extent. A catheter inserted in the common femoral vein allows selection of the renal vein as it enters the IVC and, with contrast injection, a fi filling defect or complete occlusion can be demonstrated. Therapeutic measures, such as the instillation of localized thrombolytics and the placement of an IVC filter if the thrombus is extensive, can be performed during the diagnostic procedure. Complications include damage to vessels and

Renal Vein Thrombosis Bilateral renal vein thrombosis (RVT) will present with ARF, but is very rare. If discovered, it should trigger a search for a mass compressing both renal veins or the suprarenal inferior vena cava (IVC) and a coagulopathy screen. Unilateral RVT is more frequent in contrast, but will not produce ARF if both kidneys are initially normal. Usually, a single renal vein exists on each side, but up to 30% of patients will have multiple renal veins. RVT is most common on the left because this vein is three times longer than the right vein and is more liable to extrinsic compression as it passes between the superior mesenteric artery and the aorta. RVT may be caused by hypercoagulable states, dehydration (particularly in infants), sepsis, or trauma and occurs in up to 40% of patients with nephrotic syndrome. Ultrasound can show a distended renal vein with echogenic thrombus within that vein that may extend into the IVC. Absent fl flow or a thin cuff

US

MRI or Contrast enhanced CT*

US – largely to exclude other diagnoses

? Glomerulonephritis or acute interstitial nephritis

Non contrast CT for obstructing mass or stone

US

? Obstruction

Surgical

FIGURE 2.6. Diagnostic algorithm for imaging in ARF. US, ultrasound.

Non contrast CT for ? obstructing mass

MRI or angiography if high pretest probability

? Renal vein thrombosis

Medical

Postrenal

US to confirm chronic changes, scars etc. +/MAG3 for function.

CLINICAL DDx

MAG3

US

? Aortic or renal artery dissection/occlusion

Surgical

Renal

Acute on chronic renal failure

ANATOMICAL REGION

?ATN

Medical

Prerenal

ARF with Previously normal kidneys

? ARF with previously normal kidneys or acute on chronic renal failure Answer with history clinical findings and Laboratory tests

12 T. Sutherland

TEST TO ANSWER CLINICAL QUESTION

2. Imaging of Acute Renal Failure

dislodgement of thrombus resulting in pulmonary embolism, and require the administration of potentially nephrotoxic intravenous contrast.

Renal Artery Stenosis Renal artery stenosis (RAS) is most commonly associated with hypertension and is usually caused by atherosclerotic plaques and less commonly by fibromuscular dysplasia. It can exacerbate renal fi hypoperfusion and is a cause of chronic renal impairment. In these cases, signs of chronic renal impairment, as previously mentioned, will usually be present. It is extremely unlikely to be the causative factor for ARF presenting de novo. In patients presenting with acute-on-chronic renal failure, it is one of the many possible causes of the preexisting renal failure and enters the differential diagnosis in this fashion.

Conclusion Clinical assessment in ARF is vital to construct a differential diagnosis list. Imaging can then have a targeted role to answer questions and enable the

13

fi final diagnosis to be made. Using the above discussion, a potential diagnostic algorithm is given in Figure 2.6. I thank Professor Alexander Pitman for his assistance and guidance with this work.

References 1. Liano F, Pascual J. Epidemiology of acute renal failure: a prospective, multicenter, community-based study. Kidney Int 1996; 50: 811–818. 2. Dahnert W. Radiology review manual. 5th ed. Philadelphia: Lippincott Williams & Wilkins. 2003. 3. Middleton WD, Kurtz AB, Hertzberg BS. Ultrasound— The requisites. 2nd ed. St. Louis: Mosby. 2004. 4. Sheafor DH et al. Non-enhanced helical CT and US in the emergency evaluation of patients with renal colic: Prospective comparison. Radiology 2000; 217: 792–797. 5. Brant WE, Helms CA. Fundamentals of diagnostic radiology. 2nd ed. Philadelphia: Lippincott Williams & Wilkins. 1999. 6. Urban BA, Ratner LE, Fishman EK. Three-dimensional volume-rendered CT angiography of the renal arteries and veins: Normal anatomy, variants, and clinical applications. Radiographics 2001; 21: 373–386. 7. Pitman AG, Major NM, Tello R. Radiology core review. Edinburgh: Saunders. 2003.

3 Drug-Induced Renal Injury Sara Blakeley

Drug-induced nephrotoxicity contributes to 8 to 60% of all cases of in-hospital acute kidney injury (AKI) and 1 to 23% of cases of AKI seen on the intensive care unit (ICU) (1). The wide variations are caused by different definitions fi of AKI and different patient populations. Drug-induced nephropathies are often underdiagnosed, and should be considered in every type of renal failure, both acute renal failure and chronic renal failure (CRF).

Risk Factors for Nephrotoxicity Many patients may be taking a potentially nephrotoxic drug. For example, 55% of patients admitted to a general medical ward were taking one or more of either an angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor antagonist (ARB), a diuretic, or a nonsteroidal antiinfl flammatory drug (NSAID) (2). More than 25% of patients were taking two or three of these drugs. Not all patients will develop renal failure; whether a drug is nephrotoxic or not depends on patientand drug-related factors (Tables 3.1 and 3.2).

Methods of Prevention The following general principles should be adhered to: 1. Appropriate dose alteration in patients depending on renal function, age, and ideal body weight. 2. Awareness of drug interactions. 3. Close attention to fl fluid balance and hemodynamic status.

14

4. Monitoring of drug levels (where appropriate). 5. Discontinuation or change of mediation when possible. 6. Consider specific therapies, e.g., N-acetylcysteine N (NAC; contrast), rasburicase, and allopurinol (tumor lysis syndrome), urinary alkalinization (drug-induced rhabdomyolysis). 7. Close liaison with ICU pharmacist.

Nonsteroidal Anti-Inflammatory Drugs NSAIDs are widely used and overall renal complications are uncommon, however, their use in the community has been shown to increase the risk of hospitalization with AKI by up to four-fold (4, 5). Renal effects are predominately caused by their effect on the production of renal prostaglandins.

Effects on Renal Prostaglandins Membrane-bound phospholipids are converted to arachidonic acid by phospholipase A. Arachidonic acid then enters the cyclooxygenase pathway under the action of cyclooxygenase enzyme (COX) forming prostaglandins, or enters the lipoxygenase pathway, forming leukotrienes. In health, renal prostaglandins have a number of effects: control of renin release, regulation of renal blood flow fl (RBF) through vascular tone, and control of salt and water transport in the renal tubules. They have both vasodilatory (prostaglandin [PG]-E2, PGI2) and vasoconstrictor (throm-

3. Drug-Induced Renal Injury

15

TABLE 3.1. Mechanism of drug-induced AKI Mechanism Altered intraglomerular hemodynamics: drugs that interfere with the normal regulatory alterations in preglomerular and postglomerular arteriolar resistance can compromise renal blood flow and glomerular filtration rate, especially in times of hemodynamic instabilit Drug-induced glomerulopathy: this usually presents with nephrotic syndrome or proteinuria. Renal function need not be impaired Drug-induced thrombotic microangiopathy: rare

Direct tubular cell toxicity

Tubular damaged caused by osmotic nephrosis: tubule cells take up nonmetabolizable molecules, creating an osmotic gradient. Water rapidly accumulates in the cell, causing swelling and vacuolation, thereby disrupting cell integrity. Cellular debris causes tubular obstruction Tubular damage caused by cast deposition: rhabdomyolysis Interstitial nephritis: drugs can cause an acute allergic interstitial nephritis or chronic interstitial damage

Drug examples Calcineurin inhibitors Vasopressors Amphotericin Contrast agents NSAIDs, ACEI/ARBs

Gold, D-penicillamine NSAIDs Mesalazine Cyclosporin A, OKT3, tacrolimus Clopidogrel, ticlopidine Cocaine Quinine Aminoglycosides Amphotericin Calcineurin inhibitors Cisplatin Methotrexate Cocaine Contrast media Palmidronate Mannitol Dextrans Intravenous immunoglobulin Hydroxyethyl starch

are crucial to maintain RBF and GFR. Patients who fall into this high-risk category are those with parenchymal renal disease or renal impairment, hypovolemic patients, those with congestive cardiac failure or liver disease (because of activation of the renin-angiotensin system), and the elderly. There are two isomers of the COX enzyme (6). “Traditional” NSAIDs are nonselective COX inhibitors, whereas newer “coxibs” selectively target the production of proinfl flammatory prostaglandins by COX-2. They have fewer gastric and platelet side effects, but it is now clear that they have the same effects on renal prostaglandins (7); therefore, caution should be still be taken in highrisk individuals. NSAID-induced salt and water retention occurs and the effect of loop diuretics is also diminished. This may lead to pedal edema or hypertension, but can precipitate overt cardiac failure in at-risk patients.

Other Renal Effects 1. Acute tubulointerstitial nephritis (TIN) is less common, occurring after 3 to 5 days, or even after years, of drug use. It occurs in an TABLE 3.2. Risk factors for development of drug-induced AKI Patient-related factors

Statins β-lactams, quinolones, rifampicin, macrolides, sulfonamides NSAIDs Thiazide and loop diuretics Phenytoin Cimetidine, ranitidine Allopurinol Antivirals Cocaine

Note: This list is not exhaustive. Source: Schetz et al., 2005; and Perazella, 2003.

boxane A2) effects. In certain situations associated with high levels of circulating vasoconstrictors (such as angiotensin II [ATII], endothelin, catecholamines), vasodilatory renal prostaglandins

Increased age Preexisting chronic kidney disease Diabetes mellitus Intravascular volume depletion: absolute (e.g., dehydration) or effective (e.g., massive ascites, nephrotic syndrome) Peripheral vascular disease (this increasesthe risk of renovascular disease) Sepsis Concomitant use of diuretics and other nephrotoxic drugs Metabolic disturbances: sodium depletion, hypoalbuminemia, acid-base disturbances (which may exacerbate intrarenal crystal deposition), multiple myeloma

Drug-related factors Inherent nephrotoxic potential Dose (important for drugs inducing crystal deposition, causing tubular damage, and drugs altering renal hemodynamics) Prolonged duration of treatment Frequency of administration Time of administration Rate of administration (important fordrugs causing crystal nephropathy) Route of administration (e.g., intravenous versus oral contrast) Combination of drugs causing nephrotoxic synergy (e.g., cephalosporins and aminoglycosides, aminoglycosides vancomycin and vancomycin, aminoglycosides)

16

idiosyncratic, non-dose-dependent manner. The classic features of fever, rash, arthralgia, and eosinophilia are often not present. The diagnosis is made on renal biopsy. Treatment is to stop the drug and support the patient. Corticosteroids are sometimes administered, but the evidence is lacking. 2. Renal papillary necrosis. 3. Nephrotic syndrome. 4. Hyperkalemia caused by hyporeninemic hypoaldosteronism generally occurs in patients with CRF, diabetes mellitus, and type IV renal tubular acidosis.

ACEIs and ARBs ATII is a potent vasoconstrictor causing constriction of the efferent arteriole, increasing transglomerular pressure, and, thus, GFR. It also causes systemic vasoconstriction, increasing systemic blood pressure and improving renal perfusion. In certain situations, GFR is very dependent on this postglomerular constriction and, consequently, blocking this mechanism by the use of ACEI/ARBs may lead to a marked reduction in GFR (3). If, after starting an ACEI/ARB, there is a small, but nonprogressive rise in the serum creatinine, this is generally related to alterations in intrarenal hemodynamics rather than structural injury (8). If the initial serum creatinine rises by more than 30% or if there is a progressive increase in creatinine after starting the drug, the drug should be stopped and a reason sought. This situation may arise in patients with bilateral renal artery stenosis (or stenosis of a single functioning kidney), but is also seen when there is a reduction in the absolute or effective circulating volume, in the presence of sepsis, and with the concomitant use of other drugs (e.g., NSAIDs). These factors should be addressed before restarting the drug.

Aminoglycosides Aminoglycoside toxicity is caused by partial reabsorption of the drug by the proximal renal tubular cells, and the first fi indication of renal involvement is the development of polyuria because of a defect in the urinary concentrating

S. Blakeley

ability. There is then a slow rise in serum creatinine over several days. The risks of toxicity are increased with high initial peak serum levels, prolonged treatment, hypovolemia, increasing age, liver dysfunction, hypoalbuminemia, and in combination with other drugs (e.g., diuretics, NSAIDs, ACEIs, cephalosporins) (9). Once daily dosing is associated with less nephrotoxicity than dosing multiple times daily, but may not be suitable for all patient groups (e.g., controversial in the treatment of bacterial endocarditis). The risk of nephrotoxicity is reduced when the once daily dose is given during periods of activity (daytime) or when taking food, possibly related to changes in urinary pH. Levels should still be monitored carefully according to local practice.

Contrast Nephropathy Incidence and Outcome Contrast nephropathy (CN) is the third leading cause of AKI in hospitalized patients (10), accounting for 12% of cases of AKI. It is defined fi as an acute decline in renal function, with a rise in serum creatinine of greater than 25% from baseline (or an absolute rise of 44 μmol/L), occurring 24 to 48 hours after contrast. Creatinine usually peaks at 5 days and returns to baseline by 10 days. Incidence is varied depending on definitions fi used and patient populations studied. Overall incidence is less than 3% (11, 12), but rises in the setting of increasing number of risk factors (13), up to 50% with the combination of diabetes and renal failure (14). Risk factors for development of CN: • Preexisting renal impairment • Diabetes mellitus • Absolute (e.g., dehydration) or effective volume depletion (e.g., congestive cardiac failure, nephrotic syndrome, liver disease) • Left ventricular ejection fraction less than 40% • Concurrent use of nephrotoxic drugs (e.g., NSAIDs, aminoglycosides) • High volume, high osmolar, ionic contrast given intravenously

3. Drug-Induced Renal Injury

• Pre procedure shock (e.g., hypotension, intraaortic balloon pump) • Increasing age Renal failure is normally nonoliguric and resolves with supportive care. Up to 12% of patients need renal replacement therapy (11). The development of CN increases mortality. It is unclear whether this is because of renal failure itself, or is simply a marker of increased disease severity and underlying comorbidity. In one study, the development of AKI increased mortality from 7 to 34% (11).

17

reduce the potential for ischemic injury by interfering with active transport and decreasing the oxygen demands of tubules, however, evidence is lacking. There is no evidence that mannitol, atrial natriuretic peptide, dopamine, or fenoldopam (a dopamine 1 agonist) are better than standard hydration. Calcium channel antagonists gained some interest but were not supported by large trials. Despite its properties as an adenosine antagonist, there is no evidence that theophylline is more effective, and work continues on the antioxidant, ascorbic acid.

Methods of Prevention

Suggestions for High-Risk Patients

Intravenous Hydration

• Identify high-risk patients, correct modifiable fi risks, and consider the risk/benefit fi to the patient of the procedure • 600 to 1200 mg NAC twice daily for 2 days before procedure and two doses after the procedure • Intravenous hydration with saline at 1 mL/kg/h for 6 to 12 hours before and after the procedure

Volume expansion with intravenous fluid fl before and after contrast is proven to be beneficial. fi Timing, dose, and type of fluid fl administered are less well defined. fi Isotonic fluid (using sodium bicarbonate) may be better than hypotonic fl fluid because of better volume expansion, urinary alkalinization, and reduction of free radical-mediated injury (15).

N-Acetylcysteine NAC counteracts renal vasoconstriction but also scavenges oxygen free radicals, thereby preventing direct oxidative tissue damage after exposure to contrast media (16). Data from a series of meta-analyses are mixed because of the lack of a standardized definition fi of CN, study heterogeneity, and publication bias. Despite this, NAC seems to reduce the risk of renal injury in high-risk patients.

Type of Contrast Used Studies compared high, low and iso-osmolar preparations. In high-risk patients, iso-osmolar compounds are associated with a reduced incidence of CN (17). Nonionic rather than ionic compounds have also been found to be less nephrotoxic.

Other Therapies (18, 19) A recent meta-analysis found no evidence that periprocedural renal replacement therapy reduced the incidence of CN (20). Loop diuretics may

Or 5% dextrose and H2O + 154 mEq/L sodium bicarbonate at 3 mL/kg/h for 1 hour before the procedure and 6 hours after the procedure (add 154 mL of 1000 mEq/L sodium bicarbonate to 846 mL of 5% dextrose in H2O) • Use the minimum volume of iso-osmolar or low osmolar contrast

References 1. Schetz M, Dasta J, Goldstein S, Golper T. Druginduced acute kidney injury. Curr Opin Crit Care. 2005; 11: 555–565. 2. Loboz KK, Shenfield fi GM. Drug combinations and impaired renal function—the “triple whammy”. Br J Clin Pharm. 2005; 59(2): 239–243. 3. Perazella MA. Drug induced renal failure: Update on new medications and unique mechanisms of nephrotoxicity. Am J Med Sci. 2003; 325(6): 349–362. 4. Perez Gutthann S, Garcia Rodriguez LA, Raiford DS, et al. Nonsteroidal anti-infl flammatory drugs and the risk of hospitalization for acute renal failure. Arch Intern Med. 1996; 156: 2433–2439. 5. Griffi fin MR, Yared A, Ray WA. Nonsteroidal antiinfl flammatory drugs and acute renal failure in elderly persons. Am J Epidemiol. 2000; 151: 488–496.

18 6. Barkin RL, Buvanendran A. Focus on the COX-1 and COX-2 agents: Renal effects of nonsteroidal and anti-infl flammatory drugs—NSAIDs. Am J Therapeutics. 2004; 11: 124–129. 7. Gambaro G, Perazella MA. Adverse renal effects of anti infl flammatory agents: Evaluation of selective and non selective cyclooxygenase inhibitors. J Int Med. 2003; 253: 643–652. 8. Palmer BF. Renal dysfunction complicating treatment of hypertension. N Engl J Med. 2002; 347: 1256–1261. 9. Beauchamp D, Labrecque G. Aminoglycoside nephrotoxicity: Do time and frequency of administration matter? Curr Opin Crit Care. 2001; 7: 401–408. 10. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis. 2002; 39(5): 930–936. 11. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA. 1996; 275(19): 1489–1494. 12. Rudnick MR, Berns JS, Cohen RM, Goldfarb S. Contrast-media associated nephrotoxicity. Semin Nephrol. 1997; 17: 15–26. 13. Rich MW, Crecelius CA. Incidence, risk factors, and clinical course of acute renal insuffi ficiency after cardiac catheterization in patients 70 years of age or older. A prospective study. Arch Intern Med. 1990; 150(6): 1237–1242. 14. Manske CL, Sprafka JM, Strony JT, Wang Y. Contrast nephropathy in azotemic diabetic patients undergo-

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15.

16.

17.

18.

19.

20.

ing coronary angiography. Am J Med. 1990; 89(5): 615–620. Merten GJ, Burgess WP, Gray LV, et al. Prevention of contrast induced nephropathy with sodium bicarbonate: a randomised controlled trial. JAMA. 2004; 291: 2328–2334. Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int. 2004; 65: 1366– 1374. Aspelin P, Aubry P, Fransson SG, Strasser R, Willenbrock R, Berg KJ. Nephrotoxicity in high-risk patients study of iso-osmolar and low-osmolar non-ionic contrast media study investigators. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003; 348(6): 491– 499. Maeder M, Klein M, Fehr T, Rickli H. Contrast nephropathy: Review focusing on prevention. J Am Coll Cardiol. 2004; 44: 1763–1771. Pannu N, Wiebe N, Tonelli M. Prophylaxis strategies for contrast nephropathy. JAMA. 2006; 295: 2765– 2779. Cruz DN, Perazella MA, Bellomo R, Corradi V, de Cal M, Kuang D, Ocampo C, Nalesso F, Ronco C. Extracorporeal blood purifi fication therapies for prevention of radiocontrast-induced nephropathy: a systematic review. Am J Kidney Dis. 2006; 48(3): 361–367.

4 Acute Kidney Injury Sara Blakeley

Patients may be admitted to the intensive care unit (ICU) with acute kidney injury (AKI) or it may develop during their stay. This chapter gives an overview of the definition and epidemiology of AKI, along with clinical features and initial investigations.

Definition of AKI AKI is an abrupt (<7 d) and sustained decrease in kidney function (1). It is accompanied by changes in blood biochemistry (e.g., a rise in serum creatinine), in urine output, or both. There is a spectrum ranging from a mild transient rise in serum creatinine, to overt renal failure needing renal replacement therapy (RRT); hence, the term acute kidney injury (AKI) is more precise than the term “acute renal failure”. Multiple definitions fi of ARF exist, and the reader is guided to a series of excellent reviews that highlight this problem (1–5). A rise in serum creatinine is often used as a marker of renal dysfunction, but it is affected by extrarenal factors, such as age, sex, race, and muscle bulk. It may lag behind changes in glomerular filtration fi rate (GFR), either in decline or during recovery, and, therefore, does not always give a true reflection fl of the GFR. Urine output can be used to define fi renal failure, but this can be confounded by the use of diuretics, and not all cases of renal failure are associated with oliguria. Efforts have been made to develop a universal and practical way of defining fi AKI via either serum creatinine or urine output. One such recent proposal is the RIFLE (5) system; an acronym for

three levels of renal dysfunction and two renal outcomes. The levels of renal dysfunction can be defined fi by changes in serum creatinine, GFR, or urine output. Risk of Renal Dysfunction • Serum creatinine increased 1.5 fold or • GFR decreased by more than 25% or • Less than 0.5 mL/kg/h of urine for 6 hours Injury to the Kidney • Serum creatinine doubled or • GFR decreased greater than 50% or • Less than 0.5 mL/kg/h of urine for 12 hours Failure of Kidney Function • Serum creatinine increased 3 fold or • An acute rise in creatinine of greater than 44 μmol/L so that new creatinine is greater than 350 μmol/L or • GFR decreased more than 75% or • Less than 0.3 mL/kg/h of urine for 24 hours or anuria for 12 hours • Note: This takes into consideration acute-onchronic renal failure Loss of Kidney Function • Complete loss of kidney function for longer than 4 weeks End-Stage Renal Disease • The need for dialysis for longer than 3 months

Incidence and Outcome AKI develops in 5 to 7% of hospitalized patients (6, 7). Six to 25% of patients on the ICU develop AKI (2, 8); overall, 4% of admissions require RRT.

19

20

This may underestimate the scale of the problem, however, because when all degrees of kidney dysfunction are considered using the RIFLE criteria, 20% (9) of hospital patients and 67% of ICU patients developed some form of kidney injury (10). The incidence and progression of AKI varies depending on the patient group studied. For example, up to 20% of cardiac surgery patients will develop some evidence of renal injury (11), but only 1% will need RRT (12). AKI on the ICU is associated with a hospital mortality of 13 to 80% (2, 8, 10–17) and 57 to 80% if RRT is needed. Renal failure rarely occurs on its own, with up to 80% of patients with renal failure on the ICU having another organ system failure (8). Various factors have been associated with a worse outcome; including comorbidity, increased severity of illness, presence of sepsis, need for mechanical ventilation, oliguria, hospitalization before ICU, and delayed occurrence of AKI (13–15). The development of AKI dramatically increases mortality across all patient populations studied (8–10, 12, 14). Worsening levels of renal dysfunction, as described by the RIFLE criteria, correlate well with increasing hospital mortality, with up to a 10-fold risk of death with “failure.” AKI carries an independent risk of death, but it is unclear whether this is related to the systemic effects of renal failure itself, the effects of its treatment, or is simply a refl flection of the severity of the underlying condition. After AKI needing RRT, 10 to 32% of patients are discharged from hospital still needing RRT (2, 16, 18).

S. Blakeley

nall failure) but intrarenal vasoconstriction, which could progress to tubular damage (intrinsicc renal failure). Glomerular microthrombi are associated with disseminated intravascular coagulation, and can cause intrinsic AKI (20).

Prerenal Failure Prerenal failure (Figure 4.1) accounts for 15 to 20% of cases of AKI on the ICU (13, 15). For the kidneys to be perfused and, therefore, function, adequate pressure, fl flow, volume, and patent vessels are needed. The kidney autoregulates to maintain a constant renal blood flow (RBF) through a mean arterial pressure range of 65 to 180 mmHg. “Prerenal failure” is an appropriate, albeit exaggerated, physiological response to renal hypoperfusion. Stimulation of the renin-angiotensin-aldosterone system attempts to retain salt and water and, therefore, maintain RBF. Because renal tissue is still preserved, once renal perfusion is restored, function should improve. A profound or prolonged reduction in perfusion can, however, lead to ischemic acute tubular necrosis (ATN) (intrinsic renal failure). Conditions leading to reduced renal perfusion and, therefore, causing prerenal failure are: • Hypotension (relative or absolute) secondary to vasodilation (e.g., certain drugs, loss of vascular tone, and sepsis) • Compromised cardiac function • Intravascular volume depletion (absolute or effective) • Increased intra-abdominal pressure (abdominal compartment syndrome)

Causes of AKI Causes of AKI can be divided into prerenal, intrinsic, and obstructive causes. One disease may be associated with different causes of ARF, for example, sepsis is a common cause of renal dysfunction on the ICU, accounting for up to 50% of cases of AKI. AKI occurs in 23% of patients with severe sepsis, and in 51% of patients with septic shock when blood cultures are positive (19). Sepsis is characterized by systemic vasodilation (prere(

Intrinsic Renal Failure The commonest cause of intrinsic renal failure on the ICU is ischemic ATN developing after profound or prolonged prerenal failure (Figure 4.2). Up to 80% of cases of AKI on the ICU are attributed to ATN (2, 13, 15). Although ATN is a histological diagnosis, its development is suggested by the persistence of renal failure following the restoration of adequate renal perfusion. The

4. Acute Kidney Injury

21

Pre re Pre Pr rena nall fa na faililur fail ure ur e Hypottens Hypo tensiion i on

Low card Low Lo rdi dia iac out iac outp tputt

Hypovo Hypo volla laemiia laem ia (Reduced intravascular volume)

Volu Vol Vo lume red lume edi dis istr ist tribut trib utitio ion ion

Tota Tot To tal lo tal loss loss

GI los los oss s

Redu Red Re duce duce ced d ef eff ffe fect cti tiv ive ci ive circ ircullat ati tin ing ing vollu vo lume lume

(Vomiti (Vom (V iting, d diiarr iarrhoea iarrh hoea, surgic rgical i al ffistu istulae) istu lae)

(Ascit (Asc (A ites, oed oedema dema, “3 3rdd spacing cing”, i conge ongestiv stive ti cardia rdiac di c failure)

Haem Haem Ha emor orrh rhag hag ge (Visibl (Vis (Vi ible and d occult) lt)

Altte Al tere tere red d va vasc scul ular lar cap cap pac acit itan it ance an ce (Se Sepsis: i shu h ntin nting, ti g vasod asodil dilattatio ti n. Hepat p torenall synd y drome HRS HRS))

Rena Rena Re nall lo loss loss (Diureti (Di retics tics cs, poly l uria uria) i )

Skiin Sk in los los oss s ( (Exc (E essive essi ive sweat weati ting ing ing, g, bur burns))

FIGURE 4.1. Causes of prerenal failure. GI, gastrointestinal.

Intr Int In trin tri insi sic ic re rena nall fa na fail fail ilur lur ure e

Glom Gl omer om erul ular lar

Tubular

(Glo (G lome lo meru me rulo ru lone lo neph ne phri ph riti ri tis) ti s)

Ischaemic (E Ext xtreme xtre me pre rren enal al, sepsis,, pa p nc n re reat atit at i is it is))

Inte Int In ters ters rsti titi ti tiall

Vascul Vasc Va ular lar

(Aut (A utoi ut oimm oi mmun mm une un e, tox tox oxic ic, in ic infe fect fe ctio ct ious io us)) us

Toxic

Larg Larg La ge ve vess ssell

Smal Sm allll ve vess ssell

(Ren (R enov ovas ascu culla lar di lar dise seas ase e, athe at hero he roem ro embo em bo olilic) c))

((Vas (V Vas ascu culililiti cu tiss, HRS ti HRS RS, reno re nova no vasc vasc scul ular lar ar, r, ma malililign gnan gn nan ant nt hypertension)

Intrinsic toxins ( ha (R habd bdom bd omyo om y lyysi yo siss, mas assi sive si ve hae hae aemo moly mo lyysi siss tumo tumo tu mour ur llys ysiis ys is myel is, elom loma))

Extrinsic toxins (Rad (R adio io o ccon ontr on tras tr astt, as t, dru dru rugs gs, an gs antititibi biot bi otic ot tic ics) s))

FIGURE 4.2. Causes of intrinsic renal failure (red, d commoner causes on the ICU). HRS, hepatorenal syndrome.

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pathophysiology of ischemic ATN is reviewed elsewhere (21, 22), but an alteration in glomerular hemodynamics with marked afferent arteriolar renal vasoconstriction causes a fall in glomerular filtration pressure and subsequently causes ischfi emia. This particularly affects the outer medulla. Tubular damage leads to loss of normal cell-to-cell adhesion and allows back leakage of filtrate fi into the interstitium. Shed cells precipitate, with protein obstructing the tubules and further compromising tubular function. Local infl flammatory mediators respond to cell injury, perpetuating the process. ATN can also develop secondary to a variety of intrinsic or extrinsic renal toxins. Vascular causes of renal failure may be present at a prerenal or intrarenal level, and should be considered in vasculopaths. The more classic glomerular causes for intrinsic renal failure are seen less frequently on the ICU, but are important to recognize because they require specific fi treatment.

Postrenal or Obstructive Renal Failure Obstruction can occur at any level of the urinary collecting system and can be caused by intrinsic (e.g., stones, tumor) or extrinsic causes (e.g., surrounding or infi filtrating tumor, large infl flammatory abdominal aortic aneurysms). Obstruction is an infrequent cause of AKI on the ICU but is important to be excluded in all cases.

S. Blakeley

Volume Overload Salt and water retention occurs early, and is a common reason for initiating RRT on the ICU (16). Volume overload may have deleterious effects on cardiac and respiratory function, with the development of peripheral edema affecting wound healing and pressure areas.

Acidosis There is retention of organic anions (e.g., phosphate) and reduced production of bicarbonate by the failing tubules. In critically ill patients, this may be aggravated by the presence of a nonrenal acidosis, for example, lactic acidosis from sepsis and respiratory acidosis from respiratory failure.

Electrolyte and Mineral Disturbances Hyponatremia, hyperkalemia, and hyperphosphatemia are commonly seen.

Anemia Anemia can develop because of inappropriate levels of erythropoietin (decreased synthesis) or increased red cell fragility, causing premature red cell destruction. Uremia is also associated with platelet dysfunction and increased risk of gastrointestinal bleeding.

Complications of AKI AKI is a systemic disease, having effects on practically all organ systems (23). It is becoming increasingly recognized that there is “cross talk” between the injured kidney and other organs through the release of proinfl flammatory cytokines. Complications related to other failing organs may be seen, but complications specific fi to the failing kidney are as follows.

Retention of Uremic Toxins Accumulation of toxins, including urea, can lead to nausea, vomiting, drowsiness, a bleeding tendency, uremic flap, and, rarely, coma (uremic encephalopathy) and a pericardial rub.

Immunosuppression Renal failure itself can impair humoral and cellular immunity, putting the patient at risk of infectious complications.

Metabolic Consequences Hyperglycemia occurs because of peripheral insulin resistance and increased hepatic gluconeogenesis. Protein catabolism is also activated.

Drug Accumulation Renal failure may be secondary to drugs, but, as GFR falls, renal clearance of drugs and their

4. Acute Kidney Injury

metabolites also falls. Renal failure may be exacerbated by drug accumulation, or other side effects can develop, such as morphine metabolites leading to respiratory depression.

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be interpreted in light of the clinical setting, but can act as another tool in the assessment of intravascular volume status.

Radiological Investigations

Investigation of the Cause of Renal Failure (Table 4.1) Laboratory Tests (Table 4.2) Urinalysis A standard dipstick for blood and protein should be preformed and a fresh sample spun for casts: hyaline casts (nonspecific fi markers of renal injury), brown/cellular casts (ATN), and red cell casts (acute glomerulonephritis). An estimation of protein excretion may be needed, either a 24-hour urine collection or a spot urine protein-creatinine ratio, depending on local resources. Urine osmolality and urinary electrolytes can be used to help distinguish prerenal failure from intrinsic kidney disease (Table 4.3). They should

A chest x-ray will help assess volume status, but patchy infi filtrates may also represent pulmonary hemorrhage, as seen in certain forms of vasculitis. A renal ultrasound scan should be performed; the timing will depend on the likely cause of renal failure and the patient’s clinical state. Further imaging should be guided by the clinical scenario.

Conclusion AKI is a significant fi condition affecting critically ill patients on the ICU. It is a systemic process affecting all organs, and has a major impact on patient morbidity and mortality. It is, therefore, important to be able to promptly recognize its development and institute the appropriate investigations to guide treatment.

TABLE 4.1. History and examination in AKI A full history should be take with reference to the following: • Presence of risk factors: known chronic renal disease, advanced age, diabetes mellitus, ischemic heart disease, hypertension, peripheral vascular di disease, liver li disease, di recentt hi high-risk h i k surgery • Previous episodes of renal failure • Family history of renal disease • Rashes, joint aches, sinusitis, and hemoptysis suggesting a systemic condition • Review blood pressure and anesthetic charts for periods of profound or prolonged hypotension in relation to the patients usual blood pressure • Review fluid balance charts considering hidden losses, such as sweating or “third spacing.” The sudden onset of anuria suggests obstruction or a catastrophic t t hi vascular l event.t RRemember b that th t di diuretics ti can make k th the urine i output t t llookk ““artificially tifi i ll good” d” • Drug charts should be reviewed for intravenous contrast, chemotherapeutic agents, analgesics, antibiotics, and herbal remedies, including any new medications taken in the past month • Determine baseline creatine and pattern of change (i.e., sudden jump or gradual decline). The rate of change may be more important than the absolute value • Review any previous urinalyses for previous hematuria or proteinuria that may suggest chronic disease A full examination should be performed with reference to the following: • Pressure: mean arterial pressure in relation to the patients usual readings • Flow: cardiac output studies and/or markers of end organ perfusion (e.g., lactate) • Volume: overall volume status as well as intravascular volume status • Patent vessels: evidence of generalized vascular disease • Rashes or splinter hemorrhages suggesting vasculitis, cholesterol emboli, or infective endocarditis • Palpable bladder or kidney, suggesting obstruction • Raised intra-abdominal pressure or tense limbs, suggesting compartment syndrome

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S. Blakeley

TABLE 4.2. Laboratory investigations for AKI Finding

Comment

Anemia Thrombocytopenia + microangiopathic hemolytic anemia

Normochromic, normocytic suggests chronicity Consider hemolytic uremic syndrome, thrombotic thrombocytopenic purpura, disseminated intravascular coagulation (DIC) Consider sepsis Consider vasculitis, allergic interstitial nephritis Sepsis, DIC, hepatorenal syndrome, systemic lupus erythematosus (SLE) Will rise with any cause of renal failure. A normal serum creatinine does not exclude the presence of renal dysfunction, and conversely an elevated creatinine may underestimate the degree of renal dysfunction A newer marker of renal dysfunction, but needs further evaluation on ICU patients. Freely filtered at the glomerulus, and fully metabolized by proximal tubular cells, if GFR falls, levels rise Elevated in malignancy (including hematological). Calcium may be high, low, or normal in chronic kidney disease (CKD) Extremely elevated in rhabdomyolysis and tumor lysis syndrome, but will rise with any cause of low GFR. May be normal or high in CKD Rhabdomyolysis Consider hepatorenal syndrome; sepsis; vasculitis; and hemolysis, elevated liver enzymes, and low platelet count (HELLP) syndrome Seen in preeclampsia but will rise with any fall in GFR Look for myeloma and other hematological malignancies Investigate further for systemic diseases, such as SLE and vasculitis

Neutrophilia, “left shift” + thrombocytopenia Eosinophilia Abnormal coagulation profile Elevated urea and creatinine

Elevated serum Cystatin C

Hypercalcemia Hyperphosphatemia Elevated creatinine kinase Abnormal liver function tests Elevated uric acid Abnormal immunoglobulins Elevated antinuclear factor, double-stranded DNA, antineutrophil cytoplasmic antibodies (ANCA), antiglomerular basement membrane antibodies, and low complement Positive virology/serology/microbiology

Certain forms of renal injury seen with specific infections, e.g., hepatitis B/C, HIV, leptospirosis, verotoxin-producing Escherichia coli

TABLE 4.3. Urinary findings in prerenal failure and ATNa Prerenal Urine Na Urine : plasma (U : P) urea ratio U : P creatinine ratio U : P osmolality Specific gravity Urine osmolality Urine osmolality FE sodiumb

<20 mmol/L >20

>40 mmol/L <10

>40 >2.1 >1.020 >500 High (>serum + 100 mOsm/L) <1%

<10–20 <1.2 <1.010 <400 Low (<serum + 100 mOsm/L) >1–2%

a

These results should be interpreted with caution in patients who have had diuretics, large volume resuscitation, the elderly, or patients with chronic renal failure. b FE, fractional excretion of sodium: in a prerenal state, sodium is actively reabsorbed by working tubules to maintain intravascular volume. The kidney will, therefore, produce concentrated urine with a low concentration of sodium. Creatinine is still excreted, but relatively less sodium appears in the urine. Hence, if the tubules are intact, the amount of sodium excreted compared with creatinine (fractional excretion) falls. FE Na =

References

Intrinsic

Urine Na plasma creatinine 100 Plasma Na Urine creatinine

1. Kellum JA, Levin N, Bouman C, Lameire N. Devleoping a concensus classification fi for acute renal failure. Curr Opin Crit Care. 2002; 8: 509–514. 2. Tillyard A, Keays R, Soni N. The diagnosis of acute renal failure in intensive care: mongrel or pedigree? Anaesthesia. 2005; 60: 903–914. 3. Hoste EA, Kellum JA. Acute kidney injury: epidemiology and diagnostic criteria. Curr Opin Crit Care. 2006; 12: 531–537. 4. Mehta RL, Chertow GM. Acute renal failure definifi tions and classifi fication: Time for a change? J Am Soc Nephrol. 2003; 14: 2178–2187. 5. Bellomo R, Ronco C, Kellum JA et al. Acute renal failure—Definition, fi outcome measures, animal models, fluid therapy and information technology needs. The Second International Consensus Conference of the Acute Dialysis Quality Initiative (ADQI) group. Crit Care. 2004; 8: R204–R212. 6. Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. fi Am J Kid Dis. 2002; 39(5): 930– 936.

4. Acute Kidney Injury 7. Hou SH, Bushinsky DA, Wish JB et al. Hospitalacquired renal insuffi ficiency: a prospective study. Am J Med. 1983; 74(2): 243–248. 8. Uchino S, Kellum JA, Bellomo R et al. Beginning and Ending Supportive Therapy for the Kidney (BEST Kidney) Investigators. Acute renal failure in critically ill patients: a multinational, multicenter study. JAMA. 2005; 294(7): 813–818. 9. Uchino S, Bellomo R, Goldsmith D et al. An assessment of the RIFLE criteria for acute renal failure in hospitalized patients. Crit Care Med. 2006; 34(7): 1913–1917. 10. Hoste EA, Clermont G, Kersten A et al. RIFLE criteria for acute kidney injury are associated with hospital mortality in critically ill patients: a cohort analysis. Crit Care. 2006; 10(3): R73. 11. Kuitunen A, Vento A, Suojaranta-Ylinen R, Pettila V. Acute renal failure after cardiac surgery: evaluation of the RIFLE classifi fication. Ann Thoracic Surg. 2006; 81(2): 542–546. 12. Chertow GM, Levy EM, Hammermeister KE et al. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med. 1998; 104(4): 343–348. 13. Bagshaw SM, Laupland KB, Doig CJ et al. Prognosis for longterm survival and renal revoery in critically ill patients with severe acute renal failure: A population based study. Crit Care. 2005; 9: R700– 709. 14. Metnitz PG, Krenn CG, Steltzer H et al. Effect of acute renal failure requiring renal replacement

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15.

16.

17.

18.

19.

20. 21.

22. 23.

therapy on outcome in critically ill patients. Crit Care Med. 2002; 30: 2051–2058. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ. Acute renal failure in intensive care units-causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. Crit Care Med. 1996; 24(2): 192–198. Silvester W, Bellomo R, Cole L. Epidemiology, management, and outcome of severe acute renal failure of critical illness in Australia. Crit Care Med. 2001; 29: 1910–1915. Korkeila M, Ruokonen E, Takala J. Cost of care, long term prognosis and quality of life in patients requiring renal replacement therapy during intensive care. Int Care Med. 2000; 26: 1824–1831. Bagshaw SM. Epidemiology of renal recovery after acute renal failure. Curr Opin Crit Care. 2006; 12: 544–550. Rangel-Frausto MS, Pittet D, Costigan M et al. The natural history of the systemic infl flammatory response syndrome (SIRS). A prospective study. JAMA. 1995; 273(2): 117–123. Schrier RW, Wang W. Acute renal failure and sepsis. N Engl J Med. 2004; 315: 159–169. Schrier RW, Wang W, Poole B Mitra A. Acute renal failure: definitions, fi diagnosis, pathogenesis and therapy. J Clin Invest. 2004; 114: 5–14. Lameire N, Van Biesen W, Vanholder R. Acute renal failure. Lancet. 2005; 365: 417–430. Druml W. Acute renal failure is not a “cute” renal failure! Intensive Care Med. 2004; 30: 1886–1890.

5 Medical Management of Acute Renal Failure Nerina Harley

Acute renal failure (ARF) is both common and associated with signifi ficant mortality in the intensive care unit (ICU) setting (1). With an impact on length of stay, likelihood of survival until discharge, and cost of care, it is vital that the increasing body of evidence in critical care nephrology is used to refine fi defi finitions, diagnosis, preventive strategies, investigations, and management of these patients (2). The medical management of ARF relies on the basic tenets of diagnosis, elimination of reversible factors, amelioration of exacerbating factors, treatment of complications, and optimization of the “kidney’s environment” to provide maximal recovery.

Patients with renal disease have a variety of clinical presentations: • Asymptomatic • Symptoms directly referable to the kidney, e.g., hematuria, flank fl pain • Extrarenal symptoms, e.g., edema, hypertension, uremic symptoms, consequences of hyperkalemia • Manifestations of the underlying pathology or etiology, e.g., sepsis, hypotension, rhabdomyolysis, systemic vasculitis

Investigations Assessment of Renal Function

Diagnosis of ARF Major causes of renal disease are divided, for simplicity, into three areas: • Prerenal causes, caused by volume depletion with or without relative hypotension (reduced renal perfusion) • Intrinsic renal causes, caused by vasculitis, glomerular disease, and tubulointerstitial disease • Postrenal or obstructive causes The most common causes of ARF have been found to be acute tubular necrosis (ATN) (45%), prerenal (21%), acute on chronic (13%), obstruction (10%), glomerulonephritis (GN), or vasculitis (4%) (3). Risk factors for the development of ARF are given in Table 5.1.

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Although they lack sensitivity and specificity fi serum creatinine and urine output are the most useful parameters in clinical practice. Glomerular filtration rate (GFR) assessment may be diffi fi ficult in nonsteady-state conditions. Comparison with previous results is vital in determination of baseline function, time course, and progression.

Urinalysis Urine examination may demonstrate granular and epithelial casts in ATN, eosinophils in acute interstitial nephritis, and red cell casts in acute vasculitis or glomerulonephritis and/or proteinuria. There are no prospective studies of the predictive value of urine sediment in ATN. Urinary electrolytes are of limited value in most clinical situations because of the confounding effects of

5. Medical Management of Acute Renal Failure TABLE 5.1. Risk factors for ARF Risk factor Older age Diabetes Underlying renal insufficiency Cardiac failure Sepsis Absolute or relative hypovolemia Hepatic failure Nephrotoxins (including high-osmolality radiocontrast agents) Cardiopulmonary bypass with aortic cross-clamping (particularly valve surgery) Nonrenal organ transplantation Abdominal compartment syndrome

Selected reference(s) Nash et al., 2002 (43) Parfrey et al., 1989 (44).

Brun-Buisson et al., 2004 (45) Ricci et al., (46) Han and Hyzy, 2006 (47) Barrett et al., 1993 (48) Aspelin et al., 2003 (49). McCullogh et al., 2006 (50) Mangano et al., 1998 (51) Chertow et al., 1998 (52) Lima et al., 2003 (53) McNelis et al., 2003 (54)

treatments such as diuretics. Urine volume is of little diagnostic value, although little or no output is acutely useful with causes of anuria, including shock, bilateral urinary obstruction, renal cortical necrosis, and bilateral vascular occlusion.

Other Markers of Renal Injury These have been described but are not currently generally available in the acute setting. For example, serum cystatin C has been recently proposed as a marker of ARF (4), predicting ARF by at least 24 hours.

Radiology Renal ultrasound is the modality of choice to exclude obstruction. Reduced renal size and cortical thinning (although preserved in diabetic nephropathy) is indicative of chronic renal impairment. A helical computed tomographic (CT) scan may be useful in urolithiasis, but there are risks of secondary injury with radiocontrast.

Renal Biopsy Renal biopsy is considered when noninvasive evaluation has not established the diagnosis (5); the major indications include isolated hematuria with proteinuria, nephrotic syndrome, acute nephritic syndrome, and unexplained ARF. Percutaneous biopsy is most commonly performed and the

27

inherent risks of bleeding should be weighed up in the setting of the risk-to-benefit fi ratio. Note: The “gold standard” for the diagnosis of a prerenal cause of ARF is resolution of renal impairment in response to fluid challenge. This is in contrast to significant fi ATN, in which there is prolonged time to resolution.

Primary Prevention Primary prevention of ARF in the critically ill with or without baseline risk factors consists of avoidance, amelioration, and treatment of these factors wherever possible. Strategies can be divided into nonpharmacological, for example, fluid fl administration to reduce the risk of contrast induced nephropathy (6), and pharmacological. To date, no pharmacological strategies have conclusively demonstrated prevention of ARF from any insult (7).

Loop Diuretics Although oliguria (<400 mL/24 h) is common in ATN, anuria is rare and other etiologies must be considered. Nonoliguric patients have a better prognosis than oliguric patients in terms of a greater residual GFR (8), lower peak serum creatinine, and dialysis-free survival at 21 days (9, 10), possibly reflecting fl less severe renal injury. A clinical issue of the use of loop diuretics often arises in increasing the urine output of oliguric patients. Experimentally, loop diuretics reduce active sodium chloride transport in the thick ascending limb of the loop of Henle, decreasing energy requirements and, thus, protecting the cell in the setting of decreased energy availability. Only anecdotal human evidence suggests that the use of loop diuretics may be beneficial fi in the first 24 hours in flushing tubular casts. There is no evidence of benefi fit in established ATN on duration of renal failure, requirement for dialysis, or survival (11). The increase in urine output in this setting is caused by decreased tubular reabsorption in residual functioning nephrons (not recruitment of nonfunctioning nephrons), volume expansion (initial sodium retention), and urea osmotic diuresis. A number of studies have suggested worsened outcomes in ATN with the use of loop diuretics in

28

the setting of contrast media (9, 12) and cardiac surgery. A systematic review (13, 14) comparing fluids alone with diuretics found no evidence of fl improvement in survival, incidence of ARF, or need for renal replacement therapy (RRT). Deafness, possibly permanent, is a known complication of high-dose loop diuretics.

Mannitol Mannitol may preserve mitochondrial function by minimizing postinjury edema. Human trials have failed to show benefi fit in reducing ARF with mannitol versus fluid alone in rhabdomyolysis (15), cardiac surgery (16), and vascular and biliary tract surgery (17). A trend toward harm was noted in the prevention of contrast nephropathy (12).

Dopamine Agonists Dopamine has a number of effects in the kidney via dopamine A1 and A2 receptors. In the proximal tubule, dopamine, via the generation of cyclic AMP, decreases Na+-H+ exchange and the Na+-H+ATPase pump, thus, decreasing sodium reabsorption. In the collecting tubules, this effect on Na+-H+-ATPase and decreased aldosterone secretion reduces sodium reabsorption (18). When infused in doses of 0.5 to 3 μg/kg/min, dopamine causes afferent and efferent glomerular arteriolar dilatation, increasing blood flow fl with little or no increase in GFR. At higher concentrations, dopamine causes vasoconstriction via αadrenergic receptors. There is no evidence in human studies for a “renal protective effect” of dopamine. • In 1994, Baldwin et al. studied the effect of postoperative low-dose dopamine on renal function after major elective vascular surgery. Patients were administered saline or saline plus dopamine as fluid replacement. No difference in renal function was demonstrated between the two groups (19). • In the North American Study of the Safety and Efficacy fi of Murine Monoclonal Antibody to Tumor Necrosis Factor for the Treatment of Septic Shock (NORASEPT) II study, 400 patients with septic shock and oliguria nonrandomly received no, low-, or high-dose dopamine.

N. Harley

The incidence of ARF and requirement for RRT was not significant fi different between groups (20). • A large randomized controlled trial of low-dose dopamine in 328 critically ill patients with impaired creatinine, oliguria, and at least two systemic infl flammatory response syndrome (SIRS) criteria failed to show any benefit fi in progression, need for RRT, or death (21). • Studies of fenoldopam, a relatively selective dopamine A1 receptor agonist, although shown to increase sodium excretion and renal blood flow in healthy and hypertensive patients, has fl not shown benefi fit in ARF in the critically ill (22).

N-Acetylcysteine N-Acetylcysteine (NAC) has been shown in a N number of studies to decrease the incidence of contrast nephropathy in high-risk patients (23, 24), but without improvement in RRT requirement or survival. Importantly, NAC may decrease creatinine via activation of creatinine kinase (25) but not GFR. Promising studies have led to the introduction of protocols in many institutions for the prophylactic use of NAC in the prevention of contrast-induced nephropathy. With few side effects, low cost, and ease of administration (oral or intravenous), many centers have erred on the side of possible benefit fi in the face of lack of hard evidence of long-term benefit fi (26).

Others Trials have failed to demonstrate benefi fit of natriuretic peptides (10, 27) or adenosine agonists (28). Experimental therapies, such as antioxidants and erythropoietin are unproven in humans. In the absence of further evidence, fl fluids, and possibly NAC, are the gold standards of interventional strategies.

Supportive Strategies Fluid resuscitation and correction of hypotension are clearly essential. There is no evidence of advantage of one particular inotrope over another.

5. Medical Management of Acute Renal Failure

29

No evidence exists that reversing hypotension with noradrenaline compromises mesenteric or renal blood flow (29). Van den Berghe demonstrated that tight glucose control with intravenous therapy improved outcomes in critically ill patients, including decreased incidence of ARF (30, 31). Nutritional supportt of the critically ill is the basic standard of care, although not always achieved. Early enteral nutrition is supported by meta-analyses of Level II trials; benefits fi include preservation of muscle mass, the maintenance of the gastrointestinal mucosal barrier and immune status, and a possible reduction in multiorgan dysfunction (32–34). A Level I trial is currently planned by the Australian and New Zealand Intensive Care Society (ANZICS) clinical trials group comparing early enteral nutrition with standard care in 1470 critically ill patients intolerant of early enteral nutrition (www.actr.org.au). There is no evidence to support prophylactic hemofiltration fi to prevent contrast nephropathy, despite fi filtration removal of contrast. Early recognition and adequate management of the deteriorating clinical condition of a patient is fundamental in the prevention of morbidity and mortality, including ARF. In a hospital-based study of a medical emergency team (MET) system, Bellomo et al. demonstrated reduced incidence of postoperative adverse outcomes, mortality rate, and mean hospital length of stay (35). This was not validated in a larger cluster-randomized controlled trial of 23 hospitals with no effect on incidence of cardiac arrest, unplanned admissions to ICU, or unexpected death (36). Nevertheless, the principles of early recognition, monitoring, and adequate response remain fundamental.

There is currently insufficient fi data to recommend firm therapeutic targets, suffi fi fice to say, Level III evidence suggests failure to maintain systolic blood pressure greater than 80 mmHg or MAP greater than 50 mmHg is associated with increased risk of developing ARF (39). A low cardiac output is a major risk factor for ARF after cardiac surgery (40), but supranormal cardiac output has no beneficial fi effect.

Postinjury Prevention of ARF

Avoidance of Further Insults

Secondary renal injury occurs after the primary insult has triggered the initial injury to the kidneys. Strategies for postinjury prevention of ARF overlap with those of primary prevention (37) as described above. They include maintenance of adequate intravascular volume, cardiac output, mean arterial blood pressure (MAP), avoidance of further insult, and supportive strategies.

Assessment and Correction of Volume Depletion Clinical signs of relative or absolute volume depletion include loss of tissue turgor, hypotension, postural hypotension, and decreased venous pressure (reduced jugular venous pressure). Although left ventricular end diastolic pressure (LVEDP) is the most important determinant of left ventricular output and, thus, tissue perfusion, central venous pressure is useful because it has a direct relationship to LVEDP, with the exceptions of pure left-sided or pure right-sided failure (cor pulmonale). Other clinical manifestations may be specifi fic to the source of depletion (losses or third space sequestration), type of fl fluid lost, and to the associated electrolyte and acid-base abnormalities. Recently, Vincent proposed a protocol for routine fl fluid challenge with defi fined rules based on clinical response to the volumes infused, allowing for prompt deficit fi correction while minimizing risks of fluid fl overload (38).

Maintenance of Adequate MAP and Cardiac Output

Appropriate dosage of medication and avoidance (or protective strategies) of nephrotoxins is advised.

Renal Replacement Therapy Intermittent versus continuous renal replacement strategies and dose delivery are discussed in a later chapter.

30

N. Harley

TABLE 5.2. Summary of guidelines for management of ARF Make diagnosis Exclusion of prerenal causes Exclusion of postrenal causes Exclusion of intrinsic renal causes Evaluation of urinary electrolytes

E.g., volume depletion, cardiac and liver disease, nephrotoxins Renal ultrasound E.g., review urinary sediment, consider renal biopsy Only in the absence of diuretics

Treat reversible causes Volume resuscitation Blood pressure support Treat electrolyte complications No dopamine

Maintain fluid balance but avoid overload Inotropic if necessary, however no validated physiological targets or end points have been established E.g., hyperkalemia

Address/avoid exacerbating factors Treatment of underlying etiology Adjust medication dosage Avoid further renal insult

E.g., treat sepsis, further investigation if diagnosis unclear, surgical referral if appropriate Discontinue any nephrotoxic drugs E.g., minimize contrast-induced injury with fluids and consider NAC

Optimize “kidney’s environment” Maintain renal perfusion Adequate nutrition Glucose control Appropriate RRT

Maintain fluid balance, blood pressure, and cardiac output

Timely introduction of RRT, avoidance of complications (e.g., hypotension, line-related sepsis, biocompatible dialysis membranes), and appropriate dose of dialysis

Other Constantly review diagnosis, which may multifactorial in nature Appropriate medical review

Consider further investigations, e.g., renal biopsy and radiological investigations, as appropriate E.g., MET resources, nephrology input

Summary Measures of severity of illness are limited when applied to patients with ARF and, at present, none are currently adequate to predict mortality of ARF (41). In the light of available evidence, guidelines for the management of ARF have been formulated and given in Table 5.2. Admiral efforts to clearly defi fine levels of injury in ARF and physiological end points (42) will enable further research into prevention, amelioration, and management of ARF and, thus, impact on the significant fi associated morbidity and mortality.

References 1. Levy EM, Viscoli CM, Horwitz RI. The effect of acute renal failure on mortality. A cohort analysis. JAMA. 1996; 275(19): 1489–1494. 2. Kellum JA. Acute renal failure, interdisciplinary knowledge and the need for standardization. Curr Opin Crit Care. 2005; 11(6): 525–526.

3. Liano G, Pascual J. Acute renal failure. Madrid Acute Renal Failure Study Group. Lancet. 1996; 347(8999): 479. 4. Herget-Rosenthal S, Marggraf G, Husing J, et al. Early detection of acute renal failure by serum cystatin C. Kidney Int. 2004; 66(3): 1115–1122. 5. Madaio MP. Renal biopsy. Kidney Int. 1990; 38(3): 529–543. 6. Mueller C, Buerkle G, Buettner HJ, et al. Prevention of contrast media-associated nephropathy: randomized comparison of 2 hydration regimens in 1620 patients undergoing coronary angioplasty. Arch Intern Med. 2002; 162(3): 329–336. 7. Kellum JA, Leblanc M, Gibney RT, et al. Primary prevention of acute renal failure in the critically ill. Curr Opin Crit Care. 2005; 11(6): 537–541. 8. Rahman SN, Conger JD. Glomerular and tubular factors in urine flow rates of acute renal failure patients. Am J Kidney Dis. 1994; 23(6): 788–793. 9. Lassnigg A, Donner E, Grubhofer G, et al. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephrol. 2000; 11(1): 97–104.

5. Medical Management of Acute Renal Failure 10. Allgren RL, Marbury TC, Rahman SN, et al. Anaritide in acute tubular necrosis. Auriculin Anaritide Acute Renal Failure Study Group. N Engl J Med. 1997; 336(12): 828–834. 11. Cantarovich F, Rangoonwala B, Lorenz H, et al. High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebocontrolled, multicenter trial. Am J Kidney Dis. 2004; 44(3): 402–409. 12. Solomon R, Werner C, Mann D, et al. Effects of saline, mannitol, and furosemide to prevent acute decreases in renal function induced by radiocontrast agents. N Engl J Med. 1994; 331(21): 1416– 1420. 13. Kellum JA. Diuretics in acute renal failure: protective or deleterious. Blood Puriff 1997; 15(4–6): 319–322. 14. Kellum JA. The use of diuretics and dopamine in acute renal failure: a systematic review of the evidence. Crit Care (Lond). 1997; 1(2): 53–59. 15. Homsi E, Barreiro MF, Orlando JM, Higa EM. Prophylaxis of acute renal failure in patients with rhabdomyolysis. Ren Fail. 1997; 19(2): 283– 288. 16. Ip-Yam PC, Murphy S, Baines M, et al. Renal function and proteinuria after cardiopulmonary bypass: the effects of temperature and mannitol. Anesth Analg. 1994; 78(5): 842–847. 17. Gubern JM, Sancho JJ, Simo J, Sitges-Serra A. A randomized trial on the effect of mannitol on postoperative renal function in patients with obstructive jaundice. Surgery. 1988; 103(1): 39–44. 18. Denton MD, Chertow GM, Brady HR. “Renal-dose” dopamine for the treatment of acute renal failure: scientifi fic rationale, experimental studies and clinical trials. Kidney Int. 1996; 50(1): 4–14. 19. Baldwin L, Henderson A, Hickman P. Effect of postoperative low-dose dopamine on renal function after elective major vascular surgery. Ann Intern Med. 1994; 120(9): 744–747. 20. Marik PE, Iglesias J. Low-dose dopamine does not prevent acute renal failure in patients with septic shock and oliguria. NORASEPT II Study Investigators. Am J Med. 1999; 107(4): 387–390. 21. Bellomo R, Chapman M, Finfer S, et al. Low-dose dopamine in patients with early renal dysfunction: a placebo-controlled randomised trial. Australian and New Zealand Intensive Care Society (ANZICS) Clinical Trials Group. Lancet. 2000; 356(9248): 2139–2143. 22. Tumlin JA, Finkel KW, Murray PT, et al. Fenoldopam mesylate in early acute tubular necrosis: a randomized, double-blind, placebo-controlled clinical trial. Am J Kidney Dis. 2005; 46(1): 26–34.

31 23. Birck R, Krzossok S, Markowetz F, et al. Acetylcysteine for prevention of contrast nephropathy: metaanalysis. Lancet. 2003; 362(9384): 598–603. 24. Pannu N, Manns B, Lee H, Tonelli M. Systematic review of the impact of N-acetylcysteine on contrast nephropathy. Kidney Int. 2004; 65(4): 1366–1374. 25. Genet S, Kale RK, Baquer NZ. Effects of free radicals on cytosolic creatine kinase activities and protection by antioxidant enzymes and sulfhydryl compounds. Mol Cell Biochem. 2000; 210(1–2): 23–28. 26. Bagshaw SM, McAlister FA, Manns BJ, Ghali WA. Acetyl-cysteine used in the prevention of contrastinduced nephropathy: a case study in the pitfalls in the evolution of evidence. Arch Intern Med. 2006 Jan 23; 166(2): 161–166. 27. Lewis J, Salem MM, Chertow GM, et al. Atrial natriuretic factor in oliguric acute renal failure. Anaritide Acute Renal Failure Study Group. Am J Kidney Dis. 2000; 36(4): 767–774. 28. Kramer BK, Preuner J, Ebenburger A, et al. Lack of renoprotective effect of theophylline during aortocoronary bypass surgery. Nephrol Dial Transplant. 2002; 17(5): 910–915. 29. Levy B, Bollaert PE, Charpentier C, et al. Comparison of norepinephrine and dobutamine to epinephrine for hemodynamics, lactate metabolism, and gastric tonometric variables in septic shock: a prospective, randomized study. Intensive Care Med. 1997; 23(3): 282–287. 30. Van den Berghe G, Wouters P, Weekers F, et al. Intensive insulin therapy in the critically ill patients. N Engl J Med. 2001; 345(19): 1359. 31. Van den Berghe G, Wouters PJ, Bouillon R, et al. Outcome benefi fit of intensive insulin therapy in the critically ill: Insulin dose versus glycemic control. Crit Care Med. 2003; 31(2): 359–366. 32. Doig GS, Simpson F. Evidence-based guidelines for nutritional support of the critically ill: results of a bi-national guideline development conference. Sydney: EvidenceBased.net; 2005. Download www. EvidenceBased.net. 33. Dhaliwal R, Heyland DK. Nutrition and infection in the intensive care unit: what does the evidence show? Curr Opin Crit Care. 2005; 11(5): 461–467. 34. Doig GS, Simpson F. Early enteral nutrition in the critically ill: do we need more evidence or better evidence? Curr Opin Crit Care. 2006; 12(2): 126– 130. 35. Bellomo R, Goldsmith D, Uchino S, Buckmaster J, Hart G, Opdam H, Silvester W, Doolan L, Gutteridge G. Prospective controlled trial on the effect of medical emergency team on postoperative morbidity and mortality rates. Crit Care Med. 2004; 32(4): 916–921.

32 36. Hillman K, Chen J, Cretikos M, Bellomo R, Brown D, Doig G, Finfer S, Flabouris A; MERIT study investigators. Introduction of the medical emergency team (MET) system: a cluster-randomised controlled trial. Lancet. 2005; 365 (9477): 2091–2097. 37. Bellomo R, Bonventre J, Macias W, Pinsky M. Management of early acute renal failure: focus on postinjury prevention. Curr Opin Crit Care. 2005; 11(6): 542–547. 38. Vincent JL, Weil MH. Fluid challenge revisited. Crit Care Med. 2006; 34(5): 1333–1337. 39. Kohli HS, Bhaskaran MC, Muthukumar T, et al. Treatment-related acute renal failure in the elderly: a hospital-based prospective study. Nephrol Dial Transplant. 2000; 15(2): 212–217. 40. Suen WS, Mok CK, Chiu SW, et al. Risk factors for development of acute renal failure (ARF) requiring dialysis in patients undergoing cardiac surgery. Angiology. 1998; 49(10): 789–800. 41. Uchino S, Bellomo R, Morimatsu H, et al. External validation of severity scoring systems for acute renal failure using a multinational database. Crit Care Med. 2005; 33(9): 1961–1967. 42. Murray PT, Le Gall JR, Dos Reis Miranda D, et al. Physiologic endpoints (effi ficacy) for acute renal failure studies. Curr Opin Crit Care. 2002; 8(6): 519–525. 43. Nash K, et al. Hospital-acquired renal insufficiency. fi Am J Kidney Dis. 2002; 39(5): 930–936. 44. Parfrey P, et al. Contrast material-induced renal failure in patients with diabetes mellitus, renal insuffi ficiency, or both. A prospective controlled study. N Engl J Med. 1989; 320(3): 143–149.

N. Harley 45. Brun-Buisson C, et al. EPISEPSIS: a reappraisal of the epidemiology and outcome of severe sepsis in French intensive care units. Intensive Care Med. 2004; 30(4): 580–588. 46. Ricci Z, et al. Practice patterns in the management of acute renal failure in the critically ill patient: an international survey. Nephrol Dial Transplant. 2006; 21(3): 690–696. 47. Han MK, Hyzy R. Advances in critical care management of hepatic failure and insufficiency. fi Crit Care Med. 2006; 34(9 Suppl): S225–231. 48. Barrett B, et al. Meta analysis of the relative nephrotoxicity of high- and low-osmolality iodinated contrast media. Radiology. 1993; 188(1): 171–178. 49. Aspelin P, et al. Nephrotoxic effects in high-risk patients undergoing angiography. N Engl J Med. 2003; 348(6): 491–499. 50. McCullogh PA, et al. Risk prediction of contrastinduced nephropathy. Am J Cardiol. 2006; 98(68): 27K–36K. 51. Mangano C, et al. Renal dysfunction after myocardial revascularization: risk factors, adverse outcomes, and hospital resource utilization. Ann Intern Med. 1998; 128(3): 194–203. 52. Chertow G, et al. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med. 1998; 104(4): 343–348. 53. Lima E, et al. Risk factors for development of acute renal failure after liver transplantation. Ren Fail. 2003; 25(4): 553–560. 54. McNelis J, et al. Abdominal compartment syndrome: clinical manifestations and predictive factors. Curr Opin Crit Care. 2003; 9(2): 133–136.

6 Acute Renal Failure in the Surgical Patient Marlies Ostermann

Acute renal failure (ARF) is a potential complication of any surgical procedure. In general, the risk of ARF is increased in patients with underlying vascular disease, diabetes mellitus, or chronic kidney disease. High-risk situations include cardiovascular, hepatobiliary, and trauma surgery, especially if performed as an emergency.

Pathophysiology of ARF The most common causes of postoperative renal failure are hypotension (relative and absolute) and/or volume depletion. Renal oxygen consumption is determined by blood flow, making the kidneys particularly vulnerable to ischemic injury when flow is reduced. The kidneys receive 20 to 25% of the cardiac output. In healthy individuals, renal blood flow fl is regulated by a complex interplay between intrinsic autoregulation, and hormonal and neuronal influences. fl This results in a relatively constant renal blood fl flow when mean arterial blood pressure (MAP) is 80 to 180 mmHg. Outside of these limits, renal blood fl flow becomes pressure dependent, and glomerular filtration fi ceases when MAP is less than 40 to 50 mmHg. In patients with long-standing hypertension, this mechanism of autoregulation is lost, and renal function is pressure dependent, often needing a MAP of greater than 80 mmHg. As a result, these patients need higher blood pressures to maintain glomerular filtration fi and are particularly vulnerable to hypotension or volume depletion. The whole kidney only extracts less than 10% of the oxygen carried through the kidney. The thick ascending limb of the loop of Henle in the

outer medulla is metabolically very active, despite a relatively low oxygen delivery. As a consequence, oxygen extraction in this region is approximately 80% and, in the event of ischemia, this area is often the first part of the kidney to suffer injury.

Risk Factors for ARF in the Surgical Patient (Table 6.1) Effect of Anesthesia Most inhalation and intravenous anesthetics cause some degree of cardiac depression and/or vasodilation, resulting in lowering of the blood pressure. Similarly, spinal or epidural anesthesia can cause hypotension as a result of increased venous capacitance and arterial vasodilation. In response, compensatory changes lead to renal arterial vasoconstriction and increased retention of sodium and water. Maintenance of an adequate intravascular volume and blood pressure in the range of patient’s baseline blood pressure is essential to prevent anesthesia-related renal impairment.

Effect of Drugs Certain medication may be directly nephrotoxic (e.g., aminoglycosides, amphotericin, nonsteroidal anti-infl flammatory drugs) or may alter intrarenal hemodynamics (e.g., angiotensin-converting enzyme inhibitors, nonsteroidal anti-inflammafl tory drugs). In rare situations, a drug-induced interstitial nephritis may occur. This is most commonly caused by antibiotics or nonsteroidal analgesics, but any drug can cause interstitial nephritis.

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34 TABLE 6.1. Risk factors for ARF developing in surgical patients Preoperative factors State of hydration/adequate resuscitation preoperatively Contrast media Preexisting sepsis Patient comorbidity • Advanced age • Diabetes mellitus • Hypertension • Cardiovascular disease • Preexisting renal impairment Operative factors Related to anesthesia (see text) Related to surgery • Emergency surgery • Duration of cardiopulmonary bypass • Clamping of renal arteries • Suprarenal aortic cross clamping Postoperative factors • Sepsis • Bleeding • Nephrotoxic drugs • Contrast media • Cardiovascular complications associated with a fall in cardiac output t t ((e.g., myocardial di l iinfarction, f ti pulmonary l embolus, b l pericardial effusion) • Development of intra-abdominal compartment syndrome

Treatment consists of discontinuation of the offending drug and possibly steroid therapy.

Development of Intra-abdominal Compartment Syndrome Patients with severe ileus, bowel obstruction, pancreatitis, or after trauma can develop increased abdominal pressure leading to increased pressure in renal veins and renal parenchyma resulting in decreased renal perfusion. There is a strong correlation between intra-abdominal pressure and ARF, with oliguria developing when the intraabdominal pressure is greater than 15 mmHg and anuria developing when pressure is greater than 30 mmHg. Intra-abdominal decompression is the treatment of choice.

Type of Surgery Cardiac Surgery (Table 6.2) Twenty to 40% of patients undergoing cardiac surgery experience a rise in serum creatinine by

M. Ostermann

25% or a fall in glomerular filtration rate by 25%. One to 5% of patients need renal replacement therapy. A combination of patient-specific fic comorbidities and factors related to surgery usually contribute to the development of ARF. Patient-specific fic risk factors may not be immediately obvious. A large study on 7310 patients undergoing coronary artery bypass grafting (CABG) demonstrated that 29.6% of patients reported being diabetic, but an additional 5.3% of patients were found to have previously undiagnosed diabetes. Similarly, among patients undergoing coronary angiography, 12% of patients were found to have an undiagnosed renal artery stenosis of greater than 75%. Risk factors related to surgery tend to be less predictable, but the risk of renal failure is generally higher in patients undergoing combined CABG and valve replacement compared with patients who only need one procedure. Very recently, aprotinin was identified fi as a risk factor for ARF. An observational study on 4374 patients undergoing revascularization showed that the use of aprotinin was associated with a doubling of the risk of renal failure requiring dialysis when compared with aminocaprionic acid, tranexamic acid, or no antifibrinolytic. fi

Methods of Prevention of ARF Several studies have focussed on prevention of ARF after cardiac surgery. To date, no magic bullet has been identifi fied. Prophylactic therapy with dopamine, mannitol, theophylline, and diuretics has not been effective. There is some evidence that diuretic use after cardiac surgery increases the risk of ARF. Data regarding the benefits fi of offpump surgery in patients at high risk of renal

TABLE 6.2. Risk factors after cardiac surgery Patient specific • • • • •

Advanced age Diabetes mellitus Hypertension Preexisting renal impairment Impaired left ventricular function

Surgery related • Emergency surgery • Reoperation • Prolonged duration of cardiopulmonary bypass • Reexploration for bleeding • Pericardial tamponade • Deep sternal or systemic infection

6. Acute Renal Failure in the Surgical Patient

35

TABLE 6.3. Specific tests to consider in determining the cause of ARF in surgical patientsa Blood tests

Creatinine kinase Full blood count

Urinalysis

Dipstick Biochemistry

Diagnostic imaging

Culture Ultrasound scan Imaging of renal perfusion (e.g., renal Dopplers, computed tomographic angiogram, MAG3, DTPA)

Measurement of intravesical pressure

To exclude rhabdomyolysis especially after trauma Eosinophilia is seen in 80% of patients with drug-induced interstitial nephritis Significant proteinuria/hematuria/casts suggest intrinsic renal pathology Urinary sodium and osmolality to help differentiate prerenal failure from ATN To exclude urinary tract infection To exclude obstruction and to determine renal size Renal vascular supply may be of concern after major abdominal aortic surgery. Investigation will depend on patient stability and local resources To exclude intra-abdominal hypertension and compartment syndrome

a

MAG3, mercaptoacetyltriglycine; DTPA, diethylene triamine pentaacetic acid.

failure is still confl flicting. Although low cardiac output has been shown to be a strong risk factor for ARF after cardiac surgery, there is no evidence that increasing cardiac output from adequate to supranormal has beneficial fi renal effects.

volume depletion, bleeding complications, and/or urosepsis.

Vascular Surgery

At present, there are no universally accepted criteria for the definition fi of ARF. Most arbitrary defi finitions are based on a rise in serum creatinine or fall in calculated creatinine clearance. It is important to remember that the glomerular fi filtration rate has to fall to less than 50% before serum creatinine rises, which means that any rise in serum creatinine always implies significant fi renal injury.

Patients undergoing vascular surgery generally represent a high-risk group for renal failure. The exact incidence of renal injury in this context is unknown but, again, depends on the definition fi of renal injury, patient characteristics, and type of surgery. Open surgical repair of abdominal aneurysms is associated with a high risk of renal failure, especially with suprarenal aortic cross clamping, massive bleeding, or cholesterol embolization. The emergence of endovascular repair has led to a reduced incidence of ARF, however, the risk is not completely abolished by vascular stents. In rare instances, endovascular stents have been found to migrate, resulting in occlusion of arterial orifi fices, including renal arteries.

Urological Surgery Obstruction is a common cause of ARF in patients with urological problems. Although this diagnosis is usually made before surgery, it may occur postoperatively (e.g., after renal transplantation or ureteric surgery). In general, the majority of ARF posturological surgery is because of acute tubular necrosis precipitated by hypotension,

Diagnosis (Table 6.3)

Treatment General Measures • Restoration of renal perfusion pressure • Correction of volume depletion • Avoidance of hypotension (including relative hypotension). Be guided by the patient’s preexisting blood pressure • Fluid resuscitation, as appropriate, and use of vasopressor agents if perfusing pressure still inadequate • Optimal treatment of sepsis/septic shock • Avoidance of nephrotoxic medication if possible. Close monitoring of drug levels when aminoglycosides are necessary

36

• Renal replacement therapy in case of severe metabolic acidosis, unresponsive fluid fl overload, resistant hyperkalemia, or pericarditis • Early involvement of nephrologists if an intrinsic cause of renal failure is a possibility or if the patient is likely to require ongoing renal support

Specific Measures • Removal of septic focus if possible (e.g. drainage of intra-abdominal abscess) • Relief of obstruction • Management of abdominal compartment syndrome (including consideration of abdominal decompression) • Revascularization of kidneys, if appropriate

M. Ostermann

Early Resuscitation Early recognition of patients at risk and timely resuscitation has been shown to result in signififi cant reduction of the development of ARF.

Prevention of Contrast-Induced Nephropathy

• Diuretics (unless patient is fl fluid overloaded) • Low-dose dopamine

The administration of fluids has been shown to be the most important factor in prevention of contrast-induced renal injury. Although the optimal fluid regimen is uncertain, available data support fl a regimen of 0.9% saline at 1 mL/kg/h intravenously from up to 12 hours before administration of contrast medium and for up to 12 hours after. Studies on the prophylactic role of N-acetylcysteN ine have had confl flicting results. Meta-analyses have concluded that prophylactic N-acetylcysteine N was harmless and may prevent an acute rise of serum creatinine after intravenous contrast, but survival and need for dialysis were not affected.

Vasopressor Agents and the Kidney

Tight Glucose Control

Vasopressor agents are often needed to manage septic shock, and noradrenaline and dopamine are good first-line drugs. Although there are few direct comparison studies, patients with septic shock tend to respond better to noradrenaline. Concern regarding the potential for noradrenaline to impair renal and mesenteric perfusion has been reduced by studies showing that reversal of hypotension with noradrenaline outweighed this effect and increased renal and mesenteric perfusion.

A single-center randomized controlled trial on intensive insulin therapy in postoperative ventilated patients showed a 41% decrease in the incidence of ARF requiring dialysis in the group of patients whose blood sugars were tightly controlled between 4.4 and 6.1 mmol/L compared with patients whose blood sugar was allowed to rise to 12 mmol/L before insulin was initiated. Further studies are necessary to confirm fi these results.

Prevention

Prophylactic Dopamine or Diuretics

Treatments that Have Not Been Shown to Alter the Course of ARF

General Vigilance Meticulous attention to fluid balance, blood pressure, prescribed drugs, and treatment of sepsis are the most important preventive measures. There is insuffi ficient evidence to recommend specifi fic physiological targets (MAP, cardiac output, filling pressures) that will ensure adequate renal perfusion. Instead, therapy needs to be individualized based on the baseline physiological condition of the individual patient.

A recent meta-analysis of 61 trials showed that low-dose dopamine (<5 μg/kg/min) often increased urine output but had no effect on renal function or prevention of ARF.

Natriuretic Peptides Urodilatin (renal natriuretic peptide) or anaritide (synthetic form of atrial natriuretic peptide) have failed to show any protective effect on the kidney.

6. Acute Renal Failure in the Surgical Patient

37

Future Advances At present, no agents have conclusively demonstrated a protective effect against ARF or alteration of the course of ARF. Strategies aimed at modulating renal function and renal recovery have focused on several mechanisms: 1. Reduction of renal metabolism and energy consumption of the kidneys (i.e., induction of hypothermia, use of insulin-like factor I). 2. Modulation of the inflammatory fl system (i.e., up-regulation of the acute stress response, manipulation of complement system, blockade of adhesion molecules). 3. Ischemic preconditioning. These strategies are clearly important areas of research but not ready for clinical application.

References 1. Bahar I, Akgul A, Ozatik MA, Vural KM, Demirbag AE, Boran M, Tasdemir O. Acute renal failure follow-

2.

3.

4.

5.

6.

7.

ing open heart surgery: risk factors and prognosis. Perfusion 2005; 20: 317–322. Barrett BJ, Parfrey PS. Preventing nephropathy induced by contrast medium. N Engl J Med d 2006; 354: 379–386. Chertow GM, Levy EM, Hammermeister KE, Grover F, Daley J. Independent association between acute renal failure and mortality following cardiac surgery. Am J Med d 1998; 104: 343–348. Friedrich JO, Adhikari N, Herridge MS, Beyene J. Meta-analysis: low-dose dopamine increases urine output but does not prevent renal dysfunction or death. Ann Intern Med d 2005; 142: 510–524. Lassnigg A, Donner E, Grubhofer G, Presterl E, Druml W, Hiesmayr M. Lack of renoprotective effects of dopamine and furosemide during cardiac surgery. J Am Soc Nephroll 2000; 11: 97–104. Mangano DT, Tudor IC, Dietzel C. Multicenter Study of Perioperative Ischemia Research Group; Ischemia Research and Education Foundation. The risk associated with aprotinin in cardiac surgery. N Engl J Med 2006; 354: 353–365. Van den Berghe G, Wouters PJ, Bouillon R, et al. Intensive insulin therapy in critically ill patients. N Engl J Med d 2001; 345: 1359–1367.

7 Rhabdomyolysis and Compartment Syndrome Laurie Tomlinson and Stephen Holt

Rhabdomyolysis occurs when an insult causing myocyte necrosis results in release of intracellular contents into the circulation. Renal dysfunction is caused by a combination of renal vasoconstriction, tubular damage, and tubular obstruction.

Causes Rhabdomyolysis accounts for approximately 7% of all causes of acute renal failure (ARF) during peacetime. This figure is much higher after natural disasters and in wartime. For example, after the 1998 Turkish earthquake, 12% of the hospitalized population developed significant fi renal dysfunction and 477 patients required dialysis. Direct crush or compression injury and drugs are the most important causes in clinical practice, see Table 7.1. There are often predisposing factors, for example, alcohol, which can presensitize myocytes so they may be damaged by a more trivial insult. A clinical scoring system exists (not widely used) based on levels of phosphate, potassium, albumin, creatine kinase (CK), and presence of dehydration and sepsis.

necrosis. There may be severe pain, with loss of muscle function and loss of distal pulses. The diagnosis may be occult, especially in the unconscious patient. Direct pressure measurements can be made by passing a needle connected to a pressure manometer (e.g., central venous pressure [CVP] transducer) into the affected muscle compartment. A fasciotomy should be considered if the pressure exceeds 40 mmHg or greater than 30 mmHg above diastolic pressure.

Diagnosis Serum changes consequent on rhabdomyolysis:

Creatine Kinase Very high levels of the muscle enzyme CK are pathognomic of this condition. The degree of elevation is proportional to the degree of muscle injury. Other muscle enzymes, such as aspartate transaminase (AST) and lactate dehydrogenase (LDH) are also elevated. CK levels should decline by approximately 40% per day, a plateau or an increase should prompt a search for ongoing muscle damage.

Compartment Syndrome After an appropriate precipitant, inflammation fl within a muscular compartment causes a vicious cycle of increasing pressure. This leads to further infl flammation and damage, eventually compromising blood supply, leading to further muscle

38

Hyperkalemia Hyperkalemia caused by efflux fl of potassium from damaged cells is an early and life-threatening consequence of rhabdomyolysis. It should be aggressively treated.

7. Rhabdomyolysis and Compartment Syndrome

39

TABLE 7.1. Causes of rhabdomyolysis Physical Toxins and drugs Muscle ischemia Infection Metabolic Inherited Immune

Trauma, hyperthermia, hypothermia, exercise, electric shock, seizures, delirium tremens Alcohol, statins, amphetamines, aspirin (overdose), barium, barbiturates, caffeine, carbon monoxide, ecstasy, ethylene glycol, LSD, malignant hyperpyrexia, neuroleptic malignant syndrome, opiates, toluene, snake/insect bites, vasopressin Vascular ischemia, coma, sickle cell disease, surgery, vasoconstrictors, CO2 angiography Virtually any viral or bacterial infection (e.g., influenza, HIV, Epstein-Barr virus, Legionella, tetanus, malaria, Bacillus cereus) Hypernatremia/hyponatremia, hypokalemia, hypophosphatemia, diabetic ketoacidosis, diabetic hyperosmolar coma, water intoxication, myxedema Deficiency of carnitine palmityl transferase II, phosphofructokinase, myophosphorylase (McArdles), myoadenylate deaminase, cytochrome oxidase, succinic dehydrogenase, coenzyme Q10 deficiency, King-Denborough Syndrome, Wilson’s disease Polymyositis, dermatomyositis

Acidosis Metabolic acidosis may be caused by increased lactate production and lactate release by damaged muscle. Myoglobin (Mb) is considerably more toxic in an acid milieu.

Early Hypocalcemia and Late Hypercalcemia Serum calcium levels often fall dramatically, with total calcium less than 1.7 mmol/L in the early stages. This is caused by sequestration into damaged muscle and reperfusion-induced cellular calcium uptake. In contrast, intracellular calcium concentrations in damaged muscle may rise by up to 10-fold. In the recovery phase of rhabdomyolysis, serum calcium levels normalize and may even “overshoot,” secondary to calcium release by recovering myocytes and a transient

rise in parathyroid hormone (a reflex fl to the initial hypocalcemia). Symptoms of hypocalcemia are rare and treatment with intravenous calcium should be avoided unless tetany or cardiac dysfunction is present. Pharmacologically administered calcium is taken up avidly by the damaged muscle. It may be deposited as inorganic complexes causing “heterotopic calcification,” fi which delays recovery and can lead to long-term muscle dysfunction.

Hyperphosphatemia Serum phosphate often exceeds 3 mmol/L.

Urinary Abnormalities Urine dipsticks are usually positive for blood because they detect the heme moiety present in both hemoglobin (Hb) and Mb. On microscopy, few red cells are seen (unless there is coexistent trauma), instead, the characteristic “brown sugar casts” of Mb are seen (Figure 7.1). When there is uncertainty, Mb can be specifically fi assayed in the urine, although it has a short half-life. An assay exists for myosin heavy chain, which remains positive for up to 12 days after the initial insult.

Pathophysiology of ARF Suggested causes: FIGURE 7.1. “Brown sugar” Mb casts under light microscope are similar to granular casts but have a brown/rusty tinge. Additional red cells, tubular cells, and other debris are also present within the urine.

1. A reduction in renal blood flow fl . There is a reduction in the effective blood volume caused by fluid fl shifts from the intravascular to extracellular fluid fl compartments. Mb binds to nitric oxide (NO), preventing intrarenal vasodilation

40

(especially in the medulla) and, in addition, vasodilators (e.g., endothelin) are increased. 2. Direct heme protein tubulotoxicityy occurs, probably by free radical-mediated mechanisms. 3. Tubular cast formation. Urinary Mb and Tamm-Horsfall protein (THP) complex and precipitate as tubular casts. These casts are less soluble in acidic conditions. Although there is some evidence that these complexes cause tubular obstruction, micropuncture studies have shown relatively low intratubular pressures, suggesting that these casts are as a result of reduced tubular fl flow and reduced washout rather than by obstruction per se.

Treatment Intravascular Volume Expansion Intravascular volume expansion at the first fi possible opportunity after the insult is the single most effective therapeutic maneuver in rhabdomyolysis. This not only prevents or limits renal damage but may play a role in preventing acidosis and limiting ongoing damage caused by hypoperfusion. Very large volumes of fluid fl can be lost into areas of muscle injury. In trauma situations in which there is a risk of crush injury, fl fluid resuscitation should be commenced before the victim is extricated.

L. Tomlinson and S. Holt

• Bicarbonate solutions that are more concentrated can be administered in small aliquots, e.g., 50 mL of 8.4% NaHC03 via central access in patients who are intravascularly full—remembering that this is 1 mmol of sodium per milliliter of fluid fl and may cause sodium/fluid fl overload

Mannitol Mannitol promotes an osmotic diuresis and may reduce pressure in a swollen muscle compartment, but it also causes osmotically induced tubular damage with vacuolation. There is no good evidence that it is more effective than saline alone and it has little scientifi fic rationale to recommend its routine use.

Dialysis/Hemofiltration The circulating concentration of Mb can be reduced by hemofi filtration, plasma exchange, and hemodialysis, with dialysis being somewhat less successful. It has not been shown that any physical therapy materially reduces renal Mb burden or shortens the duration of renal replacement therapy. Physical therapies may have a role, if commenced early, or if Mb release can be anticipated, such as during arterial surgery.

Prognosis Alkalinization There is much compelling evidence to suggest that urinary alkalinization greatly reduces the nephrotoxicity of Mb. However, there are no large human trials that confirm fi this consistent finding from animal research. The potential benefits fi in this setting include reduced renal vasoconstriction, a dramatic reduction in the ability of Mb to cause oxidant damage, and increased solubility of MbTHP complex. Alkalinization can lower ionized calcium still further and, if administered, it is wise to periodically check the ionized calcium. A suggested fluid fl replacement regime would be: • Isotonic bicarbonate (1.26% sodium bicarbonate) until urine pH is greater than 7 if the patient is intravascularly volume deplete (which is usual)

There is an unquantifiable fi early mortality, mainly caused by hyperkalemia or the insult. Mortality after diagnosis is up to 20%, usually caused by other associated conditions, e.g., sepsis. Survivors of the Japanese earthquake in 1995 arriving in hospital within 6 hours had an approximately 20% chance of developing ARF, whereas all of those arriving after 40 hours developed renal failure. If the patient recovers from the initial insult, the renal dysfunction almost always resolves, but can take up to 3 months.

Summary • Rhabdomyolysis is a common cause of ARF, with important early biochemical changes that may be fatal if treatment is not instituted quickly

7. Rhabdomyolysis and Compartment Syndrome

• Compartment syndromes can be occult and are important to detect and monitor to protect against further renal injury • Early treatment with volume replacement (±alkalinization) will reduce the risk of renal failure and the need for renal replacement therapy

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Suggested Reading Holt SG, Moore KP. Pathogenesis and treatment of renal dysfunction in rhabdomyolysis. Intensive Care Med. 2001 May; 27(5): 803–811. Zager R. Rhabdomyolysis and myohemoglobinuric acute renal failure. Kidney Int. 1996 Feb; 49(2): 314–326.

8 Multisystem Causes of Acute Renal Failure Tim Leach

This chapter covers some of the more specialized causes of acute renal failure, which, although more likely to present to the nephrologist, could be admitted to the intensive care unit as a consequence of their illness or because of complications of their treatment.

Systemic Vasculitis Vasculitis is the term given to inflammation fl of blood vessels. Vasculitis is a rare condition, with an incidence of approximately 6 people per million (Western) population per year (1). Vessels can be classified fi according to their size (Table 8.1) (2). Renal failure can occur in any vasculitis, but this chapter focuses on those conditions that affect renal function directly through inflammation fl within the glomeruli (small vessels), rather than affecting the kidneys indirectly through a reduction of blood supply to the kidneys (large and medium vessel diseases).

Etiology Small vessel vasculitides separate into two broad groups: those in which immune complexes are deposited within the renal glomeruli and those without evidence of deposition histologically. The latter group are termed pauci-immune; lacking (literally “few”) immune complexes. This distinction is useful for making a histological diagnosis and for estimating prognosis, but the underlying cause of these small vessel vasculitides is similar: autoimmunity.

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Normally, the immune system surveys cells and tissues within the body, recognizing and ignoring cells expressing “self” antigens while attacking cells without these protective epitopes. In autoimmune conditions, the immune system does not protect cells with “self” expression. Cells are attacked and either infl flamed or killed, or circulating self-antigens are bound with antibody-forming immune complexes. Immune complexes are very large molecules that are often unable to pass through capillaries because of their size. They can induce local infl flammation and activate the complement cascade.

Presentation Symptoms Renal failure as a result of fulminant small vessel vasculitis will present acutely, and patients may be systemically unwell, requiring organ support. More often, however, there is an indolent presentation with several months of nonspecific fi symptoms and signs (Table 8.2).

Signs Fulminant systemic vasculitis presents with the nephritic syndrome: • Azotemia (more often with oligoanuria) • Hypertension and edema from fl fluid overload (but can present with circulatory collapse caused by vasodilation and dehydration) • Hematuria with red cell casts

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TABLE 8.1. Vasculitic conditions according to the vessel size affected Vessel size Large Medium Small

Condition Takayasu’s arteritis Giant cell arteritis Polyarteritis nodosa Kawasaki disease Pauci-immune: • Wegener’s granulomatosis (WG) • Microscopic polyangiitis (MPA) • Churg-Strauss disease (CSD) Immune-complex forming • Goodpasture syndrome (GS) Immune-complex depositing: • SLE • Henoch-Schönlein purpura (HSP) • Cryoglobulins • Rheumatoid arthritis

Source: Jeanette et al., 1994.

Other features include:

FIGURE 8.1. Plain chest x-ray of fulminant pulmonary hemorrhage of 17-year-old male patient with systemic vasculitis caused by Henoch-Schönlein purpura. The patchy diffuse alveolar shadowing is clearly seen.

pneumonitis (Figure 8.1), or superadded pneumonia

• Fever • Raised purpuric rash • Respiratory failure secondary to pulmonary edema, pulmonary hemorrhage from vasculitic

Laboratory Investigations (Table 8.3)

TABLE 8.2. Nonrenal symptoms suffered in systemic vasculitis

Imaging

System affected

Relative frequency (some patients experienced more than one)

Lower respiratory

63%

Upper respiratory

50%

Skeletal

42%

Muscular

33%

Dermatological

22%

Neurological

14%

Source: Hedger et al., 2000.

Symptoms Cough Breathlessness (on exertion/at rest/orthopnea) Hemoptysis Sinusitis Nasal congestion Reduced hearing Epistaxis Arthralgia Arthritis Synovitis Myalgia Myositis Muscle weakness Rash (purpura/echinoses/ malar flush) Headache Lethargy Loss of concentration Coma

Chest x-ray may be clear or show pulmonary edema or pulmonary hemorrhage (Figure 8.1). Renal ultrasound will usually show normal-sized kidneys with no obstruction.

Renal Biopsy The ultimate investigation for renal vasculitis is the biopsy. Patients need to be hemodynamically stable, normotensive, have a normal platelet count and coagulation screen and be able to lie flat fl (see Figure 8.2).

Treatment Treatments of patients with vasculitis fall into three main areas:

Resuscitation Patients should be stabilized in terms of airway, breathing, and circulation, as in any serious illness.

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T. Leach

TABLE 8.3. Investigations for systemic vasculitis Investigation

Rationale

Expected result

Urea and electrolytes

Likely renal failure

Full blood count

Anemia

Antineutrophil cytoplasmic antibody (ANCA)

WG and MPA associated with positive ANCA

Antiglomerular basement antibody (aGBM) Complement

Goodpasture syndrome

ESR/CRP

Inflammatory markers

Involved in inflammation

Elevated urea and creatinine Potentially elevated potassium Anemia Elevated white cell count Normal/elevated platelet count (cff HUS) Positive cANCA in WG Positive pANCA in MPA Otherwise negative Positive in GS Otherwise negative Usually mildly or significantly reduced levels of C3 and C4 Usually significantly elevated

ESR, erythrocyte sedimentation rate; CRP, C-reactive protein.

Maintenance

Disease-Specific Treatment

Maintenance of adequate oxygenation, circulation, and fluid balance is vital to their recovery. Hemofi filtration, hemodiafi filtration, or hemodialysis depending on the patient’s hemodynamic stability should be used to prevent and treat complications that do not respond to standard medical therapies. Infection, bleeding, and malnutrition should be sought and remedied.

The disease is one of an abnormal immune response inducing renal and other organ inflamfl mation and treatment falls into three groups. 1. Reduction of inflammation fl with corticosteroids (e.g., intravenous methylprednisolone followed by oral prednisolone). 2. Reduction of antibody formation with immunosuppressive agents (e.g., cyclophosphamide administered intravenously every 2 to 4 weeks or orally everyday). 3. Removal of the already-formed antibodies with therapeutic plasma exchange if the patient has pulmonary hemorrhage (potentially life threatening) or is requiring renal dialysis (severe disease).

Outcome

FIGURE 8.2. Photomicrograph of renal biopsy from patient with Wegener’s (cANCA-positive) renal vasculitis. Hematoxylin and eosin stain with silver counterstain, showing features consistent with the disease. The glomerulus (black arrow) w shows segmental fibrinoid change (red arrows) and crescent formation (yellow ( arrow). w Some tubules contain red cells (white arrows). (Photo reproduced with the kind permission of Dr. Nicholas Marley.)

Renal vasculitis is a serious illness with significant fi morbidity and mortality. Before treatment, it was universally fatal; with treatment, mortality is 10% at 18 months. Up to 50% of patients require dialysis with no renal recovery. If the patient did not require dialysis at presentation, there is a 91% chance of renal survival. If dialysis dependent at presentation, 30% of patients may regain renal function with cyclophosphamide and corticosteroids alone, but 90% of patients may develop renal recovery with the addition of therapeutic plasma exchange (3, 4).

8. Multisystem Causes of Acute Renal Failure

45

Infection is the most significant fi side effect of treatment. Bacterial sepsis, viral infections such as herpes zoster and cytomegalovirus, fungal sepsis, and Pneumocystis carinii pneumonitis (PCP) occur in 40% of treated patients (5). Prophylaxis against fungi and PCP is recommended.

Systemic Lupus Erythematosus Systemic lupus erythematosus (SLE) is a multisystem autoimmune condition of primarily young (20–30 years old) women (Figure 8.3). The American College of Rheumatology defines fi the diagnosis of lupus for a patient presenting with four or more of the following features at the same time, or individually during a period of time: 1. Malar rash: redness or rash that may appear in a butterfl fly confi figuration across the nose and cheeks. It can appear on one or both sides of the face and is usually flat. fl 2. Discoid rash: thick raised patches that can occur on any part of the body and may result in scarring. 3. Sun sensitivity: a reaction to sunlight that is more severe than just sunburn. 4. Oral ulcers: frequent development of mouth or nose ulcers. 5. Arthritis: pain, tenderness, or swelling in two or more joints. 6. Pleurisy or pericarditis. 7. Nephritis: proteinuria or cellular casts in the urine. 8. Nervous system disorder: seizures or psychotic behavior that cannot be attributed to drugs or metabolic dysfunction. 9. Blood system disorder: hemolytic anemia, leukopenia, lymphopenia, or thrombocytopenia. 10. Immunologic disorder: the presence of the lupus erythematosus (LE) cell, a false-positive reaction to the tests for syphilis, or the presence of autoantibodies. 11. Positive antinuclear antibodies (ANA): antibodies against the nucleus of cells, particularly against double-stranded DNA. Lupus should also be suspected in young women presenting with purpura, easy bruising, diffuse lymphadenopathy, hepatosplenomegaly, peripheral neuropathy, endocarditis, myocarditis,

FIGURE 8.3. Magnetic resonance imaging scan of brain of 21-yearold woman with cerebral lupus. T2-weighted sagittal section shows increased white and grey matter signal, particularly in the frontal and parietal regions, in keeping with cerebral vasculitis.

interstitial pneumonitis, or aseptic meningitis. A positive Coombs test, low complement levels, and immune deposits at the dermal-epidermal junction on skin biopsy are also suggestive of lupus. Patients with SLE can present in extremis with any system involvement. The presence of a multisystem disease such as SLE should always be entertained in such patients.

Laboratory Testing Tests that provide potentially diagnostically useful information when SLE is suspected include: • • • •

Complete blood count and differential Serum creatinine Serum albumin Serologic test for syphilis (falsely positive because of cross-reactivity) • Urinalysis • 24-hour urine collection for calculation of creatinine clearance and quantifi fication of proteinuria • Autoantibody testing: ANA, antibodies to phospholipids, antibodies to double-stranded DNA, and antibodies to Smith (Sm)

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• Complement levels (total hemolytic complement [CH50], C3 and C4)

Imaging This may be valuable but is not routinely obtained unless indicated by the presence of symptoms, clinical findings, or laboratory abnormalities. Examples include: • Plain radiographs of involved joints • Renal ultrasound to assess kidney size and rule out an obstructive post-renal cause when there is evidence of acute renal failure • Chest X ray • Echocardiography (for suspected pericardial involvement or to seek a source of emboli) • CT scanning (for abdominal pain, suspected pancreatitis, lymphadenopathy) • Magnetic resonance imaging (for seizure activity, focal neurologic defi ficits or cognitive dysfunction/personality changes—see Figure 8.3) • Contrast angiography may be valuable if vasculitis affecting medium-sized arteries is suspected (mesenteric or limb-threatening ischemia).

Treatment Treatment is broad and depends on the system involved. General principles are: • Reduce inflammation fl with corticosteroids • Prevent further autoantibody production with immunosuppressant medications such as cyclophosphamide or mycophenolate mofetil • Remove circulating autoantibodies with therapeutic plasma exchange Antiphospholipid antibodies and the presence of the lupus anticoagulant increase coagulation and lead to arterial and venous thromboses. Use of antiplatelet drugs, thrombolytics, and anticoagulation in these patients often prevents further problems. Fertility and pregnancy in lupus patients are often problematic. Pregnancy alters the immune state, often leading to fl flares of lupus postpartum. Coagulation abnormalities often lead to difficulfi ties with conception and spontaneous abortion. Primary infertility or recurrent miscarriages are relatively common presenting features of SLE.

T. Leach

Thrombotic Microangiopathy Thrombotic microangiopathy (TMA) covers the acute syndrome of microangiopathic hemolytic anemia, thrombocytopenia, and variable signs of organ injury caused by platelet thromboses in the microcirculation. Two clinically distinct but pathologically identical syndromes are described: hemolytic uremic syndrome (HUS) and thrombotic thrombocytopenic purpura (TTP). HUS usually affects children with renal failure but minimal neurological involvement. TTP is a disease of adults, with predominantly neurological involvement and variable other organ disease. The two syndromes often overlap and, thus, are termed HUS/TTP.

Etiology The mechanisms behind the development of TMA are poorly understood but seem to involve endothelial injury, which triggers events leading to microvascular thrombosis, microangiopathic hemolytic anemia, and platelet consumption. Most causative factors lead to toxicity of the endothelial cells: autoantibodies, exotoxins and endotoxins, immune complexes, and certain drugs. The pathology of TMA consists of capillary and arteriolar wall widening, with swelling and detachment of the endothelium, and occlusion or severe restriction of the lumen and platelet microthrombi. In HUS, this occurs mainly in the kidney, in TTP, mainly in the brain.

Presentation HUS/TTP rarely causes specifi fic symptoms. In the situations shown in Table 8.4, vomiting, pallor, purpura, anuria, and/or neurological signs should alert the clinician to the possibility of TMA.

Differential Diagnosis • Systemic vasculitis will usually present with arthralgia/arthritis, and the platelet count will be normal and will rarely have central neurological involvement. • Disseminated intravascular coagulation (DIC) is usually associated with shock or obstetric

8. Multisystem Causes of Acute Renal Failure

47

TABLE 8.4. Conditions and situations associated with the development of HUS/TTP Acquired

Shigatoxin (Escherichia colii 0157) Pregnancy Pneumococcal infection Systemic disease HIV infection SLE Scleroderma Malignancy Drug associated Mitomycin C, tamoxifen, bleomycin, cisplatin, clopidogrel, quinine, interferon, OKT3, cyclosporine, tacrolimus (among others) Organ transplant De novo (usually drugs) Recurrent posttransplant HUS Genetic and familial forms Idiopathic and atypical forms

complications and will have consumption of all of the clotting factors. • Malignant hypertension will have classical retinal changes, signifi ficant high blood pressure (usually >210/130), and usually a history of hypertension.

Laboratory Investigations • Low hemoglobin (<7 g/dL) • Thrombocytopenia (<80 × 109 cells/L) • The blood film fi will show red cell fragments (schistocytes) and increased reticulocyte counts • Elevated lactate dehydrogenase and indirect bilirubin (caused by hemolysis) • Haptoglobin levels will usually be low because of consumption • Coombs test is negative • Moderate proteinuria (1–2 g/d) with few red cells and casts (ARF is secondary to occlusion of capillaries rather than inflammation) fl

Treatment and Outcome The epidemic or sporadic diarrhea-associated HUS/TTP of young children is usually self-limiting and mild. Renal failure requires dialysis in approximately 50% of patients, but otherwise supportive treatment is all that is required. Ninety percent of patients should recover completely. Up to 5% of

patients can die in the acute phase. Cerebrovascular accidents, seizures, and coma occur in 25% of patients, and residual impairment of renal excretory function is present in up to 40% of patients. HUS/TTP in adults or children older than 14 years old usually requires treatment. In those with an apparent cause (pregnancy, malignancy, infection, or drugs), removal of the cause is essential. Supportive treatment is required. Specific fi treatment of the condition revolves around therapeutic plasma exchange or plasma infusion if TPE is not available. There is no evidence of benefi fit of immunosuppression with corticosteroids, immunoglobulins, or vincristine, or of benefit fi from antithrombotic or antiplatelet agents. Rescue therapies from severe refractory or relapsing disease include bilateral nephrectomy and/or splenectomy.

References 1. Hedger N, Stevens J, Drey N, Walker S, Roderick P. Incidence and outcome of pauci-immune rapidly progressive glomerulonephritis in Wessex, UK: a 10year retrospective study. Nephrol Dial Transplant 2000; 15(10): 1539–1539. 2. Jennette JC, Falk RJ, Andrassy K. Nomenclature of systemic vasculitides. Proposal of an international consensus conference. Arthritis Rheum 1994; 37: 187–192.

48 3. Andrassy K, Kuster S, Waldherr R, Ritz E. Rapidly progressive glomerulonephritis: analysis of prevalence and clinical course. Nephron 1991; 59(2): 206–212. 4. Pusey CD, Rees AJ, Evans DJ, Peter DK, Lockwood CM. Plasma exchange in focal necrotizing glomeru-

T. Leach lonephritis without anti-GBM antibodies. Kidney Int 1991; 40(4): 757–763. 5. Hoffman GS, Kerr GS, Leavitt RY, et al. Wegener granulomatosis: an analysis of 158 patients. Ann Intern Med d 1992; 116: 488–498.

9 Therapeutic Plasma Exchange Tim Leach

Therapeutic plasma exchange (TPE) is an extracorporeal blood purifi fication technique designed for the removal of large molecular weight substances from plasma. Large molecular weight substances equilibrate slowly between the vascular space and the interstitium. Calculations of the rate of their removal by TPE follows fi firstorder kinetics, i.e., approximately 60% is removed by a single plasma volume exchange, and 75% by an exchange equal to 1.4 times the plasma volume. Blood is pumped through a highly permeable filter, replacing the filtrate with fluid as indicated fi (Table 9.1). Venous access on the intensive care unit (ICU) is via a double-lumen dialysis catheter, but can be via two wide-gauge peripheral venous cannulae. If chronic therapy is indicated, an arteriovenous fi fistula is used. The patient and filter are anticoagulated during the procedure.

Indications (Table 9.2) The basic premise of TPE is that removal of large molecular weight substances from the circulation will reduce further damage and may permit reversal of the pathological process. Other benefits fi include unloading the reticuloendothelial system to permit further endogenous removal of circulating toxins, stimulation of lymphocyte clones, and allowing re-infusion of large volumes of plasma without the risk of volume overload. For TPE to be appropriate, the substance to be removed should be:

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• Of molecular weight greater than 15,000 kDa so it cannot be removed in any other way, and/or • Of suffi ficient half-life that TPE is quicker than endogenous removal, and/or • Acutely toxic and resistant to conventional therapy

Prescription (Table 9.1) Calculation of plasma volume: Estimated plasma volume (L) = 0.07 × Weight (kg) × (1 − hematocrit) 1. Before each treatment, measure serum potassium calcium and clotting screen. 2. Calculate the estimated plasma volume: Volume of exchange is measured in Patient Plasma Volumes (∼3 L). 3. Prescribe the plasma exchange: a. Number and spacing of treatments b. Volume and type of fl fluid 4. Electrolyte supplementation as needed (potassium and calcium). 5. If coagulopathic consider, fresh-frozen plasma (FFP) as the final exchange volume.

After Procedure • Repeat electrolytes and clotting after 2 hours and increase supplementation as needed • FFP can be given as the final exchange volume if coagulopathic

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T. Leach

TABLE 9.1. Example of TPE prescriptiona Indication Rapidly progressive glomerulonephritis Acute renal failure caused by myeloma kidney Hyperviscosity Syndrome Anti-glomerular basement membrane (GBM) disease Hemolytic uremic syndrome/thrombotic thrombocytopenic purpura Guillain-Barré Syndrome

Plasma volumes

Replacement fluid

Number of exchanges

1 to 1.5

Albumin, with FFP if pulmonary hemorrhage

7 to 10

Daily or alternate days

1

Albumin/saline mixtureb

Daily

1.5 1 to 2

Albumin, with FFP if pulmonary hemorrhage All FFP

Until symptoms subside or plasma viscosity normal 7 to 10

2

Albumin

Until platelets normal/no red cell fragments (usually 7 to 16) 4

Exchange frequency

Daily Once or twice daily

Alternate days

a

From: Wessex Renal and Transplant Unit, United Kingdom. No more than one part saline to two parts albumin (i.e., ≤1 L saline for 2 L albumin).

b

TABLE 9.2. American Association of Blood Banks indications for TPE 1. Standard and acceptable 2. Sufficient evidence to suggest • Chronic inflammatory efficacy/acceptable adjunct demyelinating • Cold agglutinin disease polyneuropathy • Protein-bound toxins • Cryoglobulinemia (drug overdose/ • Anti-GBM disease poisonings) • Guillain-Barré syndrome • Hemolytic uremic • Familial hypercholesterolemia syndrome • Myasthenia gravis • Rapidly progressive • Posttransfusion purpura glomerulonephritis • Thrombotic • Systemic vasculitis thrombocytopenic purpura • Acute renal failure caused by myeloma kidney 3. Inconclusive evidence orr 4. No efficacy in trials uncertain benefit-to-risk ratio • AIDS • ABO-incompatible organ or • Amyotrophic lateral marrow transplantation sclerosis • Coagulation factor inhibitors • Dermato/polymyositis • Idiopathic thrombocytopenic • Psoriasis purpura • Renal transplant rejection • Multiple sclerosis • Rheumatoid arthritis • Progressive systemic sclerosis • Schizophrenia • Thyroid storm • Warm autoimmune hemolytic anemia

Complications • • • • •

Hypotension: vasovagal, hypovolemia Fluid overload Hypocalcemia causing tetany Hypokalemia Coagulopathy caused by removal of clotting factors or thrombocytopenia with heparin anticoagulation • Protein-bound drug removal (administer drugs afterr TPE) • ACE inhibitors may cause fl flushing and hypotension (stop 24 h before treatment)

10 Renal Replacement Therapy John H. Reeves

Acute renal failure (ARF) occurs in 7% of patients admitted to the intensive care unit (ICU) (1). Previously, mortality exceeded 91%, but with the introduction of dialysis, this quickly fell to approximately 50% (2). Overall mortality for ARF has remained approximately 50%, associated with increasing comorbidity (3). There is no specifi fic therapy for ARF other than removal of the cause and ongoing supportive care awaiting spontaneous recovery. Renal replacement therapy (RRT) is the cornerstone of that supportive care.

The Basics Extracorporeal RRT involves the passage of a patient’s blood outside his/her body through a dialysis or hemofilter fi machine, where the removal of unwanted solutes and excess water and the replacement of lost bicarbonate (or buffer base) take place. The “purified” fi blood is returned to the patient. Clearance can be defined fi as that volume of plasma completely cleared of a substance in a given time. During extracorporeal RRT, net solute clearance can be achieved by ultrafiltration fi across a porous membrane down a pressure gradient (fi (filtration), or by diffusion across a semipermeable membrane down a concentration gradient (dialysis), or both. During fi filtration, the filtrate is discarded and a replacement solution is added to the blood to maintain fluid fl and electrolyte equilibrium. During dialysis, a continuous stream of dialysate is passed in the opposite direction to blood, on the nonblood side of the membrane, to

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maintain a concentration gradient favoring the out-diffusion of unwanted solutes. Both dialysate and replacement solutions contain electrolytes in physiological concentrations and some form of buffer base. The hemofilter fi r or dialysis membrane’s permeability to water is determined by its surface area (typically 0.5 to 2.0 m2) and the number and size of its pores (typically 0.0055-μm diameter in a high-flux fl hemofi filter). The pore size determines the size of molecules that are freely fi filtered along with water. Current hemofilters fi freely filter substances up to approximately 5000-D molecular weight and then in decreasing amounts up to a cut off of approximately 20,000 Da. This minimizes loss of important larger molecules, such as albumin (molecular weight, 57,000 Da). The ratio between the concentration of solute in filtrate and that in plasma water is called the sieving coefficient fi , and this concept becomes important in calculating the clearance of intermediate-sized molecules. The sieving coefficient fi for a small unbound solutes is one, decreasing to zero as molecular size and or plasma protein binding increases. Theoretical small solute clearance can be predicted by knowledge of the blood flow fl through the extracorporeal circuit (QB) and the rate of ultrafilfi tration (QF) and dialysate flow fl (QD) (Figure 10.1). During continuous RRT (CRRT), when blood flow is signifi fl ficantly higher than dialysate or ultrafiltration rates, small solute clearance is deterfi mined by dialysate and ultrafiltrate fi flow. Assuming complete concentration equilibrium between dialysate and plasma water and a sieving coefficient fi equal to one:

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J.H. Reeves Haemofiltration replacement ≅ QF

Blood flow QB

Membrane

Effluent QE

Dialysate QD

FIGURE 10.1. Predicting clearance during RRT.

Clearance during CRRT = QF + QD = QE In contrast, during intermittentt hemodialysis (IHD), dialysate flow is signifi ficantly higher than blood flow, and blood flow becomes the limiting factor for solute clearance. Small solute clearance is proportional to the plasma flow fl through the dialyzer: Clearance during IHD ≅ QB × (1 − hematocrit) This simplifi fied analysis only holds for small, unbound solutes, such as urea and creatinine. Increasing molecular weight decreases diffusive clearance more signifi ficantly than convective clearance. Binding to macromolecules, such as albumin, decreases convective and diffusive clearance (4).

Classification of RRT In 1977, when Peter Kramer first fi described continuous arteriovenous hemofi filtration (CAVH) as a therapy for diuretic resistant fl fluid overload (5), the only other types of RRT were IHD and peritoneal dialysis (PD). Since then, the classificafi tion of RRT has expanded (6). See the glossary in Table 10.1.

Duration or Timing of Therapy Continuous: CRRT aims to provide support 24 h/d, but, in practice, is interrupted by factors such as patient transfer out of the ICU or circuit failure. Intermittent: IHD requires approximately 3 hours per treatment. Patients with end-stage renal failure (ESRF) may be maintained in the community with as few as three dialysis sessions per

week. In contrast, ICU patients with ARF may require daily treatment (7). Hybrid: there is increasing interest in hybrid approaches for extracorporeal RRT in the ICU (8, 9). For example, during sustained lowefficiency fi dialysis (SLED), daily intermittent therapy is reduced in intensity and extended in duration up to 8 or 12 hours. The regular breaks aid staffi fing and free patients for investigations and procedures. The reduced intensity reduces the cardiorespiratory destabilization associated with IHD.

Access Arteriovenous: arteriovenous access involves cannulation of a medium-sized artery and large vein—often the femoral artery and vein. Blood flows passively from the artery through the extracorporeal circuit (ECC) and back through the vein, driven by the mean arterial pressure. This method is reserved for situations in which resources are limited. Venovenous: venovenous access involves cannulation of central veins, most commonly with a double-lumen cannula in the femoral, internal jugular, or subclavian vein. Blood flow fl is driven by a pump in the ECC. This increases reliability of blood flow fl and maximizes solute clearance, but introduces the need for more complex safety mechanisms to detect fault conditions, such as air embolism or circuit occlusion.

Mechanism of Solute Removal Convection: when solute is cleared by ultrafiltrafi tion through a porous membrane, we say that the clearance of the solute is convective—carried by the bulk flow of plasma water. During CRRT, the process is called hemofiltration fi . Diffusion: when solute is cleared by diffusion down a concentration gradient across a semipermeable membrane, we say that the clearance of the solute is diffusive. The process is called hemodialysis. Combinations: diafiltration fi is the term applied when both convection and diffusion are operating to remove solute. Adsorption: adsorption is the binding of substances to the membrane under molecular

10. Renal Replacement Therapy

53

TABLE 10.1. RRT: A glossarya Acronym

Full Name

Notes

Seed reference

SCUF CAVH CAVHD CAVHDF CVVH CVVHD CVVHDF CHFD HVHF CPF CPFA SLED EDD PDIRRT

Slow continuous ultrafiltration Continuous arteriovenous hemofiltration Continuous arteriovenous hemodialysis Continuous arteriovenous hemodiafiltration Continuous venovenous hemofiltration Continuous venovenous hemodialysis Continuous venovenous hemodiafiltration Continuous high flux dialysis High volume hemofiltration Continuous plasma filtration Coupled plasma filtration adsorption Sustained low efficiency dialysis Extended daily dialysis Prolonged daily intermittent RRT

AV or VV

Silverstein 1974 (12) Kramer 1977 (5)

AV or VV AV or VV AV or VV AV or VV

Ronco 1996 (13) Cole 2001 (14) Reeves 1999 (15) Ronco 2003 (16) Marshall 2004 (17) Kumar 2000 (18) Naka 2004 (9)

a

AV, arteriovenous; VV, venovenous.

attraction. Adsorption is used specifi fically for toxin removal using activated charcoal cartridges (10) and it is being tested as a means of blood purifi fication in sepsis (11).

Intensity of Therapy For example, slow continuous ultrafiltration fi (SCUF) is performed to simply remove excess extracellular fl fluid. High-volume hemofi filtration (HVHF) is used to intentionally accelerate the clearance of target mediators, and high-fl flux dialysis (HFD) (dialysis performed with highly permeable membranes) is designed to accelerate the clearance of urea and larger molecules.

Indications for RRT

There is little information regarding what specific fi threshold plasma concentrations of potassium, bicarbonate, urea, or creatinine should be used for the institution of RRT. In a retrospective comparison of early versus late CRRT in trauma associated ARF, Gettings et al. (23) found that patients in whom CRRT was commenced at a mean blood urea nitrogen (BUN) of 42.6 mg/dL (15.2 mmol/L) had a survival rate of 39% compared with 20% in patients in whom the mean BUN at commencement was 94.5 mg/dL (33.7 mmol/L).

“Nonrenal” Indications • • • • •

Drug and toxin removal Sepsis and septic shock Inborn errors of metabolism Congestive cardiac failure Cerebral edema

“Traditional” indications (19) • • • •

Diuretic resistant fluid overload Life-threatening hyperkalemia Severe metabolic acidosis Symptomatic uremia

Kramer’s original description of CAVH involved the treatment of diuretic resistant fl fluid overload (5). During the intervening years, there has been controversy surrounding the use of diuretics in ARF (20), but they may be helpful in the fl fluid management of ARF before the institution of RRT (21, 22).

IHD can accelerate the elimination of small (<500 mw) unbound toxins with a low volume of distribution and minimal plasma protein binding (11), e.g., lithium, methanol, ethylene glycol, and salicylates. Continuous hemofiltration fi has been used in lithium toxicity (24), with better hemodynamic stability (25) but lower solute clearance than IHD. The use of extracorporeal blood purification fi techniques in sepsis and septic shock is attractive but unproven. There were early observations of improved cardiovascular and respiratory function

54

in patients with severe sepsis after commencement of continuous hemofiltration fi (26). This, together with the identification fi of infl flammatory mediators in filtrate fi (27), led to efforts to increase infl flammatory mediator removal during RRT. High-volume conventional hemofiltration fi (14, 28), large-pore hemofiltration fi (29), and plasma filtration with (30) or without (15) coupled adsorption have been examined in small clinical trials. There is currently no Level I evidence for the use of extracorporeal blood purifi fication therapy in sepsis. End-stage cardiac failure is characterized by progressive fl fluid retention, renal impairment, neurohumoral stimulation, and diuretic resistance (31). It was shown that patients with advanced cardiac failure can tolerate substantial fluid fl removal during ultrafiltration fi (12), with salutary effects that persist beyond the time of fl fluid removal. Improved renal function, decreased heart failure scores, lowered B natriuretic peptide levels, decreased hospital length of stay, and fewer readmissions have all been observed in case-controlled studies (32). Most recently, a small randomized controlled study showed that early ultrafiltration fi results in increased weight loss at 24 h compared with diuretics alone (33). Larger studies are warranted for this indication. Cerebral edema can complicate IHD (34) and contribute to the clinical picture of disequilibrium. In patients with hepatic encephalopathy, early studies compared the effects of IHD and CRRT (35). CRRT was associated with less decrease in mean arterial pressure, less increase in intracranial pressure, and less change in cerebral perfusion pressure.

Choosing the Dose and Mode of RRT Dialysis dose is a concept familiar to nephrologist in the setting of ESRF: Kt/V. K is clearance (the volume of solute, usually urea, cleared in a given time), t is duration of treatment, and V is volume of distribution of the solute. Kt is the volume of plasma water cleared of solute during the session, and Kt/V is Kt as a proportion of its volume of distribution. For example, a Kt/V of 1.0 for urea means that a total volume of plasma water equal to the volume

J.H. Reeves

of distribution of urea was cleared during the session. Using a single compartment exponential washout model, we can predict that the final fi concentration of the solute is approximately 37% of the starting concentration when the Kt/V is 1.0. In chronic renal failure, a minimum Kt/V of 1.2 should be delivered three times per week (36). There has been one randomized controlled trial assessing dose of dialysis in ARF (7). Schiffl fl compared daily dialysis with alternate daily dialysis in 160 patients with ARF. The 28-day mortality using intention-to-treat analysis was 28% in the daily treated patients and 46% in the patients treated every other day. Multiple other outcomes were improved in the daily dialysis group. Although this trial was controversial (37), it suggests that dialysis every second day is insufficient fi in critically ill patients with ARF. Quantifi fication of clearance during CRRT can be likened to the calculation of creatinine clearance, which is described by the formula UV/P. U is the urine concentration of the solute, V is the volume collected in a given time, and P is the plasma concentration. During CRRT, if we know the volume of effl fluent produced in a given time and the concentration of solute (e.g., urea) in both effluent fl and plasma, we can calculate its clearance (38). The result is a value in milliliters per minute. To simplify the estimate further, let us assume that the sieving coefficient fi is 1.0, and that there is full concentration equilibrium between plasma water and dialysate. Then the effluent fl concentration will equal the plasma concentration, and clearance is simply equal to the rate of production of effluent fl from the hemofi filter. Ronco, in 2000 (39), randomized 425 critically ill patients with ARF to three different doses (ultrafiltration fi rates) of CRRT: 20, 35, or 45 mL/h/ kg. Fifteen-day survivals were 41%, 57%, and 58%, respectively. This landmark study was one of the first to formally adjust dose of CRRT based on fi patient weight. Importantly, it suggests that there is a threshold minimum level of clearance required for adequate CRRT of approximately 35 mL/h/kg. Debate regarding the relative merits of CRRT and IHD has continued for nearly 30 years. From the outset (5), the attraction of CRRT was its simplicity and cardiorespiratory stability compared with IHD. Now that CRRT is as complex as IHD

10. Renal Replacement Therapy

and potentially more expensive to perform for long periods, there is a paucity of good comparative studies that report outcomes such as mortality or recovery of renal function. In 2001, Mehta randomized 166 critically ill patients to CRRT or IHD (40). The observed mortality was higher in the group receiving CRRT, but this group had a higher severity of illness. In 2002, Kellum published a meta-analysis of 13 trials, 3 randomized and 10 observational, comparing IHD and CRRT (41). Overall, there was no difference in mortality, but only six studies compared groups of equal severity. In these six studies, the mortality was lower in patients treated with CRRT. Since then, a well-designed prospective randomized controlled trial has been published comparing CRRT with IHD in 80 critically ill patients with ARF. There was no difference in survival or renal recovery between the two groups. Although there was more hemodynamic disturbance during IHD, this did not translate to a survival benefi fit for CRRT (42).

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4.

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8.

9.

Summary • RRT reduces the mortality of ARF from more than 90% to approximately 50%. • There is no proven difference in outcome between intermittent and CRRTs, as long as a minimum dose of Kt/V of 6 to 8 per week is achieved during hemodialysis or a clearance greater than 35 mL/kg/h is achieved during continuous hemofi filtration. • New hybrid therapies (slow long extended daily dialysis [SLEDD], extended daily dialysis [EDD], and prolonged daily intermittent RRT [PDIRRT]) may avoid the destabilization associated with IHD, and mitigate the cost and inconvenience of continuous hemofiltration. fi

10.

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14.

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References 1. Brivet FG, Kleinknecht DJ, Loirat P, Landais PJ. Acute renal failure in intensive care units-causes, outcome, and prognostic factors of hospital mortality; a prospective, multicenter study. French Study Group on Acute Renal Failure. Crit Care Med 1996; 24(2): 192–198. 2. Smith LH, Post RS, et al. Post traumatic renal insufficiency in military casualties. II. Management, use

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of an artifi ficial kidney, prognosis. Am J Med d 1955; 18:187. Mehta RL, Pascual MT, Soroko S, et al. Spectrum of acute renal failure in the intensive care unit: the PICARD experience. Kidney Intt 2004; 66(4): 1613–1621. Meyer TW, Walther JL, Pagtalunan ME, et al. The clearance of protein-bound solutes by hemofiltrafi tion and hemodiafi filtration. Kidney Intt 2005; 68(2): 867–877. Kramer P, Wigger W, Rieger J, et al. Arteriovenous haemofi filtration: A new and simple method for treatment of over-hydrated patients resistant to diuretics. Klin Wschr 1977; 55: 1121–1122. Ronco C, Bellomo R. Continuous renal replacement therapy: evolution in technology and current nomenclature. Kidney Int Suppl 1998; 66: S160–164. Schiffl fl H, Lang SM, Fischer R. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002; 346(5): 305–310. Marshall MR, Golper TA, Shaver MJ, Chatoth DK. Hybrid renal replacement modalities for the critically ill. Contrib Nephrol 2001(132): 252–257. Naka T, Baldwin I, Bellomo R, Fealy N, Wan L. Prolonged daily intermittent renal replacement therapy in ICU patients by ICU nurses and ICU physicians. Int J Artif Organs 2004; 27(5): 380–387. Zimmerman JL. Poisonings and overdoses in the intensive care unit: general and specifi fic management issues. Crit Care Med 2003; 31(12): 2794– 2801. Nalesso F. Plasma filtration adsorption dialysis (PFAD): a new technology for blood purification. fi Int J Artif Organs 2005; 28(7): 731–738. Silverstein ME, Ford C, Lysaght MJ, Henderson LW. Treatment of severe fl fluid overload by ultrafi filtration. New Eng J Med d 1974; 291(15): 747–751. Ronco C, Bellomo R, eds. Continuous high fl flux dialysis: an effi ficient renal replacement. Heidelberg: Springer Verlag; 1996. Cole L, Bellomo R, Journois D, et al. High-volume haemofi filtration in human septic shock. Intensive Care Med 2001; 27(6): 978–986. Reeves JH, Butt WW, Shann F, et al. Continuous plasmafi filtration in sepsis syndrome. Plasmafi filtration in Sepsis Study Group. Crit Care Med d 1999; 27(10): 2096–2104. Ronco C, Brendolan A, d’Intini V, et al. Coupled plasma filtration fi adsorption: rationale, technical development and early clinical experience. Blood Purif 2003; 21(6): 409–416. Marshall MR, Ma T, Galler D, et al. Sustained loweffi ficiency daily diafi filtration (SLEDD-f) for critically ill patients requiring renal replacement therapy:

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J.H. Reeves towards an adequate therapy. Nephrol Dial Transplantt 2004; 19(4): 877–884. Kumar VA, Craig M, Depner TA, Yeun JY. Extended daily dialysis: A new approach to renal replacement for acute renal failure in the intensive care unit. Am J Kidney Dis 2000; 36(2): 294–300. Palevsky PM. Renal replacement therapy I: indications and timing. Crit Care Clin 2005; 21(2): 347– 356. Mehta RL, Pascual MT, Soroko S, Chertow GM. Diuretics, mortality, and nonrecovery of renal function in acute renal failure. JAMA 2002; 288(20): 2547–2553. Cantarovich F, Rangoonwala B, Lorenz H, et al. High-dose furosemide for established ARF: a prospective, randomized, double-blind, placebocontrolled, multicenter trial. Am J Kidney Dis 2004; 44(3): 402–409. Uchino S, Doig GS, Bellomo R, et al. Diuretics and mortality in acute renal failure. Crit Care Med d 2004; 32(8): 1669–1677. Gettings LG, Reynolds HN, Scalea T. Outcome in post-traumatic acute renal failure when continuous renal replacement therapy is applied early vs. late. Intensive Care Med d 1999; 258: 805–813. van Bommel EF, Kalmeijer MD, Ponssen HH. Treatment of life-threatening lithium toxicity with highvolume continuous venovenous hemofi filtration. Am J Nephrol 2000; 20(5): 408–411. Maggiore Q, Pizzarelli F, Dattolo P, et al. Cardiovascular stability during haemodialysis, haemofiltration and haemodiafi filtration. Nephrol Dial Transplant 2000; 15 Suppl 1: 68–73. Gotloib L, Barzilay E, Shustak A, et al. Hemofiltrafi tion in septic ARDS. The artificial fi kidney as an artifi ficial endocrine lung. Resuscitation 1986; 13(2): 123–132. Tonnesen E, Hansen MB, Hohndorf K, et al. Cytokines in plasma and ultrafi filtrate during continuous arteriovenous haemofi filtration. Anaesth Intensive Care 1993; 21(6): 752–758. Cole L, Bellomo R, Hart G, et al. A phase II randomized, controlled trial of continuous hemofiltration fi in sepsis. Crit Care Med d 2002; 30(1): 100–106. Uchino S, Bellomo R, Goldsmith D, et al. Super high flux hemofi filtration: a new technique for cytokine removal. Intensive Care Med d 2002; 28(5): 651–655. Ronco C, Brendolan A, Lonnemann G, et al. A pilot study of coupled plasma filtration fi with adsorption

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in septic shock. Crit Care Med 2002; 30(6): 1250– 1255. Ellison DH. Diuretic therapy and resistance in congestive heart failure. Cardiology 2001; 96(3-4): 132– 143. Costanzo MR, Saltzberg M, O’Sullivan J, Sobotka P. Early ultrafiltration fi in patients with decompensated heart failure and diuretic resistance. J Am Coll Cardiol 2005; 46(11): 2047–2051. Bart BA, Boyle A, Bank AJ, et al. Ultrafiltration fi versus usual care for hospitalized patients with heart failure: the Relief for Acutely FluidOverloaded Patients With Decompensated Congestive Heart Failure (RAPID-CHF) trial. J Am Coll Cardiol 2005; 46(11): 2043–2046. Walters RJ, Fox NC, Crum WR, et al. Haemodialysis and cerebral oedema. Nephron 2001; 87(2): 143–147. Davenport A, Will EJ, Davison AM, et al. Changes in intracranial pressure during machine and continuous haemofi filtration. Int J Artif Organs 1989; 12(7): 439–444. Eknoyan G, Levin N. NKF-K/DOQI Clinical Practice Guidelines: Update 2000. Foreword. Am J Kidney Dis 2001; 37(1 Suppl 1): S5–6. Drazen JM, Ingelfinger fi JR, Curfman GD. Removal of expression of concern: Schiffl fl H, et al. Daily hemodialysis and the outcome of acute renal failure. N Engl J Med 2002; 346: 305–310. N Engl J Med 2003; 349(20): 1965. Reeves JH, Butt WW. A comparison of solute clearance during continuous hemofiltration, fi hemodiafi filtration, and hemodialysis using a polysulfone hemofi filter. ASAIO J 1995; 41(1): 100–104. Ronco C, Bellomo R, Homel P, et al. Effects of different doses in continuous veno-venous haemofiltration fi on outcomes of acute renal failure: a prospective randomised trial. Lancett 2000; 356(9223): 26–30. Mehta RL, McDonald B, Gabbai FB, et al. A randomized clinical trial of continuous versus intermittent dialysis for acute renal failure. Kidney Intt 2001; 60(3): 1154–1163. Kellum JA, Angus DC, Johnson JP, et al. Continuous versus intermittent renal replacement therapy: a meta-analysis. Intensive Care Med d 2002; 28(1): 29–37. Augustine JJ, Sandy D, Seifert TH, Paganini EP. A randomized controlled trial comparing intermittent with continuous dialysis in patients with ARF. Am J Kidney Dis 2004; 44(6): 1000–1007.

11 Technical Aspects of Renal Replacement Therapy Sara Blakeley

Since its inception in 1977 (1), methods and equipment used for the delivery of continuous renal replacement therapy (CRRT) has undergone many changes. Intermittent hemodialysis (IHD) is performed on some intensive care units (ICU), but this chapter will concentrate on continuous therapies.

Mode of CRRT There is a spectrum of treatment available and with choice comes debate; continuous versus intermittent, convective versus diffusive therapy (2, 3). Continuous therapies have been associated with better renal survival compared with IHD, although no compelling effect on overall mortality has been seen (4). Diffusion is the movement of molecules from an area of high concentration (blood) to one of a lower concentration (dialysis fl fluid circulating in a counter current direction) across a semipermeable membrane. With convection a pressure (transmembrane pressure) is applied across the membrane, this drives water out and carries with it dissolves solutes (solvent drag). The “waste” fl fluid produced is termed ultrafiltrate. fi Both diffusive and convective therapies are good at removing small molecular weight molecules (<5000 Da), such as urea and creatinine, but “middle molecules” (10,000–50,000 Da) such as β2 microglobulin and cytokines (5) may be better removed by convection. Currently, there is no definitive fi evidence to suggest one particular mode over another, and choice is often guided by local expertise.

CRRT on the ICU nowadays is almost exclusively venovenous in nature; in other words, blood is removed from a large vein and returned to a large vein. The different modes of CRRT differ mainly in their method of solute removal, and most modern machines are capable of providing the full range of modalities. Newer machines offer greater ease in switching between modes. There is much discussion regarding the relationship between dialysis dose delivered and survival (6). A prospective randomized study of post dilution CVVH in critically ill patients found improved survival with an ultrafiltration fi dose of 35 ml/kg/hour (7). Ultrafiltration fi rate is used as a dose surrogate. This finding was not repeated in a subsequent study (8) but a more recent study found did find an improvement in survival when adding a dialysis dose to CVVH (9). It is unclear whether this survival advantage was due to a higher dose of CRRT overall or due to the addition of a diffusive therapy to a convective one. These findings are being investigated further in other fi studies, to clarify what is the optimal dose and means of delivery. In the mean time 35 ml/kg/hour is often recommended as minimum that should be provided (10–12). Standard therapies in use are: Continuous venovenous hemofi filtration (CVVH), characterized by predominantly convective solute clearance (Figure 11.1A). Continuous venovenous hemodialysis (CVVHD), characterized by predominantly diffusive solute clearance but with some convection occurring because of ultrafi filtration.

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Effluent pump

Ultrafiltrate and used dialysate (waste)

Blood flow from patient - ‘arterial’ side Blood pump Replacement fluid pump

Replacement fluid entering pre filter (pre dilution)

Blood flow to patient - ‘venous’ side Haemofilter

Pressure monitor Air detector

A Anticoagulation syringe Effluent pump

Ultrafiltrate and used dialysate (waste)

Blood flow from patient - ‘arterial’ side Blood pump Replacement fluid pump

Dialysate fluid (running in a counter current direction to blood flow through the haemofilter) Dialysate pump

Haemofilter

Replacement fluid entering post filter (post dilution)

Blood flow to patient - ‘venous’ side Pressure monitor Air detector

B FIGURE 11.1. A, CVVH with prefilter replacement fluid delivery (predilution). B, CVVHDF with postfilter replacement fluid delivery (postdilution).

11. Technical Aspects of Renal Replacement Therapy

Continuous venovenous hemodiafiltration fi (CVVHDF), characterized by a mixture of diffusive and convective solute clearance (Figure 11.1B). Slow continuous ultrafi filtration (SCUF) is removal of water in response to a pressure gradient, but a degree of solute removal via convection will also occur. Therapeutic plasma exchange (TPE). Plasma is separated, removed, and replaced with either albumin or fresh frozen plasma.

Hemofiltration Machines (Figure 11.2) All machines have a similar set up. Newer machines differ in their degree of “user friendliness,” their range of pump fl flow rates, and the degree of monitoring. A roller pump controls the flow fl of blood from the patient through the fi filtration circuit and then back to the patient. Blood flow fl rate is set by the operator but is limited by vascular access quality, blood viscosity, patency of the hemofilter, fi and cardiovascular stability of the patient. The maximal achievable blood flow fl rate varies between different makes of machine (50–450 mL/min).

59

Infusion rates of replacement fl fluid and/or dialysate are set, with newer machines offering increased fluid removal rates (0–10 L/h) to perform high-volume hemofiltration fi (HVHF). A desired net fl fluid loss (0–1000 mL/h) is set by the operator and constantly monitored by the machine. The machine generally calculates the ultrafiltration fi rate depending on the rate of replacement fl fluid and fluid fl removal set by the operator. A bag then collects the effl fluent (waste), which is composed of ultrafi filtrate and spent dialysate (if being used). A series of safety mechanisms are in place to prevent the inadvertent introduction of air to the patient and to detect blood leakage. Alarms warn of pressure changes within the circuit: • Access pressure: Pressure in the “arterial” limb removing blood from the patient is a negative pressure reflecting fl blood suction. It is determined by blood flow, fl patient’s blood pressure, and intravascular fluid status. Excessively negative pressures (e.g., >300 mmHg) risk vascular injury and hemolysis and suggest occlusion somewhere in the access limb of the blood circuit, e.g., kinked line or blocked vascular access. • Filter pressure: A rise in pressure indicates that the filter may be starting to clot. • Return pressure: Pressure in the “venous” limb returning blood to the patient is a positive pressure refl flecting resistance to venous return. Low pressures may indicate disconnection but can be seen with changes in position. High pressures are seen with occlusion to flow, e.g., kinking or clotting, but also if the blood fl flow rate is too high.

Replacement and Dialysis Fluid

FIGURE 11.2. Two examples of hemofiltration machines. The Edwards’ Aquarius System (left) t and Hospal Prisma (right). t

With convective therapies, large volumes of fl fluid (effluent) fl are removed from the patient per hour. To maximize solute removal, prevent the patient from becoming hypovolemic, and replace wanted electrolytes, a replacement fluid fl is infused. With diffusive therapies, dialysate fluid fl d is run in a counterclockwise direction through the fluid fl compartment of the fi filter, against the blood flow. This fl fluid can be formulated in-house, or more commonly as commercially prepared bags of sterile fluid.

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The fluid contains a buffer, either lactate or bicarbonate, and electrolytes (sodium, chloride, magnesium, and calcium). Typically, replacement fluids are potassium- and phosphate-free, and fl these may need to be replaced as clinically indicated. Glucose is often not present.

Prefilter Versus Postfilter Infusion Replacement fluid fl is infused into the circuit either before the filter (predilution) or after the filter (postdilution). Predilution lowers the hematocrit of the blood passing through the filter, fi potentially reducing anticoagulation needs and allowing increased ultrafi filtration rates. This is at the expense of less-effective solute clearance, therefore, an increased ultrafi filtration rate is needed to achieve similar solute clearances. Newer machines allow a combination of predilution and postdilution.

Lactate Versus Bicarbonate Buffer Both lactate- and bicarbonate-buffered solutions have been shown to be effective in correcting metabolic acidosis (11, 13). Bicarbonate is preferred in patients with a preexisting lactic acidosis (e.g., septic shock) or with liver failure (11) because these patients may be unable to metabolize an exogenous lactate load normally, thus, worsening the acidosis. Lactate levels are often seen to rise in other patient groups who have a lactate buffer, but the signifi ficance of this is unclear because hyperlactatemia is not always associated with an acidosis. Bicarbonate is a more physiological buffer, but, because it is unstable in solution, it needs to be added just before use. Studies have compared outcomes of bicarbonate versus lactate buffers but the evidence is inconclusive. Lactate intolerance has been arbitrarily defi fined as a rise of greater than 5 mmol/L during CRRT (14), and a change to a bicarbonate buffer should be considered.

Hemofilters Structure Thousands of hollow fibers (membrane) are bundled together forming a hemofilter fi with a large surface area of 0.6 to 1.2 m2. Pores in the membrane allow the passage of molecules with a

S. Blakeley

molecular weight less than 50,000 Daltons (Da), i.e., smaller than albumin. Membranes are composed of two substances, cellulose (e.g., cuprophan) and synthetic fibers (e.g., polysulphone, polyamide, or polyacrylonitrile).

Membrane Characteristics Biocompatibility Contact of blood with the fi filter surface can lead to complement and leucocyte activation, triggering the coagulation cascade and infl flammatory pathways. More “biocompatible” indicates less complement/leucocyte activation. Activation of infl flammatory mediators has been suggested as one mechanism leading to ongoing renal injury, and, therefore, delay or nonreturn of renal function (4). Kidneys that have already been injured because of reduced renal perfusion lose their ability to autoregulate pressure changes and the kidney becomes very sensitive to even small changes in renal perfusion. Early reports that bioincompatible cellulose-based membranes led to a worse outcome have been debated, but, currently, the evidence is not robust enough to defi finitively recommend a synthetic membrane over cellulose or modified fi cellulose membrane (15). As it is, most membranes used in CRRT are synthetic because they have a greater degree of fl flux.

Flux This is a measure of ultrafi filtration capacity and is based on the membrane ultrafiltration fi coeffi ficient. A filter with a high permeability coeffi ficient to water will allow more ultrafi filtration (high flux) and, hence, more convective transport. Permeability is a measure of the clearance of middle molecular weight molecules and high permeability is seen with high fl flux membranes (synthetic membranes). It should be noted that high permeability does not always equate to high urea clearance (efficiency). fi

Vascular Access When initially developed, CRRT used an arterial and a venous catheter (arteriovenous) (1). A widebore (11.5–13.5 French) dual-lumen vascular dial-

11. Technical Aspects of Renal Replacement Therapy

ysis (venovenous) catheter is now generally used. Mostly composed of polyurethane, they can have an antibiotic/antimicrobial coating. Blood is pumped from the patient (arterial side) through proximal side holes into one lumen, and is then returned though a port at the distal tip of the second lumen (venous side). High blood flows without high pressures are ideal catheter fl design requirements, and the dual-lumen design allows continuity and reduces recirculation. Vascular catheters differ in length, diameter of lumen, and positioning of ports, and some have an extra lumen added for drug infusions. Remember: always assume that EACH catheter limb contains heparin and aspirate at least 5 mL of blood before using. Cuffed dialysis catheters are generally not used on the ICU, but may be indicated in stable patients who are free of infection, and who require ongoing renal replacement therapy (RRT) (Table 11.1).

Positioning A correctly positioned catheter will have a better blood flow; good access is the key to good dialysis. The tip of a jugular or subclavian catheter should extend to the superior vena cava and rest 1 to 2 cm above the right atrium. Too short, and there is the possibility of recirculation, whereas a catheter that is too long risks atrial perforation. Femoral catheters should be longer (>20 cm) to reach the inferior vena cava, therefore, minimizing recirculation and achieving better fl flow rates.

Site of Catheter Debate continues regarding the ideal site for placement of dialysis catheters in terms of safety of insertion and infection risk. Where long term dialysis is a possibility, there is concern that subclavian catheters may be associated with an increased incidence of subclavian stenosis/thrombosis, creating long-term problems for arteriovenous fistula formation.

Anticoagulation As blood flows fl through the filter and fluid is removed, viscosity increases and there is a tendency toward filter clotting. Passage of blood

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through the circuit can also result in the formation of platelet microthrombi, which can occlude the filter. Loss of the filter through clotting can lead to fi ineffective dialysis and patient blood loss, as well as being a drain on resources, both nursing and financial. Methods such as predilution and ensurfi ing adequate vascular access can be used, but some form of anticoagulation for the extracorporeal circuit is often needed. Remember: circuit failure is more often caused by inadequate vascular access rather than inadequate anticoagulation.

No Anticoagulation In the setting of deranged clotting (e.g., international normalized ratio [INR] >2, activated partial thromboplastin time [aPTT] >60 s) and/or thrombocytopenia (e.g., platelet count <50,000) or a high risk of bleeding, further anticoagulation is often not necessary or carries the risk of bleeding. With adequate access and predilution, it is possible to run the circuit without any anticoagulation for an acceptable period of time and achieve good solute clearance.

Unfractionated Heparin Unfractionated heparin (UFH) is the most commonly used extracorporeal anticoagulant. The circuit is often primed with heparin (e.g., 1000– 10,000 IU) because it is highly negatively charged and is absorbed onto the plastic circuit. Depending on the risk of bleeding, a bolus dose (e.g., 10– 20 IU/kg) can be administered and a continuous infusion started. A low-dose infusion (<5 IU/kg/h) aims NOT to prolong the aPTT. If clotting occurs, a medium dose can be considered (5–10 IU/kg/h), aiming for mild prolongation of the aPTT (1–1.4 times normal) (16). Prefilter fi heparin can be neutralized with postfilter fi protamine (e.g., 1000 IU/h to 10 mg/h), called regional heparinization. If patients require formal heparinization for conditions such as a pulmonary embolus, this should be continued, no extra “fi filter” heparin is needed. The methods, site of sampling, and frequency of anticoagulation monitoring vary depending on local protocols. Commonly used methods are the activated coagulation time (ACT) and aPTT. However, it should be remembered that there is not always a linear correlation between dose of heparin or degree of anticoagulation and filter fi life.

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Low Molecular Weight Heparin

Regional Citrate Anticoagulation

Compared with UFH, low molecular weight heparin (LMWH) is considered more effective in reducing fibrin deposition on dialyzer membranes and, thus, preventing circuit clotting, however, its superiority to UFH has not been proven in trials. There is a reduced incidence of heparin-induced thrombocytopenia syndrome (HITS) compared with UFH, but it is more costly. With more experience LMWH use has increased in popularity. Standard markers of anticoagulation are not reliable and anti-Xa levels should be monitored with prolonged use (target, 0.25–0.35 U/mL) (16). However, there is not always a correlation between anti-Xa levels and filter life.

Infused citrate complexes with calcium and prevents activation of the coagulation cascade and platelets. Post dialyser, calcium is reinfused. Regional citrate anticoagulation (RCA) is an effective form of anticoagulation, and because only the circuit is anticoagulated, it is safe to use in patients at risk of bleeding. However, its side effects and complex infusion protocol have limited its widespread use. Side effects include citrate toxicity if citrate is not metabolized rapidly or adequately (e.g., in liver failure), hypernatremia, hyper/hypocalcemia, and metabolic alkalosis (each citrate molecule is metabolized to three bicarbonates).

TABLE 11.1. Complications of RRTa Access related Complications during insertion Infection Catheter-related thrombosis Patient immobility

Bleeding, local trauma Systemic or local Particularly with femoral lines

Circuit related Membrane bioincompatibility Air embolism Blood loss Fluid balance errors Hemolysis

See text Caused by clotted filters (common) or disconnection (rare)

Dialysis related Hypotension

Anticoagulation-related complications Electrolyte disturbances Acid-base disturbances

Temperature disturbances Vitamin and micronutrient depletion Inappropriate prescribing of drugs Further renal injury

a

ACEI, angiotensin converting enzyme inhibitor.

Hypovolemia secondary to total volume removal or speed of removal, i.e., not allowing body compartments to equilibrate (commonest) t High pump speeds may be enough to precipitate hypotension in unstable patients Life-threatening anaphylactoid hypersensitivity reactions have been described with the use of certain membranes (e.g., polyacrylonitrile membranes, such as AN69) with concurrent ACEI therapy Activation of inflammatory and vasodilatory mediators (e.g., bradykinin) related to membrane bioincompatibility Local or systemic bleeding Related to specific type of anticoagulant: e.g., HITS (heparin) and hypocalcemia (RCA) Including hypokalemia, hypophosphatemia, and hypoglycemia Metabolic acidosis related to lactate buffer in replacement fluid if unable to handle a large exogenous lactate load (e.g., liver failure, septic shock) Metabolic alkalosis related to RCA A degree of cooling always occurs, this may lead to “normothermia” in febrile patients (i.e., masking a pyrexia) or cause marked hypothermia Water-soluble vitamins, trace minerals, certain hormones (e.g., glucocorticoids), amino acids Generally leads to underdosing while a patient is on the filter Systemic hypotension (see above) reducing already compromised renal perfusion Because of release of inflammatory mediators triggered by blood coming into contact with the filter and tubing

11. Technical Aspects of Renal Replacement Therapy

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Prostacyclin Prostaglandin (PG)-I2 is a natural anticoagulant that is a potent antiplatelet agent and has been shown to reduce platelet microthrombi during dialysis. It is often used in patients with a high risk of bleeding, but because it is a potent arterial vasodilator, some patients develop symptomatic hypotension. It has been used on its own and in combination with low-dose heparin.

Other Anticoagulants Heparinoids (e.g., danaparoid) have minimal effects on platelets and can be used in HITS (but remembering the potential cross reactivity in 5–10% of patients). However, standard markers of anticoagulation are not reliable and its effect is prolonged in renal failure. Factor Xa inhibitors (e.g., fondaparinux) and direct thrombin inhibitors (e.g., recombinant hirudin) can be safely used in HITS, but, to date, have limited use in CRRT.

Comment A recent systematic review (16) found that there was no conclusive evidence to suggest one strategy over another, but the chosen method should take into account patient characteristics and local facilities. Heparin (UFN and LMWH) has the greatest evidence and experience behind it, but RCA is increasing in popularity and ease of use.

References 1. Kramer P, Wigger W, Rieger J, et al. Arteriovenous haemofi filtration: a new and simple method for treatment of over-hydrated patients resistant to diuretics. Klin Wochenschr. 1977; 55: 1121–1122. 2. Palevsky PM. Dialysis Modality and Dosing Strategy in Acute Renal Failure. Sem Dialysis. 2006; 19: 165–170. 3. Van Biesen W, Vanholder R, Lameire N. Dialysis strategies in critically ill acute renal failure patients. Curr Opin Crit Care. 2003; 9: 491–495. 4. Palvesky PM, Baldwin I, Davenport A, et al. Renal replacement therapy and the kidney: minimising the impact of renal replacement therapy on recov-

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15.

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ery of acute renal failure. Cur Opin Crit Care. 2005; 11: 548–554. Ricci Z, Ronco C, Bachetoni A, et al. Solute removal during continuous renal replacement therapy in critically ill patients; convection versus diffusion. Crit Care. 2006; 10: R67–R74. Clark WR, Turk JE, Kraus MA, Gao D. Dose determinants in continuous renal replacement therapy. Artif Organs. 2003; 27: 815–820. Ronco C, Bellomo R, Homal P, et al. Effects of different dose in continuous veno-venous haemofiltrafi tion on outcomes of acute renal failure: a prospective randomised trial. Lancet. 2000; 356: 26–30. Bouman C, et al. Effects of early high-volume continuous Venovenous hemofiltratin fi of survival and recovery of renal function in intensive care patients with acute renal failure: a prospective randomized trial. Crit Care Med. 2000; 30: 2205–2211. Saudan P, et al. Adding a dialysis dose to continuous hemofi filtration increases survival in patients with acute renal failure. Kidney Int. 2006; 70: 1312– 1317. Cariou A, Vinsonneau C, Dhainaut JF. Adjunctive therapies in sepsis: an evidence-based review. Crit Care Med. 2004; 32: S562–S570. www.adqi.net Ronco C. Renal replacement therapy for acute kidney injury: let’s follow the evidence. Int J Artif Organs. 2007; 30: 89–94. Naka T, Bellomo R. Bench-to-bedside review: treating acid-base abnormalities in the intensive care unit–the role of renal replacement therapy. Crit Care. 2004; 8: 108–114. Hilton PJ, Taylor J, Forni LG, Treacher DF. Bicarbonate-based haemofiltration fi in the management of acute renal failure with lactic acidosis. QJM. 1998; 4: 279–283. Teehan GS, Liangos O, Lau J, et al. Dialysis membrane and modality in acute renal failure: understanding discordant meta-analyses. Sem Dialysis. 2003; 16: 356–360. Oudemans-van Straaten HM, Wester JPJ, de Pont ACJM, Schetz MRC. Anticoagulation strategies in continuous renal replacement therapy: can the choice be evidence based? Intensive Care Med. 2006; 32: 188–202.

Suggested Reading Bellomo R, Baldwin I, Ronco C, Golper T. Atlas of Hemofi filtration. WB Saunders. 2002.

12 End-Stage Renal Disease Emile Mohammed

There are now approximately one million people on renal replacement therapy worldwide. In the current era of chronic noncommunicable disease, this number is set to double within the next decade. Patients with end-stage renal disease (ESRD) carry a significantly fi higher cardiovascular morbidity and mortality compared with the general population. This is because of the “uremic” cardiovascular factors (Table 12.1). The result is that there will be a growing number of ESRD patients being managed within the intensive care unit (ICU) setting.

Hemodialysis and Peritoneal Dialysis Mechanisms of Dialysis There are two basic principles of dialysis that allow the body’s homeostasis to be achieved in the absence of a natural kidney. They are as follows: • Convection, in which there is movement (in large volumes) of solvent, which drags dissolved solute across a membrane with a hydrostatic pressure gradient. • Diffusion, in which there is passive movement of solute from a high- to a low-concentration gradient across a membrane (Figure 12.1). Diffusion depends not only on the transmembrane gradient but the membrane characteristics (e.g., pore size). Diffusion is more effective in clearing small molecules and convection improves mid-size molecule clearance.

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Hemodialysis Many hemodialysis (HD) techniques have been developed, particularly in the ICU setting, ranging from conventional HD, high-flux fl HD, hemodiafi filtration, and hemofi filtration. These techniques simply use varying degrees of convection or diffusion. For example, hemofiltration fi is a convective treatment with good clearance of mid-size molecules but with poor small molecule clearance. The converse holds for conventional intermittent HD.

Peritoneal Dialysis The peritoneum acts as a natural semipermeable membrane. Dissolved waste products and water pass from the blood, via the peritoneal capillaries, through the mesothelial cells and interstitium to the peritoneal dialysis (PD) fl fluid (PDF). This process is referred to as ultrafi filtration (Figure 12.2). Water-soluble waste products pass down a concentration gradient that is generated by an osmotic gradient. This, in turn, is created by glucose or glucose polymers added to the PDF. PD regimens are all based on repetitions of a basic cycle, which comprises inflow fl of PDF, a dwell time of the PDF within the peritoneal cavity, and then drainage. The various types of PD are all based on this principle. They include continuous ambulatory PD (CAPD), automated PD (APD), tidal PD, and intermittent PD. Typical regimes are illustrated in Figure 12.3.

12. End-Stage Renal Disease

65

TABLE 12.1. Cardiovascular risk factors in the uremic patient Traditional coronary risk factors (The Framingham Study)

Uremic-related cardiovascular risk factors

Hypertension

Increased extracellular fluid volume Calcification and high calcium/phosphate product Parathyroid hormone

High levels of low-density lipoprotein Low levels of high-density lipoprotein Smoking Diabetes Older age Male sex White race Physical inactivity Menopause Left ventricular hypertrophy

Anemia Oxidant stress Malnutrition Pulse pressure Triglycerides Lipoprotein remnants Lipoprotein A Homocysteine Inflammation (C-reactive protein) Sleep disorders

Clinical Parameters Much debate surrounds the “optimal” dialysis dose, although a minimal dialysis dose has been universally accepted. Within the context of thriceweekly HD, there seems to be no added benefit fi of high-dose dialysis compared with the conventional dose of dialysis (the HEMO study) (1). Dialysis adequacy is measured by urea kinetic modeling (UKM) using the urea reduction ratio, or Kt/V, where K is the dialyzer urea clearance, t is the duration of dialysis, and V is the urea distribution volume. In a well-nourished stable HD patient, a Kt/V of 0.8 to 1.0 is the minimum acceptable threshold per dialysis session. The Adequacy

of Peritoneal Dialysis in Mexico (ADEMEX) study (2) again reveals the same controversy of defining fi the optimal dialysis dose in PD patients. In this study, there was a neutral effect on patient survival between a control group on conventional CAPD compared with a study group on a modified fi prescription, which achieved increased small solute clearance, measured by peritoneal creatinine clearance and peritoneal Kt/V. There are no “fi fixed targets” that determine dialysis adequacy in the ICU setting. Dialysis dose and duration must be determined by balancing the clinical condition of the patient, while achieving as normal a physiological state as possible.

Blood flow (250-500ml/min) Sodium

Calcium, bicarbonate

Semi-pe -pe -perme perm rmeab rme ablle memb embran ranee

FIGURE 12.1. Diagrammatic representation of blood purification within the dialyzer.

Urea, creatinine

Water

Potassium

Dialysate flow (400-800ml/min)

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E. Mohammed Mesothelium

Interstitium

FIGURE 12.2. Ultrafiltration in PD.

Peritoneal cavity

Soluble waste products and water

Glucose

Capillary

Typcal CAPD regime 3

“Bag in” PDF volume (litres)

2.5 2 1.5 1 0.5 0

Bag drained out

Time (during day)

Typical APD regime

PDF volume (litres)

2.5

“Bag in” 2 1.5 1 0.5 0

wet day

overnight exchanges

FIGURE 12.3. PD regimes.

12. End-Stage Renal Disease

The following clinical parameters act as guidelines to achieve this: • Target weight and blood pressure control. Target weight is defi fined as the patient’s weight in which all the fluid compartments are physiologically normal. Excess weight (which will be essentially salt and water) results in hypertension. The target weight is achieved by gradual weight reduction on successive dialyses until the patient is free from both pulmonary and peripheral edema, but, below which, hypotension occurs. • Acid-base balance. Dialysis must be performed frequently and long enough to maintain normal acid-base balance. • Bone biochemistry. Along with vitamin D supplementation, serum calcium and phosphate levels should be maintained within normal limits. • Nutritional state. It is important to remember that a high proportion of ESRD patients within the ICU will have a low serum albumin, low body mass index, an infl flammatory and/or hypercatabolic state, and a low dietary intake. It is, therefore, necessary to obtain dietary advice, treat correctable factors, give dietary supplements, and have a low threshold for nasogastric (NG), percutaneous endoscopic gastrostomy (PEG), or even parenteral nutrition, if indicated. Dialysis prescriptions must accommodate these nutritional requirements. A good starting point for prescribing dialysis would be to continue the patient’s regular dialysis regime and adjust the dose of dialysis, in conjunction with the nephrologists, to achieve the above parameters.

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• Anaphylaxis. Anaphylaxis can occur by complement activation with the use of a bioincompatible membrane and normally occurs within the first 20 minutes of treatment. • Catheter related-sepsis. Catheter related-sepsis requires aggressive antibiotic treatment and catheter removal. If temporary catheters are being used, once weekly catheter changes are recommended. • Pyrogenic reactions. Uncommon if ultrapure water is used. • Dialysis equilibrium syndrome. Rare in established dialysis patients. It can occur from overaggressive dialysis causing a rapid reduction in serum osmolality and resulting in cerebral edema. • Modern fail-safe machines minimize other complications such as air embolism and accidental circuit disconnection.

Peritoneal Dialysis Although PD is a technically safe procedure, there may be clinical reasons to convert to temporary HD. These are as follows: • Abdominal surgery • Diaphragmatic fluid leak resulting in effusions • Respiratory compromise from splinting of diaphragm by PDF • Severe hypoalbuminemic state • Peritonitis or catheter-related sepsis • Inadequate ultrafiltration fi in the context of aggressive fl fluid management and/or hypercatabolic state of the patient

Renal Transplantation Dialysis-Related Complications Hemodialysis • Hypotension. Hypotension can be minimized with an accurate assessment of target weight, judicious use of antihypertensive medications, sodium restriction, increasing treatment duration, and careful choice of dialysis modality, e.g., hemodiafiltration fi in the cardiovascularly unstable patient.

Renal transplantation represents the best mode of therapy for ESRD patients, both in cost effectiveness and quality of life (3). There have been many improvements in renal transplantation, such as the refi finement of immunosuppression regimens, and patient-donor selection and work-up as well as their compatibilities. The major challenge facing transplantation is that its demand far outstrips the availability. Every effort should be made to increase the number of donors. In parallel to this, there is

68

E. Mohammed

much research in the development of stem cell transplantation and xenotransplantation.

allografts. Such sensitization can cause severe hyperacute rejection.

Evaluation, Selection, and Preparation of the Potential Transplant Recipient

Evaluation and Selection of Donors

General Evaluation There are few absolute contraindications to renal transplantation. These are uncontrolled cancer, HIV positivity, active systemic infections, and/or any condition with a life expectancy of shorter than 2 years. Conditions increasing the risk of posttransplant morbidity and mortality include long duration of dialysis, previous incidence of recurrent infections, cardiovascular disease, and gastrointestinal complications. Such patients require a particularly careful work-up and aggressive management of risk factors (e.g., hypertension, obesity, and vascular disease) before transplantation.

Psychological Evaluation The use of psychiatric screening is not universally adopted but may be useful in assessing compliance with immunosuppressive regimes. Poor compliance signifi ficantly worsens renal allograft outcomes.

Recurrent Renal Disease It is important to ascertain the underlying cause of renal failure because some diseases recur in the transplanted kidney, most notably, focal and segmental glomerulosclerosis.

Immunological ABO blood group must be compatible. HLA typing of donors and recipients allows assessment of compatibility. HLA DR is more important than HLA B, which is more important than HLA A. A lymphocyte cross-match is also performed: the recipient is screened for preexisting antibodies to donor lymphocytes, which arise in response to previous blood transfusions, pregnancies, or renal

There are two sources of donors: Cadaveric: Cadaveric kidneys may be either from patients with brainstem death and a maintained cardiac output or from nonheart-beating donors. Donors with sepsis, malignancy, infection with hepatitis B, hepatitis C, HIV, or tuberculosis, or irreversible renal failure are not considered for donation. Live: The use of kidneys from living donors is recommended for renal transplantation whenever possible, in light of the growing body of evidence of favorable outcomes after transplantation. Before being selected as a living donor, thorough counseling, medical, physical, and psychological evaluation is performed. Outcome studies have revealed lower mortality rates in living donors compared with the general population. This is probably caused in part by patient selection and the fact that this group of patients receive long-term medical follow-up.

Immunosuppression The immunosuppression regime is tailored to each patient in an effort to minimize rejection as well as side effects. The following is a brief summary of drugs used, usually in combination. The commonest regime is triple therapy, e.g., cyclosporin, azathioprine, and prednisolone. Corticosteroids have broad but potent immunosuppressive actions. They are used in high doses in induction therapy as well as for episodes of acute rejection. They are tapered to small maintenance doses or stopped completely over time. Because of the broad actions of corticosteroids, there are a large range of side effects. Cyclosporin is a calcineurin inhibitor. Although there is little myelotoxicity, cyclosporin is nephrotoxic and does contribute to chronic allograft rejection. It is an important agent, because its introduction improved 1-year graft survival by 15 to 20%.

12. End-Stage Renal Disease

69

Tacrolimus is also a potent calcineurin inhibitor. Its side effect profi file is similar to cyclosporin but seems to be more diabetogenic, particularly in the black population. Azathioprine has been widely used for transplantation and it continues to be an integral part of many immunosuppression regimens. It inhibits purine metabolism and, therefore, cellular proliferation. There is a significant fi side-effect profi file, most notably its myelosuppressive effect, which is worsened by concomitant use of other drugs such as allopurinol. Mycophenolate mofetill acts similarly to azathioprine but is more specifi fic for lymphocytes. Myelosuppression must also be monitored and mycophenolate mofetil has more gastrointestinal side effects than azathioprine. Daclizumab and basiliximab are anti-CD25 antibodies. They target activated T cells only and are used as an induction agent to prevent early rejection. Polyclonal antibodies to T-cells, ALG and ATG, as well as monoclonal antibody to T cells, OKT3, are used to treat refractory acute rejection and sometimes used as an induction agent to prevent rejection. These drugs are used cautiously because their administration is associated with cytokine release syndrome and pulmonary edema. Other side effects include subsequent infection and posttransplantation lymphoproliferative disease (PTLD).

Early

Complications of Transplantation

• Chronic rejection occurs secondary to a combination of immunological and nonimmunological factors. The result is an irreversible progressive decline in graft function and is often associated with proteinuria. • Recurrence of original disease may result in graft failure. There is a particularly high rate of recurrence of focal and segmental glomerulosclerosis but it is diffi ficult to predict and, therefore, is not a contraindication to transplantation. • Cardiovascular disease is the main cause of death in the transplant population and the rate of cardiovascular disease is higher than in the general population. This is because of the additional risk factors of the ESRD population (Table 12.1) as well as the adverse effects of the immunosuppressive agents. • Malignancy, in particular, skin cancer, is three times more common than the general population.

Immediate • Acute tubular necrosis is the commonest cause of early graft function and is more likely to occur with prolonged ischemic times and asystolic, hypotensive, or elderly donors. • Surgical complications are now the commonest cause of early graft loss. These include renal vein and arterial thrombosis and urinary leaks. These complications are surveyed for with Doppler ultrasound and isotope scanning. Occasionally renal angiography or surgical reexploration is required in the anuric kidney. • Hyperacute rejection is now very uncommon, with the more meticulous screening for the presence of preexisting antibodies. The only available treatment is graft nephrectomy.

• Acute rejection should be suspected in patients with established graft function who then experience a rise in serum creatinine. A biopsy is usually required to confirm fi the clinical diagnosis and the treatment involves high-dose steroids, usually with some modification fi of the immunosuppression regime. Antibodies are considered in steroid-refractory acute rejection. • Infectious complications tend to vary with time after transplantation. Within the fi first month after transplantation, most infections are surgically related, such as atelectasis and wound infection. From 1 to 6 months after transplantation, opportunistic infections can emerge, such as Pneumocystis carinii and Aspergillus fumigatus. Clinical infection caused by the effects of modulating viruses, cytomegalovirus (CMV) and Epstein-Barr virus (EBV) are serious complications for which there should be surveillance with prophylaxis administered where appropriate. PTLD in the early period tends to be an EBV-related malignancy. • Mechanical complications, such as arterial and ureteric stenoses and lymphoceles exerting local pressure, sometimes evolve as a cause of deteriorating graft function.

Late

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Other cancers that should be screened for include renal, cervical, and vaginal cancers.

Summary ESRD and its complications are becoming more commonplace, particularly in the ICU environment. The challenges associated with this group of patients also continue to rise and requires a multidisciplinary approach, which includes the intensivist and the nephrologist.

References 1. Eknoyan G, Beck GJ, Cheung AK, et al. Hemodialysis (HEMO) Study Group. Effect of dialysis dose and

E. Mohammed membrane flux in maintenance hemodialysis. N Engl J Med 2002; 347(25): 2010–2019. 2. Paniagua R, Amato D, Vonesh E, et al. Health-related quality of life predicts outcomes but is not affected by peritoneal clearance: The ADEMEX trial. Kidney Intt 2005; 67(3): 1093–1104. 3. The EBPG Expert Group on Renal Transplantation. European Best Practice Guidelines for Renal Transplantation (Part 1). Nephrol Dial Transplantt 2000; 15(Supp 7): 1–85.

Suggested Reading Davison AM, Cameron S, Grunfeld J-P, et al. Oxford Textbook of Clinical Nephrology. 3rd edition. Oxford: Oxford University Press. 2005. Levy J, Brown E, Morgan J. Oxford Handbook of Dialysis. Oxford: Oxford University Press. 2001.

13 Clinical Hyperkalemia and Hypokalemia Harn-Yih Ong

Hyperkalemia Hyperkalemia is defined fi as a plasma potassium concentration greater than 5.0 mmol/L and refers to an excess concentration of potassium ions in the extracellular fl fluid (ECF) compartment.

Causes of Hyperkalemia (Tables 13.1 and 13.2) Because of the ability of the kidneys to excrete a large amount of potassium, hyperkalemia caused by accelerated exogenous intake usually indicates the presence of a subtle or overt defect in renal potassium handling or an altered transcellular distribution.

Compartmental Shift Potassium is the principal intracellular cation, and maintenance of the normal distribution of potassium between the intracellular and extracellular compartments relies on several regulatory mechanisms. Under normal conditions, ingested potassium is absorbed into the portal circulation and rapidly shifted into cells by Na+/K+-ATPase under the influence fl of insulin and circulating βadrenergic catecholamines. When these mechanisms are perturbed, hyperkalemia may occur.

Decreased Renal Excretion The renal system maintains external potassium balance in the long term and is responsible for

excreting 90 to 95% of the daily potassium load. Decreased renal excretion of potassium is, therefore, the most important cause of hyperkalemia. Hyperkalemia may follow failure of glomerular filtration or tubular secretion of potassium. fi

Clinical Features Hyperkalemia is often asymptomatic, but severe hyperkalemia (potassium >6.5 mmol/L) may present with neuromuscular disturbances such as distal paresthesia, generalized muscle weakness, an ascending flaccid fl paralysis, or ventilatory failure. Sudden cardiac death may occur when plasma potassium concentration exceeds 7.0 to 7.5 mmol/L, and this may be the earliest and only manifestation. Acute hyperkalemia is much less well tolerated than chronic hyperkalemia.

Electrocardiogram Changes Some patients may show a gradual progression of electrocardiogram (ECG) findings fi but may progress rapidly without warning. Cardiac arrest caused by asystole, ventricular tachycardia, or ventricular fi fibrillation may occur at any point along this progression. Hyperkalemia can be life threatening even if the ECG is normal. Approximately 50% of patients with potassium levels exceeding 6.0 mmol/L have a normal ECG. • K+, 5 to 6 mmol/L: peaked T waves and shortened QT interval

71

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H.-Y. Ong

TABLE 13.1. Extrarenal causes of hyperkalemia Increased intake Exogenous sources

Endogenous sources (tissue breakdown)

Compartmental shift Inhibition of Na+/K+-ATPase

Altered transcellular electrochemical K+ gradient Increased conductance of K+ channels Familial hyperkalemic periodic paralysis

Potassium supplements (especially with advanced age, diabetes mellitus, underlying renal impairment, and/or the concurrent use of potassium-sparing diuretics) Stored packed red blood cells. Cardiac tolerance to hyperkalemia is decreased by hypocalcemia because of the presence of the anticoagulant, citrate Potassium penicillin G Salt substitutes Rhabdomyolysis. Each kilogram of lean muscle mass contains more than 100 mmol of potassium Hemolysis Tumor lysis syndrome Reperfusion syndrome. Ischemia results in acidosis in the affected area and an outflow of intracellular potassium, this potassium is “washed out” when the region is reperfused Catabolic states Insulin resistance/deficiency β2-adrenergic catecholamine deficiency or resistance; e.g., β-blockers Drugs and toxins; e.g., cardiac glycosides Inorganic metabolic acidosis ECF hypertonicity or hyperosmolar states; e.g., hyperglycemia, hypertonic solutions such as mannitol, hypertonic saline Drugs; e.g., depolarizing muscle relaxants (succinylcholine)

• K+, 6 to 7 mmol/L: prolonged PR interval, AV dissociation, flattening fl and loss of P wave, and widening of QRS complex • K+, greater than 7 to 8 mmol/L: sine wave pattern, ventricular fibrillation, and asystole

Pseudohyperkalemia Pseudohyperkalemia is caused by the release of potassium from damaged cells in vitro (during or after the removal of the blood sample from

TABLE 13.2. Renal causes of hyperkalemia Inadequate sodium delivery to the cortical collecting duct Intravascular volume depletion Acute circulatory failure, e.g., vasodilatory or septic shock Severe cardiac failure Hepatic cirrhosis with ascites Renal failure Acute (oliguric) and chronic renal failure Secondary hypoaldosteronism Low renin

Normal/high renin

Normal/high renin, low cortisol

Suppressed renin secretion, e.g., cyclosporin, tacrolimus Distal (type IV) renal tubular acidosis, e.g., associated with diabetic nephropathy, tubular interstitial nephritis, inhibitors of prostaglandin production Impaired aldosterone production, e.g., heparin Impaired angiotensin II production/action, e.g., angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers Primary adrenal insufficiency, e.g., Addison’s disease (autoimmune) Impaired adrenal enzyme biosynthesis, e.g., azole antifungals (ketoconazole), congenital adrenal enzyme defects (rare)

Primary hypoaldosteronism (rare) Tubular hyperkalemia without aldosterone deficiency (aldosterone resistance) Renal distal tubular potassium Aldosterone antagonists, e.g., spironolactone secretory defect (acquired) Luminal sodium channel blockade, e.g., amiloride, cimetidine, trimethoprim, pentamidine Inhibition of basolateral Na+/K+-ATPase, e.g., cyclosporine Acute or chronic tubulointerstitial nephritis, e.g., diabetic nephropathy, obstructive uropathy, postrenal transplant, lupus nephritis, sickle cell nephropathy, amyloidosis Pseudohypoaldosteronism Type I and II. Rare

13. Clinical Hyperkalemia and Hypokalemia

the patient) and can produce a 1 to 2 mmol/L artifactual increase in potassium levels. The major causes are: • Contamination by drip site or laboratory error • Hemolysis caused by mechanical trauma during venipuncture • Thrombocytosis (platelet count >900 × 1010 cells/L) • Leukocytosis (white cell count >70 × 109 cells/L) or mononucleosis (“leaky red blood cells”) • Familial pseudohyperkalemia or other uncommon genetic syndromes

Management Severe hyperkalemia (plasma potassium >6.5 mmol/L or with ECG changes) is a medical emergency and therapy should begin immediately.

Stabilization of Cardiac Membranes: Intravenous Calcium Although no randomized studies exist to support the use of calcium salts administered intravenously (e.g., 10 mL 10% calcium gluconate over 2–3 min into a large vein), it is still recommended as first-line therapy in the presence of ECG changes or arrhythmia. The protective effect of calcium is evident within minutes and lasts for 30 to 60 minutes. Caution should be used in patients who take digoxin because calcium has been reported to worsen the myocardial effects of digoxin toxicity. An alternative is to consider using magnesium instead of calcium to stabilize the myocardium. Calcium may reduce the immediate risk of cardiac arrest, but represents a temporizing measure only. Plasma potassium concentration is unaltered.

Transcellular Redistribution • Insulin and dextrose: Administration of insulin always causes a transient reduction in plasma potassium because the activated insulin receptor stimulates Na+/K+-ATPase, driving cellular uptake of potassium. The use of insulin and glucose (e.g., 50 mL of 50% glucose to prevent hypoglycemia) for the emergency treatment of

73

hyperglycemia is effective and rapid in onset of action. For example, 10 U intravenous insulin can be expected to lower the plasma potassium concentration by 0.5 to 1.5 mmol/L within 15 minutes, lasting 2 to 4 hours. • Sodium bicarbonate: Increasing the pH of the ECF compartment with sodium bicarbonate (e.g., 100 mmol over 1–2 hours) will shift potassium into cells as an acidosis is corrected. Its effectiveness is debated, but it is still recommended when hyperkalemia is associated with severe inorganic metabolic acidosis. Ensuring effective diuretic therapy fi first lessens the likelihood of developing volume overload as a complication. • Salbutamol: Meter-dose inhalers, nebulized, or intravenous salbutamol seem equally effective in reducing potassium levels.

Removal of Excess Potassium Treatments that shift potassium into the cells have no effect on total body potassium. Excess total body potassium may be removed by gastrointestinal elimination, renal excretion, or renal replacement therapy. • Renal excretion of potassium may be enhanced with the use of diuretics, especially loop diuretics, which increase the delivery of sodium and the urine flow rate to the cortical collecting duct, increasing tubular secretion of potassium. If the patient is volume depleted, hydration with saline can be administered with the diuretic. • Although widely used clinically in the treatment of hyperkalemia, cation exchange resins do not seem to be effective at 4 hours and should not be relied on for rapid effects. • Hemodialysis or continuous renal replacement therapies are the treatments of last resort, with the exception of patients already receiving these therapies.

Hypokalemia Hypokalemia is usually defined fi as a plasma potassium concentration of less than 3.5 mmol/L, and refers to a deficit fi of potassium ions in the ECF compartment.

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H.-Y. Ong

Causes of Hypokalemia (Table 13.3)

Familial Hypokalemic Periodic Paralysis

Hypokalemia indicates a disruption of normal potassium homeostasis and is almost always caused by potassium depletion caused by increased losses, either through the kidneys or gut. In either case, drugs are the most common cause. Less frequently, hypokalemia occurs because of an acute shift of potassium from extracellular to intracellular fluid (ICF) compartments (compartmental shift). For any given cause, the magnitude of the change is relatively small (usually <1.0 mmol/L), but a combination of factors may lead to a signififi cant fall in plasma potassium.

Familial Hypokalemic Periodic Paralysis is an uncommon inherited (autosomal dominant) disorder characterized by recurrent episodes of muscle paralysis that subside spontaneously after 6 to 24 hours. The primary defect is the gene encoding the skeletal muscle dihydropyridine receptor, a voltage-gated calcium channel. Acute attacks are precipitated by a reduction in plasma potassium, such as after carbohydrate-rich meals (increased insulin) or rest after exertion (increased catecholamines). Administration of potassium is lifesaving and should be administered to treat acute attacks.

TABLE 13.3. Causes of hypokalemia Inadequate intake of potassium (rare) Compartmental shift Stimulation of Na+/K+-ATPase-mediated cellular potassium uptake

Metabolic alkalosis Inhibition or blockade of K+ conductance channels and unopposed Na+/K+- ATPase

Endogenous or exogenous insulin β2-adrenergic receptors activation or indirect β2 sympathomimetics (e.g., salbutamol, dobutamine) Increased endogenous adrenaline release (e.g., delirium tremens, hypoglycemia, coronary ischemia, after cardiopulmonary resuscitation) Phosphodiesterase inhibition (e.g., xanthines: milrinone, theophylline, and caffeine) Thyrotoxic hypokalemic periodic paralysis Rapid cell growth (e.g., after vitamin B12 treatment for pernicious anemia) In general, [K+]Plasma falls by 0.4 mmol/L per 0.1 U increase in ECF pH Barium causes irreversible blockade of K+ conductance channels, preventing passive efflux of K+ from cells Chloroquine toxicity causes a dose-dependent reversible blockade of K+ channels Familial hypokalemic periodic paralysis: K+ channels are normal but the muscle behaves as if channels are blocked

Accelerated loss of potassium (can be classified according to acid-base status) Chloride-responsive metabolic alkalosis Gastrointestinal loss (e.g., vomiting, gastric suctioning, colonic villous adenoma) (chloride depletion causes ECF Renal loss (e.g., loop diuretics, Bartter’s syndrome, thiazide diuretics, Gitelman syndrome) contraction with secondary hyperaldosteronism, leading to renal potassium wasting) Chloride-resistant metabolic alkalosis Primary hyperaldosteronism: high aldosterone, low renin, normal cortisol levels, e.g., adrenal (the primary disturbance is adenoma, bilateral adrenal hyperplasia mineralocorticoid excess Glucocorticoid excess: normal aldosterone, normal renin and high cortisol levels, e.g., Cushing’s resulting in sodium and water syndrome retention, ECF expansion, Syndrome of apparent mineralocorticoid excess: low aldosterone level, low renin level, and hypertension, metabolic normal cortisol, e.g., liquorice, Liddle syndrome alkalosis, and the continuous Congenital adrenal hyperplasia: low aldosterone, low renin, and low cortisol stimulation of potassium secretion in the cortical collecting duct) Hyperchloremic metabolic acidosis Gastrointestinal loss of potassium, e.g., diarrhea, urinary diversion (non anion gap) Renal tubular acidosis Organic metabolic acidosis (high anion gap) E.g., lactic acidosis, ketoacidosis Magnesium deficiency (normal acid-base E.g., alcoholism, malabsorption, drugs: diuretics, gentamicin, cisplatin, amphotericin balance)

13. Clinical Hyperkalemia and Hypokalemia

Magnesium Depletion Concurrent hypomagnesemia coexists in up to 40% of cases of hypokalemia because of drugs or disease processes that cause loss of both ions. Whether hypokalemia is caused by magnesium depletion or is an independent effect, it is difficult fi to assess. Magnesium is essential in the stabilization of cellular membranes, and hypomagnesemia is associated with increased losses of intracellular potassium, and increased fecal and urinary potassium wasting. Regardless of the cause, hypokalemia becomes refractory when hypomagnesemia is also present, especially with plasma magnesium concentrations less than 0.6 mmol/L. In these circumstances, correction of hypokalemia requires initial restoration of magnesium.

75

and upper extremities, with eventual impairment of respiratory muscle function and ventilatory failure. Rhabdomyolysis can be seen with severe hypokalemia.

Cardiovascular Arrhythmias The arrhythmogenic potential of hypokalemia is significantly fi increased in the presence of digoxin, myocardial ischemia, congestive cardiac failure (CCF), or left ventricular hypertrophy. Hypokalemia predisposes to serious ventricular ectopy and is associated with increased frequency of primary ventricular fi fibrillation and mortality, particularly in the setting of ischemic heart disease and acute myocardial infarction.

Clinical Effects

ECG Changes

Hypokalemia alters the function of excitable membranes, an effect more notable in skeletal muscle than cardiac muscle. Renal and metabolic effects are also seen. The likelihood of symptoms seems to correlates with the rapidity of decrease in plasma potassium.

• Flattened T wave • U wave (delayed ventricular and Purkinje repolarization) • Ventricular ectopics • Note: When potassium is at ≤2.0 mmol/L, T and U waves combine, creating a wave with greater amplitude with risk of reentry circuits arising during the prolonged relative refractory period, leading to the development of tachyarrhythmias

Neuromuscular Mild Hypokalemia Mild hypokalemia (plasma potassium, 3.0– 3.5 mmol/L) is often asymptomatic. Skeletal muscle weakness is not usually seen with potassium greater than 3.0 mmol/L.

Worsening of Cardiac Function Chronic hypokalemia exacerbates CCF by impairing the function and contractility of myocardial muscle. This reduces stroke volume and cardiac output. Cardiac necrosis has been described.

Moderate Hypokalemia Symptoms of moderate hypokalemia (plasma potassium, 2.5–3.0 mmol/L) are nonspecific: fi lassitude, fatigue, constipation, weakness in the lower extremities, and myalgia. A paralytic ileus can occur.

Severe Hypokalemia Ascending paralysis can occur in severe hypokalemia (plasma potassium, ≤2.0–2.5 mmol/L). The lower extremities are typically involved fi first (particularly the quadriceps), followed by the trunk

Renal and Metabolic Ammoniagenesis and Metabolic Alkalosis Chronic hypokalemia results in ICF acidification, fi which stimulates ammoniagenesis in the proximal tubule. Increased ammonia trapping and net acid excretion coupled to enhanced bicarbonate production perpetuates metabolic alkalosis. Increased ammoniagenesis may be clinically important in patients with severe liver disease, in whom hypokalemia may precipitate hepatic encephalopathy.

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Nephrogenic Diabetes Insipidus Chronic hypokalemia commonly leads to irreversible tubulointerstitial changes resulting in nephrogenic diabetes insipidus (DI).

Diagnostic Approach to Hypokalemia 1. History of associated conditions, including drug history. 2. Examination: assessment of extracellular volume and acid-base status. 3. Investigations: a. Urinary potassium. i. Measured on a 24-hour urine collection, urinary potassium should be less than 10 to 15 mmol/24 hours with hypokalemia of extrarenall origin (indicating appropriate renal potassium conservation). ii. Random urinary potassium may be greater than 20 mmol/L in cases of renal potassium wasting, but this cannot be interpreted unambiguously because urinary potassium reflects fl the K+ to H2O ratio (and depends mainly on the amount of water reabsorbed). b. Urinary anion gap. 4. Serum magnesium. 5. Plasma aldosterone, renin, and cortisol levels.

Treatment The immediate objective of potassium supplementation is to prevent life-threatening cardiac and muscular complications, with the rate and

H.-Y. Ong

route of administration depending on the plasma potassium as well as the presence and seriousness of the pathophysiological consequences of hypokalemia. The underlying disorder should be treated simultaneously. Continuous ECG monitoring of cardiac rhythm is indicated for plasma potassium ≤2.5 mmol/L or intravenous infusion rates of at least 10 mmol/h. Maximum rate of intravenous potassium administration should not exceed 20 mmol/h. Large enteral doses of potassium are difficult fi to deliver because potassium salts are mucosal irritants, with both tablet and liquid forms reported to cause esophageal and gastrointestinal ulceration.

Suggested Reading Gennari FJ. Current Concepts: Hypokalemia. N Engl J Med. 1998; 339(7): 451–457. Glover P. Hypokalaemia. Crit Care Resusc. 1999; 1: 239–251. Halperin M, Kamel KS. Potassium. Lancett 1998; 352: 135–140. Mahoney BA, Smith WAD, Lo DS, et al. Emergency Interventions for Hyperkalaemia. Cochrane Database Syst Rev. 2006. Issue 1. Peterson LN, Levi M (Edited by Robert W. Schrier). Renal and Electrolyte disorders: Disorders of Potassium Metabolism. 6th ed. Lippincott, Williams and Wilkins. 2003. Rastegar A, Soleimani M. Hypokalaemia and hyperkalaemia. Postgrad Med J. 2001; 77: 759–764.

14 Clinical Hyponatremia and Hypernatremia Himangsu Gangopadhyay

Hyponatremia Hyponatremia reflects fl an abnormal ratio of sodium to water and is defi fined as a serum sodium less than 135 mmol/L. Mild to moderate hyponatremia (serum sodium 128–134 mmol/L) is seen in 20 to 30% of hospital inpatients. Severe hyponatremia (serum sodium less than 120 mmol/L) is seen in only 2 to 5% of hyponatremic patients.

Classification (Table 14.1) 1. Hyponatremia with decreased sodium and water (hypotonic dehydration). There is generally loss of sodium and water with inappropriate fluid replacement. 2. Hyponatremia with normal body sodium and normal or increased body water, the patient is usually euvolemic. Plasma osmolality may be normal, low, or high. 3. Hyponatremia with increased sodium and water.

Pseudohyponatremia Isosmolar hyponatremia (serum osmolality of 275–290 mOsm/kg) is usually caused by severe hyperlipidemia or hyperproteinemia and has been called “pseudohyponatremia.” Measurement of plasma sodium by an ion-selective electrode is not affected by the volume of plasma “solids” and, therefore, will give a true sodium level.

Transurethral Resection of the Prostate (TURP) Syndrome • Hyponatremia • Cardiovascular changes: hypertension/ hypotension, bradycardia • Neurological changes: agitation, confusion, fitting, visual disturbances, fixed dilated pupils Irrigating fluid usually containing 1.5% glycine is absorbed during the procedure. Excess fl fluid is absorbed and leads to an increase in total body water and hyponatremia. There is an increase in the osmolar gap. With the use of glycine, other features may be seen: hyperglycinemia, hyperserinemia (a metabolite of glycine), hyperammonemia, metabolic acidosis, and hypocalcemia.

Syndrome of Inappropriate Antidiuretic Hormone Secretion Syndrome of inappropriate antidiuretic hormone (ADH) secretion (SIADH) is diagnosed on the following features: • Hypotonic hyponatremia • Urine osmolality greater than plasma osmolality (inappropriately concentrated urine osmolality) • Urine sodium greater than 20 mmol/L • Other causes of hyponatremia excluded (e.g., cardiac, endocrine) • Normovolemia

77

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TABLE 14.1. Causes and classification of hyponatremia Osmolality Decreased sodium and water (hypotonic dehydration) Extra renal sodium loss Excessive sweating Burns Vomiting Diarrhea Renal sodium loss Osmotic diuretics Thiazide and loop diuretics Mineralocorticoid deficiency Salt-losing nephropathy Diuretic phase of acute tubular necrosis Renal tubular acidosis Normal body sodium and normal or increased body water High plasma osmolality Hyperglycemia Mannitol Glycerol Glycine Sorbitol Normal plasma osmolality Hyperlipidemia Hyperproteinemia (pseudohyponatremia) Low plasma osmolality Stress (physical, psychological) Antidiuretic drugs Glucocorticoid deficiency Myxedema SIADH Transurethral resection of prostate Acute/chronic renal failure Severe polydipsia Increased sodium and water Edematous states

Cardiac failure Liver failure Renal failure Nephrotic syndrome

Volume status

Low

Hypovolemic

Urine Na < 20 mmol/L

Low

Hypovolemic

Urine Na > 20 mmol/L

High

Normal or hypovolemic

Normal

Normal

Low

Normal

Urine Na > 20 mmol/L

Low

Normal

Urine Na < 20 mmol/L

Low

Edematous

TABLE 14.2. Causes of SIADH Ectopic ADH production

Central nervous system disorders

Pulmonary diseases

Other

Small cell bronchial carcinoma Pancreatic adenocarcinoma Leukemia Lymphoma Thymoma Trauma Brain tumor Central nervous system infection (meningitis, encephalitis, abscess) Subarachnoid hemorrhage Acute intermittent porphyria Guillain-Barré syndrome Systemic lupus erythematous Pneumonia Tuberculosis Lung abscess

14. Clinical Hyponatremia and Hypernatremia

Treatment is with fluid restriction and treatment of the underlying cause if possible. See Table 14.2 for a list of causes.

Clinical Presentation Clinical presentation depends on the rapidity and severity of the development of the hyponatremia as well as the underlying condition. Mild hyponatremia may be symptomless or present with anorexia, nausea, lethargy, and apathy. Signs and symptoms of severe hyponatremia include disorientation, agitation, seizures, depressed refl flexes, focal neurological signs, and, eventually, Cheyne-Stokes respiration.

Diagnosis Diagnosis of the cause of hyponatremia involves: 1. History: a. Medical history: cardiac disease, renal disease, hepatic disease, endocrine disorders b. Current and recent medication: diuretics, antidepressants 2. Physical examination: volume status, evidence of cardiac, renal, liver failure 3. Investigations: a. Serum osmolality b. Urine sodium and osmolality c. Blood glucose d. Serum lipids e. Thyroid function f. Plasma proteins

Treatment Much has been mentioned regarding treatment of hyponatremia and the potential complication of central pontine myelinolysis (CPM). This is a potentially fatal condition that can occur when the serum sodium is corrected too quickly. CPM can lead to mutism, dysphasia, spastic quadriplegia, pseudobulbar palsy, delirium coma, and even death. Risk factors for its development are alcoholism, burns, use of thiazide diuretics, a malnourished state, and hypokalemia.

79

Asymptomatic Patients It is important to fully assess the patient and treat the underlying cause. The patient’s fluid fl status should be assessed; hypovolemia should be treated with normal saline, whereas hypervolemic states (such as congestive cardiac failure) will require salt and water restriction. With patients who are euvolemic and asymptomatic, fluid fl restriction may be adequate.

Symptomatic Patients If the onset is acute and the patient is symptomatic (e.g., fitting, altered conscious level) then aggressive correction of sodium is required. This can be performed by the cautious infusion of 3% saline at a rate of 1 mL/kg/h until the sodium rises to 120 to 125 mmol/L. The patient should be closely monitored during this period, and the presence of seizure or coma may require airway protection, anticonvulsants, and other supportive care before the serum sodium is corrected appropriately. Serum sodium should not be allowed to rise more than 2 mmol/L/h and not more than 25 mmol in 48 hours. Frequent checking of serum sodium is, therefore, important. In patients with chronic hyponatremia, a more gradual rise of serum sodium is appropriate.

Hypernatremia Hypernatremia is defined fi as serum sodium greater than 145 mmol/L. It is always associated with a hyperosmolar state.

Classification (Table 14.3) 1. Decreased total body sodium (extracellular water and sodium loss with excess water loss) 2. Normal total body sodium (extracellular water deficiency fi associated with minimal sodium loss) 3. Increased total body sodium (extracellular water and sodium gain with relatively excess sodium gain)

80 TABLE 14.3. Classification and causes of hypernatremia Decreased total body sodium (water greater than sodium loss) Extra renal loss Vomiting Diarrhea Excessive sweating Dialysis Renal loss Osmotic diuretics (e.g., glucose, urea, mannitol) Normal total body sodium (water loss) Extra renal Unconscious state Thirst center dysfunction Mechanical obstruction Inappropriate intravenous therapy No access to water Renal loss Cranial diabetes insipidus Nephrogenic diabetes insipidus Increased total body sodium (sodium greater than water gain) High sodium intake Sea water ingestion Accidental/intentional salt ingestion Hypertonic saline Sodium bicarbonate infusion Low sodium output Mineralocorticoid excess

Mechanism The defence mechanisms against hypernatremia are ADH release and thirst. Any clinical condition affecting these mechanisms will lead to hypernatremia if not addressed properly.

Clinical Presentation Clinical signs and symptoms are not seen until serum sodium reaches more than 155 mmol/L. Symptoms include fever, restlessness, irritability, drowsiness, lethargy, confusion, and coma. Convulsions are rarely seen.

H. Gangopadhyay

Evaluation of Hypernatremia Diagnosis involves:

of

the

cause

of

hypernatremia

1. History a. Fluid loss/excessive water loss b. Poor fluid intake c. Increased salt intake d. Intravenous sodium bicarbonate or hypertonic saline therapy e. Clinical scenario that can lead to neurogenic/nephrogenic diabetes insipidus 2. Physical examination: assessment of volume status is most important 3. Investigations: a. Serum osmolality b. Urine sodium and osmolality

Interpretation of Urinary Osmolality A serum osmolality greater than 290 mOsm/kg should be accompanied by highly concentrated urine if the concentrating mechanism of the tubules is intact and ADH release is adequate. A urinary osmolality of less than 200 mOsm/kg usually suggests some form of diabetes insipidus.

Treatment Treating underlying cause is very important. Fluid therapy with pure water orally or nasogastrically could be suffi ficient in some situations, but intravenous therapy with 5% dextrose or pure water through a central vein is often necessary. A rapid decrease of serum sodium could be equally detrimental, and a decrease of serum sodium by 2 mmol/L/h is acceptable.

15 Clinical Metabolic Acidosis and Alkalosis Sara Blakeley

Acid-base disturbances are common on the intensive care unit (ICU) and should always prompt a search for the underlying cause (Tables 15.1–15.3). Recently another, although not all that new (1), way of understanding the mechanism behind acid-base disorders has gained popularity. This chapter starts with just a brief discussion of this approach, because there are several excellent overviews in the literature (2–6).

Traditional Versus Physiochemical Approach to Acid-Base Disturbances Most “traditional” views of acid-base balance rely on the Henderson-Hesselbach equation, but there has always been debate regarding quantification fi of the metabolic component. It can be described using plasma bicarbonate and anion gap (AG) or by using standard base excess (SBE). However, SBE is affected by changes in sodium, chloride, and albumin, and a significant fi number of abnormal AGs will be missed unless the effect of albumin is considered (7–9). The third way of quantifying the metabolic component is the strong ion difference (SID) (1), taking into consideration nonbicarbonate buffers, such as inorganic phosphate and serum albumin, both of which may be abnormal in critically ill patients. Stewart’s (physiochemical) approach relies on the principles of physical chemistry; electroneutrality, conservation of mass, and dissociation of electrolytes (1). It considers three independent variables for pH: the SID, pCO2 and total weak acid concentration (ATOT). H+ or HCO3− can only change

if one or more of these three variables changes, rather than bicarbonate itself being the main determinant of change, as in the traditional approach. “Strong ions” are ions that exist completely dissociated (charged) in water. There are more strong cations than anions and this difference is called the SID. SID has an electrochemical effect on water dissociation; as SID becomes more negative, H+ increases and pH falls. “Weak ions” exist as dissociated (A−) or associated forms (HA), and together they make up ATOT. Nonvolatile weak acids, mainly albumin but also inorganic phosphate and bicarbonate, dissociate in body fluids forming weak anions. To maintain electrical neutrality, the SID must be balanced by an equal and opposite charge, the effective SID (SIDe). The SIDe is made up of predominately weak acids (A−) and CO2 (Equation 15.1). If the SID is calculated d from the measured plasma strong ion concentrations (Equation 15.2), it is termed the apparent SID (SIDa). However, this will not be precise if there are unmeasured anions or cations present. If the SIDe and the SIDa do not match (strong ion gap [SIG]) then unmeasured ions mustt be present. SIG should be zero, although, in practice, there is a degree of normal variability. If SIG is positive, there must be more unmeasured strong anions (e.g., ketones, sulfates), and if it is negative, more unmeasured cations. Equation 15.1: SIDe = A− + HCO3− Equation 15.2: SIDa = ([Na+] + [K+] + [Ca2+] + [Mg2+]) − ([Cl−] + [lactate])

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S. Blakeley

TABLE 15.1. Classification of metabolic acidosis according to AG High AG (unmeasured anions) Lactate Ketones Renal failure Ingested toxins

Diabetic, alcoholic, or starvation ketoacidosis E.g., salicylate, paracetamol, formaldehyde, ethylene glycol, methanol

Non-AG (hyperchloremic) Gastrointestinal bicarbonate loss Renal bicarbonate loss Exogenous acid load Loss of potential bicarbonate Cation exchange resins

E.g., ketosis with ketone excretion

Low AG Hypoalbuminemia Increased concentration of unmeasured cations Accumulation of positively charged compounds normally absent from serum Interference with measurement +

+

−

E.g., diarrhea, ureterosigmoidostomy, jejunal/ileal loop, small bowel fistulae, pancreatic fistulae, biliary fistulae Renal tubular acidosis

E.g., magnesium, calcium, lithium E.g., cationic antibiotics, IgG myeloma E.g., hyperlipidemia

− 3

AG = ([Na ] + [K ]) + ([Cl ] + [HCO ]) (Normal, 10–18 mmol/L) AGadjusted = AGobserved + 0.25 × ([normal albumin in g/L] − [observed albumin in g/L])

TABLE 15.2. Pathological classification of causes of metabolic alkalosis Exogenous or endogenous bicarbonate load Acute alkali administration Milk alkali syndrome Recovery from lactic acidosis or ketoacidosis Massive blood transfusion Chloride depletion Vomiting, high gastric drainage Gastrocystoplasty Diuretics Posthypercapnia Diarrhea secondary to villous adenoma

Caused by excess regeneration of HCO3 Caused by metabolism of citrate

Villous adenomas are usually associated with hyperchloremic metabolic acidosis, but some can secrete chloride

Cystic fibrosis Potassium deficiency Primary hyperaldosteronism Secondary hyperaldosteronism Drugs Primary hyperaldosteronism Secondary hyperaldosteronism Bartter’s syndrome Gitelman syndrome Magnesium or potassium deficiency High-dose intravenous penicillins Other Severe hypoalbuminemia

Caused by adenoma, carcinoma; idiopathic or hyperplasia E.g., Cushing syndrome/disease, exogenous corticosteroids, accelerated hypertension, renal artery stenosis E.g., carbenoxolone, liquorice Caused by adenoma, carcinoma; idiopathic or hyperplasia E.g., Cushing syndrome/disease, exogenous corticosteroids, accelerated hypertension, renal artery stenosis

Caused by distal delivery of nonreabsorbable anions with an absorbable cation such as sodium E.g., nephrotic syndrome

15. Clinical Metabolic Acidosis and Alkalosis

83

TABLE 15.3. Clinical effects of metabolic acidosis and metabolic alkalosis Metabolic acidosis Cardiac

Respiratory

Neurological

Metabolic and immune

Metabolic alkalosis

• Reduced myocardial contractility and cardiac failure (but unclear association in clinical practice) • Resistance to catecholamines • Increased risk of arrhythmias • Stimulation of the carotid body and aortic chemoreceptors causing hyperventilation (Kussmaul respiration) • Impaired consciousness (mechanism not fullyy understood and not clearly correlating with the degree of acidosis) • Intracerebral vasodilation (may be clinicallyy significant in the setting of already raisedd intracranial pressure) • Hyperkalemia (extracellular potassium shifts) • Glucose intolerance (inhibition of glycolysis andd hepatic gluconeogenesis) • Immune activation

• Decreased myocardial perfusion caused by arteriolar constriction • Reduced angina threshold • Increased risk of arrhythmias • Depressed ventilation (causing compensatory respiratory acidosis), which could lead to failure to wean a patient from mechanical ventilation • Decreased cerebral blood flow caused by arteriolar constriction • Headache, confusion, mental obtundation • Neuromuscular excitability: seizures and tetany (related to reduction in ionized calcium level)l • Hypokalemia • Hypomagnesemia • Hypophosphatemia • Stimulation of aerobic glycolysis leading production of lactic acid and ketoacids • Decreased plasma ionized calcium concentration

Note: the effects of severe alkalemia (pH > 7.60) appear more pronounced with respiratory rather than metabolic alkalosis.

Equation 15.3: SIDa − SIDe = SIG (equals zero unless unmeasured anions or cations present) By using this approach, a change in the balance between strong anions and cations accounts for acid-base disturbances seen on the ICU. For example, excess chloride from a high-volume saline infusion reduces the SID, causing an acidosis. A loss of chloride from a large nasogastric output increases the SID, causing an alkalosis. The modern debate now centers on which is the best and most practical method of assessing acidbase disorders in critically ill patients, and, in particular, detecting the presence of unmeasured anions: the SIG. To date, neither the SIG, corrected AG, or corrected SBE has been found to be overwhelmingly superior to the other, but all have been found to be predictors of increased mortality (10, 11).

Lactic Acidosis (Table 15.4) When more lactate is produced than is metabolized, hyperlactatemia occurs. Elevated levels are generally taken to indicate anaerobic metabolism caused by generalized or regional tissue hypoxia (12). However, it is important to remember that

lactate can be produced under aerobic conditions, especially in the setting of infl flammatory processes. In sepsis, infl flammatory mediators can accelerate aerobic glycolysis, leading to increased glucose turnover and increased lactate production (12, 13). Specifi fic organs are also capable of producing excess lactate under times of stress, for example, the lungs and gut (12, 13). Elevated lactate levels may also indicate decreased clearance (12). Lactate is mostly metabolized by the liver (50%), and decreased clearance can occur with impaired liver function or decreased liver blood flow. Unless lactate levels are specifi fically measured, an elevated level may be “missed” by the AG or SBE because of factors such as hypoalbuminemia. In addition, hyperlactatemia is not always accompanied by an acidosis. Elevated lactate levels, particularly those that fail to clear during the fi first 24 hours, have been repeatedly shown to correlate with a poor outcome (11, 14, 15).

Use of Sodium Bicarbonate Controversy exists regarding the use of alkali therapy (e.g., sodium bicarbonate) to treat metabolic acidosis (16). No clinical studies have shown

84

S. Blakeley

TABLE 15.4. Classification of lactic acidosis Type A (hypoxic) Circulatory insufficiency (e.g., shock, cardiac arrest) Regional hypoperfusion Carbon monoxide and cyanide poisoning (caused by mitochondrial enzyme inhibition) Severe hypoxia Severe exercise/prolonged seizures (caused by increased muscle activity) Severe anemia Type B (nonhypoxic) Sepsis in general (caused by accelerated aerobic glycolysis and mitochondrial dysfunction) and with specific infections (e.g., cholera, falciparum malaria, AIDS) Thiamine deficiency (thiamine is a cofactor of pyruvate dehydrogenase) Fulminant hepatic failure, severe liver disease Alcoholism (ethanol oxidation increases the conversion of pyruvate to lactate and inhibits of pathways of pyruvate metabolism) Severe renal failure Malignancy, leukemia, and lymphoma Short bowel syndrome (D lactic acidosis) Diabetic ketoacidosis (ketones may inhibit hepatic lactate uptake) Type B: drug induced Phenformin/metformin Ethanol, methanol, ethylene glycol Salicylate poisoning Paracetamol poisoning Intravenous fructose, sorbitol Cyanide β-agonists (e.g., salbutamol, adrenaline, caused by increased glyconeogenesis, glycogenolysis, lipolysis, and cyclic AMP activity) Type B: inborn errors of metabolism Glucose 6 phosphatase deficiency Fructose 1,6 diphosphatase deficiency Deficiency of enzymes of oxidative phosphorylation

a benefi fit on outcome in patients with lactic acidosis, but it is diffi ficult to separate the effects of the acidosis from the effects of the underlying pathological condition. Sodium bicarbonate is not without risks, including: • Acute fluid overload. • Alkaline “overshoot” caused by subsequent metabolism of organic salts increasing the bicarbonate concentration. • Paradoxical intracellular acidosis. CO2 released diffuses more quickly than bicarbonate ions into cells, therefore, initially lowering the intracellular pH. There is debate regarding whether this is clinically significant. fi

Use of Renal Replacement Therapy In acute renal failure, the daily production of mineral acids is adequately matched by the effifi

cacy of renal replacement therapy (RRT) techniques, therefore, the acidosis can be cleared within 48 hours (16). Despite the fact that lactate has a low molecular weight and it is easily removed by continuous therapies, RRT has been shown to contribute to only less than 3% of total lactate clearance (17). It may be that RRT plays a role in improving the overall clinical situation (e.g., hemodynamic and fluid fl status), therefore, promoting the clearance of lactate, rather than actually removing it.

Metabolic Alkalosis Metabolic alkalosis is common, but carries an associated mortality that increases with increasing pH, especially pH higher than 7.55 (18). The cause, rather than the alkalosis itself, may be the reason for the increased mortality.

15. Clinical Metabolic Acidosis and Alkalosis

Metabolic alkalosis can be classified fi clinically (Table 15.2) or according to the underlying pathophysiology: initiating process or perpetuating processes (18).

Initiating Processes 1. Loss of hydrogen ions through the kidney (e.g., loop diuretics, primary hyperaldosteronism) or gastrointestinal tract (e.g., vomiting, nasogastric suctioning). 2. Accumulation of alkali from exogenous (e.g., sodium bicarbonate in the setting of renal insufficiency) or endogenous sources (e.g., metabolism fi of ketones after diabetic ketoacidosis). The kidneys have a large capacity to excrete excess bicarbonate and are mostly able to correct the alkalosis; however, in certain situations, the kidney will retain rather than excrete alkali, therefore, perpetuatingg the alkalosis. The persistence of a metabolic alkalosis suggests there is an ongoing, untreated process.

Perpetuating Factors 1. Hypovolemia. Decreased renal perfusion stimulates the renin-angiotensin-aldosterone system (RAAS), therefore, increasing sodium absorption and hydrogen ion secretion. 2. Chloride depletion. Stimulation of the RAAS leads to increased bicarbonate reabsorption in the absence of adequate chloride. 3. Severe hypokalemia. Caused by an intracellular shift of hydrogen ions in exchange for potassium. 4. Reduced glomerular fi filtration rate (GFR). Reduction in GFR causes a decrease in filtered fi bicarbonate.

Treatment 1. Correct the primary cause if possible, e.g., stop or reduce diuretics. 2. Address perpetuating factors. Most forms of metabolic alkalosis are chloride responsive, and isotonic sodium chloride will correct both chloride and volume depletion. As the chloride deficit fi is corrected, there will be an alkaline diuresis and the plasma bicarbonate will start to normalize.

85

3. Consider specific fi treatments, e.g., surgery for an adrenal adenoma or spironolactone for hyperaldosteronism. 4. Other: a. Hydrochloric acid: rarely used. b. Acetazolamide: increases bicarbonate loss, but only if GFR is adequate. c. RRT: in patients with severe cardiac or renal disease, RRT may assist volume and electrolyte correction. Standard replacement fl fluids will need modifi fication as they contain bicarbonate or its precursor lactate.

References 1. Stewart PA. Modern quantitative acid-base chemistry. Can J Pharmacol. 1983; 61: 1444–1461. 2. Story DA. Bench-to-bedside review: A brief history of clinical acid-base. Crit Care. 2004; 8: 253–258. 3. Kellum JA. Determinants of blood pH in health and disease. Crit Care. 2000; 4: 6–14. 4. Kaplan LJ, Frangos S. Clinical review: Acid-base abnormalities in the intensive care unit. Crit Care. 2005; 9: 198–203. 5. Morgan TJ. Clinical review: The meaning of acidbase abnormalities in the intensive care unit— effects of fl fluid administration. Crit Care. 2005; 9: 204–211. 6. Morgan TJ. What exactly is the strong ion gap, and does anybody care? Crit Care Resusc. 2004; 6: 155– 166. 7. Figge J, Jabor A, Kazda A, Fencl V. Anion gap and hypoproteinaemia. Crit Care Med. 1998; 26: 1807– 1810. 8. Fencl V, Jabor A, Kazda A, Figge J. Diagnosis of metabolic acid-base disturbances in critically ill patients. Am J Resp Crit Care Med. 2000; 162: 2246–2251. 9. Story DA, Poustie S, Bellomo R. Estimating unmeasured anions in critically ill patients: anion gap, base deficit fi and strong ion gap. Anaesthesia. 2002; 57: 1102–1133. 10. Kaplan LJ, Kellum JA. Initial pH, base deficit, fi lactate, anion gap, strong ion difference, and strong ion gap predict outcome from major vascular injury. Crit Care Med. 2004; 32: 1120–1124. 11. Smith I, Kumar P, Molloy S, et al. Base excess and lactate as prognostic indicators for patients admitted to intensive care. Intensive Care Med. 2001; 27: 74–83. 12. De Backer D. Lactic acidosis. Intensive Care Med. 2003; 29: 699–702.

86 13. Bellomo R, Ronco C. The pathogenesis of lactic acidosis in sepsis. Curr Opin Crit Care. 1999; 5: 452–457. 14. Stacpoole PW, Wright EC, Baumgartner TG, et al. for the DCA-Lactic acidosis Study Group: Natural history and course of acquired lactic acidosis in adults. Am J Med. 1994; 97: 47–54. 15. Husain FA, Martin MJ, Mullenix PS, et al. Serum lactate and base defi ficit as predictors of mortality and morbidity. Am J Surg. 2003; 185(5): 485–491.

S. Blakeley 16. Levraut J, Grimaud D. Treatment of metabolic acidosis. Curr Opin Crit Care. 2003; 9: 260– 265. 17. Levraut J, Ciebiera JP, Jambou P, et al. Effect of continuous venovenous hemofiltration fi with dialysis on lactate clearance in critically ill patients. Crit Care Med. 1997; 25(1): 58–62. 18. Galla JH. Metabolic alkalosis. J Am Soc Nephrol. 2000; 11: 369–375.

Index

A N-Acetylcysteine, 17, 28, 36 N Acid-base disturbances. See also Acidosis; Alkalosis traditional versus physiochemical approach to, 81–84 Acidosis, 22, 39 lactic, 83–84 metabolic, 60, 82, 83, 84 Acute kidney injury (AKI), 19–25 causes of, 20–22 investigation of, 23, 24 complications of, 22–23 defi finition of, 19 incidence and outcome of, 19–20 Acute tubular necrosis (ATN), 3, 20, 22 casts in, 6, 23 imaging of, 7–9 as oliguria cause, 27 as renal failure cause, 7, 21, 26, 27–28 urea-to-creatinine ratio in, 2–3 Adenosine agonists, 28 Alcohol, as rhabdomyolysis cause, 39 Alkalosis, metabolic, 74, 75, 82, 84–85 Allopurinol, 15 Aminoglycosides, nephrotoxicity of, 16, 33 Ammoniagenesis, 75 Anaphylaxis, dialysis-related, 67 Anemia, acute kidney injuryrelated, 22, 24 Anesthesia, effect on renal function, 33

Aneurysms, abdominal, 22, 35 Angiotensin, 2 Angiotensin-converting enzyme inhibitors (ACEIs), 14, 16, 33 Angiotensin receptor blockers, nephrotoxicity of, 16 Anion gap, 81, 82, 83 Anticoagulation, in renal replacement therapy, 61–63 Antidiuretic hormone (ADH), 4, 80 Anuria, 4, 19, 27 Aprotinin, as acute renal failure risk factor, 34 Aspartate transaminase, 38 Azathioprine, 68 Azotemia, 42 B Bacteriuria, 5 Bicarbonate, 40, 51, 60, 73, 83–84, 84, 85 Biopsy, renal for acute renal failure diagnosis, 27 “poor man’s,” 3 for vasculitis diagnosis, 43 Blood flow, renal effect of prostaglandins on, 14 regulation of, 33 in rhabdomyolysis, 38, 39–40 C Calcifi fication, heterotopic, 39 Calcium. See also Hypercalcemia; Hypocalcemia as hyperkalemia treatment, 73

Calcium channel antagonists, 17 Calculi, ureteric, imaging studies of, 9–10 Cardiac arrest, hyperkalemiarelated, 71, 73 Cardiac output, 29 Cardiac surgery, as acute renal failure risk factor, 34–35 Casts, 6, 23, 26, 39 Cation exchange resins, 73 Central pontine myelinolysis, 79 Chemical testing, of urine, 4–5 Chloride depletion, 82, 83 Coagulopathy, therapeutic plasma exchange-related, 50 Cockroft and Gault formula, for creatinine clearance, 3 Compartment syndromes, 20, 34, 38–39, 41 Complement, 44, 46 Compression injuries, as rhabdomyolysis cause, 38 Computed tomography (CT), renal, 7, 9–11 Contrast agents, nephrotoxicity of, 10, 11, 13, 16–17, 27–28, 36 Corticosteroids, 68 Creatine kinase, 38 Creatinine, 2–3 as acute kidney injury marker, 19 renal failure-related increase in, 24 Creatinine clearance, 3 Crush injuries, as rhabdomyolysis cause, 38 Cyclooxygenase inhibitors, 15 Cyclosporin, 68

87

88 D Daclizumab, 69 Dextrose, 17, 73 Diabetes insipidus, nephrogenic, 76 Diabetes mellitus, 6, 33, 34 Dialysis optimal dose in, 65–67 peritoneal, 64–67 principles of, 64 as renal vasculitis treatment, 44 for urinary myoglobin reduction, 39–40 Dialysis equilibrium syndrome, 67 Diethylene triamine pentaacetic acid (DTPA) studies, 7, 10 Digoxin, toxicity of, 73 1,25-Dihydroxyvitamin D3, 1 Disseminated intravascular coagulation, 46–47 Diuretics as acute renal failure prophylaxis, 34, 36 as acute renal failure treatment, 36 loop, 15, 17, 27–28 nephrotoxicity of, 16 Dopamine, as renal failure prophylaxis, 36 Dopamine agonists, 28 Drugs. See also names of specific fi drugs as hypokalemia cause, 74 impaired renal clearance of, 23–24 nephrotoxicity of, 14–18, 23, 33–34, 38, 39 as rhabdomyolysis cause, 38, 39 E Edema pulmonary, 43 renal, 9 Electrocardiography in hyperkalemia, 71–72 in hypokalemia, 75 Electrolyte disturbances. See also specific fi electrolyte disturbances acute kidney injury-related, 22 Encephalopathy, uremic, 22 Enteral support, in critically ill patients, 29 Eosinophilia, 24 Erythropoietin, 1, 22 Excretion, urinary, 1

Index F Familial hypokalemic periodic paralysis, 74 Fasciotomy, 38 Fluid composition, of the body, 1, 2 Fluid resuscitation, in acute renal failure patients, 28–29 G Glomerular filtration, fi cessation of, 33 Glomerular filtration fi rate (GFR), 2 in acute kidney injury, 19 assessment of, 3 in metabolic alkalosis, 85 Glomerulonephritis, 6, 9, 26 Glucose control, tight, 29, 36 Glycosuria, renal, 5 Goodpasture’s syndrome, 9 H Hematuria, 4, 26, 42 Hemodiafiltration, fi 64 continuous venovenous, 59 Hemodialysis, 64 complications of, 67 continuous, 57–63 as hyperkalemia treatment, 74 intermittent, 52, 54, 60 Hemofi filters, 50 Hemofi filtration, 52, 64 continuous venovenous, 52, 57, 59 high-volume, 53 prophylactic, 29 for urinary myoglobin reduction, 39–40 Hemofi filtration machines, 58, 59–60 Hemolytic uremic syndrome, 46, 47 Hemorrhage, gastrointestinal, 23 Henoch-Schönlein purpura, 43 Heparin, 61–62 Homeostasis, role of the kidney in, 1 Hypercalcemia, 24 Hyperglycemia, 22 Hyperkalemia, 16, 22, 71–73 Hypernatremia, 79–80 Hyperphosphatemia, 22, 24, 39 Hypertension, 13, 42 malignant, 47

Hypocalcemia, 39, 50 Hypokalemia, 50, 74–76, 82, 85, 8575, 73076 Hypomagnesemia, 75 Hyponatremia, 22, 77–79, 79 Hypoperfusion, renal, 9, 20.6 Hypotension acute renal failure-related, 26, 29 anesthesia-related, 33 dialysis-related, 67 as postoperative renal failure cause, 33 prerenal failure-related, 20 relative, 36 in surgical patients, 33 therapeutic plasma exchangerelated, 50 Hypovolemia, 21, 49, 85 I Imaging, of acute renal failure, 7–13. See also Computed tomography (CT); Magnetic resonance angiography (MRA); Magnetic resonance imaging (MRI); Scintigraphic imaging diagnostic algorithm for, 12 Immunosuppression, renal failurerelated, 22 Immunosuppressive therapy, in renal transplant recipients, 68–69 Infection in renal transplant recipients, 69 as rhabdomyolysis cause, 38 Inotrope therapy, for acute renal failure, 29 Insulin therapy, 36, 73 Intensive care unit (ICU) patients acute kidney injury in, 19 acute renal failure in, 26 intrinsic renal failure in, 20, 21 obstructive renal failure in, 22 Inulin clearance, 3 Ischemia, renal, 33 K Kidney hydronephrotic, 9 normal, ultrasound imaging of, 7, 8 normal functions of, 1 polycystic, 7

Index L Lactate, 60, 82, 83 Lactate dehydrogenase, 38 Left ventricular end diastolic pressure (LVEDP), 29 M Magnetic resonance angiography (MRA), renal, 10–11 Magnetic resonance imaging (MRI), renal, 7 Mannitol, 28, 34 Mean arterial pressure (MAP), 29, 33 Mercaptoacetyltriglycerine (MAG3) studies, 7, 8, 9, 10, 11 Microangiopathy, thrombotic, 46–47 Mineral disturbances, acute kidney injury-related, 22 Mycophenolate mofetil, 69 Myoglobin, in urine, 39–40 N Natriuretic peptides, 28, 36 Nephritic syndrome, 42–43 Nephritis interstitial, 6, 9, 15, 33–34 systemic lupus erythromatosusrelated, 45 Nephrotic syndrome, 5, 11, 16 Neutrophilia, 24 Nonsteroidal anti-infl flammatory drugs, nephrotoxicity of, 14–16, 33 Nutrition/nutritional support, 29, 67 O Oliguria, 4, 27, 34 Oxygen consumption, renal, 33 P Peritoneal dialysis, 64–67 Plasma exchange, therapeutic, 49–50, 59 Plasma volume, calculation of, 49 Polyclonal antibodies, 69 Polyuria, 4 Postrenal failure, 7 Potassium. See also Hyperkalemia; Hypokalemia renal excretion of, 71, 73 Potassium supplementation, 76

89 Pregnancy, in systemic lupus erythromatosus patients, 46 Prerenal failure, 7, 21 as acute kidney injury cause, 20 defi finition of, 20 differentiated from intrinsic renal failure, 23, 24 Prostacyclin, 63 Prostaglandins, renal, 14–15 Proteinuria, 4–5 Pseudohyperkalemia, 72–73 Pseudohyponatremia, 77 Purpura, thrombotic thrombocytopenic, 46, 47 R Red blood cells, in urine, 6 Renal artery, dissection or occlusion of, 10–11, 13, 16 Renal disease, end-stage, renal replacement therapy for, 64–70 Renal dysfunction. See also Acute kidney injury (AKI) RIFLE classifi fication system for, 19, 20 Renal failure acute acute kidney injury-related, 19 diagnosis of, 26, 35–36 differentiated from chronic renal failure, 7 drug-related, 14–18 imaging of, 7–13 laboratory investigations of, 26–27 medical management of, 26–32 multisystem causes of, 42–48 pathophysiology of, 33 prevention of, 27–30, 36–37 rhabdomyolysis-related, 38 risk factors for, 26, 27, 33–34 supportive strategies for, 28–29 in surgical patients, 33–37 treatment of, 35–36 chronic differentiated from acute renal failure, 7 imaging of, 8 intrinsic, 20–21 differentiated from prerenal failure, 23, 24 postrenal or obstructive, 22

Renal function abrupt and sustained decrease in. See Acute kidney injury (AKI) assessment of, 1–6, 26 Renal index (RI), 9 Renal injury. See also Acute kidney injury (AKI) drug-induced, 14–18 Renal replacement therapy, 28, 51–56. See also Dialysis; Hemodialysis; Renal transplantation for acute kidney injury, 20 anticoagulation in, 62 basics of, 51–52 continuous, 51, 52, 53, 54, 57–59, 61 for hyperkalemia, 74 effect on lactic acidosis, 84 for end-stage renal disease, 64–70 hemofi filters in, 60 hybrid, 52 indications for, 53–54 intermittent, 51, 53, 54 replacement and dialysis fluid fl in, 59–60 selection of dosage and mode in, 54–55 technical aspects of, 57–63 vascular access in, 52, 60–61 for volume overload, 22 Renal transplantation, 67–69 Renal vein, thrombosis of, 11, 13 Renin, 1, 2 Respiratory failure, 43 Resuscitation, in surgical patients, 36 Rhabdomyolysis, 28, 38–41 diagnosis of, 38–39 drug-related, 14 treatment of, 40 RIFLE system, for renal dysfunction classification, fi 19, 20 S Salbutamol, 73 Scintigraphic imaging diethylene triamine pentaacetic acid (DTPA) studies, 7, 10 mercaptoacetyltriglycerine (MAG3) studies, 7, 8, 9, 10, 11 of ureteric obstruction, 10

90 Sepsis dialysis-related, 67 treatment of, 53 Sodium bicarbonate, 40, 73, 84 Statins, as rhabdomyolysis cause, 39 Strong ion difference (SID), 81, 83 Surgical patients acute kidney injury in, 20 acute renal failure in, 33–37 Syndrome of inappropriate antidiuretic hormone secretion (SIADH), 77, 78, 79 Systemic lupus erythromatosus, 45–46 T Tacrolimus, 68 Tamm-Horsfall protein, 40 Thrombocytopenia, 24 Toxins as rhabdomyolysis cause, 38 uremic, retention of, 22 Transurethral resection of the prostate (TURP) syndrome, 77 Tubulointerstitial disease, 26 Tumor lysis syndrome, 14 U Ultrafi filtration, slow continuous, 53, 59 Ultrasound, renal, 7, 23, 27 of normal kidneys, 7, 8

Index of renal vein thrombosis, 11 of ureteric obstruction, 9 Urea accumulation of, 22, 24 measurement of, 2 Urea-to-creatinien ratio, 2–3 Uremia, 22–23 Uremic patients, cardiovascular risk factors in, 65 Ureteric obstruction, imaging studies of, 9–10 Urinalysis, 3–6 for acute kidney injury evaluation, 23, 24 for acute renal failure evaluation, 26–27 for glomerulonephritis/acute interstitial nephritis differentiation, 9 in surgical patients, 35 for systemic lupus erythromatosus evaluation, 45 Urine alkalinization of, 14, 40, 41 appearance of, 3 chemical testing of, 4–5 microscopy of, 5–6 in rhabdomyolysis, 39, 40 osmolality of, 23, 24, 80 specifi fic gravity of, 3, 24 volume of, 3–4, 27 Urine output, in acute kidney injury, 19–20 Urolithiasis, 27

Urological surgery, as acute renal failure risk factor, 35 V Vascular surgery, as acute renal failure risk factor, 34 Vasculitis as acute renal failure cause, 26, 42–45 clinical presentation of, 42–43 etiology of, 42 treatment of, 43–44 Wegener’s renal, 44 Venography, of renal vein thrombosis, 11 Volume depletion as acute renal failure cause, 26 assessment and correction of, 29 as postoperative renal failure cause, 33 prerenal failure-related, 21 Volume expansion, intravascular, 40 Volume overload, acute kidney injury-related, 22 W Wegener’s granulomatosis, 9 Wegener’s renal vasculitis, 44 White blood cells, in urine, 5–6 X X-rays chest, 23, 44 renal, 7