Handbook of Common Problems in Clinical Nephrology [1 ed.] 9781617280733, 9781608768288

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Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Handbook of Common Problems in Clinical Nephrology, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook Central,

Copyright © 2010. Nova Science Publishers, Incorporated. All rights reserved. Handbook of Common Problems in Clinical Nephrology, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook

NEPHROLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES

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HANDBOOK OF COMMON PROBLEMS IN CLINICAL NEPHROLOGY

No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services.

Handbook of Common Problems in Clinical Nephrology, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook

NEPHROLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES Nephrology - Dialysis - Transplantation Endre Krüger and Kelemen Hahn (Editors) 2009. ISBN: 978-1-60741-736-1 Nephrology - Dialysis - Transplantation Endre Krüger and Kelemen Hahn (Editors) 2009. ISBN: 978-1-61668-124-1 (Online book)

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Handbook of Common Problems in Clinical Nephrology Micah L. Thorp 2010. ISBN: 978-1-60876-828-8

Handbook of Common Problems in Clinical Nephrology, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook

NEPHROLOGY RESEARCH AND CLINICAL DEVELOPMENTS SERIES

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HANDBOOK OF COMMON PROBLEMS IN CLINICAL NEPHROLOGY

MICAH L. THORP

Nova Science Publishers, Inc. New York

Handbook of Common Problems in Clinical Nephrology, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook

Copyright © 2010 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. The Publisher shall not be liable for any special, consequential, or exemplary damages resulting, in whole or in part, from the readers‘ use of, or reliance upon, this material.

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Independent verification should be sought for any data, advice or recommendations contained in this book. In addition, no responsibility is assumed by the publisher for any injury and/or damage to persons or property arising from any methods, products, instructions, ideas or otherwise contained in this publication. This publication is designed to provide accurate and authoritative information with regard to the subject matter covered herein. It is sold with the clear understanding that the Publisher is not engaged in rendering legal or any other professional services. If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. LIBRARY OF CONGRESS CATALOGING-IN-PUBLICATION DATA Thorp, Micah L. Handbook of common problems in clinical nephrology / Micah L. Thorp. -- 1st ed. p. ; cm. Includes bibliographical references and index. ISBN:  (eBook) 1. Kidneys--Diseases--Handbooks, manuals, etc. 2. Nephrology--Handbooks, manuals, etc. I. Title. [DNLM: 1. Kidney Diseases--diagnosis--Handbooks. 2. Kidney Diseases--therapy-Handbooks. WJ 39 T517h 2009] RC903.T48 2009 616.6'1--dc22 2009048912

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CONTENTS

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Preface

vii

Chapter 1

Elevated Serum Creatinine

1

Chapter 2

Evaluation of Proteinuria

7

Chapter 3

Evaluation of Hematuria

11

Chapter 4

Chronic Kidney Disease Management

17

Chapter 5

Acute Kidney Injury

51

Chapter 6

Electrolyte Disorders

61

Chapter 7

Acid/Base Disorders

87

Chapter 8

Hypertension

97

Chapter 9

Pregnancy and the Kidney

105

Chapter 10

Nephrolithiasis

113

Chapter 11

Renal Replacement Therapies

119

Appendix 1.

131

Appendix 2.

133

Appendix 3.

135

Appendix 4.

143

Index

149

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PREFACE

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Common Problems in Clinical Nephrology has been written to assist clinicians in assessing and treating problems that arise in the course of patient care. The recommendations are general guidelines which may or may not apply to a particular patient. Individualization of drugs, dosages, assessments, tests and treatment schedules should be considered when treating specific patients. The reader is advised to carefully consult instruction and information included in the package insert of any prescribed medication and to consult the references provided at the end of each chapter.

Handbook of Common Problems in Clinical Nephrology, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook

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Chapter 1

ELEVATED SERUM CREATININE

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Step 1: Assess the validity of test. Is the elevation due to kidney dysfunction or something else? Step 2: Quantify the severity of kidney dysfunction. What is the glomerular filtration rate? Step 3: Investigate causes of kidney disease. Any abnormalities on renal ultrasound, urinalysis, history or physical examination?

EVALUATION OF AN ELEVATED SERUM CREATININE Serum creatinine is one of the most common assays measured by primary care physicians. Generally correlated with renal function, it offers a rapid, effective test. Knowing what to do with the results of an elevated study is, however, less clear. Few guidelines regarding the appropriate workup or approach to an elevated creatinine are available. The gold standard measurement of kidney function is the glomerular filtration rate (GFR). [1] Serum creatinine is a simple and effective means of estimating GFR, but must be considered in the context of other clinical factors. Elevations of serum creatinine are thus important within the context of their relationship with GFR, and should be evaluated with this in mind. This chapter offers one approach serum creatinine evaluation.

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Micah L. Thorp

PHYSIOLOGY Serum creatinine is an ideal marker of glomerular filtration when it has constant generation and excretion. [2] Alterations in creatinine production and excretion can affect clinical correlations between serum levels and glomerular filtration. Further complicating matters, 5 to 10% of excreted creatinine is secreted in the proximal tubule, rather than being filtered through the glomerulus. [3] Thus, changes in secretion can raise or lower serum levels without changes in filtration. Some common alterations include:

Condition

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Cimetidine or Trimethoprim Therapy Muscle wasting Prolonged vigorous exercise Plasma ketosis Ingesting large amounts of protein

Change in Serum Creatinine Increase Decrease Increase Increase Increase

Mechanism Inhibits urinary creatinine secretion Decreased creatinine generation Increased creatinine production Interference with picric acid assay for creatinine Transient increase in creatinine generation

ESTIMATE GFR In order to use the serum creatinine to estimate GFR a variety of methods to estimate GFR have been developed. The National Kidney Foundation currently recommends that the estimation equation from the Modification of Diet in Renal Disease study be used, especially when the GFR is less than 60 mL/min/1.73m2. [4,5] (Figure 1) Among patients with GFRs greater than 60 mL/min/1.73m2 the MDRD equation may underestimate the true GFR. [6] Other equations such as CockcoftGault may be more appropriate. (Figure 2). [7 ]Online GFR calculators are available. The NKF website (www.kidney.org) has downloadable calculators for PCs and PDAs.

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Elevated Serum Creatinine

3

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EVALUATION Among patients who have an elevated serum creatinine and a decreased eGFR, the clinician should complete a history and physical, check renal ultrasound and urinalysis. These tests should be used to determine whether renal insufficiency is acute or chronic, and determine the underlying etiology. A history should (at the very least) include questions about drug use (including over-the-counter, prescription and herbal products), edema, nocturia, overt hematuria, elevated blood pressure, family history of kidney disease, diabetes and polyuria. As with any medical history, physical examination should be used to help confirm potential diagnoses identified. Physical examination should focus on signs of vasculitis, lupus, diabetes, endocarditis and hypertension. Urinanalysis can detect proteinuria, hematuria and an active urinary sediment. When the urinanalysis is negative it is helpful, as it suggests the patient may have an extrarenal etiology for the rise in serum creatinine. Proteinuria (in significant quantities) is usually indicative of glomerular disease. Hematuria may be of glomerular or urological origin. An active urinary sediment (cellular casts) indicates active glomerular disease. Active urine sediment should prompt nephrology referral as it may be indicative of glomerulonephritis. In addition to nephrology referral, physicians should order vasculitis studies (Antineutrophilic cytoplasmic antibody, C3, C4, cryoglubulins, antineutrophilic antibody, etc.) and possibly urine protein electrophersis. Renal ultrasound reports should include renal sizes, echogenicity and the presence of absence of hydronephrosis. Patients with hydronephrosis should be referred to urology in a timely manner. Large kidneys are often indicative diabetic nephropathy, focal segmental glomerular schlerosis or myeloma kidney. Small kidneys are often suggestive of longstanding renal disease. [8] If evidence of obstruction or post-renal disease the patient should be referred to a urologist. Patients with obstructive renal disease often present with hydronephrosis on renal ultrasound, isosthenuria (urine specific gravity approximately 1.010), and bland urinary sediment. If hematuria alone is present, consider starting with a referral to a urologist. Discerning between hematuria of glomerular origin and other sources may require cystoscopy, intravenous pylorography or other imaging studies. Intrarenal hematuria will often present with increased numbers of dysmorphic red blood cells, while extrarenal disease often will not. [9] Bladder cancer is a common etiology of hematuria among patients over 50 years of age. [10] Ruling this out as a part of working up hematuria is always the first order of buisiness.

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Micah L. Thorp

Patients with significantly elevated proteinuria are likely to have an underlying glomerular disease. Chapter 2 discusses the workup of proteinuria and can be consulted for the appropriate tests to evaluate proteinuria. One of the most common causes of renal insufficiency and proteinuria is diabetic nephropathy. Aside from proteinuria evidence of diabetic nephropathy includes normal to large kidneys on ultrasound, a lack of an active urine sediment or hematuria. Patients with symptoms consistent with these findings should be managed appropriately (control blood sugars, control blood pressure and prescribe ACEI/ARB). [11] Patients with significant proteinuria who do not have diabetes should be referred to a nephrologists and UPEP and ANA should be ordered. Elevated Serum Creatinine

Consider surreptitious reasons for increase: cimetidine, trimethoprim, large protein ingestion, etc.

If present, make change and recheck

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Calculate GFR

History and Physical Examination Urinanalysis Renal Ultrasound

Hydronephrosis Isosthenuria Bland urine sediment

Urology referral

Active urine sediment (cellular casts)

Hematuria without proteinuria or active urine sediment

Proteinuria >2gm without DM

DM, proteinuria GFR > 30 Nl/large kidneys on US

GFR < 30

Order: compliments, ANCA, ANA, UPEP, Nephrology referral

Urology referral

Order: ANA, UPEP, Nephrology referral

Control BP Control DM Start ACEI/ARB

Nephrology referral

Adapted from: Thorp ML. An Approach To The Evaluation Of An Elevated Serum Creatinine. The Internet Journal of Internal Medicine. 2005 Volume 5 Number 2.

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Elevated Serum Creatinine

5

Patients with a GFR less than 30 mL/min/1.73m2 should prompt input from a nephrologist, either in the form of a referral or review.

REFERENCES

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[1]

K/DOQI clinical practice guidelines for chronic kidney disease: evaluation, classification, and stratification. Kidney Disease Outcome Quality Initiative. Am J Kidney Dis. 39(2):S1-S246. 2002. [2] Bjornsson TD. Use of serum creatinine concentrations to determine renal function. Clin Phamacokinet. 4:200-222. 1979. [3] Walser M. Assessing renal function from creatinine measurements in adults with chronic renal failure. Am J Kidney Dis. 32(1):23-31. 1998. [4] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification, Part 1, Executive Summary. Am J of Kidney Dis 39(suppl 1):S17-S31. 2002. [5] Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999. [6] Lin J. Knight EL, Hogan ML, Singh AK. A comparison of prediction equations for estimating glomerular filtration rate in adults with kidney disease. J Am Soc Nephrol. 14:2573-2580. 2003. [7] Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. Nephron 16:31-41. 1976. [8] Nishimura M, Terawaki H, Hoshiyama Y, Joh K, Hamaguchi K, Yamada K. Renal ultrasonography is useful in evaluating diabetic renal failure. Clin Nephrol. 59(3):174-9. 2003. [9] McCarthy JJ. Outpatient evaluation of hematuria: locating the source of bleeding. Postgrad Med. 101(2):125-8. 1997. [10] Mohammad KS, Bdesha AS, Snell ME, Witherow RO, Coleman DV. Phase contrast microscopic examination of urinary erythrocytes to localize source of bleeding: an overlooked technique? J Clin Pathol. 46(7):642-5. 1993. [11] Bakris GL, Williams M, Dworkin L, Elliott WJ, Epstein M, Toto R, Tuttle K, Douglas J, Hsueh W, Sowers J: Preserving renal function in adults with hypertension and diabetes: a consensus approach. Am J Kid Dis 36:646661, 2000.

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Chapter 2

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EVALUATION OF PROTEINURIA Step 1. Evidence of proteinuria (positive dipstick, urine protein/creatinine ratio > .2, 24 hour collection > 200 mg/dL) Step 2. Quantify via urine protein/creatinine ratio or via 24 hour collection. Greater than 200 mg/dL is considered abnormal. If an initial measurement suggests proteinuria, but quantification is < 200 mg/dL, patient likely has transient proteinuria. Step 3. If greater than 200 mg/dL look for other evidence of renal disease (hematuria, findings on ultrasound, etc.). This should include calculation of MDRD GFR, urinanalysis and possibly renal ultrasound. If evidence of other renal disease, consider nephrology referral. Ensure patient is not taking non steroidal anti-inflammatory medication. Step 4. For patients with 200 to 2000 mg/dL and no further evidence of renal disease requantify in 2-3 months. If repeat level is < 200 mg/dL, proteinuria was likely transient. If still present, workup for orthostatic proteinuria and if present, reassure. Continue to monitor renal function, quantify proteinuria and check urinanalysis every 6 months. Control blood pressure, consider use of an angiotension converting enzyme inhibitor or angiotension receptor blocker. Step 5. If diabetic with evidence of end organ disease (retinopathy, neuropathy, etc.) and no other evidence of renal disease and proteinuria quantified between 200 mg/dL and 5000 mg/dL, patient likely has diabetic nephropathy. Ensure patient is taking and ACEI or ARB, control blood pressure and control blood sugars.

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8

Micah L. Thorp Step 6. Patients with > 5000 mg/dL of proteinuria are highly likely to have glomerular source. Nephrology referral is indicated.

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EVALUATION OF PROTEINURIA Proteinuria is usually detected by urine dipstick testing in the outpatient setting, and results are often confounded by alkaline or concentrated urine, or if the dipstick is immersed too long. [1,2] Because dipstick testing detects albumin much more accurately than it detects immunoglobulins, even negative dipstick test results should not be used to rule out the presence of heavy or light chains in the urine. [3] Quantitative measures of protein excretion are obtained through 24-hour urine collection or by protein/creatinine ratio. Creatinine concentration should also be obtained in 24-hour urine collection to confirm that the sample is adequate. Because creatinine excretion levels correspond to muscle mass, it is possible to estimate the amount of creatinine that should be present in a 24-hour sample, and thus determine the appropriateness of the collection. Normal creatinine excretion for men is 16 to 26 mg/kg/d and women 12 to 24 mg/kg/d. Creatinine concentrations outside of these ranges suggest an inadequate collection. Routine screening for proteinuria in otherwise healthy patients is not appear a cost-effective means of detecting chronic kidney disease or of decreasing mortality. However, routine screening is appropriate in patients who have hypertension, diabetes, or coronary artery disease (CAD). [4-6] Routine laboratory tests to obtain before initiating treatment in hypertensive patients are creatinine levels or the corresponding estimated glomerular filtration rate (GFR); optional tests include measurement of urinary albumin excretion or albumin/creatinine ratio. Obtain yearly tests for the presence of microalbuminuria (urinary albumin excretion 30 mg/24 h) in patients who have had type 1 diabetes longer than 5 years and in those with type 2 diabetes at diagnosis. In patients with CAD or who are at high risk for it, obtain spot urine albumin-tocreatinine ratio or a total protein-to-creatinine ratio, as well as estimation of GFR by serum creatinine and prediction equations. [7] Patients at increased risk of developing chronic kidney disease should undergo testing for markers of kidney damage and estimation of GFR.

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Evaluation of Proteinuria

9

Etiology of Proteinuria Glomerular Primary or secondary glomerulopathy Gold Penicillamine

Tubular Hypertensive nephroschlerosis Tubulointerstitial disease

Overflow Multiple Myeloma Amyloidosis Hemoglobinuria

Evidence of proteinuria

Quantify via 24 hour collection or protein/creatinine ratio Proteinuria > 5000 mg/dL Likely glomerular source, consider nephrology referral

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Evaluate for other evidence of renal disease (UA, ultrasound, GFR)

Proteinuria < 200mg/dL Nondiabetic, no other evidence of renal disease

Proteinuria 2005000 mg/dL Diabetic, no other evidence of renal disease

Proteinuria 2002000 mg/dL No other evidence of renal disease

Proteinuria 2000-5000 mg/dL Non diabetic, no other evidence of renal disease

Transient proteinuria, no further workup required

Likely diabetic nephropathy. Control blood sugar, blood pressure, use ACEI/ARB, monitor creatinine

Possible renal disease. Workup for orthostatic proteinuria. Ensure patient not taking NSAIDs, control blood pressure, monitor creatinine.

Possible glomerular etiology. Consider nephrology referral.

Adapted from: Thorp ML, A stepwise approach to evaluating proteinuria. Patient Care. 39(2):37-39. 2005.

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PHYSIOLOGY Normally urine protein is composed of albumin (40%), immunoglobulins (20%), and Tamm-Horsfall mucoproteins (40%). Pathologically high levels of proteinuria are categorized by the mechanism involved in the cause. Overflow proteinuria is the result of increased production of low-molecular-weight proteins; common overflow causes are monoclonal gammopathies and amyloidosis. Glomerular proteinuria results from increased glomerular permeability to protein that can be caused by diabetes, lupus, and other glomerulopathies. Tubular proteinuria results from diminished proximal tubular reuptake of low-molecularweight proteins, most commonly from tubulointerstitial disease.

REFERENCES [1]

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[2]

[3]

[4] [5] [6]

[7]

Garg AX, Kiberd BA, Clark WF, et al. Albuminuria and renal insufficiency prevalence guides population screening: results from the NHANES III. Kidney Int. 2002;61:2165-2175. Beethan R, Cattell WR. Proteinuria: pathophysiology, significance and recommendation for measurement in clinical practice. Ann Clin Biochem.1993;30:425-434. Chobanian AV, Bakris GL, Black HR, et al. Seventh report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. Hypertension. 2003;42:1206-1252. Boulware LE, Jaar BG, Tarvar-Carr ME, et al. Screening for proteinuria in US adults: a cost-effectiveness analysis. JAMA. 2003;290:3101-3114. Standards of medical care in diabetes. Diabetes Care. 2004;27(suppl 1):S15-S35. Sarnak MJ, Levey AS, Schoolwerth AC, et al. Kidney disease as a risk factor for development of cardiovascular disease: a statement from the American Heart Association Councils on Kidney in Cardiovascular Disease, High Blood Pressure Research, Clinical Cardiology, and Epidemiology and Prevention. Circulation. 2003;108:2154-2169. Laffeyette RA, Perrone RD, Levey AS. Laboratory evaluation of renal function. In: Schrier RW, Gottschalk CW, eds. Diseases of the Kidney. Boston, Mass: Little Brown; 1996.

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Chapter 3

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EVALUATION OF HEMATURIA Step 1. Rule out/treat urinary tract infection (urinalysis, culture) Step 2. Rule out possible urological cancers (imaging studies, urine cytology, cystoscopy). Step 3. Assess for glomerular vs non-glomerular etiology (i.e. presence of dysmorphic rbcs suggests glomerular etiology). Step 4. If glomerular perform serological workup: ANCA, ANA, C3, C4, Hep C studies, cryoglobulins, spep and upep. Step 5. If non-glomerular etiology, consider further imaging studies and nephrolithiasis workup.

EVALUATION OF HEMATURIA The potential etiologies of hematuria are many and range from the rather insignificant to the potentially lethal. Hematuria is often classified as either microscopic or macroscopic. Macroscopic hematuria referes to hematuria visible to the naked eye. Patients often confuse dark or red urine with bloody urine, so a careful analysis of whether or not color changes are due to blood or not is often necessisary. Microscopic hematuria refers to the presence of blood visible only under the microscope. Most authorities suggest that greater than 3-5 red blood cells per high power field is abnormal and should trigger further testing. [1] A number of substances can cause urinary discoloration that mimics macroscopic hemoglobinuria. When patients present with symptoms of hemoglobinuria, and no evidence of red blood cells can be found, a good history may reveal clues to another etiology. [2]

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Hematuria Myoglobinuria Hemoglobinuria Porphyria Foods Beets Rhubarb Blackberries

Micah L. Thorp Causes of Urinary Discoloration Medications Phenacetin Rifampin Dilantin Methyldopa Levodopa Doxorubicin

The first evidence of hematuria frequently comes from urinalysis dipstick testing. It should be understood that a dipstick test alone is not enough to confirm the diagnosis of hematuria, but rather microscopic analysis must be undertaken as dipstick testing may be only indicative of hemaglobinuria or myoglobinuria. [1] In those instances where a dipstick test is strongly positive, but no red blood cells are identified under the microscope, CPK, LDH and bilirubin can help clarify whether or not the patient has rhabdomyolysis (causing myoglobinuria and elevated CPK) or hemolysis (causing hemoglobinuria and increased LDH and bilirubin). Once the diagnosis of hematuria has been confirmed, infections should identified/treated or ruled out. Dipstick testing may reveal the presence of nitrates and leukocyte esterase which can be helpful to identify possible infections. White blood cells in the urine add a further clue. The ultimate diagnostic test, however, is a urine culture, which can not only identify the specific bacteria, but may provide further information to help identify the source of the infection and preferred antibiotics. [3] Aside from infection, the other diagnosis that should be aggressively excluded is cancer. Three approaches can be undertaken to identify kidney and urinary tract cancers, each of which has strengths and weaknesses. In the course of working up hematuria, the clinician must recognize that 1) most hematuria is not the result of cancer and 2) no single test perfectly identifies all cancers in the kidney/urological tract. There is no defined sequence of testing for malignancy in patients with hematuria and usually some combination of approaches is used. The most commonly undertaken initial test to identify cancer involves an imaging studies, which may include renal ultrasound (can identify kidney masses), CT (can also identify kidney masses) or intravenous pylography (identifies masses in the kidney and/or ureters). A second approach to identifying cancers involves urine cytology. Urine cytology is helpful in identifying superficial bladder cancers and cancer in situ. It is non-invasive and may pick up cancers missed by imaging

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Evaluation of Hematuria

13

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or cytoscopy. Finally, cystoscopy is the test of choice for possible bladder cancers. Cystoscopy is invasive, but should be considered in patients with risk factors for bladder cancer, including smoking, cyclophosphamide exposure, exposure to benzidine or other aromatic amines, schistosomiasis and pelvic irradiation. [4] Once both infections and cancers have been eliminated as possible sources for hematuria, it is important to attempt to distinguish whether the blood in the urine is from a glomerular or non-glomerular souce. This is evaluation is assisted by assessing whether or not red blood cells in the urine are dysmorphic or not. Dysmorphic cells indicate a potentially glomerular etiology, which should invoke testing for glomerulonephritis and other glomerular etiologies. Other signs of a glomerular etiology include proteinuria and the presence of cellular casts in the urine. When signs of a glomerular etiology are present, serological workup should be undertaken. The most definitive test for glomerular disease is a renal biopsy, which is usually preformed following serological studies. Non-glomerular causes of hematuria (excluding infections and cancers) include nephrolithiasis, trauma and bleeding disorders. The list is long (the following is merely a sampling), but can be used to begin asking the historical questions that will lead to a diagnosis. [5,6] Glomerular Glomerulonephritis IgA nephropathy Membranous GN Membranoproliferative GN Lupus Nephritis Cryoglobulinemia Anti-GBM disease Post-infectious GN Diabetic nephropathy Thin Basement Membrane Disease Alport‘s syndrome Intersitial nephritis

Non-Glomerular Bleeding disorders Nephrolithiasis Infection Prostatitis Cystitis Malignancy Trauma Malignant hypertension Hemorrhagic cystitis Papillary necrosis Renal infarct Polycystic kidney disease Medullary sponge kidney

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Micah L. Thorp

Urinalysis Confirmed RBCs in urine Infection

Treat, recheck uninalysis

Rule out cancer: urine cytology, imaging studies, urology referral

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Glomerular vs Non-Glomerular

Glomerular Cellular casts Dysmorphic RBCs Proteinuria

Non-Glomerular

Glomerulonephritis workup See Chapter 5

Stones – IVP Coagulation disorders – PTT/PT

If non-glomerular hematuria is identified, and an etiology is not readily apparent, the clinician should reconsider nephrolithiasis and cancer. Repeated urinalysis may be helpful as well to identify the transience of the underlying disorder.

REFERENCES [1] [2]

Rao PK, Jones JS. How to evaluate ‗dipstick microhematuria‘: What to do before you refer. Clev Clinic J of Med. 75(3):227-233. 2008. Grossfeld GD, Wolf JS Jr, Litwan MS, Hricak H, Shuler CL, Agerter DC, Carroll PR. Asymptomatic microscopic hematuria in adults: summary of the AUA best practice policy recommendations. Am Fam Physician. 2001 Mar 15;63(6):1145-54.

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Evaluation of Hematuria [3] [4] [5]

Yun EJ, Meng MV, Carroll PR. Evaluation of the patient with hematuria. Med Clin North Am. 2004 Mar;88(2):329-43. McDonald MM, Swagerty D, Wetzel L. Assessment of microscopic hematuria in adults. Am Fam Physician. 2006 May 15;73(10):1748-54. Cohen RA, Brown RS. Clinical practice. Microscopic hematuria. N Engl J Med. 2003 Jun 5;348(23):2330-8. Grossfeld GD, Carroll PR. Evaluation of asymptomatic microscopic hematuria. Urol Clin North Am. 1998 Nov;25(4):661-76.

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[6]

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Chapter 4

CHRONIC KIDNEY DISEASE MANAGEMENT

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Step 1. Step 2. Step 3. Step 4. Step 5.

Define (if possible) the chronicity of the underlying kidney disease. Estimate the glomerular filtration rate and stage the disease. Determine underlying etiologies and (if possible) treat them. Control blood pressure and avoid nephrotoxins. Consider possible metabolic effects of CKD (i.e. secondary hyperparathyroidism, anemia) , and if present, treat them. Step 6. Estimate rate of progression. Step 7. Prepare for renal replacement therapy.

CHRONIC KIDNEY DISEASE MANAGEMENT At the time of publication, it is estimated that some 20 million Americans suffer from chronic kidney disease (CKD). [1] A variety of adverse outcomes and conditions are associated with CKD, including cardiovascular disease, congestive heart failure [3] and premature death. Patients who survive the conditions associated with CKD develop end stage renal failure (ESRD) and subsequently require dialysis or transplantation. [2] The number of patients with ESRD in the United States is expected to double over the next decade, posing significant financial and logistical problems for health care systems in the United States. In an effort to decrease the burden of CKD, the National Kidney Foundation has established clinical practice guidelines to define, stratify and associate complications of CKD with the level of kidney function. The application of these guidelines will help primary care physicians identify patients with CKD, and subsequently manage these patients. [3]

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Micah L. Thorp

MEASURING GLOMERULAR FILTRATION RATE (GFR)

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The NKF guidelines revolve around measuring or estimating glomerular filtration rate (GFR). Direct measurement of GFR (such as inulin or iothalamate clearance) is too expensive and time consuming to use in most clinical settings. As a result, indirect estimates, either via creatinine clearance or equations to predict GFR are generally relied upon. While these tests are reliable, there are certain pitfalls clinicians should remember when applying them. Creatinine clearance often suffers from collection errors and tends to overestimate GFR when it is significantly decreased. [4] The Cockcroft-Gault equation was initially created to estimate creatinine clearance. [5] As a result, it tends to overestimate GFR in the same manner. Recently, a GFR prediction equation developed in the Modification of Diet in Renal Disease (MDRD) study has been found to be reliable when compared to the gold standard iothalamate GFR. [6] The equation is difficult to memorize, but is available on the internet at a variety of sites, and can be easily programmed into a calculator. Due to the equal or superior estimation of GFR provided by GFR prediction equations, they should be employed in place of creatinine clearance or creatinine clearance prediction equations when quantifying chronic kidney disease.

STRATIFYING CHRONIC KIDNEY DISEASE Once GFR has been established the NKF guidelines stratify patients into one of five groups (Table 1). [3] CKD is defined as ―structural or functional abnormalities of the kidneys, manifest by either pathological abnormalities or markers of kidney damage, including abnormalities in the compositions of the blood or urine or imaging tests‖ or ―a GFR < 60 mL/min/1.73m2 for > 3 months without kidney damage.‖ [3] Markers of kidney damage include proteinuria, abnormalities of the urinary sediment or abnormal radiological findings. The first two stages of CKD involve patients with evidence of kidney damage, but with a (potentially) normal GFR. Patients with GFRs less than 60 mL/min/1.73m2 are all classified as suffering from chronic kidney disease.

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MANAGING THE STAGES

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Physician managing patients with chronic kidney disease in stages 1 or 2 should focus on finding an underlying diagnosis and developing a treatment plan. A treatment plan should include treatment of comorbid conditions as well as the etiology of kidney disease. Comorbid conditions associated with chronic kidney disease include hypertension, hypercholesterolemia and cardiovascular disease. Slowing the progression of chronic kidney disease includes controlling diabetes, [7] hypertension [8] and the use of an angiotension converting enzyme inhibitor [9] or angiotension receptor blocker. As CKD advances to GFRs less than 60 mL/min/m2, physicians should additionally focus on the specific complications of CKD. These complications include the development of bone disease, anemia and protein malnutrition. Anemia develops among patients with CKD due to a relative deficiency of erythropoetin. [10] Bone disease occurs as a result of vitamin D deficiency and hyperparathyroidism. [11] Protein malnutrition may result from disturbances in protein and energy metabolism, hormonal disturbances and nausea and vomiting secondary to uremic toxicity. [12] National Kidney Foundation K/DOQI Stages of Chronic Kidney Disease Stage 1

GFR (mL/min) >90

2

60 – 89

3 4 5

30 – 59 15 – 29 3 months manifest by pathological abnormalities or markers of kidney damage in blood, urine or on imaging tests Kidney damage > 3 months manifest by pathological abnormalities or markers of kidney damage in blood, urine or on imaging tests

Available on the National Kidney Foundation website, www.kidney.org. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J of Kidney Dis 39(suppl 1):S120-S127. 2002.

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Micah L. Thorp

Bone disease in CKD may manifest as high bone turnover disease with high parathyroid hormone levels, or low turnover bone disease with low or normal parathyroid hormone levels. [11] Patients with GFRs less than 60 mL/min/m2 should be evaluated for evidence of bone disease with longitudinal measurements of parathyroid hormone, phosphorus and ionized calcium levels. Less commonly, vitamin D levels and bone biopsy may be of benefit. Treatment of bone disease involves vitamin D replacement and/or phosphate binders. Patients with stage 3 CKD should have hemoglobin levels checked and if less than 12.5 g/dL should undergo an evaluation of their anemia. [13] If the workup is unremarkable and the patient is not iron deficient, treatment with erythropoetin should be undertaken. Erythropoetin levels are generally not useful in discerning whether a patient's anemia is related to CKD or something else, as the deficiency of erythropoetin is a relative deficiency, and the measured levels may be within a normal range. Protein malnutrition is common among dialysis patients and occurs at varying times during the development of end stage renal disease. CKD patients with protein malnutrition have greater morbidity and mortality than those who do not. [14] Early and ongoing dietary assessments, usually in conjunction with a dietician are generally necessary to avoid malnutrition. Complicating treatment of protein malnutrition are continued questions regarding possible benefits of a low protein diet during the early stages of chronic kidney diseases. The results of the Modification of Diet in Renal Disease study (which studied whether low protein diets slow the rate of progression of CKD) were inconclusive, further fueling the controversy. [6] As a result the NKF has recommended that patients with a GFR < 25 mL/min consume 0.60 g/kg/d of protein, but does not make recommendations for patients with higher GFR. As the recommended dietary allowance (RDA) of protein for adults with a normal GFR is 0.75 g/kg/d, it seems reasonable that patients with GFRs > 25mL/min consume this amount. [15] Finally, as patients with CKD approach end stage renal disease, efforts to prepare for renal replacement therapy should be undertaken in a timely manner. Patients who are referred to a nephrologist within a few months of starting dialysis have poorer outcomes that those referred earlier. [16] Nephrologists can help patients obtain dialysis access or transplantation referral prior to the onset of renal failure and can aid in managing the complications and comorbidities of CKD.

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Chronic Kidney Disease Management Stage Patients at increased risk of CKD Stage 1 Stage 2

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Stage 3 Stage 4

Stage 5

Assessment Blood Pressure, Serum creatinine (to estimate GFR) Urine studies protein/creatinine ratio sediment examination Studies, referrals to establish diagnosis of renal disease (i.e. ultrasound of kidneys, biopsy, nephrology referral, etc.) Monitor disease progression

Assess patient for specific complications of CKD anemia (if hemoglobin < 12.5, reticulocyte count, iron studies) bone disease (serum calcium, phosphorous, PTH) malnutrition (albumin nPNA, nutrition consultation) hypertension neuropathy (restless legs, ataxia, paresthesias, etc.) Prepare patient for renal replacement therapy Begin renal replacement therapy

21

Action plan If evidence of renal disease, begin diagnostic workup Treat hypertension Establish diagnosis Take steps to minimize progression of CKD (control blood pressure, blood sugar,etc.) Treat/manage complications as warranted (for example: erythropoetin administration, phosphate binders, rocaltrol, control hypertension, etc.)

Dialysis, transplantation

In conclusion, physicians should (1) identify and monitor CKD using GFR prediction equations (2) stratify patients based on the NKF guidelines (3) identify and treat the underlying the cause of CKD, comorbidities and complications of CKD.

REFERENCES [1]

Keith DS, Nichols GA, Gullion CM, Brown JB, Smith DH. Longitudinal follow up and outcomes among a population with chronic kidney disease in a large managed care organization. Arch Intern Med 2004 March 22;164(6):659-63.

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22 [2] [3]

[4]

[5] [6]

[7]

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[8]

[9] [10]

[11]

[12]

[13]

[14]

Micah L. Thorp McCullough PA. Scope of cardiovascular complications in patients with kidney disease.: Ethn Dis12(4):S3-44-8. 2002. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification, Part 1, Executive Summary. Am J of Kidney Dis 39(suppl 1):S17-S31. 2002. Levey AS, Coresh J, Balk E, et.al.. National Kidney Foundation practice guidelines for chronic kidney disease: evaluation, classification and stratification. Ann Intern Med 139:137-147. 2003. Shemesh O, Golbetz H, Kriss JP, Myers BD. Limitations of creatinine as a filtration marker in glomerulopathic patients. Kidney Int 28:830-838. 1985. Levey AS, Bosch JP, Lewis JB, Greene T, Rogers N, Roth D: A more accurate method to estimate glomerular filtration rate from serum creatinine: A new prediction equation. Modification of Diet in Renal Disease Study Group. Ann Intern Med 130:461-470, 1999. Bakris GL, Williams M, Dworkin L, et.al.. Preserving renal function in adults with hypertension and diabetes. A consensus approach. National Kidney Foundation Hypertension and Diabetes Executive Committees Working Group. Am J Kidney Dis. 36:646-661. 2000. Ruggenenti P, Remuzzi G. Angiotension converting enzyme inhibitor therapy for nondiabetic progressive renal disease. Curr Opin Nephrol Hypertens. 6:489-495. 1997. Barrett BJ. Applying multiple interventions in chronic kidney disease. Semin Dial. 16(2):157-64. 2003. McGonigle RJ, Wallin JD, Shadduck RK, Fisher JW: Erythropoietin deficiency and inhibition of erythropoiesis in renal insufficiency. Kidney Int 25:437-444, 1984. Sherrard DJ, Hercz G, Pei Y, Maloney NA, Greenwood C, Manuel A, Saiphoo C, Fenton SS, Segre GV: The spectrum of bone disease in endstage renal failure—An evolving disorder. Kidney Int 43:436-442, 1993. Kinchen KS, Sadler J, Fink N, Brookmeyer R, Klag MJ, Levey AS, Powe NR. The timing of specialist evaluation in chronic kidney disease and mortality. Ann Intern Med 2002 Sep 17;137(6):479-86. National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J of Kidney Dis 39(suppl 1):S120-S127. 2002. Holland D, Lam M: Predictors of hospitalization and death amongst predialysis patients: A retrospective study. Nephrol Dial Transplant 15:650658, 2000.

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[15] National Kidney Disease Education Program. Meeting on Creatinine Assay and Reporting of Estimated GFR 2003. http://www.nkdep.nih.gov. [16] National Kidney Foundation. K/DOQI Clinical Practice Guidelines for Chronic Kidney Disease: Evaluation, Classification, and Stratification. Am J of Kidney Dis 39(suppl 1):S46-S64. 2002.

4.1. MANAGING DIABETIC NEPHROPATHY

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Step 1. Ensure diagnosis. Check serologies for other potential etiologies (ANCA, ANA, C3, C4 etc.) Step 2. Maximize blood sugar control. Step 3. Maximize hypertension control (SBP < 130) Step 4. Add angiotension converting enzyme inhibitor or angiotension receptor blocker. Step 5. Maximize ACEI/ARB dose to highest tolerated level. It is estimated that one quarter to one third of patients with diabetes develop diabetic nephropathy. Given the significant prevalence of diabetes in the population, it has become the leading cause of end stage renal disease (ESRD) in the United States. [1] Evidence suggests that early identification and management of diabetic kidney disease can ameliorate the course of the disease. It is important for clinicians practicing adult medicine to have an intricate knowledge of diabetic nephropathy, it‘s general course and appropriate measure to treat it.

Diagnosis of Diabetes with Renal Manifestations Diabetic kidney disease presents in its earliest stage (incipient nephropathy) with low levels of albumin (microalbuminuria) in the urine. [2] The usual arch of progression of diabetic nephropathy is apparent when urine albumin levels increase until the patient develops overt nephropathy. Overt nephropathy often occurs in conjunction with a hyperfiltrative period, in which the creatinine clearance and glomerular filtration (GFR) rate are high. [2] It is important to understand that the elevation in clearance is deceptive, as it is followed by a gradual decrease in GFR that ultimately leads to end stage renal disease (ESRD).

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Micah L. Thorp

Twenty to thirty percent of patients with diabetes will develop diabetic kidney disease.n Microalbuminuria rarely develops in Type 1 diabetics during the first few years of disease. For these reasons, the American Diabetes Association (ADA) recommends screening begin only after the patient has had Type 1 diabetes for 5 years. [3] Perhaps due to the long duration that often precedes diagnosis of Type 2 diabetes, patients are more likely to have micoalbuminuria (or overt nephropathy) when diabetes is diagnosed. Thus, patients with Type 2 diabetes should be screened at the time of diagnosis for the presence of microalbuminuria. [3] There are a number of ways of screening for diabetic nephropathy. Three commonly applied approaches include measurement of albumin to creatinine ratio on a spot urine, albumin measurement from a twenty-four hour urine collection or albumin from a timed collection (for example 10 hours overnight). The ratio from a spot urine is the least likely to be affected by collection error. A ratio greater than 30mg albumin/g creatinine is considered abnormal. Transient elevations of microalbuminuria due to conditions other that diabetic kidney disease (exercise, urinary tract infections, etc.) make it necessary to confirm an initial test with repeated measures. The ADA guidelines suggest that two of three tests for microalbumin need to be positive in a three to six month period to suggest a patient has diabetes with renal disease. [3] It should be noted that it is pointless to check urine microalbumin levels in patients with overt nephropathy (defined as > 300mg urine albumin/g creatinine), as the level of protein in the urine is great enough to be easily detected and quantified by other means. Diagnosis of diabetes with renal manifestations is made by the presence of sustained protein in the urine, either as microalbuminuria or proteinuria. It should be suspected and screened for among patients who have had type 1 diabetes for more than five years and among patients with type 2 diabetes at diagnosis. The most expedient screening test for albuminuria is the spot urine albumin/creatinine ratio (>30mg albumin/g creatinine is positive). When two of three tests within a three to six month period are positive, incipient nephropathy is present. (ADA Guidelines)

Definitive Treatment of Diabetic Kidney Disease It is important for both clinicians and patients to appreciate that there is no definitive ―cure‖ for diabetic nephropathy. Slowing the progression of the disease by optimizing blood pressure and glycemic control (for example) should thus be

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the primary focus of clinicians. With this in mind, it is interesting to note the results of a recent study that followed nearly 400 patients with type 1 diabetes and microalbuminuria for six years. More that half the patients in the study had a regression of microalbuminuria, suggesting patients with this finding may not be summarily assigned the fate of overt nephropathy. Patients with low systolic blood pressure, low levels of cholesterol and low levels of glycosylated hemoglobin were more likely to enjoy a regression, revealing benefits of early intervention. [4] While there is no ―cure‖ for diabetic kidney disease, a recent study suggests microalbuminuria may resolve in some patients (when optimally managed) and avoid development of overt nephropathy.

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Management of Diabetes with Renal Disease Slowing the progression of diabetic kidney disease includes optimizing glycemic control (as demonstrated by the United Kingdom Prospective Diabetes Study [5] and Diabetes Control and Complications Trial [6]), controlling hypertension and use of an angiotension converting enzyme inhibitor (ACEI) or angiotension receptor blocker (ARB). More controversial recommendations include a protein restricted diet [7] (which is theorized to be effective only after the GFR begins to decline) and the use of nondihydropyridine calcium channel blockers (NDCCB) in the event ACEIs or ARBs cannot be used. Based on the aforementioned trials, optimum hemoglobin A1c levels should be kept less than 7%. Ideal blood pressures are unclear, but based on the UKPDS and Hypertension Optimal Treatment (HOT) studies [8], a reasonable blood pressure target is less than or equal to 130/80 mmHg. There is significant evidence that ACEIs slow the progression of diabetic kidney disease among type 1 diabetics [9, 10] and some evidence that the progression is slowed among type 2 diabetics as well [11,13]. The Reduction of Endpoints in NIDDM with Angiotension II Antagonist Losartan (REENAL) study [14] and the Irbasartan Diabetic Nephropathy Trial (IDNT) [15] showed ARBs significantly slow the progression of diabetic kidney disease among type 2 diabetics. If one class cannot be tolerated, the other may be substituted. [16] Once the diagnosis is made, optimize glycemic control, control blood pressure and prescribe either an ACEI or ARB. (ADA Guidelines)

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Micah L. Thorp

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Prescribing ACEIs/ARBs to Diabetic Patients with Microalbuminuria who Are Normotensive, or Diabetic Patients who Are Hypertensive but without Microalbuminuria Studies have shown that there is benefit in reducing the progression of microalbuminuria in normotensive patients with type 1 diabetes and normotensive patients with type 2 diabetes. [17, 18] The ADA currently recommends the use of ACEIs in patients with type 1 diabetes, microalbuminuria and normal blood pressure, but is not specific regarding the use of ACEIs or ARBs in normotensive patients with type 2 diabetes and microalbuminuria. Despite the lack of a specific recommendation, it seems reasonable to presume that normotensive type 2 diabetic patients with microalbuminuria are likely to obtain benefit from these classes of drugs. Patients without hypertension clearly benefit from lowering of blood pressure, as noted previously. A number of studies suggest a variety of agents may be appropriate first line agents in treating blood pressure. As ACEIs have been shown to decrease or slow the progression of a number of complications of diabetes it seems reasonable to use ACEIs as first line agents in hypertensive diabetic patients without microalbuminuria. [19,20] The ADA states as much: ―Because many studies demonstrate the benefits of ACE inhibitors on multiple adverse outcomes in patients with diabetes, including both macrovascular and microvascular complications, in patients with either mild or more severe hypertension and in both type 1 and type 2 diabetes, the established practice of choosing an ACE inhibitor as the first-line agent in most patients with diabetes is reasonable.‖ ACEIs should be prescribed to diabetic patients with microalbuminuria who are normotensive, and to patients who are hypertensive but do not have microalbuminuria.(ADA Guidelines)

Prescribing ACEI or ARBs to Patients with Elevated Serum Creatinine There is no specific creatinine beyond which ACEIs or ARBs cannot be used. In fact, patients with more advanced renal disease may obtain greater benefits from these medications that those with mild renal disease. A review of twelve randomized clinical trials evaluating renal disease progression among patients with preexisting renal insufficiency found a strong association between acute increases in serum creatinine of up to 30% that stabilize

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within the first 2 months of ACEI therapy and long-term preservation of renal function. [21] Thus, withdrawal of an ACEI in such patients seems reasonable when the rise in creatinine exceeds 30% above baseline within the first 2 months of ACEI initiation. With this in mind, patients initiated on ACEI (and presumably ARB) therapy should have a creatinine checked shortly after starting the medication. Based on limited studies, it appears that while there is no maximum creatinine above which an ACEI can be prescribed, rises in creatinine greater than 30% above baseline should lead to withdrawal of the medication.

Antihypertensive Choices when ACEI/ARBs Are not Tolerated

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A number of small studies have demonstrated that non-dihydropyridine calcium channel blockers (NDCCB) can reduce the level of albuminuria, though no studies to date have shown a reduction in the rate of fall of GFR with their use. NDCCBs may have some benefit in reducing the progression of diabetic nephropathy and should be considered in patients who cannot tolerate ACEIs or ARBs. (ADA Guidelines)

Diabetes + proteinuria or hypertension

Diabetes control BP control ACEI

Tolerates ACEI Maximize dose

Intolerant of ACEI Start ARB

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Micah L. Thorp

References

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[1]

US Renal Data System. Chronic Kidney Disease. USRDS, 2005 Annual Data Report.Bethesda: National Institute of health, National Institute of Diabetes and Digestive and Kidney Diseases; 2005. p. 45-65. [2] Gall MA, Hougaard P, Borch-Johnsen K, Parving HH. Risk Factors for development of incipient and overt diabetic nephropathy in patients with non-insulin dependant diabetes mellitus: prospective, observational study. BMJ 314:783-788. 1997. [3] American Diabetes Association: Diabetic Nephropathy (Position Statement). Diabetes Care 27:(Suppl. 1) S79-S84, 2004. [4] Perkins BA, Ficociello LH, Silva KH, et.al. Regression of Microalbuminuria in Type 1 Diabetes. N Engl J Med. 348:2285-2293. 2003. [5] UK Prospective Diabetes Study Group: Efficacy of atenolol and captopril in reducing the risk of macrovascular complications in type 2 diabetes (UKPDS 39). BMJ 317:713–720, 1998. [6] Diabetes Control and Complications Trial Research Group: The effect of intensive treatment of diabetes on the development and progression of longterm complications in insulin-dependent diabetes mellitus. N Engl J Med 329:977–986, 1993. [7] Waugh NR, Robertson AM. Protein restriction for diabetic renal disease (Cochrane Review) In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley and Sons, Ltd. [8] Hansson L, Zanchett A, Carruthers SG, Bahlof B, Elmsfeldt D, Julius S, Menard J, Rahn KH, Wedel H, Westerling S: Effects of intensive blood pressure lowering a low-dose aspirin in patients with hypertension: Principal results of the Hypertension Optimal Treatment (HOT) randomized trial. The HOT Study Group. Lancet 351:1755-1762, 1998. [9] Chobanian AV, Bakris GL, Black HR, et.al.. The Seventh Report of the Joint National Committee on Prevention, Detection, Evaluation, and Treatment of High Blood Pressure. JAMA. 289:2560-2572. 2003. [10] National Kidney Foundation. K/DOQI Clinical Practice Guidelines on hypertension and Antihypertensive Agents in Chronic Kidney Disease. Am J Kidney Dis 43:S1- S290, 2004 (suppl 1). [11] Lewis EJ, Hunsicker LG, Bain RP, Rohde RD, for the Collaborative Study Group: The effect of angiotension converting enzyme inhibition on diabetic nephropathy. N Eng J Med 329:1456–1462, 1993.

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[12] Viberti G, Mogensen CE, Groop LC, Pauls JF:Effect of captopril on progression to clinical proteinuria in patients with insulin-dependent diabetes mellitus and microalbuminuria. JAMA 271:275-279, 1994. [13] Ravid M, Lang R, Rachmani R, Lishner M. Long-term renoprotective effect of angiotension converting enzyme inhibition in non-insulindependant diabetes mellitus. A 7-year follow up study. Arch Intern Med. 156:286-289. 1996. [14] Brenner BM, Cooper ME, de Zeeuw D, Keane WF, Mitch WE, Parving HH, Remuzzi G, Snappinn SM, Zhang Z, Shahinfav S: The RENAAL Study Investigators. Effects of losartan on renal and cardiovascular outcomes in patients with type 2 diabetes and nephropathy. N Engl J Med 345:861-869, 2001. [15] Lewis EJ, Hunsicker LG, Clarke WR, Berl T, Pohl MA, Lewis JB, Ritz E, Atkins RC, Rohde BS, Raz I: Renoprotective effect of the angiotensinreceptor antagonist irbesartan in patients with nephropathy due to type 2 diabetes. N Eng J Med 345:851–860, 2001. [16] American Diabetes Association: Standards of Medical Care in Diabetes (Position Statement). Diabetes Care 27:(Suppl. 1) S15-S35, 2004. [17] ACE Inhibitors in Diabetic Nephropathy Trialist Group. Should all patients with type 1 diabetes mellitus and microalbuminuria receive angiotensinconverting enzyme inhibitors? A meta-analysis of individual patient data. Ann Intern Med. 2001 Mar 6;134(5):370-9. [18] Ravid M, Rosh D, Levi Z, Bar-Dayan Y, Ravid D, Rachmani R: Use of enalapril to attenuate decline in renal function in normotensive, normoalbuminuric patients with type 2 diabetes. Ann Intern Med 128:982988, 1998. [19] Lovell HG. Angiotension converting enzyme inhibitors in normotensive diabetic patients with microalbuminuria (Cochrane Review). In: The Cochrane Library, Issue 1, 2004. Chichester, UK: John Wiley and Sons, Ltd. [20] Ravid M, Lang R, Rachmani R, Lishner M: Long-term renoprotective effect of angiotension-converting enzyme inhibition in non-insulindependent diabetes mellitus: a 7-year follow up study. Arch Intern Med. 156:286-289, 1996. [21] Bakris GL, Weir MR. Angiotension-Converting Enzyme InhibitorAssociated Elevations in Serum Creatinine: Is This a Cause for Concern? Arch Intern Med. 160:685-693. 2000.

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4.2. GLOMERULONEPHRITIS Step 1. Consider acuity of glomerulonephritis and possible etiologies. Decide whether or not patient will need a kidney biopsy. Step 2. Based on results of kidney biopsy, determine whether or not patient will require treatment.

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Defining “Glomerulonephritis” Intrinsic renal diseases can be catagorized based on the site of injury. Diseases are frequently classified as glomerular or interstitial, though in many diseases impact both areas. Since the cause and pathogenesis of many primary renal diseases are unknown, a number of diseases are diagnosed and classified based on little more than a pathologist's description of the biopsy findings. As the mechanism of many renal diseases are poorly understood, deciding whether a disease is primary or secondary can be a bit tricky. Simply put, the occurance of a given kidney disease in the presence of a known risk factor is considered enough evidence of causality to label it "secondary", while the inability to discover the etiology of the same disease makes it "primary". The result of these seemingly imprecise terms are a group of syndromes, that in many cases encompass one or more mechanisms of disease. Catagorizing these syndromes is not difficult as long as one remembers that there is some overlap in both symptoms and histopathological desciption. Diseases are commonly considered "nephrotic" or "nephritic" based on the quantity of protein in a 24 hour urine specimen. As with histopathological description, the nephrotic and nephritic syndromes frequently overlap. In it's purest form nephrotic syndrome results in greater than three grams of protein in a 24 hour urine specimen, hypoalbuminuria, hypercholesterolemia, edema and a bland urinary sediment. Nephritic syndrome generally involves an active sediment (blood, casts, etc.) hypertension and varing amounts of protien.

Minimal Change Disease Minimal Change Disease, sometimes call Nil Disease, appear on light microscopy just that: minimally changed (compared to a normal specimen). It is the most common glomerular disease in children, and not uncommon in adults

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accounting for 10-15% of patients with nephrotic syndrome. [1] The disease usually presents with the sudden onset of a classic nephrotic syndrome, including lower extremity edema, nephrotic range proteinuria and hypercholesterolemia. While nephritic elements are present in 10-20% of patient (hematuria, hypertension, etc) the presence of more than one symptom is rare. [2] On occasion the symptoms will manifest following an upper respiratory infection. Examination of the urine usually reveals little more than oval fat bodies. Renal biopsy is considered diagnostic, as long as enough glomeruli are sampled to ensure focal glomerulonephridities are not overlooked. As stated above, the light microscopy of minimal change disease is indistinguishable from a normal biopsy. Electron microscopy will often reveal effacement of foot processes and immunoflorescence IgM. [1] Serological immunoglobulins will usually reveal low IgA and IgG levels, predisposing patients to infections with encapsulated organisms. A variety of etiological agents have been implicated as potential causes of secondary minimal change disease. Chief among these are the non steroidal antiinflammatory agents, which are associated with MCD at any point during the course of their use. The newer COX-II inhibitors appear to fare no better. Other potential culprits include heavy metals (lead, mercury), infections (HIV, mononucleosis) and tumors (Hodgkin's lymphoma). Whenever a potential secondary cause is identified, it should obviously be discontinued/treated. In cases where removal does not lead to improvement the usual route of therapy should be adopted. Primary minimal change disease responds remarkably well to steroid therapy. Treatment with either 1mg/kg/day of prednisone for six weeks (maximum 80 mg/day) or 2mg/kg every other day for three months will result in 85 to 90% remission rates. If steroids fail a variety of salvage regimines have been tried with varying success. Salvage regimines have included chlorambucil, cyclosporine, cyclophosphamide and most recently rituximab. [3] The general approach is to treat for at least twelve weeks before considering steroids a failure. It is important to remember that twelve weeks is a minimum trial of steroids, and a longer period of treatment may be required. As with all nephrotic syndromes, treat the associated effects, (hypercholesterolemia, edema, etc). Angiotension converting enzyme inhibitors may be of benefit as well in decreaseing proteinuria. [2] Finally, relapses are common. As many as 70% of steroid responders will relapse (thats the bad news). Fortunately most will respond to a eight to ten week repeat of steroid therapy (thats the good news). Patients should be warned ahead of time about the possibility of relapse.

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In general minimal change disease is a favorable prognosis. Treatment is effective. If treatment does not succeed, reconsider the accuracy of the diagnosis.

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Focal Segmental Glomerular Schlerosis The "focal" in focal segmental glomerular schlerosis denotes that only some glomeruli show histopathological changes. The "segmental" denotes only a portion of the glomeruli is affected. Thus FSGS histopathologically is little more than schlerosis affecting part of some of the glomeruli. [4] As one might expect, the broad histopathological definition may include multiple mechanisms of disease, but to date the pathogenesis of FSGS is not understood. Indeed, it appears that histopathologically there are variations, including "collapsing", and "tip lesion". [1] FSGS accounts for approximately 15 to 20% of adult nephrotic syndrome. Unlike other glomerulonephridities, the prevalence of FSGS appears to be increasing. [5] Like MCD, FSGS usually presents with the nephrotic syndrome. A renal biopsy is diagnositic, but due to the focal nature of the disease, enough glomeruli must be obtained to ensure that a "normal" appearing biopsy does not harbor FSGS. Immunoflorescence studies usually reveal IgM and C3 deposits in the areas of schlerosis. [1] Serological studies are generally unremarkable and the urine sediment bland. Secondary causes of FSGS are many and include a wide array of infections, drugs and disease states. Obesity, heroin use, reflux nephropathy, Alport's syndrome and HIV are all included as possible causes of FSGS. [5] Treating FSGS is diffcult and often frustrating. The mainstay of treatment, like MCD is steroids. Unlike MCD the likelihood of successful remission is uncertain. [4] With no therapy, less than 5% of patients will spontaneously remit, with aggressive steroid therapy (1mg/kg/d of prednisone for six months) only 3040% of patients respond. [4] If a patient does respond the long term outcome is quite favorable with a renal survival rate of nearly 90% at 10 years. If the patient has a partial remission, renal survival rates approach 90%. Favorable prognositic signs include serum creatinine less than 2.5mg/dl and less than 20% fibrosis on biopsy. [4] One variant of FSGS deserves comment. Collapsing FSGS is commonly associated with particularly high levels of proteinuria and rapid decline in renal function. It is sometimes a manifestation of secondary FSGS related to HIV (HIV associated nephropathy or HIVAN). The prognosis for patients with HIVAN prior

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to retroviral therapy had been quite poor, though treatment with retrovirals has significantly improved outcomes in recent years. Collapsing FSGS that does not occur in the presence of HIV still bodes poorly even when aggressively treated. [6] Salvage regimines for FSGS include long term cyclosporin (which appears to arrest the disease, but is less likely to lead to improvement), chlorambucil and cyclophosphamide. The likelihood of benefit with a salvage regimine is considered less than 30%, though a number of trials are currently underway to more accurately validate this observation. It is important to remember that at least four months of steroid therapy is required before a patient is considered steroid resistant. [7] As always adjunctive therapy is appropriate including ACEIs, treatment of hypercholesterolemia and edema. [4]

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Membranous Glomerulonephritis Membranous glomerulonephritis is diagnosed histologically and is characterized by subendothelial deposits along an often thickened glomerular basement membrane. [8] The prevalence of membranous nephropathy (MGN) is very low in children, but gradually increases with age. The peak incidence occurs at age 50 and accounts for 35 to 40% of idiopathic nephrotic syndrome in patients above this age. [9] In addition to a changing prevalence among age groups, the etiologies of MGN appear to change with age as well. While idiopathic MGN is common at all ages, MGN secondary to malignancy is uncommon in younger age groups but may account for as much as 20% of cases over age 60. Males tend to have more severe disease than females. [9] Secondary MGN is associated with a multitude of clinical entities. Included among these are infections (hepatitis B, malaria, schistosomiasis, filariasis), malignancies (lung, breast, stomach, esophogus, lymphoma) and immunological disorders (systemic lupus erythematosis, rheumatoid arthritis, Guillian-Barre). [8] Among these MGN secondary to SLE deserves particular note. The World Health Organization Lupus Nephritis histopathological class V is membranous nephropathy. It is generally considered more indolent than the other more proliferative classes of the disease. As with idiopathic MGN, treatment of lupus MGN is controversial. [10] MGN usually presents with nephrotic syndrome, though often much more gradually than FSGS or MCD. Microscopic hematuria is a common feature. Diagnosis is generally made by renal biopsy. The pathogenesis of the subendothelial deposits is thought to occur as a result of immune complex

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formation at the basement membrane. As the subendothelial deposits grow the basement membrane gradually projects "spikes" that finger their way between the deposits. At this point the disease is visible on light microscopy. [9] Treatment of idopathic MGN is difficult given a wide variation in prognosis. Prognosis seems to vary a great deal depending upon factors present at the time of diagnosis. Patients with non-nephrotic range proteinuria may have less than a 5% risk of ESRD. In contrast those with nephrotic range proteinuria may have a 3050% risk of ESRD within 10 years. [9] Differentiating which patients are likely to fall into the different prognostic catagories is difficult. Realizing the potential complications of steroids and cytotoxic therapies and the prognostic indecision noted above, many authors recommend primarily pallative therapyies, including ACEIs, Nsaids and treatment of nephrotic syndrome complications. Patients with secondary MGN may improve upon removal of the aggravating factor. If these less aggressive measures fail, or it a patient is considered at risk for progression of disease (elevated creatinine, nephrotic syndrome, >25% fibrosis on biopsy, male gender) then either high dose steroids or cytotoxic therapies are often recommended (including chlorambucil, cytoxan). [11] One nephrotic syndrome complication that appears to be more common with MGN than other glomerulonephridities is renal vein thrombosis. In patients with MGN who have a sudden worsening of their renal insufficiency, renal vein thrombosis should be considered as a possible diagnosis. If discovered long term anticoagulation is the appropriate therapy. [9] As with other glomerular diseases, adjunctive therapy with ACEIs and control of nephrotic syndrome complications is appropriate.

Membranoproliferative Glomerulonephritis There are three forms of idiopathic membranoproliferative glomerulonephritis. Type I MPGN is the most common and is the result of increased mesangial proliferation and increased matrix composed of immune deposits. Subendotheial deposits are present in the capillaries as well. Type I MPGN is clearly an immune complex disease with circulating immune complexes and hypocomplementemia. Type II MPGN may also be secondary to circulating immune complexes, but the evidence for is less available. Type II disease is sometimes referred to as "dense deposit disease" owing to the presence of a band like thickening of the lamina densa of the glomerular basement membrane. Type III disease is similar to type I but with subendothelial deposits that form ―spikes‖. [12] It is sometimes categorized with Type I.

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All three types of MPGN usually present with nephrotic range protienuria and microscopic hematuria. Some patients have an upper respiratory infection at the onset of disease. Others will have an episode of gross hematuria. Patients with both MPGNs have low C3 levels, but type II MPGN often presents with a normal or only slightly low C4, while type I MPGN more frequently presents with a decreased C4. [13] Both MPGNs present with significant anemia, out of proportion to their level of renal insufficiency. Renal biopsy is needed to establish the diagnosis. Glomeruli appear lobular with an expanded mesangial matrix. Subendothelial dense deposits are seen and there is frequently a marked area of interposed matrix and mesangial cells between the basement membrane and endothelial cells. [12] Type II MPGN immunoflorescencne often has a "railroad track" C3 appearance, with the inner and outer areas of the basement membrane stained in a linear fashion which the membrane itself does not. [13] Treatment of idiopathic MPGN is controversial. The presence of MPGN and nephrotic syndrome together suggests a poor prognosis, with 60% of patients progressing to ESRD within ten years. Persons without nephrotic range protienuria only have a 15% chance of developing ESRD in ten years. Steroids are generally considered the recommended therapy for MPGN, though evidence of benefit is somewhat mixed. [13] As with other glomerular diseases, adjunctive therapy with ACIs and control of nephrotic syndrome complications is appropriate.

IgA Nephropathy IgA Nephropathy, also called Berger's Disease or IgA mesangial nephropathy, is one of the most common causes of hematuria worldwide. It occurs more commonly in the young, with more than 80% of cases discovered between ages 16 and 35. [14] Males are approximately twice as likely to be affected as females and is more common in white and Asian populations, than in blacks. IgA is the antibody of the mucosal immune system, thus IgA nephropathy is stimulated by recurrent infections of the GI tract, respiratory system or bladder and vaginal mucosa. Episodes of infection often exacerbate the underlying disease. IgA nephropathy ususally presents with microscopic hematuria and is a indolent disorder, however, it may produce a nephritic syndrome with hypertension, rapidly worsening renal insufficiency and erythrocyte casts. Diagnosis is made with renal biopsy. Light microscopy reveals an expanded

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mesangial matrix. Immunoflorescence obviously reveals prominent IgA immunoglobulin particularly in the mesangium. [14] The overall prognosis for IgA nephropathy is generally considered favorable with only 10 to 20% of affected individuals developing ESRD in 10 years. Favorable prognositic signs include onset during childhood, less than 1 gram of protein in a 24 hour urine collection and episodes of gross hematuria 24 to 48 hours after a mucosal infection. [15] Proven therapeutic interventions for IgA nephropathy are few and of questionable value, with one exception. A variety of studies have shown that fish oil in large quantities (6 grams daily) reduce the rate of progression. The benefit of immunosuppressants are not proven, however, some studies have suggested benefits of azathioprine and prednisone given over a two year period. It has been suggested the intravenous immunoglobulin is of benefit, though large studies are lacking. Finally, some investigators have reported remission of IgA nephropathy in patients with tonsilitis undergoing tonsilectomy. [16]

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Henoch-Scholein Purpura A severe form of IgA nephropathy, Henoch-Schlein Purpura is found primarily in children. It presents with the acute onset of purpuric rash, abdominal pain, arthralgias and acute renal failure. Patients usually have a transient hematuria and hypertension at presentation. Renal biopsy reveals IgA deposits and crescents. The presence of 50% crescents predicts poor outcomes. Treatment for acute HSP has consisted primarily of high dose steroids, though the benefit of treatment is unclear. As cases are infrequent, evidence for long term benefit of any treatment regimine is limited. Other potential therapies include cyclophosphamide, and plasmapheresis. [17]

Acute Postinfectious Glomerulonephritis Infectious glomerulonephritis occurs by one of two mechanisms. Nephritogenic antigens either bind glomerular sites and form in situ complexes, or complex elsewhere and become trapped in the glomeruli. The term "postinfectious glomerulonephritis" is sometimes used synonomously with "poststreptococcal glomerulonephritis" though not all postinfectious glomerulonephridities are the result of a streptococcal infection. [18]

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The classical description of PSGN is a patient presenting one to three weeks following an acute group A beta hemolytic streptococcal infection with hematuria, edema and hypertension. It is particularly common in children. PSGN is an immune complex disease and patients frequently have low C3 levels and an elevated antistreptolysin O titer. [18] Cryoglobulins are frequently detected. Biopsy reveals glomerular hypercellularity with a large number of neutrophils. Sometimes crescents are present. On either light or electron microscopy, subendothelial "humps" are ususally present. Immunoflorescence is often unremarkable. [19] Though not as common, PIGN may be secondary to a variety of other infections besides streptococcus. Group D streptococcus, gram negative bacteria, staphylococcus and gonococci have led to the same syndrome described above with a nearly identical clinical picture. A variety of chronic infections are associated with a PIGN clinical syndrome. [18] Endocarditis, osteomyelitis and shunt nephritis are common causes of this more indolent form of PIGN. Treatment of the underlying infection ususally ameliorates PIGN. PSGN often resolves on its own and antibiotics may not be necessary. Resolution often occurs within seven to ten days following remediation of the infection. Hematuria and proteinuria usually persist for a protracted period following resolution. At the end of one year 60% of adults will still have hematuria and proteinuria. Control of nephritic symptoms and treatment of infection is the primary therapeutic modality. [20]

Lupus Nephritis Systemic Lupus Erythematosis is a B cell disorder characterized by deposition of immune complexes in a wide variety of tissues. A wide range of symptoms and syndromes characterizes SLE nephritis and the diagnosis of SLE is obtained by noting the presence of four critieria from a list of eleven symptoms and findings. Patients with SLE may present with lupus nephritis, having little more than proteinuria and/or hematuria discovered during routine examination. A renal biopsy is exceptionally helpful in lupus nephritis, not only in obtaining a diagnosis, but in staging the disease. The World Health Organization has classified the morphology of lupus nephritis into six catagories based on morphological biopsy findings. They range from minimal abnormality without immune deposits (catagory 1) to scherlosis with tubular atrophy and interstitial fibrosis (class 6). Classes 1 through 4 follow a kind of progression to a diffuse proliferative morphology with mesangial and subendothelial immune deposits.

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Crescents are usually apparent at this stage. Class 6 is the final endpoint of this progression, where glomeruli have become schlerosed and tubules atrophied. Class 5 is a departure from the seemingly logical progression of the disease. [21] Class 5 is a membranous picture, with capillary loop thickening and subendothelial immune deposits. It presents as a nephrotic syndrome, in contrast to the other classes which typically present with a more nephritic picture. [22] The outcome of lupus nephritis is generally favorable if discovered and appropriately treated. The likelihood of ESRD or death within 10 years is less than 20% in most populations. [23] Treatment is indicated for patients with actively proliferating disease. Stabilization and improvement with corticosteroids and cyclophosphamide usually occurs within a few weeks. Mycophenalate may be used in leui of cyclophosphamide and appear to produce similar outcomes. Laboratory values frequently improve during this period as well, though complete remission often does not occur for a number of months. Patients with mild disease are sometimes treated with corticsteroids alone, though there is little consensus on how to treat patients with class 1 or 2 lupus nephritis. Treatment of membranous, or class 5 lupus nephritis, is an area of controversy as well. Generally considered more indolent than the proliferative forms of lupus nephritis, membranous lupus nephritis has a poor prognosis in male patients and those with greater than 10 grams/day of proteinuria. [21]

Pauci-Immune Vasculitis It is important to remember that the term pauci-immune vasculitis applies to a number of different vasculitidities, all of which have a lack of immune complexes on immunoflorescence or electron microscopy. Antibodies to lysosomal enzymes (P-ANCA and C-ANCA) are often present in these vasculidities, though there is great variation in the prevalence from one disease to another. [24] The pauciimmune vasculidities include Peri-arteritis nodosa, microscopic polyangiitis, Wegner's granulomatosis and Churg-Strauss disease. Diagnosis is often suspected based on ANCA and renal insufficiency, though a conclusive diagnosis necessitates a biopsy.

Wegner's Granulomatosis Wegner's granulomatosis most frequently occurs during the fifth and sixth decades. As a small/medium vessel vasculitis, it is typified by granulomatous

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inflammation of the upper and lower respiratory tract as well as renal disease. Patients often present with an active urinary sediment and rapidly rising creatinine. Proteinuria tends to be moderate (1-2 g/24hrs). Wegner's is ANCA positive in approximately 90% of cases, with the majority of cases being CANCA positive. Presenting symptoms often include manifestations of respiratory disease and include hemoptysis, epistaxis and sinusitis. Other presenting symptoms include fever, arthralgias and palpable purpura on the lower extremities. [25]

Polyarteritis Nodosa Like Wegner's, Polyarteritis Nodosa is a medium vessel vasculitis. Renal imaging will often reveal infacts and aneuysms within the kidney and on occasion subcutaneous nodules are palpable. Only 20% of patients will present with a positive ANCA (usually C-ANCA). While polyarteritis nodosa rarely causes renal failure, it is occasionally associated with retroperitoneal or intraperitoneal hemorrhage. [24]

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Microscopic Polyangiitis Patients with microscopic polyangiitis usually present (90%) with positive ANCA, fairly evenly divided between C-ANCA and P-ANCA. A small vessel vasculitis, microscopic polyangiitis frequently presents with an acute rise in creatinine, sometimes associated with pulmonary capillaritis. [24]

Churg-Strauss Syndrome Churg-Strauss is characterized by eosinophilia and asthma, but is rarely associated with renal failure. Patients with Churg-Strauss are ANCA positive 70% of the time, usually P-ANCA positive (60%). [24] Treatment of the Pauci-immune vasculidities includes prednisone tapered over a year. Cyclophophamide is employed in a manner similar to SLE nephritis. In addition to these therapies, there is some evidence that trimethprim and sulfamethoxazole sustain remissions following treatment. It is estimated that approximately 80% of patients will respond to the combination of cytotoxic and

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steroid therapy. Relapses are frequently treated with steroids alone. [25] An alternative to treatment with cyclophosphomide may be mycophenalate mofitil.

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Goodpasture’s Syndrome and Antiglomerular Basement Membrane Antibody Disease The hallmark of both Goodpasture‘s syndrome and Antiglomerular Basement Membrane Antibody Disease are the presence of antiglomerular basement membrane antibodies. Both Goodpasture‘s and Anti-GBM disease present with acute renal failure, an active urinary sediment and modest proteinuria (1 to 4 grams). Goodpasture‘s syndrome involves the lungs as well as the kidneys, while anti-GBM disease is confined to the kidney. Goodpasture‘s syndrome typically involves young women or old men. Patients frequently present with a combination of acute renal failure and hemoptysis. In approximately 70% of cases the hemoptysis precedes the renal failure. Anemia out of proportion to the level of renal failure is common. Patients will often have a prodrome of fever and arthralgias. Environmental agents, such as cigarette smoke or hydrocarbon fumes may precipitate the onset of pulmonary symptoms. Goodpasture‘s and Anti-GBM disease biopsies usually reveal crescent formation. [26] Treatment of Goodpastures generally involves steroids, cyclophosphomide and pheresis. Pheresis is employed in the face of active disease (rapidly rising creatinine, pulmonary disease etc). Once it has been determined that disease is stable pheresis is no longer employed.

Acute Interstitial Nephritis Though acute interstitial nephritis is not a glomerular disease, it is worth discussing it within the context of glomerulonephritis due the frequent concurrence with a number of glomerular diseases. Patients with acute interstitial nephritis uniformly present with acute kidney injury. Though AIN sometimes presents with other symptoms including rash, fever, eosinophilia and eosinophiluria, it is important to recognize that these symptoms frequently do not occur. The variability in the time from etiological exposure, particularly with regard to drugs, should be recognized as well. The assumption that 2 to 3 weeks must pass before AIN presents is incorrect, it can occur at any time following exposure. [27]

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The gold standard for diagnosis of AIN is renal biopsy. Unfortunately little else is available to assist the clinician in making a definitive diagnosis. It is worth noting that examination of the urine for eosinophils has a positive predictive value of 38%, sensitivity of 40% and specificity of 72% among patients clinically suspected of having AIN. [28] Proteinuria varies greatly, ranging from nephrotic levels in NSAID associated AIN to less than one gram per day in other subgroups. Renal ultrasound often reveals normal sized kidneys with increased cortical echogenicity. [29] Given the heterogeneous presentation and timing of AIN, it should always be suspected in patients with renal disturbances. Those patients deemed likely to suffer from AIN need not necessarily undergo renal biopsy. Removal of offending agents, if possible, is both a potentially diagnostic and therapeutic first step. A renal biopsy should be obtained in patients who fail to improve, if the offending agent is critical to therapy or if the diagnosis remains in question. The most important facet of treating AIN is the removal of offending agents. A difficult situation often arises when more than one agent may be likely to be the cause of a patient‘s AIN. A reasonable approach in this situation involves consideration of the likelihood of each potential agent and the subsequent substitution of the most likely agents (if possible). If drug removal or treatment of underlying infection does not improve renal function, corticosteroid therapy may be considered. It is important to note that no prospective randomized controlled trials have been done to demonstrate the value of this treatment. Despite this, it is frequently recommended that biopsy proven AIN be treated with Prednisone 1mg/kg/day for approximately four weeks, if the patient continues to have a decline in renal function despite removal of the inciting agent. [29] Other potential treatments have included cyclophosphomide 1 to 2 mg/kg per day if there is no improvement with corticosteroid treatment. This therapy is based on little more than anecdotal evidence. Cyclosporin A has been reported to be of benefit as well. [30] If AIN is detected early and the offending agent removed, the likelihood of a return to baseline creatinine is generally good. If the diagnosis is overlooked, or if the patient is rechallenged with the same agent, the initial inflammatory response becomes chronic and fibrotic with some tubular atrophy. Prognosis can be further delineated by the pathology found at biopsy. Patients with a diffuse infiltrate have a poorer prognosis than those without. In addition, the presence of 1 to 6% neurtophils on biopsy suggests a poorer prognosis. [31]

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Micah L. Thorp Nephrotic Glomerulonephridities Presentation

Minimal Change Disease

Nephrotic Syndrome

Focal Segmental Glomerular Schlerosis

Nephrotic Syndrome

Membranous glomerulonephritis Diabetic nephropathy

Nephrotic Syndrome Microlbuminuria gradually increasing to proteinuria Anemia, hypercalcemia, nephrotic syndrome

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Myeloma/Amyloidosis

Pathologic Findings Normal with possible podocyte effacement Sclerosis among some glomeruli in some nephrons Subendothelial ―humps‖ Kussmal Wilson nodules

Treatment

Nodular Schlerosis

Treat underlying disorder

Prednisone

Prednisone

Unknown See Chapter 4.1

Treatment Regimines Minimal Change disease Focal Segmental Glomerular Schlerosis Membranous Glomerulonephritis

Diabetic nephropathy Myeloma/amyloidosis

Steroid taper Steroid taper (4 month minimum) Calcineurin inhibitors Cyclophosphamide Chlorambucil Possibly Mycophenate ACEIs or ARBs Melphalan and prednisone Possibly rituximab Possibly bone marrow transplantation

References [1]

Fogo AB. Minimal change disease and focal segmental glomerulosclerosis. Nephrol Dial Transplant. 2001;16 Suppl 6:74-6.

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Chronic Kidney Disease Management [2] [3]

[4]

[5] [6] [7]

[8] [9]

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[10]

[11] [12] [13]

[14] [15] [16]

43

Saha TC, Singh H. Minimal change disease: a review. South Med J. 2006 Nov;99(11):1264-70. Yang T, Nast CC, Vo A, Jordan SC. Rapid remission of steroid and mycophenolate mofetil (mmf)-resistant minimal change nephrotic syndrome after rituximab therapy. Nephrol Dial Transplant. 2008 Jan;23(1):377-80. Epub 2007 Nov 2 Shiiki H, Dohi K. Primary focal segmental glomerulosclerosis: clinical course, predictors of renal outcome and treatment. Intern Med. 2000 Aug;39(8):606. Cameron JS. Focal segmental glomerulosclerosis in adults. Nephrol Dial Transplant. 2003 Aug;18 Suppl 6:vi45-51. Schwimmer JA, Markowitz GS, Valeri A, Appel GB. Collapsing glomerulopathy. Semin Nephrol. 2003 Mar;23(2):209-18. Braun N, Schmutzler F, Lange C, Perna A, Remuzzi G, Risler T, Willis NS. Immunosuppressive treatment for focal segmental glomerulosclerosis in adults. Cochrane Database Syst Rev. 2008 Jul 16;(3):CD003233 Ponticelli C. Membranous nephropathy. J Nephrol. 2007 MayJun;20(3):268-87. Review. Wasserstein AG. Membranous glomerulonephritis. J Am Soc Nephrol. 1997 Apr;8(4):664-74. Kolasinski SL, Chung JB, Albert DA. What do we know about lupus membranous nephropathy? An analytic review. Arthritis Rheum. 2002 Aug;47(4):450-5. Cattran D. Management of membranous nephropathy: when and what for treatment. J Am Soc Nephrol. 2005 May;16(5):1188-94. Epub 2005 Mar 30. Nakopoulou L. Membranoproliferative glomerulonephritis. Nephrol Dial Transplant. 2001;16 Suppl 6:71-3. Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M, Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR, Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP, Walker P, Welsh M, Würzner R, Zipfel PF. Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol. 2005 May;16(5):1392-403. Epub 2005 Mar 30. Barratt J, Feehally J. IgA nephropathy. J Am Soc Nephrol. 2005 Jul;16(7):2088-97. Epub 2005 Jun 1. Dillon JJ. Treating IgA nephropathy. J Am Soc Nephrol. 2001 Apr;12(4):846-7. Glassock RJ. IgA nephropathy: challenges and opportunities. Cleve Clin J Med. 2008 Aug;75(8):569-76.

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Micah L. Thorp

[17] Tizard EJ, Hamilton-Ayres MJ. Henoch Schonlein purpura. Arch Dis Child Educ Pract Ed. 2008 Feb;93(1):1-8. [18] Vinon CS, Oliveira DBG. Acute Glomerulonephritis. Postgrad Med. 2003;79:206-213. [19] El-Husseini AA, Sheashaa HA, Sabry AA, Moustafa FE, Sobh MA. Acute postinfectious crescentic glomerulonephritis: clinicopathologic presentation and risk factors. Int Urol Nephrol. 2005;37(3):603-9. [20] Raff A, Hebert T, Pullman J, Coco M. Crescentic post-streptococcal glomerulonephritis with nephrotic syndrome in the adult: is aggressive therapy warranted? Clin Nephrol. 2005 May;63(5):375-80. [21] Tumlin JA. Lupus Nephritis: Histology, Diagnosis and Treatment. Bull NYU Hosp Jt Dis. 2008;66(3):188-94. [22] Kolasinski SL, Chung JB, Albert DA. What do we know about lupus membranous nephropathy? An analytic review. Arthritis Rheum. 2002 Aug;47(4):450-5. [23] Contreras G, Pardo V, Cely C, Borja E, Hurtado A, De La Cuesta C, Iqbal K, Lenz O, Asif A, Nahar N, Leclerq B, Leon C, Schulman I, RamirezSeijas F, Paredes A, Cepero A, Khan T, Pachon F, Tozman E, Barreto G, Hoffman D, Almeida Suarez M, Busse JC, Esquenazi M, Esquenazi A, Garcia Mayol L, Garcia Estrada H. Factors associated with poor outcomes in patients with lupus nephritis. Lupus. 2005;14(11):890-5. [24] Mansi IA, Opran A, Rosner F. ANCA-associated small-vessel vasculitis. Am Fam Physician. 2002 Apr 15;65(8):1615-20. [25] Belmont HM. Treatment of ANCA-associated systemic vasculitis. Bull NYU Hosp Jt Dis. 2006;64(1-2):60-6. [26] 25. Kluth DC, Rees AJ. Anti-glomerular basement membrane disease. J Am Soc Nephrol. 1999 Nov;10(11):2446-53. [27] Fried T. Acute interstitial nephritis. Why do the kidneys suddenly fail?. Postgrad Med. Apr 1993;93(5):105-6, 111-2, 117-20. [28] Michel DM, Kelly CJ. Acute interstitial nephritis. J Am Soc Nephrol. Mar 1998;9(3):506-15. [29] Kleinknecht D. Interstitial nephritis, the nephrotic syndrome, and chronic renal failure secondary to nonsteroidal anti-inflammatory drugs. Semin Nephrol. May 1995;15(3):228-35. [30] Reddy S, Salant DJ. Treatment of acute interstitial nephritis. Ren Fail. Nov 1998;20(6):829-38. [31] Ruffing KA, Hoppes P, Blend D, et al. Eosinophils in urine revisited. Clin Nephrol. Mar 1994;41(3):163-6.

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4.3. CYSTIC DISEASES 1. Determine if the patient has a family history of polycystic disease. If so do they meet the criteria for the diagnosis of ADPKD? 2. Does the patient have other morphological findings consistent with other cystic diseases (i.e. tubers)? 3. Monitor progression of disease and treat complications.

Simple Cysts Renal cysts are common, increasing in frequency with increased age. Simple cysts are benign and generally of little clinical concern. [1] None the less, it is important to ensure the cysts are not solid masses, which are more likely to be cancerous and may require surgical excision. If there is any question regarding whether or not a mass is cystic or solid, further imaging and consultation is necessary.

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Acquired Renal Cystic Disease Acquired cystic disease occurs among patients with end stage renal disease and does not appear to be hereditary. Patients who have been on dialysis for many years have the highest prevalence of the condition, with as many as 90% of patients on dialysis for more than 5 years harboring the condition. [2] Even though ACD is not hereditary, many of the complications secondary to polycystic disease are often present, including cyst rupture, pain and hematuria. ACD should be suspected among ESRD patients who present with these symptoms.

Polycystic Kidney Disease Polycystic kidney disease is the most common heritable kidney disorder, affecting more than 1 in 500 births. PKD may be the result of an autosomal dominant mutation, an autosomal recessive mutation or a new mutation. Most cases are the result of mutations to the PKD1 or PKD2 genes that code for polycystins 1 and 2. The polycystins appear to be responsible for cues in epithelial

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cells that affect morphogenesis. As a result, cells that should develop into tubular shapes (such as renal tubules) become cystic instead. [3] Patients with autosomal dominant polycystic disease (ADPKD) are usually aware they may be at risk for the disease. Determining when they should be screened is often difficult, as there are often implications for insurance and, at least to date, there is not a definitive treatment for the disease. Screening is generally undertaken either with genetic tests or renal ultrasound. Less commonly, a patient will present with PKD discovered on an imaging study (CT, MRI or US) that was unexpected as the patient had no family history of PKD. These cases may be either new ADPKD mutations, autosomal recessive polycystic kidney disease (ARPKD) or anther cystic disorder. Both ADPKD and ARPKD are systemic disorders and are associated with other related morphological anomalies. These include hepatic cysts, diverticulosis, cardiac valvular abnormalities, intracranial aneurysms and ovarian cyst. [4] Regardless of etiology, patients with PKD often suffer from a series of specific problems:

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Back Pain

Cyst Hemorrhage

Infection

Hypertension

Cyst Pain Nephrolithiasis

Clinical Presentation Patient will often have enlarged abdomen, increasing strain on muscles in back. Patient will have sudden onset of gross hematuria, sometimes with associated flank pain. May present with flank, pain, fever, evidence of UTI. If treatment of UTI isn‘t effective, suspect cyst infection. Hypertension will often be difficult to treat. Can be the result of cysts stretching renal capsule Hematuria and pain.

Treatment NSAIDs – benefits of pain control must be weighed against risk of increased progression. Hydration and pain management. If bleeding continues, surgical intervention may be necessary. Treat with antibiotics that accumulate well within cysts: TMP/SMX, Ciprofloxin, Chloramphenacol ACEIs are considered ideal as they may decrease rate of interstitial disease. May benefit from cyst decompression procedures. May require acute urological procedure. Long term patients should stay hydrated. May benefit from thiazide.

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Ultrasound ADPKD diagnostic criteria in patients with one parent with known ADPKD Age (yrs) 15-29 30-59 > 60

Number of cysts Two or more, unilateral or bilateral Two or more in each kidney Four or more in each kidney

Tuberous Sclerosis Tuberous Sclerosis is characterized by but the presence of ―tubers‖ (which are skin lesions), as well as epilepsy, mental retardation, angiomyolipomas and renal cysts. Patients often develop renal cysts as children and may be misdiagnosed with ARPKD. [6]

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Von Hippel-Lindau Syndrome Patients with Von Hippel-Lindau (VHL) frequently have retinal angiomas, cerebellar and/or spinal hemangioblastomas, islet cell carcinomas, pheochromocytomas as well as renal cysts. Renal cell carcinomas are common and account for many deaths among patients with VHL. [7]

References [1]

[2] [3] [4] [5] [6]

Chang CC, Kuo JY, Chan WL, Chen KK, Chang LS. Prevalence and clinical characteristics of simple renal cyst. J Chin Med Assoc. 2007 Nov;70(11):486-91. Ishikawa I. Acquired cystic disease: Mechanisms and manifestations. Semin Nephrol. 11:671-684. 1991 Rapoport J. Autosomal dominant polycystic kidney disease: pathophysiology and treatment. Q J Med. 100:1-9. 2007. Pei Y. Diagnostic Approach in Autosomal Dominant Polycystic Kidney Diseaes. Clin J Am Soc Nephrol. 1:1108-1114. 2006. Nahm AM, Henriquez DE, Ritz E. Renal cystic disease (ADPKD and ARPKD). Nephrol Dial Transplant. 2002 Feb;17(2):311-4. Roach ES, Delgado MR. Tuberous Sclerosis. Dermatol Clin 13:151-165. 1995.

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Micah L. Thorp Choyke PL, Glenn GM, Walther MM, Patronas NJ, Linehan WM, Zbar B. von Hippel-Lindau disease: Genetic, clinical, and imaging features. Radiology. 194:629-642. 1995.

4.4. DYSPROTEINEMIA AND AMYLOIDOSIS Step 1. When suspected, check UPEP and SPEP – consider renal biopsy. Step 2. Correct hypercalcermia and hypovolemia. Consider urine alkalinization if cast nephropathy. If rapidly progressive renal failure due to cast nephropathy consider plasmapheresis. Step 3. Treat underlying disorder.

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Plasma cell dyscrasias are responsible for a number of renal disorders through the over production of immunoglobulins. Some are the result of systemic disease (e.g. AL amyloidosis) while others seem to manifest primarily within the kidney (e.g. cast nephropathy). Treatments and prognosis vary widely, so identifying the correct disorder is important.

Multiple Myeloma Multiple myeloma (MM) is the result of a plasma cell dyscrasia that results in an overproduction of lambda or kappa light chains. Patients will often present with anemia, hypercalcemia, renal insuffiency and lytic bone lesions. Proteinuria is often significant, but may not be easily identified by urinalysis. Quantitative tests are generally helpful if the disease is expected. Diagnosis of MM requires bone marrow biopsy, though the specific effects of MM on the kidney may require renal biopsy as well. Serum protein electrophoresis and urine protein electrophoresis are a minimally invasive means of diagnosing MM. In some cases, the aggregation of light chains in the distal nephron causes obstruction and results in cast nephropathy. Clinically, this is manifest by renal failure at widely varying rates. The primary goals of treatment of cast nephropathy involve reduction of circulating light chains through treatment of the underlying myeloma. Plasmapheresis has been advocated by some as a means of treating acute renal failure, though the benefits may be of limited value. Volume repletion and urine alkalinization is often helpful as well. [1]

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Other complications associated with cast nephropahty include Fanconi syndrome, which usually improves with treatment of the underlying disease. Hypercalcemia is common and is treated with volume repletion and bisphosphenates (which are nephrotoxic and should be administered only after the patient is made euvolemic).

Amyloidosis

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“Primary Amyloidosis‖ generally refers to AL amyloidosis which (unlike AA amyloidosis) is the result of a plasma cell dyscrasia. AL Amyloidosis is a systemic disease, with light chain deposition in multiple organs. The AL amyloid light chains are usually lambda, as opposed to light chains deposited in monoclonal IgG deposition disease which are usually kappa light chains. [2] Diagnosis of amyloidosis involves biopsy of an affected organ (often the kidney) and examination with Congo Red Stain. The preferred treatment of amyloidosis is unclear and the prognosis is usually quite poor. Unlike AL amyloid, AA amyloidosis (or ―secondary amyloidosis‖) is a much less frequent cause of renal disease. As the term ―secondary‖ suggests AA amyloid is usually the result of chronic inflammation. Treatment involves treating the underlying inflammatory disorder.

Monoclonal IgG Deposition Disease Monoclonal IgG deposition disease (MIDD) is usually the result of kappa light chains (in isolation called light chain deposition disease) [3] but may include heavy chains as well. Renal dysfunction is commonly the presenting symptom, though it usually affects other organs as well. [1] As with amyloidosis and cast nephropathy, renal biopsy can be helpful in distinguishing the specific disorder. Treatment with chemotherapy (also like amyloid and cast nephropathy) is the primary means of treatment. Prognosis is generally poor.

References [1] [2]

Korbet SM, Schwartz MM. Multiple myeloma. J Am Soc Nephrol. 2006 Sep;17(9):2533-45. Gertz MA, Lacy MQ, Dispenzieri A. Immunoglobulin light chain amyloidosis and the kidney. Kidney Int. 2002 Jan;61(1):1-9.

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Peniket AJ, Littlewood TJ, Winearls CG. The radical treatment of paraprotein disorders affecting the kidney. Nephrol Dial Transplant. 2003 Aug;18(8):1431-4.

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[3]

Micah L. Thorp

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Chapter 5

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ACUTE KIDNEY INJURY Step 1. Idenitify acute kidney injury risk factors and institute preventative measures when possible. Step 2. Assess acuity of injury. Step 3. On most patients perform a history and physical, renal ultrasound and urinalysis. Step 4. Based on results of step 3, workup potential causes of AKI (check CPK, urine eosinophils, urine sodium, etc.) and treat underlying condition. Step 5. Make sure patient is euvolemic. Step 6. Initiate renal replacement therapy when patient has indication that can’t be rectified via an alternative modality (Acidosis, Electrolyte disorder, Ingestion of dialyzable toxin, volume Overload, Uremia). This usually means the patient is oliguric or anuric.

DEFINITION AND CLASSIFICATION Acute kidney injury (AKI) is commonplace in the inpatient setting and associated with increased mortality. Identification of AKI at its outset can often help in early institution of therapy and avoid the short and long term negative effects. AKI will often present in the setting of chronic kidney disease and must be differentiated and anticipated. In the most ideal situations, an astute clinician will note risk factors that precipitate AKI and mitigate them before they have an effect.

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Over the years numerous definitions of AKI (previously acute renal failure) have been developed. Currently, the RIFLE (Risk, Injury, Failure, Loss, ESKD) criteria have gained acceptance as the most useful diagnostic tool for defining and evaluating AKI. [1] The criteria use both urine production and serum creatinine (or eGFR) as measures of kidney function. The RIFLE criteria are widely cited in the critical care literature and appear to be well suited for that venue. Of course many patients with AKI develop renal failure outside the acute care setting. For these patients the RIFLE definition may be less meaningful. Additionally, one of the weakness of the RIFLE criteria is the use of serum creatinine (or eGFR) in assessing kidney function, as these are lagging measures of kidney function in the acute setting. Still, RIFLE provides a definition/classification scheme for AKI and can be integrated with the National Kidney Foundation‘s CKD definition (discussed in Chapter 4). RIFLE definition/classification of Acute Kidney Injury Risk Increased Serum Creatinine x 1.5 Urine output < .5 or decrease eGFR by > 25% ml/kg/h x 6h Injury Increased serum creatinine x 2 or Urine output < .5 decreased eGFR by > 50% ml/kg/h x 12 h Failure Increased serum creatinine x 3 or Urine output < .3 decreased eGFR by > 4 mg/dL ml/kg/h x 24 h Loss Persistent acute renal failure = complete loss of kidney failure > 4 weeks End Stage End Stage Kidney Disease > 3 months Kidney Disease Adapted from: 2. Bellomo R, Ronco C, Kellum JA, Mehta RL, Palevsky P., Acute Dialysis Quality Initiative workgroup. Acute renal failure – definition, 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. doi: 10.1186/cc2872.

EVALUATION Most methods of evaluating AKI begin by differentiating possible etiologies into three categories: prerenal, intrinsic and post renal. While there is often overlap between these categories, it is quite helpful to conceptualize these groups when assessing AKI. [1] A simple approach to assessing AKI in all patients begins with a history and physical, renal ultrasound and urinalysis. While far from

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complete, these three simple steps usually allow the clinician to identify the category of AKI and presumed diagnosis. Examples of Findings on Initial Workup that Can help Classify AKI Etiology

Prerenal

Intrarenal

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Postrenal

History and Physical Recent dehydration, evidence of CHF, liver failure etc. History of exposure to toxins, signs of vasculitis, exposure to antibiotics (AIN) History of BPH, Cancer, urethral stricture etc.

Urinalysis High specific gravity

Renal Ultrasound Normal

Casts, proteinuria, RBCs

Large kidneys with infiltrative diseases

Isosthenuria (specific gravity about 1.010)

Hydronephrosis, large post void residual

Prerenal causes of AKI include anything that leads to a decrease in renal perfusion. Etiologies include hypovolemia, decreased cardiac output or obstruction of renal blood flow. When considering effective renal blood flow (the ultimate etiology of prerenal AKI) both systemic and renal specific etiologies should be considered. Laboratory manifestations of prerenal AKI frequently include a low urine sodium, low fractional excretion of sodium and low fractional uric acid excretion. It is important to note that without intervention, prerenal AKI will often progress to intrarenal AKI. Etiologies of intrarenal AKI are sometimes divided into glomerular and tubular etiologies, though this is often an artificial differentiation as many diseases have some effect on both. Urinalysis is often helpful in identifying intrarenal etiologies. Urine sodium can help assess whether or not a patient has prerenal disease or acute tubular necrosis (its low in prerenal AKI and high in ATN). Urine eosinophils can be helpful in detecting acute interstitial nephritis, though they lack sensitivity and specificity. Often a renal biopsy is necessary when the cause is unclear or cannot be easily assumed. Post renal AKI can usually be diagnosed by renal ultrasound. Hydronephrosis and large postvoid residuals are often apparent. More complex situations involve ureter encasing tumors (in which case there may be no hydronephrosis) or intratubular obstruction involving crystallized uric acid or calcium oxalate. A thorough history and physical can often help the clinician suspect the presence of these less common postrenal etiologies.

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Pre Renal Hypovolemia Hemorrhage Vomiting Diarrhea, vomiting Burns Diuretics Medications ACEIs NSAIDS Cyclosporin Radiocontrast Hypercalcemia Congestive Heart Failure Hypotension Hepatorenal syndrome

Intrarenal Atheroembolism Acute tubular necrosis Acute interstitial Nephritis Toxins Aminoglycosides Cisplatinum Ifosfamide Rhabdomyolysis Sepsis Acute Glomerulonephritis

Post Renal Prostatic hypertrophy Intratubular obstruction Calcium oxalate Uric acid Acyclovir Nephrolithiasis Tumor Neurogenic bladder

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PREVENTION/MANAGEMENT OF SPECIFIC CONDITIONS Acute Tubular Necrosis When renal hypoperfusion is severe and/or prolonged, tubular damage ensues and the AKI persists after the underlying hypoperfusion resolves. At the inception of ATN, prerenal physiology is often apparent (which makes sense as hypoperfusion causes ATN). As tubular injury occurs, with or without correction of the underlying hypoperfusion, urine sodium rises and GFR declines. ATN can be differentiated from prerenal AKI by: 1) a continued decline in renal function despite correction of the underlying hypoperfusion and 2) an elevated urine sodium (in contrast to prerenal azotemia which has a low urine sodium). [3] Once ATN has occurred, there is little that can be done to alter its course. When ATN occurs, the primary treatment is supportive care. The patient should be made euvolemic, medications dose adjusted and the underlying cause of hypoperfusion corrected. In most cases, renal function will eventually improve. Given the lack of potential treatments, prevention of ATN may be the most important intervention that can be undertaken. Risk factors for ATN include advanced age, diabetes, time on a cardiobypass pump and ACEIs. [3] Patients at risk for ATN who may be undergoing any procedure that might involve

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hypoperfusion should be adequately hydrated and every effort made to minimize hypotension.

Contrast Nephropathy The use of iodinated contrast is a common cause of a transient rise in serum creatinine. Radiocontrast produces a severe and persistant renal vasoconstriction that causes a decrease in serum sodium (due to prerenal physiology). Oliguria is often present during the first twenty four hours following administration of the contrast and (in most patients) improves over the next few days. As with prerenal AKI or ATN, most efforts to manage contrast nephropathy involve prevention. Numerous regimines have been developed to prevent contrast nephropathy, including pretreatment with mannatol, bicarbonate, lasix and N-acetyl cysteine. Results from clinical studies of these agents have been disappointing. Many studies use intermediate outcomes To date the only reliably beneficial preventative measure is pre contrast hydration with normal saline. [4]

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Acute Interstitial Nephritis The most common presentation of acute interstitial nephritis (AIN) occurs following the onset of antibiotic use, though many (perhaps most) medications may be causative. The most common (and often only) presenting symptom of AIN is acute renal insufficiency. A decline in renal function is often described 710 days following etiologic exposure, though it is important to recognize that AIN can occur at any time. [5] A maculopapular rash may be present, though the finding is neither sensitive nor specific for AIN. Though urine eosinophils are often ordered as a part of the workup for AIN, the positive predictive value has been estimated to be only 38%. [6] Urinanlysis often reveals a sterile pyuria. The gold standard diagnostic test for AIN is a renal biopsy. The most important treatment for AIN is cessation of the underlying cause. If removing the offending agent fails, corticosteroid treatment is generally considered the next most appropriate therapy. Early consultation with a nephrologist in any patient with suspected AIN should be considered, especially if they fail to improve after removal of the suspected offending medication. Prognosis is associated with the length of time a patient has AIN. Further information about AIN is available in Chapter 4.

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Rhabdomyolytis

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Rhabdomyolytis occurs when large quantities of myoglobin are released due to muscle injury. As myoglobin makes it‘s way through the nephron, tubular necrosis ensues. Patients with crush or other traumatic injuries or myopathies are particularly at risk for the development of rhabdomyolysis. A markedly elevated creatinine protein kinase (CPK) is adequate to diagnose rhabdomyolysis (typically in the thousands). History and physical examination and urinalysis often provide clues that lead to the suspicion of rhabdomyolysis. Often patients will note pink tinged urine and urinalysis will reveal a strongly positive heme dipstick with a very small number (if any) red blood cells on microscopic examination. Any suspicion should stimulate the clinician to check a CPK. Management of rhabdomyolysis involves hydration and alkalinization of the urine. Both measures can be accomplished via rehydration with bicarbonate laden intravenous fluids. Hemodialysis is often necessary, at least as a temporary measure, to remove excess myoglobin if the patient becomes oliguric or anuric. Once CPK levels return to normal, patients will usually recover, though the time to recovery may be dependant upon the extent of tubular damage.7

Hepatorenal Syndrome A number of relationships exist between renal and hepatic diseases. These range from the immunologic effects of hepatitis viruses (mainly B and C) to the impact of liver failure on renal perfusion. Additionally, drug dosing in the setting of both kidney and liver disease may be difficult as both organs typically contribute to drug elimination. Hepatorenal syndrome usually occurs among patients with cirrhosis and/or portal hypertension. The lack of intrinsic renal disease is a hallmark of the syndrome and patients typically present with decreased urine output, low urine sodium and decreased glomerular filtration rate. As these findings would suggest, the syndrome is the result of decrease renal perfusion, thought secondary to vasoactive hormones and prostaglandins. Patients with liver disease often have massive amounts of third spacing, making it difficult to determine if AKI is the result of HRS or prerenal azotemia. A fluid or colloid bolus is often administered to differentiate the two diagnoses. Patients with prerenal azotemia will show an improvement in renal function, while those with HRS remain unchanged. [8]

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Diagnostic Criteria for Hepatorenal Syndrome (Only major criteria are necessary for a diagnosis) Major Criteria Serum creatinine >1.5 mg/dl or 24-h creatinine clearance 20

Renal loss DI

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Patients with hypertnatremia resulting from normal total body sodium and decreased total body water are euvolemic. Urine sodium is generally not helpful in determining the underlying etiology. Potential causes of euvolemic hypernatremic include diabetes insipidis or hypodipsia. [4] True hypodipsia is uncommon, more often individuals simply lack access to water or suffer a neurological defect. Diabetes insipidis results from a lack of vasopressin (central) or an inadequete response to released vasopressin (nephrogenic). [5]

References [1] [2] [3]

[4]

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[5]

Reynolds RM, Padfield PL, Seckl JR. Disorders of sodium balance.BMJ. 2006 Mar 25;332(7543):702-5. Adrogue HJ, Madias NE. Primary care: hypernatremia. New Engl J Med2000; 342: 1493–1499. Barsoum NR, Levine BS. Current prescriptions for the correction of hyponatraemia and hypernatraemia: are they too simple? Nephrol Dial Transplant. 2002 Jul;17(7):1176-80. Kugler JP, Hustead T. Hyponatremia and hypernatremia in the elderly. Am Fam Physician. 2000 Jun 15;61(12):3623-30. Rose B, Rennke H. Disorders of water balance. In: Rose B, Rennke H, eds. Renal Pathophysiology – The Essentials. Baltimore: Williams & Wilkins; 1994:91.

6.2. HYPONATREMIA Step 1) First ensure patient is assymptomatic. If symptomatic give hypertonic saline (and if necessary furosemide) until resolved. Once patient is assymptomatic remember to raise Na slowly – should check Na frequently. Step 2) If Hyperosmolar: Remove osm (i.e. treat hyperglycemia, hyperlipidemia etc.) For every 100 mg/dl increase in glucose >100, Na will decrese 1.5 mg/dl. Some osms may require dialysis to be removed. Step 3) If Hypoosomolar Hypovolemic: Calculate Na deficit. Na deficit = (140 – current Na) x (.6 x wt in kg)

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Can replace with Na deficit with normal saline. Should replace no more than half of deficit in first 24 hours. Volume can be replaced with dextrose or .45% saline, but must be factored into Na deficit. Step 4) If Hypoosmolar Euvolemic: Restrict free water intake. Remove causes of SIADH, treat thyroid/adrenal deficiencies. If necessary consider demecloycline. Step 5) If Hypoosmolar Hypervolemic: Promote loss of Na and water (with furosemide) replace with normal/hypertonic saline. Like hypernatremia, hyponatremia must be considered in the context of sodium, water and tonicity. Hyponatremia may present as either an acute or chronic condition and may pose a danger if too low, or if corrected too quickly. Patients with severe (and usually acute or acute/chronic) hyponatremia will often present with symptoms that include confusion, nausea, vomiting, seizure activity and coma. [1] The most severe symptoms usually occur once the patient‘s sodium has fallen below 120 meq/L and require immediate attention. Infusion of hypertonic saline is recommended, though only until the symptoms subside. It is important not to overcorrect too quickly to avoid pontine mylenolysis. Most authorities recommend a rate of around 0.5 mg/h, replacing no more than half the deficit within the first 24 hours. [2,3] Once stabilized, workup of the underlying disorder can be undertaken. Tonicity and intravascular volume should be assessed – tonicity by checking serum osmolality and intravascular volume via physical examination. [1] Hypertonic (or hyperosmolar) hyponatremia, an added solute is present, either decreasing the relative percentage of plasma sodium or by increasing plasma osmolality pulling water from the intracellular to extracellular space. Excessive levels of serum glucose (usually due to diabetes), proteins (myeloma, amyloidosis), glycerol and mannitol (iatrogenic) or lipids (severe hyperlipidemia) are frequent culprits. [4] Hypotonic hyponatremia can be assessed by considering the patient‘s intravascular volume and urine sodium. Patients who are hypovolemic usually have lost sodium and water that has subsequently been replaced with hypotonic fluids. Urine sodium can help to determine whether the losses are intra or extra renal in origin. Hypervolemic patients are likely to suffer from heart, renal or liver failure. Euvolemic patients usually suffer from an underlying endocrine disorder (hypothyroidism, glucocorticoid deficiency or syndrome of antidiuretic hormone). Often when euvolemic patients undergo a work up that rules out underlying endocrine disorders and SIADH is a resulting diagnosis of exclusion. While this is

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not necessarily an inappropriate approach, the diagnostic criteria for SIADH should be reviewed to assure the accuracy of the diagnosis. [4] Treatment of hyponatremia is dependant upon the underlying diagnosis. One of the strengths of the diagnostic approach outline about, is its easy integration with an approach to treatment. Patients with hyperosmolar hyponatremia are treated by the removal of the added osm (sometimes necessitating hemodialysis). Treatment of patients with hypoosmolar hyponatremia involves an initial estimate of the sodium deficit as outlined above. It is important to consider replacement of both volume and sodium separately (though obviously replacement of one can improve the other). Sodium replacement can be undertaken using normal saline, volume can be replaced with any colloid solution. Hyperosmolar hyponatremia is treated by removal of both sodium and water with diuretics. Euvolemic hyponatremia is treated with free water restriction. It is important to remind patients and providers that ―free water‖ is anything that is less salty than, say, broth. This includes milk, tea, coffee, soda and even sports drinks. If free water restriction fails, demeclocycline (which is theorized to block the production of ADH binding proteins) or one of the vaptans (ADH antagonists) can be attempted. [5]

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Hyponatremia Serum Osmolality

Normal/Hig h Hyperglycemia Added Osm (mannitol, triglyceride etc.) Hypovolemic c UNa 20

Extra renal loss Vomiting Diarrhea Third spacing

Low Assess Volume Euvolemic UNa 20

Renal Failure

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UNa >20

Nephrotic syndrome Cirrhosis CHF

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Hyponatremia Treatment Infuse hypertonic saline, lasix if necessary

Symptomatic Asymptomatic

Hyperosmolar Remove added osm

Hypoosmolar Hypovolemic: Calculate Na deficit, replace volume and Na

Hypoosmolar Euvolemic: Fluid restrict, if fails, demeclocycline or vaptan

Hypoosmolar Hypervolemic: Diurese with lasix, replace with nl saline

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SIADH Diagnositic Criteria Essential: 1- Serum Osm < 270 2- Urine Osm > 100 3- Clinical Euvolemia 4- Increased Urine Na with normal Na/water intake 5- No adrenal, pituitary, thyroid or renal insufficiency 6- No diuretic use Additional: 1- Abnormal water load test* 2- Elevated ADH level relative to plasma osmolality 3- No correction of Na with volume expansion, but improvement with volume restriction * Water loading test: 20mL/kg D5W given, patient should excrete 90% in 4 hours with urine osm < 100.

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REFERENCES [1]

[2] [3] [4] [5]

Verbalis JG. Adaptation to acute and chronic hyponatremia: Implications for symptomatic diagnosis and therapy. Seminars in Nephrology. 1998;18:3-19. Douglas I. Hyponatermia: Why it matters, how it presents, how we can manage it. Cleve Clin J Med. 2006 Sep;73 Suppl 3:S4-12. Han DS, Cho BS. Therapeutic approach to hyponatremia. Nephron. 2002; 92(Suppl 1):9-13. Goh KP. Management of hyponatremia. Am Fam Physician. 2004 May 15;69(10):2387-94. Dixon MB, Lien YH. Tolvaptan and its potential in the treatment of hyponatremia. Ther Clin Risk Manag. 2008 Dec;4(6):1149-55.

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6.3. HYPERKALEMIA Step 1. Severe hyperkalemia is an Emergency. Any assessment and treatment should be mindful of this… Check an EKG. Hyperkalemia changes progress as follows: Peaked T waves Prolonged QRS and PR interval Diminished P wave QRS becomes sine wave Ventricular fibrillation Step 2. Stablize the myocardium: Give Calcium Gluconate 10-30ml of 10% Ca Gluconate over 4 minutes Increase cellular uptake. Redistribute K from extracellular to intracellular compartments: Give an amp of D50 and 10 units of regular insulin intravenously. Step 3. Remove K from the body: 1) Kayexalate 20-50g PO every few hours until diarrhea or PR 50- 100g in 250cc water rectally. 2) Furosemide – intravenous dose depends on renal function. 3) Dialysis. Patients with hyperkalemia may present with lethargy, weakness and nausea. Alternatively, they may present with no symptoms at all. Patients at risk of

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hyperkalemia should have a serum potassium level checked if there is any suspicion that the condition may be present. When an elevated serum potassium level is present, consideration should be given to the possibility of hemolysis and a false positive test. Rechecking suspicious elevated potassium levels should be undertaken, but should not delay treatment. At the first sign of hyperkalemia an electrocardiogram should be obtained. The EKG changes that occur with hyperkalemia start with a peaking of T-waves which is followed by a widening of the QRS complex and ends with a sine wave. Any of evidence of these EKG changes should be followed by attempts to stabilize the myocardium with calcium gluconate and an aggressive effort to rapidly decrease serum potassium levels. [1] Hyperkalemia Diagnosis Possible pseudohyperkalemia

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yes

blood cell lysis marked leukocytosis

no

TTKG* > 7

TTKG 20

RAS Malignant hypertension

No hypertension

Renin < 20

Cushing's Primary hyperaldostronism Exogenous steroids

Urine Cl > 20

Diuretics Bartter's/Gitelman's

* TTKG = (Urine K / Plasma K)/(Urine osm/Plasma osm)

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Urine Cl 13 mg/dL) with adequate urine output: hydrate with normal saline and consider addition of loop diuretic. If symptomatic with limited urine output or renal failure: consider hemodialysis. Step 3. 80-90 % of hypercalcemia is due to either malignancy or hyperparathyroidism - check an intact PTH level and examine patient for possible malignancy. Step 4. If calcium levels continue to remain high, try oral phosphorus, intranasal calcitonin and/or bisphosphonate. Make sure thiazide diuretics have been stopped. Step 5. Discuss dietary phosphorus, intake of vitamins (especially D/calcitriol) and modify as necessary. Patients with hypercalcemia present with signs of lethargy and somulence. As hypercalcemia worsens, patients gradually become comatose. Severe muscle weakness and polyuria are generally present as well. Polyuria is an important symptom, as it often leads to dehydration, which worsens the patients hypercalcemia. [1]

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The initial assessment of hypercalcemia should include measurement of both ionized and total calcium levels, as well as albumin to allow for correction. Most patients with hypercalcemia, particularly those with severe hypercalcemia, have either hyperparathyroidism or malignancy. [2] As a result, measurement of intact parathyroid hormone and assessment for possible malignancy (chest x-ray, prostate specific antigen, breast exam etc.) [3] are the first steps in a diagnostic workup. Treatment Intravenous fluid and loop diuretics Oral phosphorus Calcitonin Bisphosphonates Pamidronate Etidronate

Action Calciuresis

Time to Onset Minutes

Binds calcium in diet, prevents absorption Inhibits osteoclastic activity Inhibits osteoclastic activity

Hours Minutes/hours Hours/days

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Total Calcium Correction: Decrease serum calcium 1 mg/dL for every .8 g/L decrease in serum albumin PTH, Phosphorous, Urine Calcium

PTH elevated

Phos Elevated Secondary or Tertiary HyperPTH: Check serum creatinine for kidney disease

PTH NL/Low

Phos Nl/Low Primary HyperPTH Lithium

High Urine Ca

NL/Low Urine Ca

Malignancy Granulomatous disease Hyperthyroidism Immobilization

Thiazides Milk-Alkali Syndrome FHH

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Electrolyte Disorders Causes of Hypercalcemia Hyperparathyroidism Primary Secondary Malignancy PTH related hormone Solid tumors Increased bone reabsorbtion Multiple myeloma (OAF) Bone metastases Hypervitaminosis D Lymphoma Increased Ca intake Milk Alkali Syndrome Hypervitaminosis D Granulomatous disease Acromegaly Decreased Ca loss Thiazide diuretics Familial hypocalcuric Hypercalcemia Renal failure Increased bone reabsorption Immobilization Hyperthyroidism Theophylline toxicity

75

Serum Phosphorous

Urine Calcium

NL/Low High or Low

High High

NL/Low

High

NL

High

Low

High

NL/High

Low

NL/High

High

NL/Low NL

Low Low

High

NL/High

NL/High NL NL

NL/High NL/High NL/High

Less common causes of hypercalcemia include milk-alkali syndrome, [4] characterized by large ingestions of calcium (usually in the form of antacids – think TUMS), granulomatous diseases (sarcoidosis and tuberculosis) [5] and the use of thiazide diuretics. Large doses of vitamin D can lead to hypercalcemia as can thyrotoxicosis. Finally, immobilization causes increased bone resorption. Treatment of hypercalcemia generally begins with hydration. A loop diuretic can be added to enhance calcium excretion. In patients with renal failure, dialysis may be necessary to remove excess calcium. Other treatment options include biosphosphonates, calcitonin and oral phosphorus. Bisphosphonates (pamidronate and etiodronate) inhibit osteoclasts and provide a decrease in serum calcium that lasts for days. Calcitionin provides a more transient decrease, but has the added benefit of decreasing bone pain due to malignancy. [1]

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6.6. HYPOCALCEMIA

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Step 1. Calculate corrected calcium level (for every 1mg/dL in serum albumin, serum calcium should decrease by .8 mg/dL) – or just check ionized calcium level to ensure diagnosis of hypocalcemia. Step 2. If symptomatic, adminster intravenous calcium. Step 3. Measure serum magnesium and intact parathyroid hormone. Step 4. Replace magnesium in low. Oral calcium and vitamin D can be administered to treat chronic hypocalcemia. The overwhelming majority of calcium in the body is sequested in bone. Much of what remains in circulation is protein bound (40%) or complexes with small anions, with the remainder free or ionized. It is the free/ionized calcium that is biologically active. As a result, serum protein level may affect total serum calcium levels. Albumin is the most prevalent serum protein and for every 1 g/dL decrease in serum albumin (below 4) total serum calcium levels should fall by .6 to .8 mg/dL. Ionized levels will not change. Thus, when the total serum calcium level is low, a first step is to check serum albumin and/or ionized calcium level. [1] Hypocalcemia may present with tetany, Chvostek‘s sign and a widened QT interval. More commonly it is asymptomatic. After measuring serum albumin and/or checking ionized calcium levels, the next test that should be undertaken is a careful history and physical examination. A variety of etiologies cause hypocalcemia, most of which are immediately apparent when examining the patient. These include, but are not limited to: sepsis, acute pancreatitis, rhabdomyolysis, tumor lysis syndrome, hungry bone syndrome (present following parathyroidectomy and chronic renal failure. [6] A variety of medications may lead to hypocalcemia as well, including gentamiacin, dilantin and cisplatin. Citrate and oral phosphorus causes hypocalcemia. Citrate is used to anticoagulate blood products, so transfusions may lead to hypocalcemia as well. If a patient presents with hypocalcemia and is symptomatic, intravenous calcium can be given via infusion. Calcium gluconate may be administered directly as well. Oral calcium is not quickly absorbed, but is often helpful over longer periods of time. Ergocalciferol (if renal function is intact) or calcitriol (if kidney function is impared) will help raise serum calcium levels, particularly if the patient is vitamin D deficient or has recently had a parathyroidectomy (and has hungry bone syndrome). [7]

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Hypocalcemia Correct Calcium = Ca decrease of .8 mg/dl for every 1 mg/dl decrease in albumin and/or check ionized serum calcium Low corrected Calcium and ionized calcium

Serum PTH

Low

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Hypoparathyroidism Hypomagnesemia

High

High Serum phosphorous

Renal Failure Rhabdomyolysis Laxatives Phosphate administration

Normal/Low Serum phosphorous Pancreatitis Hypovitaminosis D Drugs/Toxins Table x

Drugs/Toxins causing Hypocalcemia Gentamiacin Cisplatinum EDTA Mithramyacin Dilantin Phenobarbitol Citrate (including when as a part of transfusions) Colchicine Ethylene Glycol Foscarnet Bisphosphonates Oral phosphorus Floride

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Hyper/hypocalcemia References [1] [2] [3] [4] [5] [6] [7]

Moe SM. Disorders involving calcium, phosphorus, and magnesium. Prim Care. 2008 Jun;35(2):215-37, v-vi. Bilezikian JP, Silverberg SJ. Clinical practice. Asymptomatic primary hyperparathyroidism. N Engl J Med. 2004;350:1746. Stewart AF. Clinical practice. Hypercalcemia associated with cancer. N Engl J Med. 2005;352:373. Fuss M, Pepersack T, Gillet C, et al. Calcium and vitamin D metabolism in granulomatous diseases. Clinical Rheumatology. 1992;11:28. Felsenfeld AJ, Levine BS. Milk alkali syndrome and the dynamics of calcium homeostasis. Clin J Am Soc Nephrol. 2006 Jul;1(4):641-54. Zivin JR, Gooley T, Zager RA, et al. Hypocalcemia: a pervasive metabolic abnormality in the critically ill. Am J Kidney Dis. 2001;37:689. Fadem SZ, Moe SM. Management of chronic kidney disease mineral-bone disorder. Adv Chronic Kidney Dis. 2007;14:44.

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6.7. HYPERPHOSPHATEMIA Step 1. Check renal function. If the patient has acute kidney injury treat underlying disorder. If patient has chronic kidney disease, start phosphate binders. Step 2. If renal function normal, check urine phosphate level. If elevated, consider either increased tissue breakdown (rhabdomyolysis, tumor lysis syndrome) or exogenous sources (phosphasoda enemas, phosphate antacids). Treat underlying disorder. Step 3. If normal renal function and decreased urine phosphate level, check intact parathyroid hormone level. Overwhelmingly, the primary cause of hyperphosphatemia is renal disease. [1] As glomerular filtration rates decline, phosphorus is not excreted from the kidney and hyperphosphatemia ensues. [1] This is usually associated with a decrease in serum calcium levels, and eventually, secondary hyperparathyroidism. If treatment of the underlying cause of kidney disease (and thus the etiology of the hyperphosphatemia) cannot be achieved, a decrease in dietary phosphorus and/or administration of phosphate binders should be tried. Daily phosphorus intake less than 1000 mg/day is recommended to decrease serum levels. A variety of

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phosphate binders are available. Administration of each is associated with an inherent set of advantages and disadvantages. [2] If renal function is normal, urine phosphate excretion can be measured. Causes of hyperphosphatemia and increased urine phosphate excretion are usually pretty obvious with a careful history and physical examination. Causes include tissue breakdown (rhabdomyolysis or tumor lysis syndrome) or exogenous sources (phosphasoda enemas or Carafate). [3] Treatment involves treatment of the underlying disorder or removing the exogenous source. When renal function is normal and urine phosphate levels are low, increased renal reabsorbtion of phosphorous is a likely etiology. Hyperphosphatemia Most hyperphosphatemia is due to renal failure – either acute or chronic Glomerular filtration rate

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< 20 ml/min (approximately)

> 20 ml/min (approximately)

Urinary Phosphate Excretion Renal Failure

< 1500mg/day

> 1500mg/day

Common causes of ARF associated with Hyperphosphatemia:

Common causes of ARF associated with Hyperphosphatemia:

Tumor lysis syndrome Rhabdomyolysis Trauma/Surgery Hypercatabolic states

Tumor lysis syndrome Rhabdomyolysis Trauma/Surgery Hypercatabolic states

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Phosphate binder Calcium Calcium carbonate (Tums) Calcium acetate (Phoslo)

Advantages Effective

Sevelamer (Renagel/Renvela)

No tissue deposition May improve cholesterol levels

Aluminum

Very effective

Lanthanum (Fosrenol) Magnesium

Disadvantages Potential high calcium load and subsequent vascular and tissue calcium deposition Expensive, may require more pills to achieve same phosphate lowering as other binders Aluminum deposition in bone and brain* Expensive Diarrhea, may cause hypermagnesemia

* not recommended for long term use.

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6.8. HYPOPHOSPHATEMIA Step 1. History and physical examination to assess whether or not the patient has adequate intake and/or excess losses of phosphorus. Step 2. Measure serum calcium and urine phosphorus levels. If urine phosphorus elevated check for loss of amino acids, glucose and other electrolytes (Fanconi’s syndrome). Step 3. If serum phosphorus > 1 mg/dL replace with oral phosphorus. If < 1 mg/dL replace with intravenous phosphorus. Patients with mild hypophosphatemia may be asymptomatic upon presentation. Those with more severe phosphorus depletion may have a variety of symptoms, ranging from neurological deficits to profound lethargy and weakness. Those with the most severe depletions are at risk for respiratory failure and death. One of the most critical concepts to understand in the assessment and treatment of hypophosphatemia is that of refeeding syndrome. Phosphorus is a necessary component of ATP metabolism. When total body phosphorus levels are low in a patient who is nutritionally depleted, the sudden introduction of food provides a stimulus for increased metabolism among a variety of cell types. [4] If adequate phosphorus is not available to handle the increased metabolic needs, severe hypophosphatemia may ensue over the next few days. In the worst case scenario, respiratory failure and rhabdomyolysis follow. Thus, before attempting

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to nutritionally replete a malnourished patient, begin repleting phosphorus stores. [5] Finding the etiology of hypophosphatemia often requires little more than a history and physical examination. Malnutrition due to poor oral intake or gastrointestinal losses from diarrhea or vomiting are common causes of low phosphorus levels. When an etiology is not readily apparent, urine phosphorus and serum calcium levels can be helpful in determining an etiology. High levels of urine phosphorus indicate hyperparathyroidism, Fanconi‘s syndrome or losses from thiazide diuretic administration. In the immediate aftermath of renal transplantation, patients will often become hypophosphatemic due to the effect of secondary hyperparathyroidism superimposed upon newly functioning kidney. [6] Hypophosphatemia Urine Phosphorous Excretion

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< 100 mg/dL

> 100 mg/dL

No Alkalosis Malabsorbtion Diarrhea/Vomiting Aluminum/Magnesium ingestion

Yes

Fanconi’s Syndrome

Hypercalcemia

Primary hyperparathyroidism

Normal Serum Calcium

Thiazides ATN Recovery Renal Transplantation Androgen administration Secondary hyperparathyroid

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Micah L. Thorp Fanconi’s Syndrome: Glucose, Amino Acid, Uric Acid, Phosphorous and Bicarbonate Wasting in Urine Cystinosis Heavy Metal poisoning: Lead, Cadmium Multiple myeloma Amyloidosis Wilson‘s disease Idiopathic

Treatment of hypophosphatemia involves replacement with either oral or intravenous phosphorus. Oral replacement is generally effective for mild hypophosphatemia while intravenous replacement is often necessary for more severe cases. [7]

Hyper/hypophosphatemia References

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[1]

[2]

[3]

[4] [5]

[6] [7]

Delmez JA, Slatopolsky E. Hyperphosphatemia: its consequences and treatment in patients with chronic renal disease. American Journal of Kidney Diseases. 1992;19:303. Kovesdy CP, Mehrotra R, Kalantar-Zadeh K. Battleground: chronic kidney disorders mineral and bone disease--calcium obsession, vitamin d, and binder confusion. Clin J Am Soc Nephrol. 2008 Jan;3(1):168-73. Markowitz GS, Stokes MB, Radhakrishnan J, et al. Acute phosphate nephropathy following oral sodium phosphate bowel purgative: an underrecognized cause of chronic renal failure. J Am Soc Nephrol. 2005;16:3389. Friedlander G. Regulation of renal phosphate handling: recent findings. Current Opinion in Nephrology & Hypertension. 1996;5:316. Marik PE, Bedigian MK: Refeeding hypophosphatemia in critically ill patients in an intensive care unit. A prospective study. Arch Surg 131 : 1043 –1047, 1996. Brame LA, White KE, Econs MJ. Renal phosphate wasting disorders: Clinical features and pathogenesis. Semin Nephrol. 2004;24:39. Brunelli SM, Goldfarb S. Hypophosphatemia: clinical consequences and management. J Am Soc Nephrol. 2007 Jul;18(7):1999-2003. Epub 2007 Jun 13.

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6.9. HYPERMAGNESMIA Step 1. Check kidney function and urine magnesium level. Step 2. If kidney function normal, assess possible sources of intake. Step 3. If kidney function diminished and urine magnesium low, assess thyroid and parathyroid function, diet. If kidney function diminished and urine magnesium level elevated, assess sources of intake.

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Most cases of hypermagnesemia are iatrogenic and can be easily identified with a careful patient history. Renal insufficiency markedly increases the risk of hypermagnesemia especially when patient with severe renal disease take magnesium containing laxative or antacids. A number of other conditions can cause mild hypermagnesemia including hyperparathyroidism, lithium use, familial hypercalcemic hypercalcuria and milk alkali syndrome. The administration of large doses of intravenous magnesium is common among women with preeclampsia and is used to prevent seizures. [1] Patient with hypermagnesemia present initially with nausea and vomiting which progresses to sedation, muscle weakness and decreased deep tendon reflexes. In cases of severe hypermagnesemia hypotension and bradycardia are followed by cardiac arrest. [2] Hypermagnesemia Urine Magnesium GFR

Normal Renal Function

Massive Mg overload – usually iatrogenic

Decreased Renal Function

Urine Mg < 5 mEq/day

Urine Mg > 5 mEq/day

Hyperparathyroidism Hypothyroidism Low sodium diet Volume Contraction

Milk of Magnesia Maalox Epson Salts Iatrogenic

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Treatment of hypermagnesemia involves removing the offending source, fluid and diuretics for patients with good renal function and dialysis for patients with renal failure. [3]

6.10. HYPOMAGNESEMIA

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Step 1. History and physical examination. Consider obvious etiologies. Step 2. Replace magnesium orally if possible with magnesium oxide. If unable to replace orally (magnesium oxide 12.5-25 mEq/day), can give intravenously if patient is symptomatic (magnesium sulfate 60100 mEq over 24 hours). Step 3. If no obvious etiology, check urine magnesium level. If low, consider GI lossess. If elevated consider renal losses. Hypomagnesemia is most commonly the result of gastrointestinal losses due to starvation, diarrhea or malnutrition. Other causes include medications (gentamicin, cisplatnin) and acute medical conditions (DKA, hungry bone syndrome). History and physical examination is generally sufficient to identify many of these diagnoses. [4] When an etiology is not obvious, urine magnesium levels can be helpful. Low urine magnesium levels generally indicate either a lack of adequate intake or sequestration. [5] High urine magnesium levels can result from SIADH or hyperaldostronism. Hypomagnesemia Hypomagnesemia Urine Mg

< 1-2 mEq/day

GI Loss Starvation Diarrhea Malabsorption

Hungry Bone Syndrome post PTH surgery

> 3-5 mEq/day

Hyperaldosteronsim SIADH DKA

Renal losses ATN recovery Gentamicin Cisplatnum

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Treatment of hypomagnesemia requires treatment of the underlying disorder and replacement of lost magnesium. Replacement can be given orally with magnesium oxide or intravenously with magnesium sulfate. [6]

Hyper/hypomagensemia References [1] [2] [3] [4] [5]

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[6]

Onishi S, Yoshino S. Cathartic-induced fatal hypermagnesemia in the elderly. Intern Med. 2006;45(4):207-10. Wagner CA. Disorders of renal magnesium handling explain renal magnesium transport. J Nephrol. 2007;20:507. Innerarity S. Hypomagnesemia in acute and chronic illness. Crit Care Nurs Q. 2000;23:1 Tosiello L. Hypomagnesemia and Diabetes Mellitus. A Review of Clinical Implications. Arch Intern Med. 1996;156(11):1143-1148. Pham PC, Pham PM, Pham SV, Miller JM, Pham PT. Hypomagnesemia in patients with type 2 diabetes. Clin J Am Soc Nephrol. 2007 Mar;2(2):36673. Moe SM. Disorders involving calcium, phosphorus, and magnesium. Prim Care. 2008 Jun;35(2):215-37, v-vi.

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Chapter 7

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ACID/BASE DISORDERS Step 1. Begin by looking at pH. It is not possible to “overcompensate”, so the direction of the pH is indicative of at least one disorder (i.e. if the pH is 7.48 the patient has an alkalosis). Step 2. Check the direction of PCO2 and bicarbonate. In simple acid base disorders they should move the same direction. Step 3. Calculate compensation: Respiratory acidosis: (Acute) Change Bicarbonate = .1 x change in PCO2 (Chronic) Change Bicarbonate = .35 x change in PCO2 Respiratory alkalosis: (Acute) Change Bicarbonate = .2 x change PCO2 (Chronic) Change Bicarbonate = .5 x change PCO2 Metabolic acidosis: PCO2 = 1.5(Bicarbonate) + 8 or PCO2 = last 2 digits of pH Metabolic alkalosis: PCO2 = .6 x Bicarbonate Step 4. If metabolic acidosis calculate anion gap: AG = Na – (Cl + Bicarbonate) Step 5. Calculate osmolar gap: OG = Measured Osmoles – [2(Na) + (BUN/2.5) + (Glucose/18)] Step 6. Calculate Δ/ Δ = decrease in bicarbonate/rise in AG Acid/base disorders are common disorders that provide an opportunity to identify and diagnose underlying disorders. A systematic approach to assessing acid base disorders is helpful in the interpretation of the conditions that may have led to a specific disorder. This chapter will not discuss the detail of acid/base

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physiology, but will provide an outline of how clinicians can use acid/base levels to diagnose specific conditions. When assessing the acid/base status of a patient, it is helpful to start with a blood gas. While an arterial gas is preferable, a venous sample can be used as well. The first step is blood gas analysis is the pH. When the pH is greater than 7.40, the patient has an alkalosis, when less than 7.40 – an acidosis. Recognize that the body does not overcompensate for either an acidosis or alkalosis, thus when the pH is elevated (alkalosis) but other evidence suggests an acidosis, the patient MUST have an alkalosis. Situations may arise where both an acidosis and alkalosis are present at the same time. In these cases the disorders may effectively cancel each other out and the pH is half way between the two (7.40). Thus, a normal pH does not exclude an acid base disorder. [1] Following assessment of the pH, the pCO2 and bicarbonate levels should be considered. Acidotic patients with an elevated pCO2 have a respiratory acidosis, those with low bicarbonate a metabolic acidosis. Alkalotic patients with an elevated serum bicarbonate have a metabolic alkalosis and those with a decreased pCO2 suffer from a respiratory alkalosis. Simple acid base disorders are modified by compensatory processes to minimize change in pH. Following assessment of the primary disorder, these compensatory processes should be measured to identify whether or not a secondary disorder might be present. The metabolic disorders compensate rather quickly. Metabolic alkalosis compensates via hypoventilation leading to a rise in pCO2. Metabolic acidosis compensates by hyperventilation lowering pCO2, raising pH. Respiratory disorders compensate more slowly and have a wider variation in response (the kidneys moves slower than the lungs). Respiratory alkaloses are compensated by a decrease in serum HCO3. Respiratory acidosis are compensated by a rise in serum HCO3. Following calculation of compensation, assessment of the anion gap is necessary among patients with metabolic acidosis. The anion gap (serum sodium – serum chloride + serum bicarbonate) allows the clinician to determine whether or not an unidentified anion. Laboratories vary a bit in terms of how different anions are measured, but in an individual without a metabolic acidosis (or anything else) the anion gap should be approximately 12. [2] If the anion gap suggests the presence of an unmeasured anion, the clinician can narrow down the possible causes of the metabolic acidosis. If the anion gap is normal, the clinician can then check a urine anion gap (urine sodium + urine potassium – urine chloride) to determine whether or not an unmeasured anion is present in the urine. If the urine anion gap is > 10, it suggests the unmeasured ion is bicarbonate,

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indicating a likely loss of alkali through the kidney. If the urine anion gap is < 10, the unmeasured ion is likely ammonium, indicating a probable loss of alkali through the bowel. Finally, a diminished serum anion gap often suggests low levels of serum albumin. [2] Determining the underlying cause of an acid base disorder among patients with metabolic acidosis can often be enhanced by performing two other calculations, the osmolar gap and delta/delta. The osmolar gap is the difference between the measured and calculated serum osmolality. A large difference suggests an unmeasured osmole is present. Among patients with an anion gap metabolic acidosis the difference can be secondary to alcohol such as methanol or ethylene glycol. [2] Finally the delta/delta can allow the clinician to appreciate the presence of a secondary acid base disorder when an anion gap metabolic acidosis is present. The two ―deltas‖ are the changes from normal in anion gap and serum bicarbonate. Essentially, among patients with a solitary anion gap metabolic acidosis, every 1 mEq/L decrease in serum bicarbonate (from 24 mEq/L) the anion gap should rise by 1 (from 12). Thus a patient with a serum bicarbonate of 18 mEq/L (decrease of 6) should have an anion gap of 18 (increase of 6). If the patient has an anion gap that has not increased the appriopriate amount, a nonanion gap metabolic acidosis must be present. If the anion gap is greater than the decrease in serum bicarbonate, the secondary disorder is a metabolic alkalosis. pH

< 7.40 Acidosis

> 7.40 Alkalosis

PCO2

< 45 Metabolic

PCO2 - Equals last two digits of pH or 1.5 x Bicarbonate change + 8

PCO2

> 45 Respiratory

Bicarbonate change - Equals .1 x PCO2 change (acute) or .35 x PCO2 change (chronic)

> 45 Metabolic

PCO2 - Equals .6 x bicarbonate change

< 45 Respiratory

Bicarbonate - Equals .2 x PCO2 change (acute) or .5 x PCO2 change (chronic)

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7.1. RESPIRATORY ACIDOSIS/ALKALOSIS Step 1. How is the patient ventilating? If not, treat (intubate, treat sedation, drain pleural effusion etc…) Step 2. Measure compensation and assess chronicity of underlying disorder. Step 3. Treat underlying disorder.

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Respiratory acidosis and alkalosis are ultimately the result of changes in ventilation and respiration. Most causes of respiratory acidosis are the result of decreased ventilation, due to mechanical changes (i.e. kyphoscholiosis or pneumothorax) or respiratory drive (i.e. narcotics or neuromuscular disorders). Conversely, most respiratory alkaloses are the result of conditions that increase respiratory drive. The ultimate management of these disorders requires assessing and treating the disease that might underlies changes in respiration and/or ventilation. [3] Respiratory Acidosis Neuromuscular disorders Mechanical impediments to ventilation Kyphscholiosis Schleroderma Pleural effusion Pneumothorax CNS depression Narcotics Stroke Pneumonia Pulmonary Edema

Respiratory Alkalosis CNS disorders Tumor Infection CVA Anxiety Salicylates Progesterone Catecholamines Hyperthyroidism Pregnancy

7.2. METABOLIC AKALOSIS Step 1. Assess urine chloride. If elevated indicates vomiting, posthypercapnea or diarrhea. If normal, probable mineralocorticoid excess state. Step 2. Correct underlying disorder, intravascular volume (if depleted), serum chloride and serum potassium.

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Metabolic Alkalosis Exogenous source of alkali

Yes – remove source

No – Check urine chloride

Low Gastric losses Diuetics

High Check blood pressure

Low/NL Gitelman‘s Bartter‘s Hypokalemia

High Check plasma renin

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High ? malignant htn

High Primary hyperaldostronism

Low Check serum aldosterone

Low Cushing‘s Exogenous mineralcorticoids Licorice Liddles syndroms

Metabolic alkaloses are characterized by high serum pH and bicarobonate levels. Following assessment of compensation, urine chloride levels can direct the clinician to the underlying disorder. Initiating causes of metabolic alkalosis can be divided into hypochloremic/ hypovolemic/NaCl responsive states and normochloremic/normovolemic/NaCl unresponsive states. Thus, one of the first steps in determining the etiology is assessing a patient‘s intravascular volume and urine chloride levels. Vomiting, diuretics and chloride losing diarrhea exemplify the NaCl responsive states. The NaCl unresponsive states can be further divided based upon blood pressure. Those

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patients who are hypertensive may suffer from a perturbation in the reninaldosterone pathway. Checking renin and aldosterone levels are thus helpful in this situation. Patients who are normotensive may suffer from Bartter‘s or Gitelman‘s syndromes, or hypokalemia. [4] Conceptually, it is often helpful for clinicians to consider separate initiating and perpetuating causes of metabolic alkalosis. A metabolic alkalosis may have a definitive cause that resolves, but the alkalosis is perpetuated by: 1) hypochloremia, 2) volume contraction and/or 3) hypokalemia. For example, patients with persistent nausea and vomiting may develop a metabolic alkalosis due to the loss of hydrochloric acid from the stomach. [5] Patients will simultaneously be hypochloremic (due to chloride loss) and volume depleted. Once the vomiting has ceased, the low intravascular volume leads to increased proximal absorption of bicarbonate (increasing serum pH) and increased aldosterone levels which increases kaliuresis. Until intravascular volume, serum chloride and potassium levels are restored, the condition will self perpetuate. [6]

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7.3. METABOLIC ACIDOSIS Step 1. Determine if patient has elevated anion gap. Anion gap = Na – (Cl + HCO3) Step 2. If anion gap elevated, check osmolar gap – if gap is large, consider possible alcohol ingestion. If osmolar gap is normal consider salicylate ingestion, ketoacidosis, lactic acidosis or renal failure. Osmolar gap = measure serum osmolality – calculated serum osmolality Calculated serum osmolality = 2(Na) + BUN/2.8 + glucose/18 Step 3. If anion gap is normal, check urine anion gap. If urine anion gap is is elevated (positive) consider possible renal losses of alkali (such as renal tubular acidosis). If urine anion gap is decreased (negative) consider gastrointestinal losses of alkali. Urine anion gap = (Urine sodium + Urine potassium) – Urine chloride Determining the etiology of a metabolic acidosis can be extremely helpful in the assessment of an acutely ill patient. Metabolic acidoses can be divided into anion gap and non-anion gap acidoses. Anion gap acidoses have a relatively limited number of potential causes, which can be quickly assessed by measuring serum osmolality, serum creatinine,

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serum salicylate levels, lactic acid and serum ketones. [7] The can be done simultaneously and in an emergent setting are usually available within a short period of time. Patients with high osmolar gaps are most likely to have ingested either methanol or ethylene glycol (antifreeze). Patients presenting with these disorders may have ingested ethanol in addition, and will generally appear intoxicated. Ethylene glycol ingestion leads to calcium oxalate crystals in the urine (so look at the urine under a microscope…), and ultimately renal failure. Methanol (wood alcohol) is present in varnish and shellac. It often has a delayed presentation and ultimately can cause blindness. Lactic acid and ketones can be measured directly and are the result of an underlying disorder (starvation, diabetic ketoacidosis, etc). Lactic acidoses are often divided into Types A and B. Type A is the result of tissue hypoxia (sepsis, shock, respiratory failure, carbon monoxide poisoning, etc). Type B includes everything else (liver failure, leukemia, metformin, etc). Salicylate intoxication leads to stimulation of the respiratory center (thought due to the uncoupling of oxidative phosphoralation). Patients will thus present with a respiratory alkalosis in addition to an aniog gap metabolic acidosis. Patients with salicylate intoxication will often present with tinnitus and confusion. [8]

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Metabolic Acidosis Serum anion gap Na – (K + Cl) > 12

Check levels of: Methanol Uremia Diabetic Ketoacidosis Lactic Acid Ethylene Glycol Asprin Ketoacidosis

< 12

Check Urine Anion Gap Urine Na + Urine K – Urine Cl > 10

Renal loss Ureteral diversion Renal Tubular Acidosis

< - 10

GI loss Diarrhea

If alcohol: (Ethylene Glycol, Methanol) Check osmolar gap

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Non-anion gap metabolic acidoses tend to have a much larger number of potential etiologies. Broadly speaking, these can be broken down into those disorders caused by alkali loss from the gastrointestinal tract and those disorder with alkali loss from the kidney. The urine anion gap can help differentiate these sources by assessing whether or not ammonium is present in the urine. An elevated urine anion gap suggests renal losses of alkali. Patients with an elevated urine anion gap may have an underlying renal tubular acidosis. A decreased urine anion gap suggests a gastrointestinal loss of alkali. [9] Causes/associated findings/treatment of anion gap metabolic acidoses Methanol

Osmolar gap, methanol level, ingestion of varnish or shellac Elevated blood urea nitrogen, myoclonic jerks, confusion

Bicarbonate, ethanol, dialysis Myoclonic jerks, confusion

Elevated serum glucose, confusion, hypokalemia

Volume, Insulin

Alcoholic

Elevated β hydroxybuterate, follows binge drinking

Volume, watch for withdrawl

Starvation

Physical evidence of prolonged starvation Lactic acid level Osmolar gap, presence of calcium oxalate crystals in the urine Salicylate level, patient likely to have combination of metabolic acidosis and respiratory alkalosis, tinnitus, confusion

Improved nutrition, watch for refeeding syndrome Treat underlying problem Bicarbonate, ethanol, dialysis Gastic lavage, activated charcoal, alkalinize the urine

Uremia

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Ketoacidosis Diabetic

Lactic acidosis Ethylene Glycol Salicylates

Acid/Base References [1] [2]

Herd AM. An approach to complex acid-base problems: keeping it simple. Can Fam Physician. 2005 Feb;51:226-32. Kraut JA, Madias NE. Serum anion gap: its uses and limitations in clinical medicine. Clin J Am Soc Nephrol. 2007 Jan;2(1):162-74.

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.

Acid/Base Disorders [3] [4] [5] [6] [7]

[8]

Williamson JC. Acid-base disorders: classification and management strategies. Am Fam Physician. 1995 Aug;52(2):584-90. Galla JH. Metabolic alkalosis. J Am Soc Nephrol. 2000 Feb;11(2):369-75. Khanna A, Kurtzman NA. Metabolic alkalosis. J Nephrol. 2006 MarApr;19 Suppl 9:S86-96. Palmer BF, Alpern RJ. Metabolic alkalosis. J Am Soc Nephrol. 1997 Sep;8(9):1462-9. Fall PJ. A stepwise approach to acid-base disorders. Practical patient evaluation for metabolic acidosis and other conditions. Postgrad Med. 2000;107(3):249–258. Fall PJ. A stepwise approach to acid-base disorders. Practical patient evaluation for metabolic acidosis and other conditions. Postgrad Med. 2000 Mar;107(3):249-50, 253-4, 257-8 passim. Schlichtig R, Grogono AW, Severinghaus JW. Human PaCO2 and standard base excess compensation for acid-base imbalance. Crit Care Med. 1998 Jul;26(7):1173-9.

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[9]

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Chapter 8

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HYPERTENSION Step 1. Ensure patient has hypertension – measure correctly (resting for 5 minutes, appropriate cuff size). Step 2. Classify patient’s blood pressure based on two (or more) measures from two (two or more) office visits. Step 3. Among patients with prehypertension encourage lifestyle changes. Step 4. Patients with stage 1 or 2 hypertension should be started on pharmacologic therapy. Those without other “compelling indications” should be started on a thiazide with or without an angiotension converting enzyme inhibitor. Patients with indications for other medications (i.e. beta blocker for post myocardial infarction) should be initiated on these medications first. Step 5. Patients started on antihypertensive medications should initially be rechecked monthly to ensure blood pressure goals have been achieved. If they are not achieved with one medication a second medication should be added. Medication should be optimized before another is added. Step 6. Among patients with resistant hypertension secondary etiologies should be considered and pursued. Hypertension is the most common diagnosis recorded by outpatient physicians seeing adult patients. It is prevalent, leads to numerous adverse outcomes and has many treatment options. This chapter is not a comprehensive guide to hypertension management, but will provide an outline of assessment and treatment focusing on some of the specific issues relevant to practicing nephrologists. Any clinician providing care to adult patients should read the Joint

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National Committee‘s Seventh Report on the Diagnosis and Treatment of Hypertension. [1] The diagnosis of hypertension begins with an office measurement. While evidence is building that home blood pressure monitoring or 24 hour ambulatory monitoring may provide equivalent or better longitudinal association with adverse outcomes, office blood pressure measurements remain the standard of care. It is important that office blood pressures be measured correctly. Training staff to use the appropriate cuff size (the width of the cuff should extend at least 80% of then way around the upper arm), sit for the appropriate amount of time before checking (five minutes) and ensuring the arm is in the correct position may be the most important steps the clinician can take to ensure appropriate blood pressure management. [2] A single elevated blood pressure does not mean a patient has hypertension. Follow up blood pressures are necessary to formally make a diagnosis, though the length of follow up between the first blood pressure measurement and second blood pressure measurement is not clearly defined by JNC 7 or most other authoritative bodies. All patients, but especially those with ―prehypertension‖ should be encouraged to make lifestyle changes. These include weight loss, moderation of alcohol consumption, decreasing dietary sodium and starting the ―DASH‖ diet. Increase physical activity and stopping the use of non-steroidal anti-inflammatory (NSAID) medications should also be undertaken. [3] For those patients who have stage 1 or 2 hypertension, starting pharmacological therapy is likely to be necessary. Most antihypertensive regimines (including JNC 7) recommend starting treatment with a thiazide diuretic. Thiazides are often effective at very low doses. Increasing dosages seldom adds to antihypertensive effectiveness and only increases adverse effects. Major adverse effects of thiazides include gout, hypokalemia and hyponatremia, the latter particularly problematic among frail elderly women. [4] Following administration of thiazides, angiotension converting enzyme inhibitors (probably interchangeable with angiotension receptor blockers) are the next drug to add. Thiazides and ACEIs may have a somewhat synergistic effect that optimizes blood pressure control at low doses of both agents with modest adverse effects. The major adverse effect of ACEIs is a cough. This effect is far less prominent among patients taking an ARB. Both ACEIs and ARBs pose a risk of hyperkalemia and renal insufficiency. It should be noted that most patients who develop these effects have an acute illness (infection, heart failure exacerbation, etc.). [1] Additionally, a small increase in serum creatinine may be appropriate and indicate decreased glomerular pressure, which is often desirable. Checking

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serum creatinine and potassium a week or so after starting an ACEI or ARB can be helpful in avoiding these complications, though it may be as important to instruct patients to hold the medication when they become dehydrated or very ill. A variety of compelling indications may be present among patients being treated for hypertension. These include ischemic heart disease, congestive heart failure and diabetes. Many medications recommended for these chronic conditions are antihypertensives. Thus the recommended medications should be started among all patients with these conditions. [1]

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SECONDARY HYPERTENSION Many patients will require numerous medications. When a seemingly excessive number of medications is required for hypertension control, or there are symptoms of a secondary etiology for the patient‘s hypertension a workup for secondary causes of hypertension should be undertaken. While there are few clinical clues with high degrees of sensitivity and specificity they may provide a starting point at which to direct a workup of secondary causes. The most common cause of secondary hypertension is chronic kidney disease. Though the presence of chronic kidney disease may be apparent, whether or not it is the underlying etiology of hypertension is far more difficult (if at all possible) to determine. Aggressive treatment of hypertension in CKD is obviously relavent not only in terms of hypertension outcomes, but CKD outcomes as well. [5] Common mistakes are the underutilization of ACEIs/ARBs. These much be used with a bit more care as renal disease progresses, but are still a cornerstone of slowing CKD progression. [6] Often switching from thiazides to loop diuretics is necessary among hypertensive CKD patients to improve hypertension control. [7] Finally, it is important to consider the underlying cause of CKD, as it may be contributing to hypertension. Vasculitidies, outlet obstruction and nephrotic syndrome can all lead to increased treatment resistant blood pressure, and if remediated can substantially reduce or end the need for antihypertensive therapy. Hyperaldostronism due to adrenal hyperplasia may be evident by hypertension resistant to treatment with associated hypokalemia. Renin/aldosterone ratios are commonly used to assess whether or not hyperaldostronism is present. Both a ratio greater than 20 and an aldosterone level greater than 20 are necessary to confer a positive screen. A salt load can provide an easy means of confirmation. Once hyperaldosteronism is confirmed, imaging of the adrenal glands is often appropriate to ensure a adrenal hyperplasia, as opposed to the presence of an adrenal adenoma, which may need to be surgically

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removed. Since the presence of incidentalomas is a constant problem when imaging adrenal glands, if Conn‘s syndrome is suspected, both endocrinologic and surgical help may be warranted. More commonly, patients with adrenal hyperplasia respond to spironolactone or epleranone therapy. The response is often impressive at low doses of medication and can lead to a reduction or removal of other medications. [8] Renovascular hypertension is most apparent among patients with associated vascular disease, though occasionally younger patients with retroperitoneal fibroplasia will also develop the syndrome. A variety of tests are available to assess whether or not renovascular disease is present. These tests can be divided into ―functional‖ and ―anatomical‖ tests. Functional tests reflect changes associated with high levels of renin/aldosterone and include the captopril renogram. Anatomic tests include imaging of the renal arteries by MRI or CT. Studies of the sensitivity and specificity of all tests are quite variable and are all affected by assumptions about the efficacy of treatment. [9] Treatment options include surgical bypass (rarely used anymore), angioplasty and aggressive medical management. Anatomic repair is generally considered appropriate in the setting of RAS and CKD, when the goal is not just better hypertension control, but salvaging kidney function. More difficult are decisions regarding patients with renovascular hypertension and normal kidney function. Angioplasty offers improvements (cure) to some patients, but the longevity of the benefit is often unclear. Medication management is dependant upon the compliance and tolerance of the patient taking multiple medications, each with adverse effects, often with on a rigorous schedule. [10]

Normal Prehypertension Stage 1 Stage 2

SBP (mmHg)

DBP (mmHg)

Lifestyle modification

20 weeks

Yes

Yes

No

Increased

Anytime

No

Yes

Increased

Yes

LDH only

Normal

3rd trimester Late or post partum

Proteinuria Bland Sediment Proteinuria Active Sediment Normal

Acute Fatty Yes Liver Hemolytic Yes Uremic Syndrome

Proteinuria Hematuria

REFERENCES [1]

[2]

Chapman AB, Abraham WT, Zamudio S, Coffin C, Merouani A, Young D, Johnson A, Osorio F, Goldberg C, Moore LG, Dahms T, Schrier RW: Temporal relationships between hormonal and hemodynamic changes in early human pregnancy. Kidney Int54 :2056 –2063,1998Magee LA, Ornstein MP, von Dadelszen P. Management of hypertension in pregnancy. BMJ. 1999. 318:1332-6. Wagner LK. Diagnosis and management of preeclampsia. Am Fam Physician. 2004 Dec 15;70(12):2317-24.

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Pregnancy and the Kidney [3]

[4]

[5] [6]

Bernheim J, Plotkin E, Bernheim J, Korzets Z. It looks like, it smells like but is it just pre-eclampsia? Nephrol Dial Transplant. 2005 Feb;20(2):4512. Haram K, Svendsen E, Abildgaard U. The HELLP syndrome: clinical issues and management. A Review. BMC Pregnancy Childbirth. 2009 Feb 26;9:8. Magee LA, Ornstein MP, von Dadelszen P. Management of hypertension in pregnancy. BMJ. 1999 May;318:1332-6. Kong NC. Pregnancy of a lupus patient--a challenge to the nephrologist. Nephrol Dial Transplant. 2006 Feb;21(2):268-72. Haase M, Morgera S, Bamberg C, Halle H, Martini S, Hocher B, Diekmann F, Dragun D, Peters H, Neumayer HH, Budde K. A systematic approach to managing pregnant dialysis patients--the importance of an intensified haemodiafiltration protocol. Nephrol Dial Transplant. 2005 Nov;20(11):2537-42.

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[7]

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Chapter 10

NEPHROLITHIASIS

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Step 1. Get a stone! If stone analysis can be done it simplifies the diagnostic workup. If a stone analysis can’t be done, check a twenty four hour urine collection for uric acid, citrate, oxalate, creatinine, calcium, phosphorus, sodium and a urinalysis. Step 2. The kind of kidney stone should determine further workup and treatment. For all stone diseases, adequate hydration is helpful. Most diseases benefit from avoidance of NSAIDs and a low salt diet.

EPIDEMIOLOGY AND INITIAL APPROACH Nephrolithiasis is common disorder, estimated to affect 0.2% of the population annually. Approximately half of affected patients will not have another stone, half will within 5 years. Five to fifteen percent of the population will pass a stone at some point in their lifetime. A variety of acute presentations may be encountered requiring diagnostic workup and possibly referral to a urologist. Once the acute episode has past, patients often inquire about etiologies and preventative measures. [1] When considering potential metabolic evaluation of nephrolithiasis it is important to consider the context in which the individual patient presents. Patients who have had a single stone may be best served by a limited or even no work up. For those patients unfortunate enough to suffer multiple events, investigation and prevention is often a more serious matter as continued insults, besides being painful, can compromise renal function. The rationale for a minimal workup in the patient with a single stone relates to the low reoccurance rate (50% at one year, 75% at 20 years) and the need for

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lifetime therapy to prevent such an event. [1] Physician and patient need to weight the risk of stone reoccurance against the liklihood of compliance over the protracted period in which therapy will need to be maintained. If a limited workup is undertaken, it should be aimed at ruling out hyperparathyroidism. Patients with recurrent nephrolithiasis require a more extensive evaluation. The first step in the workup is to attempt to obtain a stone or gravel and determine it‘s makeup. Approximately 80-85% of stones are composed primarily of calcium oxalate or phosphate, 5% are uric acid, 1-2% are struvite and 1-2% are composed of cystine. [1,2]

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CALCIUM STONES A variety of factors can contribute to calcium stone formation. These include increased calcium excretion, increased uric acid excretion, reduced citrate excretion, low urine volume and increased oxalate excretion. Hypercaluria is most often idiopathic, usually resulting from increased intestinal absorption of calcium, though an impairment of renal tubular absorption (due to secondary hyperparathyroidism) and resorptive hyperparathyroidism (due to primary hyperparathyroidism) can occur as well. It is important to remember that hyperuricosuria contributes to both calcium and uric acid stones. Among these patients 10-20% will suffer from gout. Citrate inhibits stone formation by binding calcium. Acidosis, from a variety of etiologies, leads to hypocitrauria and is thought to be the mechanism in 20-60% of patients. Finally, hyperoxaluria often occurs as the result of increased intestinal absorption of calcium or, rarely, due to primary hyperoxaluria. [1]

URIC ACID STONES The formation of uric acid stones is greatly influenced by two factors: uric acid saturation and urine pH. Uric acid saturation typically occurs as the result of either overproduction of uric acid or increased secretion. Overproduction occurs as the result of increased purine consumption, myeloproliferative disorders or Lesch-Nyhan syndrome. Increased excretion may result from a decrease in renal tubular uric acid reabsorbtion, probenecid use and decreased intestinal uptake of uric acid (the intestine is normally responsible for approximately 50% of uric acid degredataion). [2]

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Urine pH has a profound impact on uric acid stone formation. Uric acid has two hydrogen ions that may be dissociated at pKs of 5.35 and 10 respectively. [2] The removal of one or both of these hydrogen ions significantly increases solubility of uric acid and decreases the likelihood of stone formation.

STRUVITE STONES Urea-splitting bacteria produce ammonium and hydroxyl ions which lead to the production of trivalent phosphate, carbonate apatite and struvite (magnesium ammonium). Urea splitting bacteria include Proteus, Klebsiella and Serratia. In the presence of a low urine volume, struvite and/or carbonate apatite can crystalize. Struvite stones are typically staghorn and will often cause hematuria and obstruction. [1]

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CYSTINE STONES Cystinuria results from a hereditary defect in amino acid transport. The defect results in cystine, ornathine, lysine and arginine (sometimes called COLA) excretion. [3] Patients with the disorder lose between 5 and 20 times the normal amount of cystine in their urine per day. Patients with hypercystinuria often develop stone disease in the third or fourth decades of life. Large numbers of stones often develop and patients occasionally require nephrectomy to aleviate the disorder.

WORKUP/INTERVENTION Acute stone disease is typically treated with fluids, pain medication and a urology consult. [4] Following the acute event, patients are often referred to nephrologists to evaluate and potentially intervene to prevent future nephrolithisis. Ideally, such an evaluation starts when the stone(s) are retained and analysed to determine composition. Unfortunately, in many cases stones are passed and never captured. In this case a more extensive workup may be necessary to determine how best to intervene. Additionally, it is important at the outset of a workup to determine whether a patient is likely to benefit from intervention. For example, a patient with a single epidsode of calcium nephrolithiasis is likely to have a second

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episode in seven years. Thus, a patient may decide that the necessary interventions (dietary changes, medicine administration, etc) are simply not worth the prevention of another episode. As a result, it is necessary for the clinician and patient to decide how extensive a workup to undertake prior to initiation. It should be noted that for all patients, regardless of the kind of stone produced, increased fluid intake is a cornerstone of preventing further episodes of nephrolithiasis.

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CALCIUM STONES The most limited workup for patients with a calcium phosphate or oxalate stone should probably include a serum calcium (to help identify hypercalcemia and thus hyperparathyroidism). More extensive efforts should include an imaging study (such as an intravenous pyelorogram) to ascertain whether more stones are present and whether the patient suffers from medullary cystic disease. Further studies might include 24 hour urine calicum, phosphorous, oxalate, citrate and sodium levels. [1,2] Interventions can be tailored to the outcomes from these 24 hour studies. Hypercalcemic hypercalciuria is a common etiology for calicum stones. High urine calcium levels are generally present and are treated with thiazide diuretics. Decreased urine citrate levels can result from increased protein intake and can be treated with dietary changes (decreased protein intake) or oral citrate/bicarbonate replacement. Increased urine oxalate levels can occur as a result of increased intestinal absorbtion. Oxalate forms an insoluable salt when combined with calcium. When intestinal calcium levels are low (due to diarrhea, malabsorbtion, etc) patients may experience increased oxalate absorbtion and subsequent increases in urinary levels of oxalate. [1] Thus treatment of patients with hyperoxaluria may involve decreasing oxalate in the diet and calcium supplementation.

URIC ACID STONES The workup of uric acid stones should include a serum uric acid level as well as a 24 hour urine uric acid collection. High serum uric acid levels may result from overproduction and may be treated with allopurinol. Excess excretion may

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be countered by increased fluid intake and urine alkalinization with oral citrate or bicarbonate. Efforts should be made to keep urine pH greater than 6. [2]

STRUVITE STONES As the etiology of struvite stones results from urea splitting bacteria, identifying and eradicating the offending bacteria is the primary approach to the disease. [1] Care should be made to ensure any anomaly that may predispose the patient to recurrent infections is addressed as well.

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CYSTINE STONES Once a patient with cystinuria has been identified, they should be followed both by a nephrologist, as recurrent nephrolithiasis may ultimately affect renal function, and a urologist owing the possibility of frequent stone formation. Treatment is relatively limited. It is impractical to attempt limiting cystine (and precursor methionine) in the diet. Increasing fluid intake helps. D-Penacillamine is sometimes used to bind cystine and prevent excretion. The extensive negative effects of D-Penacillamine limit long term use. [1] Often stones result from multiple etiologies. Patients with hypercalcuric hypercalcuria may have a nidus of uric acid resulting from overproduction. Thus, treatment may require a multiple therapies depending on the etiology.

REFERENCE [1]

[2] [3] [4]

Reynolds TM. ACP Best Practice No 181: Chemical pathology clinical investigation and management of nephrolithiasis. J Clin Pathol. 2005 Feb;58(2):134-40. Worcester EM, Coe FL. Nephrolithiasis. Prim Care. 2008 Jun;35(2):36991. Coe FL, Evan A, Worcester E. Kidney stone disease. J Clin Invest. 2005 Oct;115(10):2598-608. Portis AJ, Sundaram CP. Diagnosis and initial management of kidney stones. Am Fam Physician. 2001 Apr 1;63(7):1329-38.

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Chapter 11

RENAL REPLACEMENT THERAPIES

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INTRODUCTION One of the great successes of modern medicine has been the ability to provide treatment for patients with end stage renal disease, which previously meant certain death. The appropriateness of each modality varies depending on the patient‘s initial presentation and preferences. Hemodialysis and continuous replacement therapies are generally used in the setting of acute renal failure, while hemodialysis, peritoneal dialysis and renal transplantation are used once long term failure has been established. Each modality offers different advantages and disadvantages which must be taken into account prior to initiating therapy. While little preparation for renal replacement can be made for those patients with acute renal failure, those with chronic renal failure can greatly benefit from early intervention by their primary care physician. This chapter is by no means intended to be an exhaustive review of these therapies, nor will it present the stepwise approach to patient management provided by other chapters. The RRTs should be provided and overseen by a qualified nephrologist. Still, patients requiring RRT are commonplace and from time to time will be seen by other nonnephrologist clinicians. It is therefore encumbant that all clinicians have a basic understanding of RRT and some knowledge of common problems. With that in mind, this chapter will present a brief overview of the three primary modalities followed by a number of common problems related to RRT and how these might be addressed. A simple rule of thumb for physicians to follow when dealing with the chronic renal failure patient is the 30-20-10 rule. When the creatinine clearance has reached 30, preparation for hemodialysis needs to begin. If the patient has not

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been previously referred to a nephrologist, this is a good time to do it. A lengthy discussion regarding which renal replacement modality the patient will choose needs to be undertaken, and the subsequent social and financial referrals made to prepare for this particular choice. Many patients by this time will have seen a dietician regarding low potassium diets, further consultation regarding the diet the patient will need to follow while on dialysis or following transplantation. When the creatinine clearance reaches 20 access needs to be placed if the patient is to begin hemo or peritoneal dialysis. Final plans regarding the logistics of hemodialysis need to be made if this modality is selected. Finally, when the creatinine clearance reaches 10 to 15 renal replacement therapy should be initiated. GFR < 30

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< 20 < 10

Patient Preparation Should be seen by nephrologists, begin HD preparation, education, check for anemia, secondary hyperparathyroidism (if not already done) etc. Place hemodialysis access Begin dialysis

By closely monitoring the patient‘s progress in all of these areas, it is often possible to avoid acute intervention. Some patients may develop a rapid decline in renal function which precludes this methodical approach, but if possible, the transition to renal replacement therapy should be as smooth as is possible. One of the most important decisions the patients needs to make is the modiality of renal replacement therapy that will best suit their needs. There are clear advantages and disadvantages to each modiality. These need to be very clearly articulated to the patient prior to selection. Often the assistance of a social worker, trained in renal replacement therapy is helpful.

HEMODIALYSIS Hemodialysis can be preformed both in a dialysis unit or at home, though it is usually preformed in a centralized unit. The procedure of hemodialysis requires access to significant blood flows, which are generally accomplished via: 1) an arterial-venous fistula, 2) a graft or 3) central venous catheter. There are advantages and disadvantages to each kind of vascular access. Central catheters can be quickly placed and used immediately, but are more likely to have poor blood flows and become infected more readily than grafts or fistulas. Grafts are

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synthetic tubes that connect an artery and vein. Grafts are less likely to become infected or clotted than catheters, but more likely than fistulas. A fistula simply is simply the connection of a patient‘s own artery and vein. Over a matter of weeks (usually 6-12) the increased pressure from the artery causes the vein to enlarge. Fistulas are considered to be the most ideal means of vascular access due to the lower risk of infection or clot. Fistulas are not, however, immediately usable as they need time to mature. In many cases they never mature and are unusable. As a result, early placement of vascular access (think fistula) is considered an important goal of hemodialysis preparation. Once hemodialysis access is usable, dialysis can be started. The actual mechanics of dialysis are relatively straightforward. Two needles are placed in the patient‘s fistula or graft, one is used to withdraw blood and one returns it. Blood is then pumped from the arterial access through a semipermiable membrane. The membrane is constructed in a manner in which blood runs through lots of very small cellulose tubes housed within a larger tube. Within the larger tube dialysate is pumped in the opposite direction of the blood, bathing it. Molecules small enough to squeeze through the holes in the membrane are pulled across by the osmotic gradient and washed away with the dialysate. Blood is then returned via the venous access, creating a circuit of sorts. It is possible to dialyze a patient without using dialysate. This is accomplished by pushing blood through the membrane with the blood pump. Since there is no dialysate, the pressure from the blood pump pushes molecules small enough to pass through the membrane out. The resulting ultrafiltrate is subsequently removed. Electrolyte levels in the blood are controlled by adjusting levels in the dialysate. Thus, dialysate with a very low potassium level may be used in the treatment of a patient with very high serum levels, increasing the osmotic gradient and the subsequent amount removed from the blood. Hemodialysis is usually preformed three days a week on alternating days for an average of about 4 hours a session. There is no reason it can‘t be undertaken more frequently, but for obvious logistical reasons usually isn‘t. Common problems during dialysis runs include hypotension and poorly functioning dialysis access. Other issues include electrolyte problems and allergic reactions to antigens within the dialysate, though these are less common. Patients are weighed at the beginning of each dialysis run and over time a dry weight is established. Each time the patient presents to the dialysis unit they are weighed and the quantity of weight gained beyond the dry weight is removed. A variety of problems can occur with the dialysis procedure and are encapsulated in the table below.

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122 Problem Fistula or Graft won‘t work

Consider: Listen for bruit - if not present, fistula or graft likely clotted. May require angiographic procedure to assess. Vascular surgeon or interventional radiologist/nephrologists shuld be consulted.

Catheter won‘t flow

Attempt to manipulate catheter Can drip TPA into catheter - May have clotted or developed a fibrous sheath over the end of the catheter or may be misplaced. Stop ultrafiltration and assess patient. Common etiologies include: 1) inaccurate dry weight – overly aggressive ultrafiltration 2) decreased cardiac output. Other mitigation strategies include lowering dialysate temperature, administration of saline and holding blood pressure medications prior to dialysis If the patient has a catheter, likely has a catheter infection. Get blood cultures and administer antibiotics. If blood cultures are positive may need to remove catheter. Need to assess accuracy of dry weight. Usually indicates too much ultrafiltration. Can give hypertonic saline, quinine or Vitamin E to acutely help. Need to ensure dialysis access is working properly. May need greater time on dialysis.

Patient dialysis

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Micah L. Thorp

hypotensive

during

Fever during dialysis

Muscle cramping

Inadequate dialysis clearance

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PERITONEAL DIALYSIS Peritoneal dialysis uses the peritoneal membrane as a dialyzing surface. Patients on peritoneal dialysis have a catheter placed into the abdominal cavity. Dialysate is then instilled into the abdominal cavity creating an osmotic gradient with the dialysate on one side of the membrane and the small blood vessels on the inside of the abdominal wall. Solutes and fluid are transported across the membrane. The abdominal cavity is then drained and the solute replaced. This dialysis modality is undertaken primarily by patients at home and allows mobility and flexability of schedule and lifestyle. The dialysate most commonly used in peritoneal dialysis is composed of saline, lactate, calcium, magnesium and dextrose. The dextrose concentration is variable and can be used to increase or decrease the rate of solute transport. Commonly used concentrations include 1.5, 2.5 and 4.25 g/dL. These high concentrations lead to greater ultrafiltration. Early in the dwell the rate of ultrafiltration is rapid, but diminishes as the dextrose is gradually absorbed and the concentration across the peritoneal membrane equilibrates. If left in long enough, the hydrostatic pressure of the dialysate eventually overcomes the osmotic gradient and the ultrafiltrate (along with the dialysate) is reabsorbed. Thus a really, really long dwell time leads to less, rather than more, ultrafiltration. Peritoneal dialysis is sometimes done at fixed intervals (i.e. every 6 hours, four times a day). It can also be done with varying time intervals and is often done at night with the help of a machine (called a cycler). Continuous Cycler Peritoneal Dialysis (CCPD) is often done by having a series or short dialysate instiallations at night followed by a long one during the day. Other variations exist as well. Problem Peritoneal dialysis catheter isn‘t working

Cloudy dialysate

Erythema or exudates from catheter exit site

Consider Is the patient constipated? Often the catheter may be obstructed by bowel. Once the patient has had a bowel movement, consider and x-ray to see whether or not the catheter is positioned correctly. Peritonitis is the primary worry. Check for abdominal pain, send peritoneal fluid for cell counts and cultures. Treatment with intraperitoneal antibiotics is appropriate. For both diagnosis and treatment, use the ISPD guidelines at www.ispd.org. Consider possible exit site infection. Need to culture exudates and treat based on ISPD guidelines at www.ispd.org.

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As dialysate has significant quantities of dextrose, which is absorbed, diabetic patients may have difficulty controlling their blood sugars. To counter this problem, insulin can be injected into the dialysate and is absorbed along with the sugar. Another common problem with peritoneal dialysis is peritonitis. Patients who develop cloudy dialysate, elevated white blood cell counts and/or abdominal pain are likely to have peritonitis and should be worked up and treated with this in mind. Treatment of peritonitis is often accomplished using intraperitoneal antibiotics, which are both effective and convenient.

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RENAL TRANSPLANTATION In many ways renal transplant is the most ideal form of renal replacement therapy. No other form of renal replacement can totally replicate the functioning of an actual kidney. There are, however, risks associated with transplantation and not all ESRD patients are appropriate renal transplantation candidates. It is important at the outset to realize that renal transplantation, unlike other forms of solid organ transplantation, is typically not a life saving procedure. While the patient‘s quality of life may be markedly improved with a renal allograft, it is choice rather than a necessity. In this context one must remember to ―first do no harm‖. Careful screening and preparation are necessary to minimize the risk of harm as much as possible and should not be expidited at the expense of increasing the risk. The pretransplantation evaluation of a potential transplant recipient is often lengthy. Referral of a potential recipient can occur either before or after dialysis is started. If care is taken in timing the referral the patient may limit or even avoid spending time on dialysis. Renal allografts are placed in the iliac fossa, with the renal artery anastomosed end to end to the internal iliac artery. The renal vein is anastomosed end to end with the external iliac vein. The ureter is attached to the interior of the bladder after going through a long subcutaneous tunnel. The procedure usually takes three to five hours. Living related transplants often make urine during surgery. Cadaveric transplants often do not. Various techniques are used to anastamose multiple vessels. Patient undergoing renal transplantation require immunosuppression (the only exception to this are identical twins). Over the last two decades the number of immunosuppressive medications and strategies have markedly increased. Some commonly prescribed medications include azathioprine, mycophenalate mofitil,

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cyclosporine, tacrolimus and prednisone. A variety of antibodies have been developed and are applied at the time of transplantation.

Azathioprine AZA is a purine analog that is metabolized in the liver to 6-mecaptopurine, which is then converted to thioinosinic acid. Thioinosinic acid interferes with the synthesis of guanylic and adenylic acids from inosinic acid, thus interfering with the synthesis of DNA. AZA thus suppresses the proliferation of activated T and B lymphocytes. The dosage of AZA is usually 1-3mg/kg/day, given as a single daily dose. Consistent with its mode of action, the primary side effect of AZA is bone marrow suppression. Frequently, all three cell lines are effected. In the early postoperative period, careful monitoring of blood counts is important. If cell lines are suppressed, AZA should be suspected and stopped. Great care must be taken when giving AZA to patients taking allopurinol, which inhibits the breakdown of AZA. If given together, reduce the allopurinol dose 33%.

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Mycophenolate Mofenti MMF is converted to mycophenolic acid and subsequently inhibits inosine monophosphate dehydrogenase. A deficiency of guanine and deoxyguanine nucleotides with a corresponding increase in adenosine nucleotides shuts down the de novo purine synthesis pathway. Lymphocytes are quite dependent on this pathway and are thus selectively inhibited. The dosage of MMF is 2g/day, usually in divided doses. The primary side effects of MMF are gastrointestinal. Diarrhea frequently is associated with use and a rise in hepatic enzymes is sometimes associated as well. The occurrence of these symptoms should lead to a reduction in dosage.

Cyclosporin CsA binds to cyclophilin and the complex blocks calcinurin. Calcinurin normally activates several transcription factors including the nuclear factor of activated T-cells. T-cell activation is thus inhibited.

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Two forms of cyclosporin are currently available. Neoral is the brand name of a hydrophilic form of the drug, which is given in divided doses twice daily. Sandimmune is more hydrophobic and is only given once daily. Levels fluctuate much less during the course of the day with Neoral, in part due to consistent absorption. The usual oral starting dose of cyclosporin is 7 mg/kg/day. Intravenous cyclosporin is given via 24 hour infusion at approximately 1 to 2 mg/kg. Cyclosporin is nephrotoxic. Naturally it is difficult to differentiate between cyclosporin nephrotoxicity and other insults that affect renal transplant function, such as rejection. CsA levels need to be closely monitored during the post operative period, and dose changes made accordingly. As the patient‘s dose becomes more fixed, levels may be checked less frequently.

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Tacrolimus Tacrolimus is also a calcinurin inhibitor. It complexes with FK binding protein and the complex interacts with calcinurin. The usual dose of tacrolimus is mg twice daily. It is not given intravenously. Patients on tacrolimus who temporarily cannot take oral medications can be switched to intravenous cyclosporin if needed. Like cyclosporin, tacrolimus levels need to be monitored and dosage adjusted as needed. Like CsA, tacrolimus is nephrotoxic and similar difficulties exist in differentiating between nephrotoxicity and other renal insults. In addition to nephrotoxicity, neurotoxicity is common. Patients will often present with a slight tremor in addition of a multitude of other peripheral neurological manifestations. One of the benefits of using tacrolimus instead of CsA is the lack of hirsutism that occurs with tacrolimus.

Corticosteroids CS bind to intercytoplasmic receptors and form an active complex. Migrating to the nucleus they bind DNA in an area that induces immunoregulatory gene transcription. Various inflammatory mediators are subsequently inhibited. CSs are usually administered in tapering doses. During the perioperative period, very large doses are often given. These are tapered over two or three months to a maintenance dose of 5 to 15 mg/day.

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Side effects of long term steroid use are extensive. Monitoring for osteoporosis, cataracts, acne, psychosis, diabetes and opportunistic infections are one of the most important aspects of long term care since CS side effects are one of the greatest contributors to transplant morbidity.

COMPLICATIONS

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Medications/Interactions One of the frequent problems encountered by primary care physicians and nephrologists is managing transplant patient medications in conjunction with immunosuppressive therapy. A multitude of potential interactions exist, with variable clinical significance. Most frequent are drug interactions with cyclosporin and FK-506. CsA and FK are metabolized by the P450 CYP34A hepatic enzyme pathway, as are many other commonly used medications. As a result, CsA/FK levels may be increased or decreased depending of the effect of the other medication. In addition toxicities of all the immunosuppressive medications may be enhanced in the presence of antibiotics, antihypertensives or other commonly prescribed pharmaceuticals. Tables x-z denote many of the common clinically significant interactions between various medications and immunosuppressive. While by no means a complete list, it may provide a general guide for the sorts of interactions commonly encountered. For more detailed information, consultation with a pharmacist versed in the use of immunosuppressive is advisable. General principles that are often helpful: 1) ACEI are beneficial in treating erythrocytosis. This is a common, poorly understood complication of transplant. It responds well to ACEIs. 2) Treatment of community acquired pneumonia with outpatient antibiotics takes some careful consideration. Cephalosporins and penicillins have few interactions with immunosuppressives, but many of the macrolides and newer floroquinolones do. Trovafloxacin and azithromyacin are effective treatments with minimal interaction. 3) NSAIDs should be used only for short periods of time with close monitoring of renal function. 4) While TMP/SMX poses many potential risks and interactions, it is often used and works well, particularly for pneumocystis prophylaxis.

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Micah L. Thorp Gancyclovir is also commonly used in patients who have received a CMV positive graft, despite many potential toxicities.

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Infections When working with the infectious complications of a transplanted kidney, it is helpful to discern when the infection has occurred in relationship to transplantation. In the broadest context, one can consider infections occurring within the first month following transplant as likely surgically related. Infections occurring between one and six months are often opportunistic and those occurring after six months common community acquired. During the initial one month period, more than 90% of infections are due to lines, drains, post op pneumonias and other operative related infections. Great care in the post operative setting needs to be taken to prevent, diagnose and treat these infections. In the one to six month period the net immunosuppressive effect begins to increase risk substantially. Viruses, bacteria and parasites such as CMV, HSV, EBV, HBV and PCP all become more frequent. Fungal infections including aspergillous are common during this period as well. The late period is marked by the usual viral respiratory infections; community acquired pneumonia‘s and urinary tract infections as the rest of the population.

Malignancies The incidence of cancer rises during the course of immunosuppression such that by the fifteenth year post transplant, nearly 50% of patients have developed a malignancy. Most of these cancers involve the skin and with careful surveillance are easily identified and treated. Visceral malignancies including lymphomas, leukemia‘s and endocrine tumors also occur, with rates of 10-15%. The key to management of malignancy involves close surveillance and aggressive treatment. Skin surveys, stool guiacs, pap smear and mammography should all be undertaken with regularity. Early biopsy of skin lesions, appropriate referral for colonoscopy and other diagnostic maneuvers need to be aggressively pursued. Once a malignancy is discovered, particularly one not amenable to resection, decreasing immunosuppression should be considered. This is particularly true of

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lymphomas, which have been reported to completely remit to discontinuation of immunosuppression.

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Rejection Graft rejection is a frequent, though often subtle, problem faced by transplant recipients and physicians. Three mechanisms are used to catagorize rejection into hyperacute, acute, subacute and chronic categories, each of which has a different presentation and prognosis. Hyperacute rejection seldom occurs with modern crossmatching techniques. Prior exposure to class I HLA antigens or transplantation between ABOincompatible individuals leads to rapid leukocyte clumping and intravascular coagulation, sometimes precipitating on the operating table. The graft must immediately be removed if this occurs. Acute rejection usually occurs within the first three months following transplantation, presenting as little more than a rise in serum creatinine. Cellular infiltrates characterize both acute and subacute rejection. HLA differences are thought to lead to monocyte and T-cell recruitment which form these infiltrates. A biopsy is often employed when rejection is suspected, and aggressive immunosuppressive treatment started. Treatment strategies either involve high dose steroids or antilymphocyte antibody infusions. Most episodes of acute rejections are amenable to therapy. Sometimes multiple courses are needed. Chronic rejection is a poorly understood phenomenon that occurs over many years. It may represent the accumulation of many subacute events, chronic effects of immunosuppressive therapy or other as yet unidentified etiology. No therapy yet exists for chronic rejection.

Recurrent Disease Recurrent disease accounts for only approximately 5% of graft loss. Alport‘s disease, polycystic kidney disease, chronic pyelonephritis and chronic interstitial nephritis generally do not reoccur. Focal segmental glomerular sclerosis has a high risk of reoccurance if the time from diagnosis to end stage renal disease is less than 3 years or if it occurs in children. Hemolytic uremic syndrome has a variable risk of reoccurance. Wegner‘s reoccurence is approximately 15%. Lupus and anti-GBM disease need to be quiescent for a period of time prior to

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transplantation (perhaps 6 months). Patients with primary oxalosis may benefit from preemptive liver transplantation.

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APPENDIX 1.

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TREATMENT REGIMENS Intravenous Cyclophosphamide Therapy Calculate Body Surface Area (m2) = √Height(in) x Weight (lbs)/3131 1) Estimate glomerular filtration rate 2) If eGFR greater than one third of expected normal, cyclophosphamide dose of 0.75 g/ m2 can be administered in 150 mL of normal saline over an hour. 3) Induce diuresis with intravenous fluid or oral intake, such that urine output is approximately 250 cc/hour over the ensuing 24 hours. 4) If possible, administer mesna every 3-4 hours orally or intravenously. 5) Administer dexamethasone 10mg orally with zofran 4-8mg orally approximately 4 hours after starting cyclophosphamide infusion. Zofran may be repeated every 4-6 hours for another 3-4 doses. 6) Check leukocyte counts weekly. Nadir should occur after about 10-14 days. Common Adverse effects of Cyclophosphamide: Bladder cancer (particularly with prolonged therapy) Hair loss (usually after 4 weeks) Gonadal Failure Myopathy Lethargy Nausea/Vomiting

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Micah L. Thorp Oral Cyclophosphamide Therapy

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1) Calculate Body Surface Area (m2) = √Height(in) x Weight (lbs)/3131 2) Estimate glomerular filtration rate 3) If eGFR greater than one third of expected normal, cyclophosphamide dose of 0.75 g/ m2 can be administered in 150 mL of normal saline over an hour. 4) Induce diuresis with intravenous fluid or oral intake, such that urine output is approximately 250 cc/hour over the ensuing 24 hours. 5) If possible, administer mesna every 3-4 hours orally or intravenously. 6) Administer dexamethasone 10mg orally with zofran 4-8mg orally approximately 4 hours after starting cyclophosphamide infusion. Zofran may be repeated every 4-6 hours for another 3-4 doses. 7) Check leukocyte counts weekly. Nadir should occur after about 10-14 days.

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APPENDIX 2. THE DASH DIET (DIET APPROACHES TO STOP HYPERTENSION)

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Type of food

Grains and grain products (include at least 3 whole grain foods each day) Fruits Vegetables Low fat or non fat dairy foods Lean meats, fish, poultry Nuts, seeds, and legumes Fats and sweets

Number of servings Servings on a for 1600 - 3100 2000 Calorie Calorie diets diet

6 - 12 4-6 4-6 2-4 1.5 - 2.5 3 - 6 per week 2-4

7-8 4-5 4-5 2-3 2 or less 4 - 5 per week limited

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APPENDIX 3. DRUG DOSAGE IN CHRONIC KIDNEY DISEASE

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Drug

Antiarrythmics and Antihypertensives ACEIs Captopril Benzipril Lisinopril Fosinopril Ramipril ARBs Losartan Candisartan

Beta-Blockers Acetabutol Atenolol Carvedilol Labetolol Metoprolol Propanolol Sotalol

Usual Dosage (Normal Renal Function)

Dosage Adjustment (proportion of dose) CKD Stages 3-4 5*

5-25 mg q 8h 10 mg q 24h 10-40 mg q 24h 10 mg q 24h 10-20 mg q 24h

75% or q 1218h 75% 75% 100% 75%

25-100 mg q 24h

50% or q 24h 50% 50% 75% 50% 100%

100%

400-600 mg q 1224h 25-100 mg q 24h 6.25-50 mg q 12-24h 200-60 mg q 12h 25-100 mg q 12h 80-160 mg q 12h 160 mg q 24h

50% 50% or q 24h 100% 100% 100% 100% 30%

30-50% 50% or q 24h 100% 100% 100% 100% 15-30%

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APPENDIX 3. CONTINUED Alpha-Blockers Clonidine Methyldopa Doxazosin Terazosin Prazosin

0.1-0.6 mg bid 250-500 mg tid 1-8 mg q d 1-10 mg q d 1-10 mg q d

100% 100% bid 100% 100% 100%

100% 100% 100% 100% 100%

Vasodialators Hydralazine Minoxidil

25-50 mg tid 5-30 mg bid

100% 100%

100% bid 100%

25-75% check levels

25% bid check levels

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Cardiac Glycosides Digoxin

1 mg load 0.25-0.5 mg q d

Calcium Channel Blocker Amlodipine Diltiazem Felodipine Nifedipine Verapimil

5-10 mg bid 10 mg q d 10mg q d 10-20 mg tid 80 mg tid

100% 100% 100% 100% 100%

100% 100% 100% 100% 100%

Diuretics Acetazolamide Amiloride Bumetanide Chlorthalidone Ethacrynic acid Furosemide Metolazone Spironolactone Thiazides Torasemide Triamterene

250 mg q 12h 5 mg q d 1-2 mg q 12h 25 mg q d 50-100 mg tid 20-80 mg bid 5-10 mg q d 25 mg tid 25-50 mg q d 5 mg bid 25-50 mg bid

100% 50% 100% 100% 100% bid 100% 100% 100% bid 100% 100% 100%

avoid avoid 100% avoid avoid 100% 100% avoid avoid 100% avoid

Nitrates Isosorbide

10-20 mg tid

100%

100%

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Appendix 3

137

Antibiotics Aminoglycosides Gentamicin Streptomycin Tobramycin

1.7 mg/kg tid 7.5 mg/kg bid 1.7 mg/kg tid

100% q 24-48h 100% q 24-72h 100% q 24-48h

100%q 24-72h 100%q 72-96h 100%q 48-72h

Cephalosporins Cefazolin Cefepime Cefixime Cefotaxime Cefoxitin Cefpodoxime Ceftazidime Ceftriaxone Cephalexin

0.5-1.5 g q 6h 250 mg – 2 g q 8h 200 mg q 12h 1 g qid 1-2 g q 6-8h 200 mg bid 1-2 g tid .2 – 1 g bid 250-500 mg qid

100% q 12h 100% q 24h 150 mg q 12h 100% q 12h 100% q 12h 100% q 12h 100% q 24h 100% 100% tid

100% q 24h 100% q 24h 100 mg q 12h 100% q 24h 100% q 24h 100% q 24h 100% q 48h 100% 100% bid

Other Azithromycin Aztreonam Clarithromycin Clindamycin Dapsone Erythromycin Imipenum Meropenem Metronidazole Nitrofurantoin Sulbactam Sulfamethoxazole Trimethoprim Vancomycin

250-500 mg q d 12.5 mg/kg q 12h .5-1 g q 12h 150-300 mg q 6h 50-100 mg q 24h 150-300 mg qid .25-1 g qid .5-1 g q 6h 7.5 mg/kg q 6h 50-100 mg q 6h .75-1.5 mg qid 1 g q 12h 100-200 mg bid .5-1 g q 12h

Penicillins Amoxicillin Ampicillin Dicloxicillin Methicillin Nafcillin Penicillin G Penicillin VK Piperacillin Ticarcillin

250-500 mg tid 250 mg – 2 g qid 250-500 mg qid 1-2 g q 4h 1-2 g q 4-6h .5-4 million units 6h 250 mg q 6h 3-4 g q 4h 3 g q 4h

100% 50% q 12h 75% 100% unknown 100% 50% 500 mg q 12h 100% 100% bid 100% q 18h 100% q 18h 1 g q 1-3 d (check levels) 100% bid 100% bid 100% 100% q 6h 100% 75% 100% 100% q 6h 1-2 g q 8h

100% 25% q 12h 75% 100% unknown 50% 25% 500mg q 24h 50% don‘t use qd 100% q d 100% q d 1 g q 4-7 d (check levels) 100% q d 100% q d 100% 100% q 12h 100% 50% 100% 100% q 8h 1-2 g q 12h

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APPENDIX 3. CONTINUED

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Quinilone Ciprofloxin Levofloxin Norfloxacin Ofloxacin Sparfloxacin Tetracycline Doxycycline Minocycline Tetracycline Antimycobacterial, Antiparasitic and Antituberculous agents Atovaquinone Chloroquine Ethambutol Isoniazid Pentamidine Primaquine Pyrimethamine Quinine Rifampin Antifungal Amphotericin B Colloidal Lipid complex Fluconazole Flucytosine Griseofulvin Itraconazole Ketoconazole Miconazole Antivirals Acyclovir Amantadine Foscarnet Gancyclovir

500-750 mg q 12h 500 mg q 24h 400 mg q 12h 200-400 mg q 12h 400 mg q 24h

50% 250 mg q 24h 400 mg q 12h 200 mg q 12h 400 mg q 24h

50% 250 mg q 48h 400 mg q 24h 200 mg q 24h 50% q 48h

100 mg q 24h 100 mg q 12h 250-500 mg qid

100% 100% 100% q 12-24h

100% 100% 100% q 24h

750 mg q 12h 1.5 g over 72h 15-25 mg/kg q 12h 300 mg q 24h 4 mg/kg q 24h 15 mg q 24h 25-75 mg q 24h 650 mg q 8h 600 mg q 24h

100% 100% 100% q 24h 100% 100% 100% 100% 100% 100%

100% 50% 100% q 48h 100% 100% q 36h 100% 100% 100% q d 50%

20-50mg q 24h 3-6 mg/kg q 24h 5 mg/kg q 24h 200-400 mg q 24h 37.5 mg/kg q 6h 125-250 mg q 6h 100-200 mg q 12h 200 mg q d 200-1200 mg q 8h

100% 100% 100% 50% 100% q 16h 100% 100% 100% 100%

100% q 36h 100% q 36h 100% q 36h 50% 100% q 24h 100% 50% 100% 100%

5 mg/kg q 8h 100 mg bid 40 mg/kg q 8h 5 mg/kg q 12h

100% q 12-24h 100% q 48-72h 15 mg/kg q 12h 100% q 24-48h

50% q 24h 100% q 7d 6 mg/kg q 12h 100% 48-96h

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Appendix 3

139

Indinavir Lamivudine Ribavirin Saquinavir Tenofovir Zidovudine Antiparkinson Carbidopa Levodopa Arthritis Drugs Allopurinol Colchicine Probenicid

800 mg q 8h 150 mg bid 200 mg q 8h 600 mg q 8h

100% 33-100% q 24h 100% 100%

100% 15-33% q 24h 50% 100%

200 mg q 8-12h

100%

50%

1-6 tabs tid .25-8g q 8-24h

100% 50%

100% 50%

300 mg 24h 2mg then .5mg q 6h 500 mg bid

50% 50% don‘t use

25% 25% don‘t use

Diclofenac Etodolac Ibuprofen Indomethacin Ketoprofen Nabumetone Naprosyn Anticoagulants Warfarin Ticlodipine Enoxaparin Anticonvulsants Carbamazepine Gabapentin Phenytoin Sodium Valproate Topiramate Antihistamines Cetirizine Chlorpheniramine Diphenhydramine Fexofenadine Hydroxyzine Promethazine

25-75 mg bid 200 mg bid 800 mg tid 25-50 mg tid 25-75 mg tid 1-2 g q d 500 mg bid

50% 100% 100% 100% 100% 100% 100%

25% 100% 100% 100% 100% 50% 100%

Varies, monitor INRs 250 mg bid 30-40 mg bid

Monitor INRs 100% 100%

Monitor INRs 100% 50%

200-1200 mg 12-24h 300-600 mg tid 300-400 mg q d 15-60 mg/kg q d 100-400 mg q 12-24h

100% 300 mg 12-24h 100% 100% 50%

100% 150 mg q d 100% 100% 25%

5-20 mg q 24h 4 mg q 4-6 h 25 mg tid 60 mg bid 50-100 mg qid 12.5-25 mg q d

50% 100% 100% 100% q 24h 50% 100%

25% 100% 100% 100% q 24h 50% 100%

400 mg bid 20-40 mg q d 150-300 mg q d

50% 25% 50%

25% 10% 25%

Cimetidine Famotidine Ranitidine

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APPENDIX 3. CONTINUED Antidepressants Fluoxetine Paroxetine Sertraline

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Amitriptyline Despiramine Doxepin Imipramine Nortriptyline Bupropion Trazadone Venlafaxine Lithium (follow levels) Benzodiazepines Alprazolam Clonazepam Diazepam Lorazepam Temazapam Proton Pump Inhibitors Lansoprazole Omeprazole Corticosteroids Cortisone Dexamethasone Hydrocortisone Methylprednisolone Prednisolone Prednisone Hypoglycemics Acarbose Glipizide Glyburide Metformin

20 mg q d 20-60 mg q d 50-200 mg q d

100% 75% 100%

100% 50% 100%

25 mg tid 100-200 mg q d 25 mg q 8h 25 mg q 8h 25 mg q 8h

100% 100% 100% 100% 100%

100% 100% 100% 100% 100%

100 mg tid 150-400 mg q d 75-375 mg q d .9-1.2 g q d

100% 100% 50% 50%

100% 100% 50% 25-50%

.25-5 mg q 8h 1.5 mg q d 5-40 mg q d 1-2 mg q 8-12h 15-30 mg q d

100% 100% 100% 100% 100%

100% 100% 100% 100% 100%

15-60 mg q d 20-60 mg q d

100% 100%

100% 100%

25-500 mg q d .75-10 mg q d 20-500 mg q d 4-48 mg q d 5-60 mg q d 5-80 mg q d

100% 100% 100% 100% 100% 100%

100% 100% 100% 100% 100% 100%

50-200 mg tid 2.5-15 mg q d 1.25-20 mg q d

Do not use 50% Do not use

Do not use 50% Do not use

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Appendix 3

Hypolipidemics Atorvastatin Cholestyramine Colestipol Gemfibrazol Lovastatin Nicotinic Acid Pravastatin Narcotics Codiene Meperidine Methadone Morphine Propoxyphene Misc. Acetaminophen Asprin Buspirone Halperidol

141

500-850 mg bid

25%

Do not use

4 g q 4-6h 13-30 g q d 600 mg bid 20-80 mg q d 1-2 g tid 10-40 mg q d

100% 100% 100% 100% 50% 100%

100% 100% 100% 100% 25% 100%

30-60 mg q 4-6h 50-100 mg q 4h 2.5-10 mg q 8h 2.5-25 mg q 4h 65 mg q 8h

75% 75% 100% 75% 100%

50% Avoid 50% 50% Avoid

650 mg q 4h 325-650 mg q 6h 5 mg q 8h 1-2 mg q 8-12h

100% q 6h 100% q 6-8h 100% 100%

100% q 8h Avoid 100% 100%

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* Not on dialysis.

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APPENDIX 4. COMMON DRUG INTERACTIONS WITH IMMUNOSUPPRESSIVE MEDICATIONS Drug

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Cyclosporin/Tacrolimus Interactions Penicillins Penicillin Nafcillin Pipericillin Macrolides Clarithromyacin Erythromycin Azithromyacin Aminoglycosides Tobramyacin Vancomyacin Genamiacin Floroquinalones Trovafloxacin Sparfloxacin Ofloxacin Norfloxacin Lomefloxacin Levofloxacin Ciprofloxacin

Azathioprine/ Mycophena-late Interactions

Decreased CsA/FK levels

Increased CsA/FK levels Increased CsA/FK levels

Potentiates renal dysfunction As Above As Above

Decreased CsA/FK levels As above As above As above Decreased CsA/FK levels

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APPENDIX 4. CONTINUED Sulfonamides TMP/SMX

Misc Pentamidine

Increased CsA/FK metabolism, increased risk of nephrotoxicity

Increased risk of myelosuppression with AZA

Potentiates Nephrotoxicity Decreased CsA/FK levels

Increased metranidazole excretion

Rifampin Metranidazole

Isoniazid Antifungals Amphotericin B

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Antifungals Clotrimazole Fluconazole Ketoconazole

Itraconazole Nystatin Antivirals Acyclovir Gancyclovir Retinovir Zidovidine Stauvudine Zalcitabine Indinavir Saquinovir

Increased neurotoxicity with FK Increased nephrotoxicity

Increased risk of myelosuppressio n with AZA

Increased FK levels (mild) Increased CsA/FK levels Increased CsA/FK levels (severe)

Enhanced adrenal suppressive effects

Increased CsA levels

Increased risk of neurotoxicity Increased risk of neurotoxicity

Increased risk of myelosuppressio n with AZA

Decreased CsA levels

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Appendix 4

145

APPENDIX 4. CONTINUED Ca Channel Blockers Amlodipine Diltiazem

Felodipine

Nifedipine Verapamil

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Beta Blockers Atenolol

Labetolol Metoprolol Propanolol ACEIs Captopril

Enalapril Lisinopril Ramipril DIURETICS Furosemide Bumetamine Hydrochlorothiazides Amiloride Spirnolactone

Increase gingival hyperplasia with CsA Increased CsA, FK levels, Increased gingival hyperplasia with CsA Increased CsA levels (mild), increased gingival hyperplasia with CsA Increased gingival hyperplasia with CsA Increased CsA/FK levels, increase gingival hyperplasia with CsA Increased hyperlipidemia, hyperkalemia As above As above As above

May enhance hyperkalemia, reduces erythrocytosis As above As above As above

Increased hyperlipide mia As above As above As above May induce leucopenia As above As above As above

May increase hyperkalemia As above

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APPENDIX 4. CONTINUED Alpha-Blockers Clonidine Prazosin Terazosin Methyldopa Minoxidil

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Hydralazine NSAIDs

Antihistamines Benadryl Terfenadine Loratidine Astemizole Decongestants pseudoephedrine H2-Blockers Cimetidine

Ranitidine Famotidine Nizatidine Proton-Pump Inhibitors Lansoprazole Omeprazole Cholesterol Lowering Medications Cholestyramine Fluvastatin

Enhances hirsutism with CsA Potential decreased GFR, increased Na retention, edema

Increased risk of GI bleeding

Increased CsA/FK levels As above As above May worsen hypertension Mild increased CsA/FK levels, increased neuro and nephrotoxicity with CsA/FK

Increased myelosuppression

Decreased CsA/FK levels Increased risk of rhabdomyolysis, increased risk of hepatotoxicity with CsA

Decreased MMF levels

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Appendix 4 Lovastatin Pravastatin Simvastatin Gemfibrozil Antigout Allopurinol Colchicine Probenicid Anticonvulsants Carbamazepine Phenytoin Phenobarbital Other Cisapride

147

As above As above As above Increased risk of rhabdomyolysis Increased CsA/FK levels Increased risk of myopathy with CsA

Increased AZA levels, increased myelosuppression

Decrease CsA/FK levels As above As above

Increased CsA/FK levels As above

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Metoclopramide Sulcrafate

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INDEX

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A A1c, 25 abdomen, 46 abnormalities, 1, 18, 19, 46 absorption, 74, 92, 114, 126 accounting, 31 accuracy, 32, 66, 122 ACE inhibitors, 26, 109 ACEI, 4, 7, 23, 25, 26, 27, 99, 100, 101, 102, 127 acetate, 80 acid, 2, 53, 54, 71, 87, 88, 89, 92, 93, 94, 95, 113, 114, 115, 116, 117, 125, 136 acidosis, 69, 72, 87, 88, 89, 90, 92, 94 activation, 125 acute, 3, 26, 36, 37, 39, 40, 44, 46, 48, 51, 52, 53, 55, 58, 59, 65, 68, 70, 72, 76, 78, 79, 84, 85, 98, 102, 109, 113, 115, 119, 120, 129 acute interstitial nephritis, 40, 44, 53, 55 acute kidney injury, 40, 51, 58, 78 acute rejection, 129 acute renal failure, 36, 40, 48, 52, 59, 109, 119 acute tubular necrosis, 53, 59 ADA, 24, 25, 26, 27 adenoma, 99 adenosine, 125 ADH, 66, 67, 106 adjunctive therapy, 33, 34, 35

adrenal glands, 71, 99 adrenal hyperplasia, 99 agent, 26, 41, 55 agents, 26, 31, 40, 41, 55, 62, 98, 138 aggregation, 48 aggressive therapy, 44 albumin, 8, 10, 21, 23, 24, 58, 74, 76 albuminuria, 24, 27 alcohol, 89, 92, 93, 98 alcohol consumption, 98 aldosterone, 61, 70, 71, 92, 99, 100 aldosteronism, 71, 73, 103 alkali, 78, 83, 89, 92, 94 alkaline, 8 alkalosis, 87, 88, 90, 92, 93, 94, 95, 106 allergic reaction, 121 allograft, 124 allografts, 110, 124 allopurinol, 116, 125 alpha, 108 alternative, 40, 51 American Diabetes Association (ADA), 24, 28, 29 American Heart Association, 10 amiloride, 71, 72 amines, 13 amino acid, 80, 115 amino acids, 80 amlodipine, 136, 145 ammonium, 89, 94, 115

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150

Index

amyloid, 49 amyloidosis, 10, 42, 48, 49, 65 analog, 125 ANCA, 11, 23, 38, 39, 44 anemia, 17, 19, 20, 21, 35, 40, 42, 48, 59, 107, 110, 120 angiogram, 102 angioplasty, 100 angiotensin, 103 angiotensin-converting enzyme, 29 animal models, 52, 59 anion, 92 antacids, 75, 78, 83 antagonist, 29 antagonists, 66 anther, 46 antibiotic, 55 antibiotics, 12, 37, 46, 53, 57, 58, 122, 123, 124, 127 antibodies, 38 antibody, 3, 35, 129 anticoagulation, 34 anticonvulsant, 107 antidiuretic hormone, 65 antigen, 74 antihypertensive drugs, 100 anti-inflammatory drugs, 44 antiparasitic, 138 antiphospholipid antibodies, 109 anuria, 57 aorta, 102 apatite, 115 application, 17 ARB, 4, 7, 23, 25, 27, 98, 100, 101 ARBs, 25, 26, 27, 42, 98, 99, 105, 106, 135 arginine, 115 arteries, 100 arteritis, 38 artery, 8, 103, 121, 124 ascites, 57, 59 assessment, 68, 70, 71, 74, 80, 88, 91, 92, 97 assumptions, 100 asthma, 39 asymptomatic, 15, 76, 80 ataxia, 21

ATP, 80 ATPase, 61 atrophy, 37, 41 autoantibodies, 58 autosomal dominant, 45, 46 autosomal recessive, 45, 46 avoidance, 113 Azathioprine, 125, 143 azotemia, 54, 56

B B cell, 37 B lymphocytes, 125 bacteria, 12, 37, 115, 117, 128 bacterial infection, 57 balloon angioplasty, 102 basement membrane, 33, 34, 35, 40, 44 benefits, 20, 25, 26, 36, 46, 48, 126 benign, 45 beta blocker, 69, 97, 101 bicarbonate, 55, 56, 63, 70, 87, 88, 89, 92, 116, 117 bilirubin, 12 binding, 58, 66, 114, 126 binge drinking, 94 biopsies, 40 biopsy, 13, 20, 21, 30, 31, 32, 33, 34, 35, 36, 37, 38, 41, 48, 49, 53, 55, 107, 128, 129 Bisphosphonates, 74, 75, 77 bladder, 13, 35, 54, 124 bladder cancer, 12 bleeding, 5, 13, 46, 146 blindness, 93 blocks, 125 blood, 3, 4, 7, 11, 12, 13, 17, 18, 19, 21, 23, 24, 25, 26, 28, 30, 53, 71, 72, 76, 88, 91, 94, 97, 98, 99, 101, 102, 103, 105, 106, 108, 120, 121, 122, 123, 124, 125 blood cultures, 122 blood flow, 53, 120 blood gas analysis, 88 blood pressure, 3, 4, 7, 17, 21, 24, 25, 26, 28, 71, 72, 91, 97, 98, 99, 102, 103, 105, 108, 122

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Index blood urea nitrogen, 94 blood vessels, 123 body weight, 63 bolus, 56 bone marrow, 42, 48, 125 bone marrow biopsy, 48 bone marrow transplant, 42 bone resorption, 75 bowel, 82, 89, 123 bradycardia, 83 brain, 80 breakdown, 78, 79, 125 bruit, 102, 122 Bupropion, 140 burns, 62 bypass, 100

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C CAD, 8 calcitonin, 73, 75 calcium, 20, 21, 25, 27, 53, 69, 70, 73, 74, 75, 76, 78, 80, 81, 82, 85, 93, 94, 101, 109, 113, 114, 115, 116, 123 calcium channel blocker, 25, 27, 101, 109 calcium oxalate, 53, 93, 94, 114 cancer, 3, 12, 14, 78, 128, 131 candidates, 124 capillary, 38 carbon monoxide, 93 carcinomas, 47 cardiac arrest, 83 cardiac output, 53, 122 cardiovascular disease, 10, 17, 19 cast, 48, 49 cataracts, 127 catecholamine, 102 catecholamines, 90 catheter, 120, 122, 123 catheters, 120 cell, 37, 47, 48, 49, 80, 123, 125, 129 cell lines, 125 cellulose, 121 charcoal, 94 chemotherapy, 49

151

chewing, 71 CHF, 53 childbearing, 109 childhood, 36 children, 30, 33, 36, 37, 47, 58, 129 chlorambucil, 31, 33, 34 chloride, 63, 71, 72, 88, 90, 91, 92 cholesterol, 25, 80 chronic illness, 85 chronic kidney disease (CKD), 8, 17, 19, 21, 22, 51, 78, 99, 103 chronic rejection, 129 chronic renal failure, 5, 44, 76, 82, 119 cigarette smoke, 40 circulation, 76 cirrhosis, 56, 57, 59 cisplatin, 76 CKD, 17, 18, 19, 20, 21, 52, 99, 100, 102, 135 classes, 26, 33, 38 classical, 37 classification, 5, 22, 52, 95 clinical syndrome, 37 clinical trial, 26 clinical trials, 26 clinically significant, 127 clinician, 3, 12, 14, 41, 51, 53, 56, 61, 88, 89, 91, 97, 98, 116 CMV, 128 CNS, 90 coagulation, 106, 129 coffee, 66 COLA, 115 colonoscopy, 128 coma, 65 community, 127, 128 compensation, 87, 88, 90, 91, 95 complete remission, 38 complexity, 61 compliance, 100, 114 complications, 17, 19, 20, 21, 22, 26, 28, 34, 35, 45, 49, 99, 109, 128 composition, 115 concentration, 8, 57, 123 confusion, 65, 82, 93, 94 congestive heart failure, 17, 99

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152

Index

consensus, 5, 22, 38 conservation, 62 consumption, 98, 114 control, 4, 7, 21, 23, 24, 25, 34, 35, 46, 98, 99, 100, 109 controlled trials, 41 conversion, 71 coronary artery disease, 8 correlations, 2 corticosteroid therapy, 41 corticosteroids, 38, 110 cortisol, 71 Cortisone, 140 cost-effective, 8, 10 cough, 98 Coumadin, 107 CP, 82, 117 CPAP, 102 creatinine, 1, 2, 3, 5, 7, 8, 18, 21, 22, 23, 24, 26, 27, 32, 34, 39, 40, 41, 52, 55, 56, 57, 92, 98, 102, 113, 119, 129 crescentic glomerulonephritis, 44 critically ill, 78, 82 crystals, 93, 94 cues, 45 culture, 11, 12, 123 cyclophosphamide, 13, 31, 33, 36, 38, 110, 131, 132 Cyclosporin, 41, 54, 125, 126, 143 cyclosporine, 31, 125 cyst, 45, 46, 47 cysteine, 55 cystine, 114, 115, 117 cystinuria, 117 cystitis, 13 cystoscopy, 3, 11, 13 cysts, 45, 46, 47 cytology, 11, 12 cytotoxic, 34, 39

D dairy, 133 danger, 65 DBP, 100, 101

death, 22, 38, 80, 119 deaths, 47 decision making, 106 decisions, 100, 120 decompression, 46 deficiency, 19, 20, 22, 65, 72, 125 deficit, 61, 62, 64, 65, 66, 71 definition, 32, 52, 59 dehydration, 53, 70, 73 dehydrogenase, 71, 125 delivery, 70, 105, 107 deposition, 37, 49, 80 deposits, 32, 33, 34, 35, 36, 37, 38 depression, 90 dexamethasone, 131, 132 dextrose, 62, 65, 70, 123, 124 diabetes, 3, 4, 5, 8, 10, 19, 22, 23, 24, 25, 26, 28, 29, 54, 62, 64, 65, 85, 99, 127 diabetes mellitus, 28, 29 diabetic ketoacidosis, 93 diabetic kidney disease, 23, 24, 25 diabetic nephropathy, 3, 4, 7, 23, 24, 27, 28 diabetic patients, 26, 29, 124 diagnostic criteria, 47, 57, 59, 66 dialysis, 17, 20, 22, 45, 58, 62, 63, 64, 75, 84, 94, 110, 111, 119, 120, 121, 122, 123, 124, 141 diarrhea, 58, 62, 68, 81, 84, 90, 91, 116 diastolic blood pressure, 101, 106, 108 diet, 20, 25, 74, 83, 98, 113, 116, 117, 120, 133 dietary, 20, 73, 78, 98, 116 diets, 20, 120, 133 differentiation, 53 disease progression, 21, 26 diseases, 30, 45, 53, 75, 113 disorder, 14, 22, 35, 37, 42, 45, 46, 48, 49, 51, 58, 65, 72, 78, 79, 85, 87, 88, 89, 90, 91, 93, 94, 106, 113, 115 distribution, 58 diuretic, 57, 62, 67, 72, 73, 75, 81, 98, 106 diuretics, 62, 66, 70, 71, 72, 73, 74, 75, 84, 91, 99, 106, 107, 109, 116 DNA, 125, 126 dosage, 125, 126

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Index dosing, 56, 58 drinking, 94 drug interaction, 127 drug metabolism, 58 drug therapy, 100 drug use, 3 drugs, vii, 26, 32, 40, 106, 109 duration, 24 dyscrasia, 48, 49

153

ethylene glycol, 89, 93 etiology, 3, 11, 13, 14, 19, 30, 46, 53, 62, 64, 70, 71, 78, 79, 81, 84, 91, 92, 99, 102, 106, 108, 116, 117, 129 excision, 45 exclusion, 65 excretion, 2, 8, 53, 75, 79, 114, 115, 116, 117, 144 exercise, 2, 24 exposure, 13, 40, 53, 55, 57, 58, 129

E

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F eclampsia, 107 edema, 3, 30, 31, 33, 37, 105, 107, 108, 146 effusion, 90 EKG, 68, 69, 70 electrocardiogram, 69 electrolyte, 61, 121 electrolytes, 61, 62, 80 electron microscopy, 37, 38 electrophoresis, 48 encapsulated, 31, 121 endocarditis, 3 endocrine, 65, 128 endocrine disorders, 65 endothelial cells, 35 endothelium, 58 enemas, 78, 79 energy, 19 enzyme inhibitors, 29, 31, 98, 103 enzymes, 38, 107, 125 eosinophilia, 39, 40, 57 eosinophils, 41, 51, 53, 55 epidemiology, 59 epilepsy, 47 epistaxis, 39 epithelial cell, 46 epithelial cells, 46 erythrocyte, 35 erythrocytes, 5 erythrocytosis, 127, 145 esterase, 12 estimating, 1, 5, 18 estrogen, 106 ethanol, 93, 94

facies, 102 failure, 31, 40, 59, 75, 109, 119 false positive, 69 familial, 83 family history, 3, 45, 46 fat, 31, 133 females, 33, 35 fetal, 108, 109 fetus, 106, 107, 109 fever, 39, 40, 46, 58 fibrillation, 68 fibrosis, 32, 34, 37 filariasis, 33 filtration, 1, 2, 5, 8, 17, 18, 22, 23, 56, 78, 131, 132 fish, 36, 133 fish oil, 36 fistulas, 120 flow, 53, 61, 122 flow rate, 61 fluid, 52, 56, 57, 58, 59, 74, 84, 110, 116, 117, 123, 131, 132 focal segmental glomerulosclerosis, 42, 43 focusing, 97 food, 80, 133

G gas, 88 gastrointestinal, 81, 84, 92, 94, 125 gastrointestinal tract, 94

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154

Index

gender, 34 gene, 126 generation, 2 genes, 45 gentamicin, 84 gestation, 108 gingival, 145 glomerulonephritis, 3, 13, 30, 33, 36, 40, 42, 43 glomerulopathy, 9, 43 glomerulus, 2 glucocorticoids, 71 glucose, 64, 65, 70, 80, 92, 94 glycerol, 65 glycol, 93 glycosylated, 25 glycosylated hemoglobin, 25 gold standard, 1, 18, 41, 55 gout, 98, 114 grafts, 120 grain, 133 gram negative, 37 gravity, 3, 53 groups, 18, 33, 52 guanine, 125 guidelines, vii, 1, 5, 17, 18, 21, 22, 24, 73, 110, 123 gut, 71

H H2, 146 handling, 82, 85 harm, 124 HBV, 128 health, 17, 28, 60, 109 health care system, 17 heart, 10, 17, 54, 65, 98, 99, 102, 103, 109 heart attack, 103 heart block, 109 heart disease, 99 heart failure, 98 heavy metals, 31 hematuria, 3, 4, 5, 7, 11, 12, 13, 14, 15, 31, 33, 35, 36, 37, 45, 46, 115

heme, 56 hemodialysis, 66, 70, 73, 110, 119, 120, 121 hemodynamic, 110 hemoglobin, 20, 21, 25 hemolytic anemia, 109 hemolytic uremic syndrome, 59, 109 hemoptysis, 39, 40 hemorrhage, 39 hepatitis, 33, 56 hepatitis B, 33 hepatorenal syndrome, 57, 59 hepatotoxicity, 146 herbal, 3 heroin, 32 heterogeneous, 41 high risk, 8, 129 hirsutism, 126, 146 HIV, 31, 32 HLA, 129 homeostasis, 78 hormone, 20, 65, 74, 75, 76, 78, 106 hormones, 56, 71 hospitalization, 22 HRS, 56, 58 HSP, 36 human, 110 HUS, 58, 59, 110 hydrate, 73 hydration, 46, 55, 56, 57, 75, 113 hydro, 126 hydrocarbon, 40 hydrochloric acid, 92 hydrogen, 115 hydronephrosis, 3, 53, 106 hydrophilic, 126 hydrophobic, 126 hydrostatic pressure, 123 hydroxyl, 115 hyperaldosteronism, 72, 99 hypercalcemia, 42, 48, 73, 74, 75, 116 hypercalciuria, 116 hypercalcuria, 83, 117 hypercholesterolemia, 19, 30, 31, 33 hyperglycemia, 64 hyperkalemia, 68, 69, 70, 73, 98, 145

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Index

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hyperlipidemia, 64, 65, 145 hypernatremia, 62, 64, 65 hyperoxaluria, 114, 116 hyperparathyroidism, 17, 19, 73, 74, 78, 81, 83, 114, 116, 120 hyperphosphatemia, 78, 79 hyperplasia, 99, 145 hypertensive, 8, 26, 92, 99, 103, 108 hypertonic saline, 64, 65, 122 hypertrophy, 54 hyperventilation, 88 hypochloremia, 92 hypokalemia, 71, 72, 73, 92, 94, 98, 99 hypomagnesemia, 85 hyponatremia, 62, 65, 66, 68, 98 hypoperfusion, 54, 55 hypophosphatemia, 80, 81, 82 hypotension, 55, 57, 83, 121 hypotensive, 122 hypothalamus, 61, 62 hypothyroidism, 65 hypoventilation, 88 hypovolemia, 48, 53 hypoxia, 93

I iatrogenic, 62, 65, 83 identical twins, 124 identification, 23, 61 idiopathic, 33, 34, 35, 114 IgG, 31, 49, 109 imaging, 3, 11, 12, 18, 19, 39, 45, 46, 48, 99, 100, 116 immobilization, 75 immune system, 35 immunoglobulin, 36 immunoglobulins, 8, 10, 31, 48 immunological, 33 immunosuppression, 124, 128 immunosuppressive, 124, 127, 128, 129 in situ, 12, 36 incidence, 33, 128 indication, 51, 100 indolent, 33, 35, 37, 38

155

infection, 11, 12, 31, 35, 36, 37, 41, 46, 57, 98, 121, 122, 123, 128 infections, 12, 13, 24, 31, 32, 33, 35, 37, 117, 127, 128 infectious, 13, 128 inflammation, 39, 49 inflammatory, 7, 41, 44, 49, 98, 126 inflammatory mediators, 126 inflammatory response, 41 information technology, 52, 59 infusions, 129 ingestion, 72, 92, 93, 94 inhibition, 22, 28, 29, 102 inhibitor, 7, 19, 22, 23, 25, 26, 58, 97, 101, 126 inhibitors, 29, 31, 42, 98, 103, 110 initiation, 27, 116 injuries, 56 injury, 30, 51, 54, 58 insulin, 28, 29, 68, 69, 70, 124 intensive care unit, 82 interaction, 127 interactions, 127 interstitial, 30, 37, 40, 44, 46, 53, 54, 55, 59, 129 interstitial nephritis, 40, 44, 59, 129 interval, 68 intervention, 25, 46, 53, 54, 106, 108, 115, 119, 120 intestine, 114 intoxication, 93 intracranial, 46 intracranial aneurysm, 46 intraperitoneal, 39, 123, 124 intravascular, 65, 90, 91, 92, 109, 129 intravenous, 3, 12, 36, 56, 68, 76, 80, 82, 83, 116, 126, 131, 132 intravenous fluids, 56 intravenously, 68, 84, 85, 126, 131, 132 intrinsic, 52, 56 inulin, 18 invasive, 13, 48 iodinated contrast, 55 ionized calcium level, 20, 76 ions, 115

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156

Index

iron, 20, 21 irradiation, 13 ischemic heart disease, 99 isolation, 49

K kappa, 48, 49 ketoacidosis, 92 ketones, 93 kidney, 1, 2, 3, 5, 8, 12, 13, 17, 18, 19, 20, 21, 22, 23, 25, 30, 39, 40, 45, 47, 48, 49, 50, 51, 52, 56, 58, 70, 71, 76, 78, 81, 82, 83, 89, 94, 99, 100, 103, 113, 117, 124, 128 kidney failure, 52 kidney stones, 117 kidneys, 3, 4, 18, 21, 40, 41, 44, 53, 59, 88 kinase, 56

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L lactic acid, 92, 93 lambda, 48, 49 lamina, 34 LDH, 12, 110 legumes, 133 lesions, 47, 48, 128 lethargy, 68, 73, 80 leukemia, 93, 128 leukocyte, 12, 129, 131, 132 leukocyte esterase, 12 lifestyle changes, 97, 98 lifetime, 113, 114 likelihood, 32, 33, 38, 41, 115 limitations, 94, 106 linear, 35 lipid, 103, 138 lipids, 65 lithium, 83, 140 liver, 53, 56, 57, 58, 65, 93, 109, 125, 130 liver disease, 56, 57, 58 liver failure, 53, 56, 65, 93 liver transplantation, 130 low-dose aspirin, 28

lung, 33 lungs, 40, 88 lupus, 3, 10, 33, 37, 38, 43, 44, 109, 111 lymphocytes, 125 lymphoma, 31, 33 lymphomas, 128, 129 lysine, 115 lysis, 76, 78, 79 lysosomal enzymes, 38

M magnesium, 76, 78, 83, 84, 85, 107, 115, 123 maintenance, 126 malaria, 33 malignancy, 12, 33, 73, 74, 75, 128 malnutrition, 19, 20, 21, 84 mammography, 128 management, 23, 46, 59, 73, 82, 90, 95, 97, 98, 100, 103, 107, 110, 111, 117, 119, 128 mannitol, 65 matrix, 34, 35, 36 measurement, 1, 7, 8, 10, 18, 24, 71, 74, 98 measures, 8, 24, 34, 51, 52, 56, 59, 61, 97, 113 mediators, 126 medical care, 10 medication, vii, 7, 27, 55, 97, 99, 100, 115, 127 medications, 26, 54, 55, 58, 76, 84, 97, 98, 99, 100, 108, 122, 124, 126, 127 medicine, 23, 94, 116, 119 medullary cystic disease, 116 membranoproliferative glomerulonephritis, 34 membranous glomerulonephritis, 107 membranous nephropathy, 33, 43, 44 men, 8, 40 mental retardation, 47 mercury, 31 mesangial cells, 35 meta-analysis, 29, 103 metabolic, 17, 70, 72, 78, 80, 87, 88, 89, 91, 92, 93, 94, 95, 113 metabolic acidosis, 70, 72, 87, 88, 89, 92, 93, 94, 95

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Index metabolic alkalosis, 88, 89, 91, 92 metabolic disorder, 88 metabolism, 19, 58, 61, 62, 78, 80, 106, 144 metabolites, 102 metastases, 75 metformin, 93 methanol, 89, 93, 94 methionine, 117 microangiopathic hemolytic anemia, 58 microscope, 11, 12, 93 microscopic polyangiitis, 38, 39 microscopy, 30, 31, 34, 35, 37, 38 microvascular, 26 milk, 66, 75, 83 milk-alkali syndrome, 75 mineralocorticoid, 70, 71, 90 minimal change disease, 31, 32 minimal change nephrotic syndrome, 43 mobility, 123 modalities, 119 modality, 37, 51, 119, 120, 123 models, 52, 59 molecules, 121 monoclonal, 10, 49 monocyte, 129 mononucleosis, 31 morbidity, 20, 127 morphogenesis, 46 morphological, 37, 45, 46 morphology, 37 mortality, 8, 20, 22, 51 mothers, 109 movement, 123 MPGN, 34, 35 MRI, 46, 100, 102 mucous membranes, 62 muscle, 8, 56, 57, 73, 83 muscle injury, 56, 57 muscle mass, 8 muscle weakness, 73, 83 muscles, 46 mutation, 45 mutations, 45, 46 Mycophenolate, 125 myeloma, 3, 48, 49, 65, 75, 82

157

myeloproliferative disorders, 114 myocardial infarction, 97 myocardium, 68, 69, 70 myoglobin, 56 myopathies, 56 myopathy, 147

N N-acety, 55 NaCl, 91 narcotics, 90 nausea, 19, 65, 68, 83, 92 nebulizer, 70 neck, 62 necrosis, 13, 53, 54, 56, 59 needles, 121 nephrectomy, 115 nephritic syndrome, 30, 35 nephritis, 13, 37, 38, 39, 40, 44, 53, 55, 59, 109, 129 nephrolithiasis, 11, 13, 14, 113, 114, 115, 116, 117 nephrologist, 5, 20, 55, 111, 117, 119, 120 nephron, 48, 56 nephropathy, 4, 13, 23, 24, 25, 29, 32, 35, 36, 42, 43, 48, 49, 55, 82 nephrotic syndrome, 30, 31, 32, 33, 34, 35, 38, 42, 44, 99, 107 nephrotoxic, 49, 57, 126 nephrotoxic drugs, 57 nephrotoxicity, 126, 144, 146 neurogenic, 54 neurological deficit, 80 neuropathy, 7, 21 neurotoxicity, 126, 144 neutrophils, 37 nifedipine, 106 nitrates, 12 nitrogen, 94 nocturia, 3 nodules, 39, 42 non-invasive, 12 normal, 4, 18, 20, 26, 30, 31, 32, 35, 41, 55, 56, 62, 64, 65, 66, 67, 70, 72, 73, 78, 79,

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158

Index

83, 88, 89, 90, 92, 100, 106, 108, 115, 131, 132 NSAIDs, 46, 113, 127, 146 nuclear, 125 nucleotides, 125 nucleus, 126 nutrition, 21, 94

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O obesity, 102 obstruction, 3, 48, 53, 54, 99, 115 obstructive uropathy, 57 oil, 36 oral, 73, 75, 76, 80, 81, 82, 116, 117, 126, 131, 132 organ, 7, 49, 124 orthostatic hypotension, 62 osmolality, 57, 65, 67, 89, 92, 106 osmotic, 121, 123 osteoclastic, 74 osteoclasts, 75 osteomyelitis, 37 osteoporosis, 127 outpatient, 8, 73, 97, 127 overproduction, 48, 114, 116, 117 over-the-counter, 3 oxalate, 53, 54, 93, 94, 113, 114, 116 oxalosis, 130 oxidative, 93 oxide, 84, 85

P PaCO2, 95 pain, 36, 45, 46, 75, 115, 123, 124 pain management, 46 palpitations, 102 pamidronate, 74, 75 pancreatitis, 76 pap smear, 128 parasites, 128 parathyroid, 20, 74, 76, 78, 83 parathyroid hormone, 20, 74, 76, 78

parathyroidectomy, 76 parenchymal, 57 paresthesias, 21 pathogenesis, 30, 32, 33, 82 pathologist, 30 pathology, 41, 117 pathophysiology, 10, 47, 59 patient care, vii patient management, 119 PCP, 128 PCs, 2 PDAs, 2 pelvic, 13 perfusion, 53, 56, 57, 58 peritoneal, 119, 120, 123, 124 peritonitis, 124 pH, 87, 88, 91, 92, 114, 115, 117 pharmaceuticals, 127 pharmacological, 98 phosphate, 20, 21, 71, 72, 78, 79, 80, 82, 114, 115, 116 phosphorous, 21, 79, 116 phosphorus, 20, 73, 74, 75, 76, 77, 78, 80, 81, 82, 85, 113 physical activity, 98 physicians, 1, 3, 17, 19, 21, 97, 119, 127, 129 physiology, 54, 55, 88, 106 pituitary, 67 PKD, 45, 46 placenta, 108, 109 plasma, 48, 49, 57, 58, 65, 67 plasmapheresis, 36, 48, 58, 110 platelet, 58 platelet aggregation, 58 pleural, 90 pleural effusion, 90 pneumonia, 127, 128 pneumothorax, 90 poisoning, 82, 93 polycystic kidney disease, 46, 47, 129 polydipsia, 63 polyuria, 3, 73 poor, 33, 35, 36, 38, 44, 49, 81, 120 population, 10, 21, 23, 58, 113, 128 portal hypertension, 56

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Index post-streptococcal glomerulonephritis, 44 potassium, 61, 69, 70, 71, 72, 73, 88, 90, 92, 99, 120, 121 potassium channels, 70 poultry, 133 prediction, 5, 8, 18, 21, 22 predictors, 43 Prednisolone, 140 Prednisone, 31, 32, 36, 39, 41, 42, 125, 140 preeclampsia, 83, 105, 107, 108, 109, 110, 111 pregnancy, 105, 106, 107, 108, 109, 110, 111 pregnant, 110, 111 premature death, 17 prematurity, 109 pressure, 3, 4, 7, 17, 21, 24, 25, 26, 28, 71, 72, 91, 97, 98, 99, 101, 102, 103, 105, 106, 108, 121, 122, 123 prevention, 54, 55, 113, 116 primary care, 1, 17, 103, 119, 127 primary hyperparathyroidism, 78, 114 prodrome, 40 production, 2, 10, 48, 52, 58, 66, 115 progesterone, 106 prognosis, 32, 34, 35, 36, 38, 41, 48, 49, 129 proliferation, 34, 125 prophylaxis, 127 prostaglandins, 56 prostate, 74 prostate specific antigen, 74 protein, 2, 3, 7, 8, 10, 19, 20, 21, 24, 25, 30, 36, 48, 56, 76, 107, 116, 126 proteins, 10, 65, 66 proteinuria, 3, 4, 7, 8, 9, 10, 13, 18, 24, 29, 31, 32, 34, 37, 38, 40, 42, 53, 105, 106, 107, 108 protocol, 111 psychosis, 127 PTT, 110 pulmonary edema, 102 pulses, 102 purpura, 39, 44 pyelonephritis, 129 pyuria, 55

159

Q QRS complex, 69 QT interval, 76 quality of life, 124 quinine, 122

R radiological, 18 Ramipril, 135, 145 range, 11, 20, 31, 34, 35, 37, 56, 107 RAS, 100, 102 rash, 36, 40, 55 RDA, 20 receptors, 71, 126 recovery, 56 red blood cells, 3, 11, 12, 13, 56, 57 reflexes, 83 reflux nephropathy, 32 refractory, 57, 59 regression, 25 regular, 68, 70 regulation, 61, 62 rehydration, 56 rejection, 126, 129 relapse, 31 relapses, 31 relationship, 1, 62, 128 relationships, 56, 110 remediation, 37 remission, 31, 32, 36, 38, 43 renal artery stenosis, 103 renal cysts, 47 renal disease, 3, 7, 20, 21, 22, 23, 24, 26, 28, 30, 39, 45, 49, 56, 57, 62, 78, 82, 83, 99, 103, 107, 108, 109, 119, 129 renal dysfunction, 143 renal failure, 5, 17, 20, 22, 39, 40, 48, 52, 59, 70, 73, 75, 79, 84, 92, 93, 109 renal function, 1, 5, 7, 10, 22, 27, 29, 32, 41, 54, 55, 56, 57, 68, 70, 76, 78, 79, 84, 109, 113, 117, 120, 127

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160

Index

renal replacement therapy, 17, 20, 21, 51, 120, 124 renin, 71, 92, 100 repair, 100 resection, 128 residuals, 53 resolution, 37, 58 respiration, 90 respiratory, 31, 35, 39, 80, 88, 90, 93, 94, 106, 128 respiratory acidosis, 88, 90 respiratory failure, 80, 93 retention, 58, 70, 106, 146 retinopathy, 7 returns, 121 Rhabdomyolysis, 12, 54, 56, 57, 59, 76, 78, 79, 80, 146 rheumatoid arthritis, 33 risk, 8, 10, 13, 21, 28, 30, 34, 44, 46, 51, 54, 56, 60, 68, 80, 83, 98, 107, 109, 114, 121, 124, 128, 129, 144, 146, 147 risk factors, 13, 44, 51 risks, 106, 109, 124, 127 rituximab, 31, 42, 43 RTA, 72

S safety, 108 saline, 55, 62, 64, 65, 66, 73, 122, 123, 131, 132 salt, 99, 113, 116 sample, 8, 88 sampling, 13 sarcoidosis, 75 saturation, 114 SBP, 23, 100, 101 schistosomiasis, 13, 33 sclerosis, 129 secretion, 2, 71, 114 sedation, 83, 90 sediment, 3, 4, 18, 21, 30, 32, 39, 40, 107 segmental glomerulosclerosis, 43 seizure, 65 seizures, 83, 107

sensitivity, 41, 53, 99, 100 sepsis, 76, 93 serum, 1, 2, 3, 5, 8, 21, 22, 26, 32, 52, 55, 57, 62, 63, 65, 69, 70, 71, 73, 75, 76, 78, 80, 81, 88, 89, 90, 91, 92, 94, 98, 106, 116, 121, 129 serum albumin, 73, 76, 89 serum bicarbonate, 70, 88, 89 shock, 57, 93 short period, 93, 127 SIADH, 65, 67, 84 side effects, 125, 127 sign, 69, 76 signs, 3, 13, 32, 36, 53, 62, 73 sine, 68, 69 sine wave, 68, 69 single test, 12 sites, 18, 36, 62 skin, 47, 128 SLE, 33, 37, 39 sleep apnea, 101 smoking, 13 snoring, 102 social work, 120 sodium, 51, 53, 54, 55, 56, 57, 61, 62, 64, 65, 66, 70, 71, 82, 88, 92, 98, 106, 113, 116 solubility, 115 sorbitol, 70 specific gravity, 3, 53 specificity, 41, 53, 99, 100 spectrum, 22 sports, 66 SRD, 17, 23 stabilization, 70 stabilize, 26, 69 stages, 18, 19, 20 staphylococcus, 37 starvation, 84, 93, 94 sterile, 55 steroid, 31, 32, 33, 40, 42, 43, 127, 143 steroids, 31, 32, 34, 36, 40, 107, 110, 129 stimulus, 80 stomach, 33, 92 strain, 46 strategies, 95, 103, 122, 124, 129

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Index stratification, 5, 22 stretching, 46 subacute, 129 subgroups, 41 substances, 11 substitution, 41 suffering, 18, 107 sugar, 21, 23, 124 sugars, 4, 7, 124 sulfate, 84, 85, 107 superficial bladder cancer, 12 suppression, 102, 125 surgery, 102, 124 surgical, 45, 46, 100 surgical intervention, 46 surveillance, 128 survival, 32, 58, 109 survival rate, 32 sweets, 133 switching, 99 symptom, 31, 49, 55, 73 symptoms, 4, 11, 30, 31, 37, 39, 40, 45, 58, 65, 68, 71, 80, 99, 107, 109, 125 syndrome, 13, 30, 31, 32, 34, 35, 37, 40, 49, 54, 56, 57, 59, 60, 62, 65, 71, 72, 76, 78, 79, 80, 81, 83, 84, 94, 100, 101, 102, 107, 109, 111, 114, 129 synergistic, 98 synergistic effect, 98 synthesis, 125 systolic blood pressure, 25, 101

T tacrolimus, 125, 126 T-cell, 125, 129 T-cells, 125 TCP, 59 temperature, 122 tendon, 83 tension, 100 teratogenic, 107 therapeutic interventions, 36

161

therapy, 22, 27, 31, 32, 33, 34, 35, 40, 41, 43, 51, 52, 55, 59, 68, 72, 97, 98, 99, 100, 107, 109, 114, 119, 120, 127, 129, 131 thiazide, 46, 62, 72, 73, 75, 81, 97, 98, 116 thiazide diuretics, 62, 72, 73, 75, 116 thrombocytopenia, 58 thrombocytopenic purpura, 59, 60 thromboembolism, 107 thrombosis, 34, 58 thrombotic, 59, 60 thyroid, 65, 67, 83 thyrotoxicosis, 75 time consuming, 18 timing, 22, 41, 107, 124 tinnitus, 93, 94 tissue, 78, 79, 80, 93 TMP, 46, 127, 144 tobacco, 71, 72 tolerance, 100 Topiramate, 139 toxicities, 127, 128 toxicity, 19, 69, 75 toxin, 51, 58 toxins, 53 TPA, 122 transaminases, 109 transcription factors, 125 transfusions, 76, 77 transition, 120 transplant, 124, 126, 127, 128, 129 transplant recipients, 129 transplantation, 17, 20, 21, 42, 81, 119, 120, 124, 128, 129, 130 transport, 85, 115, 123 trauma, 13 tremor, 126 trial, 28, 31, 103, 107 tuberculosis, 75 tubers, 45, 47 tubular, 10, 37, 41, 46, 53, 54, 56, 59, 61, 70, 72, 92, 94, 114 tumor, 76, 78, 79 tumors, 31, 53, 75, 128 turnover, 20 type 1 diabetes, 8, 24, 25, 26, 29

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162

Index

type 2 diabetes, 8, 24, 26, 28, 29, 85

U

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ultrasonography, 5 ultrasound, 1, 3, 4, 7, 12, 21, 41, 46, 51, 52, 53, 106 upper respiratory infection, 31, 35 urea, 117 ureter, 53, 124 ureters, 12 uric acid, 53, 113, 114, 115, 116, 117 uric acid levels, 116 urinalysis, 1, 3, 11, 12, 14, 48, 51, 52, 56, 107, 113 urinary, 2, 3, 5, 8, 11, 12, 18, 24, 30, 39, 40, 106, 116, 128 urinary tract, 11, 12, 24, 128 urinary tract infection, 11, 24, 128 urine cytology, 11, 12 urologist, 3, 113, 117 urology, 3, 115 usual dose, 126

V variability, 40 variation, 34, 38, 88 vascular disease, 100 vascular surgeon, 122 vasculitis, 3, 38, 39, 44, 53 vasoconstriction, 55

vasopressin, 61, 62, 64 vein, 34, 121, 124 ventilation, 90 venue, 52 vessels, 124 viruses, 56 visible, 11, 34 vitamin D, 19, 20, 75, 76, 78 vitamin D deficiency, 19 vitamins, 73 vomiting, 19, 54, 65, 81, 83, 90, 92 Von Willebrand factor, 59

W Warfarin, 139 water, 61, 62, 63, 64, 65, 66, 67, 68, 106 weakness, 52, 68, 73, 80, 83 weight gain, 121 weight loss, 98 white blood cell count, 124 whole grain, 133 withdrawal, 27, 57 women, 8, 83, 98, 109 wood, 93 World Health Organization, 33, 37 worry, 123

Y young women, 40

Handbook of Common Problems in Clinical Nephrology, Nova Science Publishers, Incorporated, 2010. ProQuest Ebook