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(BQ) Part 1 book “Manual of nephrology” has contents: The patient with hyponatremia or hypernatremia, the patient with hypokalemia or hyperkalemia, the patient with an acid–base disorder, the patient with kidney stones,… and other contents.
MANUAL OF nephrology Eighth Edition 92957_fm_pi-x.indd 05/04/14 2:34 PM 92957_fm_pi-x.indd 05/04/14 2:34 PM MANUAL OF nephrology Eighth Edition Edited by Robert W Schrier, MD Professor Emeritus Division of Renal Disease and Hypertension University of Colorado Health Sciences Center Aurora, Colorado 92957_fm_pi-x.indd 05/04/14 2:34 PM Acquisitions Editor: Julie Goolsby Product Development Editor: Leanne Vandetty Production Project Manager: Alicia Jackson Senior Manufacturing Coordinator: Beth Welsh Strategic Marketing Manager: Stephanie Manzo Design Coordinator: Teresa Mallon Production Service: Integra Software Services Pvt Ltd © 2015 by Wolters Kluwer Health Two Commerce Square 2001 Market Street Philadelphia, PA 19103 USA LWW.com Seventh edition, © 2009 by LIPPINCOTT WILLIAMS & WILKINS, a Wolters Kluwer business Sixth edition, © 2005 Lippincott Williams & Wilkins Fifth edition, © 1999 Lippincott Williams & Wilkins Fourth edition, © 1995 Little, Brown & Co All rights reserved This book is protected by copyright No part of this book may be reproduced in any form by any means, including photocopying, or utilized by any information storage and retrieval system without written permission from the copyright owner, except for brief quotations embodied in critical articles and reviews Materials appearing in this book prepared by individuals as part of their official duties as U.S government employees are not covered by the above-mentioned copyright Printed in China Library of Congress Cataloging-in-Publication Data Manual of nephrology / edited by Robert W Schrier — Eighth edition p ; cm Includes bibliographical references and index ISBN-13: 978-1-4511-9295-7 ISBN-10: 1-4511-9295-9 I Schrier, Robert W., editor [DNLM: Kidney Diseases—diagnosis—Handbooks Kidney Diseases—therapy— Handbooks Metabolic Diseases—diagnosis—Handbooks Metabolic Diseases—therapy— Handbooks WJ 39] RC903 616.6'1—dc23 2014008807 Care has been taken to confirm the accuracy of the information presented and to describe generally accepted practices However, the authors, editors, and publisher are not responsible for errors or omissions or for any consequences from application of the information in this book and make no warranty, expressed or implied, with respect to the currency, completeness, or accuracy of the contents of the publication Application of the information in a particular situation remains the professional responsibility of the practitioner The authors, editors, and publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accordance with current recommendations and practice at the time of publication However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any change in indications and dosage and for added warnings and precautions This is particularly important when the recommended agent is a new or infrequently employed drug Some drugs and medical devices presented in the publication have Food and Drug Administration (FDA) clearance for limited use in restricted research settings It is the responsibility of the health care provider to ascertain the FDA status of each drug or device planned for use in their clinical practice To purchase additional copies of this book, call our customer service department at (800) 638-3030 or fax orders to (301) 223-2320 International customers should call (301) 223-2300 Visit Lippincott Williams & Wilkins on the Internet: at LWW.com Lippincott Williams & Wilkins customer service representatives are available from 8:30 am to pm, EST 10 92957_fm_pi-x.indd 05/04/14 2:34 PM Contributors Phyllis August, MD Laurence Chan, MD Professor of Medicine and Obstetrics and Gynecology Weill Medical College of Cornell University New York, New York Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado William M Bennett, MD Professor of Medicine (Retired) Department of Medicine Oregon Health and Science University Medical Director Transplant Services Legacy Good Samaritan Medical Center Portland, Oregon Tomas Berl, MD Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Judy Blaine, MD Assistant Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Godela M Brosnahan, MD Associate Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Michel Chonchol, MD Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado James E Cooper, MD Assistant Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Charles L Edelstein, MD, PhD Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado David H Ellison, MD Professor of Medicine Head, Division of Nephrology and Hypertension Oregon Health and Science University Portland, Oregon v 92957_fm_pi-x.indd 05/04/14 2:34 PM vi CONTRIBUTORS Sarah Faubel, MD Marilyn E Levi, MD Associate Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Associate Professor Department of Medicine Division of Infectious Diseases University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Seth Furgeson, MD Stuart L Linas, MD Assistant Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Diana I Jalal, MD Associate Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado William D Kaehny, MD Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Jessica B Kendrick Assistant Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado 92957_fm_pi-x.indd Charles R Nolan, MD Professor of Medicine University of Texas Health Sciences Center at San Antonio San Antonio, Texas Ali Olyaei, PharmD Professor School of Medicine Division of Nephrology and Hypertension Oregon Health and Science University Portland, Oregon College of Pharmacy Department of Pharmacy Practice Oregon State University Corvallis, Oregon Sarah E Panzer, MD Assistant Professor Department of Medicine Division of Nephrology University of Wisconsin Madison Madison, WI 05/04/14 2:34 PM CONTRIBUTORS vii Jeffrey G Penfield, MD Jie Tang, MD, MSc, MPH Associate Professor Department of Medicine Division of Nephrology University of Texas Southwestern Medical Center VA North Texas Health Care System Dallas, Texas Assistant Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Robert F Reilly, MD Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Professor Department of Medicine Division of Nephrology University of Texas Southwestern Medical Center VA North Texas Health Care System Dallas, Texas L Barth Reller, MD Professor of Medicine and Pathology Department of Medicine and Pathology Duke University Medical Center Durham, North Carolina Robert W Schrier, MD Professor Emeritus Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado 92957_fm_pi-x.indd Isaac Teitelbaum Joshua M Thurman, MD Associate Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado Alexander Wiseman, MD Professor Department of Medicine Division of Renal Diseases and Hypertension University of Colorado Health Sciences Center University of Colorado Hospital Aurora, Colorado 05/04/14 2:34 PM Preface The eighth edition of the Manual of Nephrology continues to focus on the practical clinical aspects of the diagnosis and management of patients with electrolyte and acid–base disorders, urinary tract infections, kidney stones, glomerulonephritis and vasculitis, acute or chronic renal failure, hypertension, hypertension and renal disease in pregnancy, and drug dosing with renal impairment Because of the growing number of patients with endstage renal disease (ESRD), there are separate chapters on treatment by chronic renal replacement therapy with dialysis and kidney transplantation The Manual of Nephrology should continue to be of excellent clinical value for those caregivers encountering patients with the above disorders This would include house officers, medical students, primary care physicians, nephrology fellows, nurse practitioners, and busy subspecialists outside of nephrology I am very appreciative of the outstanding contributions by the authors who have made every effort to update each chapter with recent advances in the diagnosis and management of the spectrum of hypertensive and kidney disorders There are new lead authors on eight chapters who are outstanding clinician-educators The Manual of Nephrology is dedicated to Professor Hugh de Wardener who just died at age 97 He made enormous contributions to the fields of hypertension and nephrology as a clinician, scientist, and educator for over 60 years Robert W Schrier, MD viii 92957_fm_pi-x.indd 05/04/14 2:34 PM Contents Contributors v Preface viii The Edematous Patient: Cardiac Failure, Cirrhosis, and Nephrotic Syndrome 01 Robert W Schrier and David H Ellison The Patient with Hyponatremia or Hypernatremia 28 Robert W Schrier and Tomas Berl The Patient with Hypokalemia or Hyperkalemia 48 Jie Tang and Stuart L Linas The Patient with an Acid–Base Disorder 62 William D Kaehny The Patient with Disorders of Serum Calcium and Phosphorus 79 Jeffrey G Penfield and Robert F Reilly The Patient with Kidney Stones 106 Robert F Reilly The Patient with Urinary Tract Infection 125 Jessica B Kendrick, L Barth Reller, and Marilyn E Levi The Patient with Hematuria, Proteinuria, or Both, and Abnormal Findings on Urinary Microscopy 158 Godela M Brosnahan The Patient with Glomerular Disease or Vasculitis 180 Sarah E Panzer and Joshua M Thurman 10 The Patient with Acute Kidney Injury 201 Sarah Faubel and Charles L Edelstein 11 The Patient with Chronic Kidney Disease 241 Michel Chonchol and Jessica B Kendrick 12 The Patient Receiving Chronic Renal Replacement with Dialysis 253 Seth Furgeson and Isaac Teitelbaum ix 92957_fm_pi-x.indd 05/04/14 2:34 PM x CONTENTS 13 The Patient with a Kidney Transplant 263 James E Cooper, Laurence Chan, and Alexander Wiseman 14 The Patient with Kidney Disease and Hypertension in Pregnancy 286 Phyllis August, Diana I Jalal, and Judy Blaine 15 The Patient with Hypertension 318 Seth Furgeson, Charles R Nolan, and Robert W Schrier 16 Practical Guidelines for Drug Dosing in Patients with Impaired Kidney Function 351 Ali Olyaei and William M Bennett Index 409 92957_fm_pi-x.indd 10 05/04/14 2:34 PM Chapter • The Patient with Hematuria, Proteinuria 165 Figure 8-5. The particle in Figure 8-4, when viewed with polarized light, shows the classic “Maltese cross.” (From Fairley KF Urinalysis In: Schrier RW, Gottschalk CW, eds Diseases of the kidney, 4th ed Boston, MA: Little, Brown and Company, 1988 Reprinted with permission.) II CAUSES OF HEMATURIA Hematuria can arise from any part of the kidneys or urogenital tract and may be due to a transient problem or to serious and progressive disease It may be useful to distinguish between renal parenchymal causes of hematuria, which are best evaluated by a nephrologist, and urological causes, which may need surgical intervention In cystic kidney diseases, hematuria is thought to be due to cyst ruptures Figure 8-6 may be helpful for the differential diagnosis of hematuria III APPROACH TO THE PATIENT WITH HEMATURIA A General Principles: The approach to the evaluation of gross and microscopic hematuria depends on the age of the patient and the likelihood of an underlying serious disease For instance, malignancy is a much greater possibility in individuals who are older than 40 years than in younger p eople, particularly if they have other risk factors such as smoking or a h istory of chemotherapy, particularly with cyclophosphamide which can cause bladder cancer Other risk factors for malignancy are occupational exposure to chemicals or dyes, history of pelvic irradiation, and analgesic or Chinese herb nephropathy The latter is due to the contaminant aristolochic acid, which also appears to be the cause of Balkan nephropathy, a chronic interstitial nephritis leading to end-stage renal disease (ESRD) and an increased risk of urothelial cancer Evaluation of hematuria also depends on associated signs and symptoms For instance, a patient with acute onset of dysuria and gross hematuria most likely has an infection, that is, acute cystitis, whereas the patient with colicky unilateral flank pain and microscopic or macroscopic hematuria most likely has a ureteral stone However, if these symptoms occur in an older patient, they may be a manifestation of bladder or renal cancer, and therefore the evaluation needs to rule out malignancy In patients with renal transplants, gross hematuria can be due to infection with adenovirus or cytomegalovirus 92957_ch08_p158-179.indd 165 4/3/14 5:53 PM 166 Chapter • The Patient with Hematuria, Proteinuria a Renal parenchymal causes of hematuria: Glomerular Nonglomerular Acquired glomerulonephritis Genetic Genetic Interstitial nephritis Immunologic Infectious Sickle cell disease or trait Alport syndrome TBMN ∗ Fabry disease Poststreptococcal nephritis Endocarditis Visceral abscess Hepatitis B and C, HIV ∗ Other viruses IgA nephritis Systemic lupus GN ∗ Membranoproliferative GN Membranous GN Vasculitis Rapidly progressive GN Pyelonephritis Drug-induced acute interstitial nephritis Autoimmune acute or chronic interstitial nephritis Viral interstitial nephritis b Urological causes of hematuria: Infectious cystitis/urethritis Noninfectious cystitis Urolithiasis Malignancy: Hypercalciuria Renal cell carcinoma, Hyperuricosuria Bladder cancer, other Papillary necrosis urothelial cancers, Benign prostatic hyperplasia Prostate cancer c.Cystic kidney diseases: Genetic Autosomal dominant polycystic kidney disease Autosomal recessive polycystic kidney disease Van Hippel−Lindau Disease Tuberous Sclerosis Acquired Simple renal cysts Acquired cystic disease in patients with chronic renal failure ∗TBMN: Thin Basement Membrane Nephropathy; HIV: Human immunodeficiency virus; GN: Glomerulonephritis; IgA: Immunoglobulin A Figure 8-6. Differential diagnosis of hematuria GN, glomerulonephritis; HIV, human immunodeficiency virus; IgA, immunoglobulin A If the hematuria is clearly of glomerular origin, that is, if the urine contains mostly dysmorphic RBCs and/or red cell casts, an acute or chronic glomerulonephritis is likely, and this directs the diagnostic tests, including renal biopsy If the family history is positive for Alport syndrome, autosomal dominant polycystic kidney disease, or sickle cell disease, the finding of microscopic or macroscopic hematuria indicates that the proband likely also has the disease In these cases (glomerular and genetic hematuria), a workup for malignancy is not necessary, particularly if the patient is young and has no other risk factors Other historical clues pointing to the diagnosis are a recent upper respiratory or gastrointestinal infection Onset of gross hematuria to days later suggests 92957_ch08_p158-179.indd 166 4/3/14 5:53 PM Chapter • The Patient with Hematuria, Proteinuria 167 a diagnosis of immunoglobulin A (IgA) nephropathy, particularly in young adults In children, Alport syndrome and sickle cell disease or sickle cell trait are also diagnostic considerations If the hematuria appears to weeks after a pharyngitis (or impetigo in c hildren), acute poststreptococcal glomerulonephritis is a possibility Younger subjects with a purpuric rash, arthralgias, and gross or m icroscopic hematuria may have Henoch– Schönlein purpura, whereas older patients with hematuria, proteinuria, profound constitutional symptoms, arthralgias, or respiratory symptoms may have vasculitis such as Wegener’s granulomatosis (granulomatosis with polyangiitis) or microscopic polyangiitis (see Chapter 9) Patients with known SLE should be screened regularly for the d evelopment of hematuria and/or proteinuria, because these findings indicate renal involvement and the need for a kidney biopsy and further treatment Gross or microscopic hematuria can occur after strenuous exercise This includes contact sports with direct trauma to the kidneys and noncontact sports, such as marathon running, bicycling, rowing, and even swimming The hematuria has been attributed to trauma to the bladder due to up and down movement with running and biking; however, other studies using phase-contrast microscopy have found significant numbers of dysmorphic RBCs and even red cell casts in the urine after running, indicating that exercise-induced hematuria may be of glomerular origin Purely exercise-induced hematuria disappears within to days after vigorous exercise and is benign; however, it is a diagnosis of exclusion Hematuria that occurs after exercise may also uncover an underlying condition, such as autosomal dominant polycystic kidney disease Another cause of exerciseinduced hematuria is the nutcracker syndrome, which describes the compression of the left renal vein between the aorta and superior mesenteric artery; this may be accompanied by left flank pain Hematuria (microscopic or macroscopic) that occurs in an anticoagulated patient should not be attributed to the anticoagulation per se unless bleeding is observed from multiple sites and there is clear evidence for overanticoagulation Prospective studies in anticoagulated patients have shown that hematuria is not significantly more common than in the general population, and when it occurs, an underlying urological condition, including malignancy, is found in a high percentage of subjects Therefore, hematuria in anticoagulated patients should be evaluated as in other individuals B Specific diagnostic recommendations: All patients with hematuria should have a urine culture, microscopic urinalysis by a trained clinician, and quantitation of proteinuria The urine culture will detect infection as a cause of hematuria, particularly if associated with dysuria and pyuria It will also rule out infection before any invasive procedures such as cystoscopy are undertaken (contraindicated during active infection) Infection, if present, should be treated appropriately and urinalysis should be repeated in to weeks If the hematuria has resolved completely and there are no other risk factors, further tests are not necessary 92957_ch08_p158-179.indd 167 4/3/14 5:53 PM 168 Chapter • The Patient with Hematuria, Proteinuria Microscopic examination of the urine and quantitation of roteinuria help to determine whether hematuria is of glomerular origin p (see above) Dysmorphic red cells, red cell casts, and proteinuria of more than to g/day point to glomerulonephritis, and referral to a nephrologist for kidney biopsy is indicated Serum chemistries to assess renal function and specific serologic tests to look for immunologic or infectious disease should be ordered as well (for details, see Chapter 9) If there is clear evidence for a glomerular source of hematuria and the patient has no risk factors for malignancy, imaging of the urinary tract and cystoscopy are not necessary Isolated dysmorphic hematuria without proteinuria can be due to Alport syndrome, thin basement membrane nephropathy, or mild IgA nephropathy Alport syndrome is a genetic disorder of glomerular basement membrane (GBM) collagen chains and leads to end-stage renal failure, often in young adults In 50% to 80% of patients, it is associated with sensorineural hearing loss and ophthalmologic abnormalities Inheritance is x-linked in 80% to 85% of families and autosomal recessive in about 15% The diagnosis can be made by renal biopsy and/or genetic testing Thin basement membrane nephropathy has also been called benign familial hematuria It affects about 1% of the population, is an autosomal dominant trait, is characterized by very thin GBMs, and has usually a benign course Subjects with isolated glomerular hematuria are often not biopsied because the prognosis is good, unless Alport syndrome is a possibility and cannot be diagnosed otherwise However, patients with isolated glomerular hematuria should be followed for the development of proteinuria, elevated blood pressure, or decreased renal function Imaging is usually performed in the evaluation of hematuria The choice of test depends on the patient’s age and history In children, adolescents, and pregnant women a renal ultrasound should be ordered first to avoid the significant radiation associated with computed tomography (CT) Renal ultrasound will detect polycystic kidney disease, other congenital abnormalities of the kidneys and urinary tract, kidney stones, particularly if associated with obstruction, and Wilms tumor in children Renal u ltrasound is also helpful in patients with suspected glomerular hematuria, to determine kidney size If both kidneys are small, renal biopsy may not be indicated because of limited diagnostic utility (scarred kidneys) and increased risk of bleeding If the patient’s history or symptoms suggest nephrolithiasis, a computed tomography scan of kidneys, ureters and bladder (CT-KUB) should be ordered, which does not need the administration of intravenous contrast Most patients with unexplained hematuria, particularly if over age 40 years, or with risk factors for malignancy should undergo multi detector CT urography with and without contrast This is c urrently the most sensitive imaging modality for the detection of cancers of the urogenital tract, as well as calculi However, the radiation dose is significant, and intravenous contrast can precipitate acute kidney injury, particularly in patients with underlying renal disease In such cases, magnetic resonance imaging without gadolinium contrast can be done 92957_ch08_p158-179.indd 168 4/3/14 5:53 PM Chapter • The Patient with Hematuria, Proteinuria 169 Cystoscopy: Cystoscopy should be performed in patients with hematuria and dysuria or other bladder/urethral symptoms, after infection has been ruled out It should be performed in most patients with unexplained gross hematuria, unless the patient is young (less than 35 to 40 years for men and less than 45 years for women) and has no risk factors for bladder cancer Cystoscopy is not necessary in young patients with a known diagnosis of autosomal dominant polycystic kidney disease, Alport syndrome, sickle cell disease, or IgA nephropathy; these disorders are typically associated with episodes of gross hematuria However, cystoscopy is mandatory in older patients, smokers, patients who had been treated with cyclophosphamide, or with other risk factors for bladder cancer (see above) Cystoscopy also allows visualization of the prostate and urethra Prostate cancer and benign prostatic hyperplasia can give rise to hematuria, due to increased vascularity and fragile blood vessels However, other causes should be ruled out before attributing hematuria to benign prostatic hyperplasia Urine cytology has been reported to be 90% sensitive for bladder cancer but much less sensitive for upper tract malignancies It is usually performed as an ancillary test before cystoscopy, but may be ordered instead of cystoscopy in patients at low risk for bladder cancer, such as individuals younger than 40 years, particularly if female and nonsmoker A 24-hour urine collection should be ordered in children and young adults with unexplained nonglomerular hematuria to look for hypercalciuria and hyperuricosuria These conditions have been reported as a cause of hematuria in up to 35% of children with an otherwise negative evaluation, as well as in young adults Decreasing urinary calcium excretion with a thiazide diuretic or urinary urate excretion with allopurinol usually leads to resolution of the h ematuria These treatments also reduce the risk of stone formation in these patients (see Chapter 6) Rarely arteriography may be needed to diagnose arteriovenous fistulas or malformations, which may be congenital or acquired, or aneurysms of the renal arterial branches in polyarteritis nodosa or microscopic polyangiitis Renal venography or Doppler ultrasound can establish a diagnosis of nutcracker syndrome Other rare conditions are hereditary hemorrhagic telangiectasia, radiation cystitis, and schistosomiasis in endemic areas Despite extensive testing, hematuria may remain unexplained These patients should be followed with repeat urinalysis, cytology, monitoring of blood pressure and renal function, and in some cases repeat imaging, depending on the clinical situation and risk for malignancy IV EVALUATION OF PROTEINURIA A Physiologic Considerations: Healthy adults excrete less than 150 mg protein/day Less than 20 mg of that is albumin, which is normally filtered by the glomerulus in higher amounts (the exact amount is still controversial) 92957_ch08_p158-179.indd 169 4/3/14 5:53 PM 170 Chapter • The Patient with Hematuria, Proteinuria and then reabsorbed and broken down by proximal tubular epithelial cells About half of the normally excreted protein consists of Tamm–Horsfall protein, also called uromodulin, which is secreted by tubular cells lining the loop of Henle and distal tubules The other half of the normal protein excretion consists of filtered plasma proteins and polypeptides, including albumin (about 15% of total urinary protein), immunoglobulins (about 5%), light chains (also about 5%), beta-2 microglobulin, and others The normal protein excretion rate in children is less than 100 mg/m2/day Increased urinary protein excretion is often a sign of kidney disease Abnormal proteinuria can be due to increased glomerular filtration of proteins, decreased tubular reabsorption, or both Increased glomerular filtration occurs with overproduction of filterable proteins, usually immunoglobulin light chains due to multiple myeloma, or due to increased permeability of the glomerular filtration barrier, indicating glomerular disease Therefore, based on physiology, abnormal proteinuria can be classified as follows: Overflow Proteinuria: Overflow proteinuria is due to the filtration of an abnormally large amount of small molecular weight proteins that exceed the capacity of the tubules for reabsorption Causes of overflow proteinuria include intravascular hemolysis (hemoglobinuria), rhabdomyolysis (myoglobinuria), and multiple myeloma (light chains) These proteins and light chains are not detected by the urine dipstick test (see above) but are detected in a 24-hour urine collection, or by determination of a urine protein–creatinine ratio (UPCR) Evaluation of overflow proteinuria is guided by the clinical context Hemoglobinuria and myoglobinuria are usually recognized by the presence of red urine, with red, heme-positive supernatant after centrifugation (see above) Urinary light chains are detected by urine immunofixation (IFE) Tubular Proteinuria: In contrast to overflow proteinuria, in which normal tubular reabsorption is overwhelmed by the large amount of filtered proteins, tubular proteinuria is caused by damage to the renal tubulointerstitium leading to a failure to reabsorb normally filtered small molecular weight proteins, mostly beta-2 m icroglobulin, light chains, retinol-binding protein, and breakdown products of albumin In addition, brush border and cellular enzymes (such as N-acetylglucosamine and lysozyme) may appear in the urine when proximal tubular epithelia are injured, and uromodulin may be secreted in increased amounts with injury to epithelial cells of the loop of Henle and distal nephron As in overflow proteinuria, these tubular proteins are not detected by the urine dipstick test and may therefore remain undiagnosed However, they will be measured if a 24-hour urine collection is ordered for e valuation of an elevated serum creatinine or hematuria Proteinuria due to t ubulointerstitial disease is no more than to g/day Higher amounts of proteinuria (>3 g/day) are due to glomerular disease or overflow of filtered light chains If the source of proteinuria is unclear, urine protein electrophoresis (UPEP) and IFE should be used to aid in diagnosis In glomerular proteinuria, UPEP demonstrates primarily albumin, whereas tubular proteinuria demonstrates a predominance of small molecular weight proteins UPEP and IFE will 92957_ch08_p158-179.indd 170 4/3/14 5:53 PM Chapter • The Patient with Hematuria, Proteinuria 171 detect abnormal light chains Tubular and glomerular proteinuria are not mutually exclusive as most glomerular diseases are accompanied by tubulointerstitial injury and inflammation, and tubulointerstitial diseases eventually lead to focal segmental or global glomerulosclerosis Glomerular Proteinuria: Glomerular proteinuria results from injury to the glomerular filtration barrier, which consists of the fenestrated endothelial cells, the GBM, and the visceral glomerular epithelial cells or podocytes Damage to any one of these barriers may be responsible for increased glomerular permeability to macromolecules For instance, the endothelial cell layer is disrupted in preeclampsia, the GBM is defective in Alport syndrome, and the podocytes are injured in focal segmental glomerulosclerosis, all diseases characterized by proteinuria In the last decade, the importance of the slit-diaphragm between the foot processes of podocytes has been recognized through the discovery of genetic m utations in slit-diaphragm proteins in infants and children with heavy glomerular proteinuria Other genetic mutations of podocyte enzymes or of protein constituents of the GBM also lead to glomerular proteinuria Injury to the filtration barrier may change its size-selective properties, allowing the passage of higher molecular weight proteins or even of cells (as in crescentic glomerulonephritis), or may change its charge-selective properties, permitting the ultrafiltration of negatively charged albumin (as in minimal change nephropathy), or both Finally, mesangial injury may also contribute to proteinuria by interfering with normal mesangial clearance functions Glomerular proteinuria can be mild, with albumin excretion rates of 30 to 300 mg/day (high albuminuria), moderate, in the range of to g/day, or heavy (nephrotic), more than g/day and up to over 20 g/day (see below) In general, the heavier the proteinuria, the worse is the prognosis of the underlying kidney disease “Postrenal” Proteinuria occurs with inflammation in the urinary tract, that is, with infection, nephrolithiasis, gross hematuria, and tumors The amounts are small to moderate B Definitions used clinically to classify proteinuria: High Albuminuria (formerly called microalbuminuria because dipstick tests are usually negative due to low urine albumin concentrations): albumin excretion 30 to 300 mg/day, or spot urine albumin to creatinine ratio >30 mg/g Overt Proteinuria (also called macroalbuminuria, dipstick positive): Albumin excretion >300 mg/day, or spot urine albumin to creatinine ratio >300 mg/g Nephrotic Range Proteinuria: Protein excretion >3 to 3.5 g/day, or spot UPCR >3 g/g Nephrotic Syndrome: Nephrotic range proteinuria, hypoalbuminemia (