Practical Algorithms in Pediatric Nephrology

Practical Algorithms in Pediatric Nephrology Editors Israel Zelikovic, Haifa Israel Eisenstein, Haifa

Basel · Freiburg · Paris · London · New York · Bangalore · Bangkok · Shanghai · Singapore · Tokyo · Sydney

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56 graphs, 1 figure and 10 tables, 2008

Contents 1

Contributors

2

Preface

Urinary tract disease/tubulointerstitial nephropathy 22

Z. Hochberg 3

Introduction I. Zelikovic; I. Eisenstein

28

Acute nephritic syndrome

30

Proteinuria

32

12

Nephrotic syndrome in the first year of life

34

F. Santos; S.P. Makker

36

14

Rapidly progressive glomerulonephritis

Vesicourethral reflux

Tubular disease 54

Dysfunctional voiding Loin pain with hematuria Renal trauma Tubulointerstitial nephritis

Aminoaciduria I. Eisenstein; P. Goodyer; I. Zelikovic

56

Cystinuria P. Goodyer; I. Eisenstein; I. Zelikovic

58

Glycosuria I. Eisenstein; P. Goodyer; I. Zelikovic

60

Renal tubular acidosis I. Eisenstein; P. Goodyer; I. Zelikovic

R. Adelman; S. Hulton 62

A.L. Friedman; S. Turi

Nephrotic syndrome in the child and adolescent S.P. Makker; F. Santos

Fetal hydronephrosis

J. Smith; F.B. Stapleton

F. Santos; S.P. Makker 10

Pediatric hypertension S. Turi; A.L. Friedman

S. Hulton; R. Adelman

F. Santos; S.P. Makker 8

52

R. Adelman; S. Hulton

A.L. Friedman; S. Turi 6

S. Turi; A.L. Friedman

Dilated/obstructed urinary tract

J.-P. Guignard; R.N. Fine

Glomerular and vascular disease Hematuria

Neonatal hypertension

S. Hulton; R. Adelman 26

4

50

Urinary tract infection R. Adelman; S. Hulton

24

Hypertension

Proximal tubulopathy (Fanconi syndrome) P. Goodyer; I. Eisenstein; I. Zelikovic

64

Structural/congenital abnormalities 38

Single kidney (renal agenesis)

Polyuria P. Goodyer; I. Eisenstein; I. Zelikovic

66

G. Rizzoni †; M.A. Linshaw

Hypouricemia J. Smith; F.B. Stapleton

S.P. Makker; F. Santos 16

Chronic nephritic syndrome

40

Renal hypoplasia-dysplasia

68

G. Rizzoni †; M.A. Linshaw

Hyperuricemia F.B. Stapleton; J. Smith

S.P. Makker; F. Santos 18

Vasculitis

42

Nephromegaly M.A. Linshaw; G. Rizzoni †

70

Rickets G. Ariceta; B. Hoppe; C.B. Langman

W. Proesmans; U.S. Alon 20

Hemolytic uremic syndrome

44

Hyperechoic kidney M.A. Linshaw; G. Rizzoni †

W. Proesmans; U.S. Alon 46

Cystic kidneys G. Rizzoni †; M.A. Linshaw

48

Renal mass M.A. Linshaw; G. Rizzoni †

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II

Fluid/electrolyte/acid base balance 72

Hyponatremia

Divalent ion metabolism 92

S. Watkins; D. Okamura; J. Rodríguez Soriano 74

Hypernatremia Hypochloremia

94

Hyperchloremia

96

Hypokalemia

98

Hyperkalemia

100

Metabolic acidosis U.S. Alon; W. Proesmans

86

110

Hyperphosphatemia Hypomagnesemia

102

112

Chronic renal failure R.N. Fine; J.-P. Guignard

114

Renal osteodystrophy R.N. Fine; J.-P. Guignard

Hypercalciuria F.B. Stapleton; J. Smith

104

Acute renal failure (child/adolescent) R.N. Fine; J.-P. Guignard

I. Eisenstein; P. Goodyer; I. Zelikovic

J. Rodríguez Soriano; D. Okamura; S. Watkins 84

Hypophosphatemia

Neonatal acute renal failure J.-P. Guignard; R.N. Fine

C.B. Langman; G. Ariceta; B. Hoppe

D. Okamura; J. Rodríguez Soriano; S. Watkins 82

108

C.B. Langman; G. Ariceta; B. Hoppe

D. Okamura; J. Rodríguez Soriano; S. Watkins 80

Hypercalcemia

Oliguria/anuria J.-P. Guignard; R.N. Fine

B. Hoppe; G. Ariceta; C.B. Langman

J. Rodríguez Soriano; D. Okamura; S. Watkins 78

106

G. Ariceta; B. Hoppe; C.B. Langman

S. Watkins; D. Okamura; J. Rodríguez Soriano 76

Hypocalcemia

Renal failure

116

Index of Signs and Symptoms

120

Abbreviations

Nephrolithiasis/urolithiasis F.B. Stapleton; J. Smith

Metabolic alkalosis U.S. Alon; W. Proesmans

88

Hypovolemia U.S. Alon; W. Proesmans

90

Edema W. Proesmans; U.S. Alon

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III

IV

Practical algorithms in pediatric nephrology / editors, Israel Zelikovic, Israel Eisenstein. p. ; cm. -- (Practical algorithms in pediatrics) Includes bibliographical references and index. ISBN 978-3-8055-8539-2 (soft cover : alk. paper) 1. Pediatric nephrology--Handbooks, manuals, etc. 2. Medical protocols--Handbooks, manuals, etc. I. Zelikovic, Israel. II. Eisenstein, Israel, 1964- III. Series. [DNLM: 1. Kidney Diseases--diagnosis. 2. Adolescent. 3. Child. 4. Decision Trees. 5. Diagnosis, Differential. WS 320 P895 2008] RJ476.K5P73 2008 618.92‘61--dc22 2008019859

Disclaimer. The statements, options and data contained in this publication are solely those of the individual authors and contributors and not of the publisher and the editor(s). The appearance of advertisements in the book is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements. Drug Dosage. The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord 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 and/or infrequently employed drug.

All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher. © Copyright 2008 by S. Karger AG, P.O. Box, CH–4009 Basel (Switzerland) Printed in Switzerland on acid-free and non-aging paper (ISO 9706) by Reinhardt Druck, Basel ISBN 978–3–8055–8539–2

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Library of Congress Cataloging-in-Publication Data

Contributors Raymond Adelman, MD

Bernd Hoppe, MD

Juan Rodríguez Soriano, MD

Department of Pediatrics Phoenix Children’s Hospital Phoenix, AZ, USA

University Children’s Hospital Division of Pediatric Nephrology Cologne, Germany

Uri S. Alon, MD

Sally Hulton, MD

Division of Pediatric Nephrology Department of Pediatrics Hospital de Cruces and Basque University School of Medicine Baracaldo, Vizcaya, Spain

Section of Pediatric Nephrology The Children’s Mercy Hospital and Clinics University of Missouri Kansas City, MO, USA

Department of Pediatric Nephrology The Birmingham Children’s Hospital NHS Trust Birmingham, United Kingdom

Gema Ariceta, MD

Craig B. Langman, MD

Division of Pediatric Nephrology Hospital de Cruces Baracaldo, Vizcaya, Spain

Feinberg School of Medicine Northwestern University Kidney Diseases, Children’s Memorial Hospital Chicago, IL, USA

Pediatric Nephrology Rambam Medical Center Faculty of Medicine – Technion Haifa, Israel

Michael A. Linshaw, MD Division of Pediatric Nephrology Massachusetts General Hospital Boston, MA, USA

Richard N. Fine, MD

Sudesh Paul Makker, MD

School of Medicine State University of New York at Stony Brook Stony Brook, NY, USA

Pediatric Nephrology UC Davis Medical Center Sacramento, CA, USA

Aaron L. Friedman, MD

Daryl Okamura, MD

Department of Pediatrics University of Minnesota Minneapolis, MN, USA

Division of Pediatric Nephrology Children’s Hospital and Regional Medical Center University of Washington Seattle, WA, USA

Paul Goodyer, MD Division of Pediatric Nephrology The Montreal Children’s Hospital McGill University Montreal, Quebec, Canada

Willem Proesmans, MD Renal Unit, Department of Pediatrics University Hospital Gasthuisberg Leuven, Belgium

1

Jean-Pierre Guignard, MD

Gianfranco Rizzoni †, MD

Division of Pediatric Nephrology Department of Pediatrics Lausanne University Medical School Lausanne, Switzerland

Division of Nephrology Children’s Hospital and Research Institute Bambino Gesu Rome, Italy

Division of Pediatric Nephrology Hospital Central de Asturias University of Oviedo Oviedo, Asturias, Spain

Jodi Smith, MD Division of Pediatric Nephrology Children’s Hospital and Regional Medical Center University of Washington Seattle, WA, USA

F. Bruder Stapleton, MD Department of Pediatrics Children’s Hospital and Regional Medical Center University of Washington Seattle, WA, USA

Sandor Turi, MD Department of Pediatrics and Child Health Center University of Szeged Szeged, Hungary

Sandra Watkins, MD Division of Pediatric Nephrology Children’s Hospital and Regional Medical Center University of Washington Seattle, WA, USA

Israel Zelikovic, MD Pediatric Nephrology Rambam Medical Center Faculty of Medicine – Technion Haifa, Israel Downloaded by: Univ. of California San Diego 198.143.33.65 - 8/6/2015 3:20:27 PM

Israel Eisenstein, MD

Fernando Santos, MD

Preface The term ‘algorithm’ is derived from the name of the ninth century Arabic mathematician Algawrismi, who also gave his name to ‘algebra’. His ‘algorismus’, indicated a well-defined procedure for step-bystep logical approach to mathematical problem-solving. In reading the final product, written by some of the finest pediatric nephrologists in the world and edited by my friends Drs. Israel Zelikovic and Israel Eisenstein, it is obvious that the spirit of the algorismus has been utilized in its best. The algorithm input are physical symptoms and signs, or laboratory results, which lead to a number of effective steps, and produces the diagnoses for an output.

Practical Algorithms in Pediatric Nephrology is meant as a pragmatic text to be used at the patient’s bedside. The experienced practitioner applies step-by-step logical problem-solving for each patient individually. Decision trees prepared in advance have the disadvantage of unacquaintedness with the individual patient. Yet, for the physician who is less experienced with a given problem, a prepared algorithm would provide a logical, concise, cost-effective approach prepared by a specialist who is experienced with the given problem.

This is the third in the Series of Practical Algorithms in Pediatrics, following Practical Algorithms in Pediatric Endocrinology and Practical Algorithms in Pediatric Hematology-Oncology. Hopefully, this volume will provide residents, fellows, general pediatricians and family practitioners some important clinical tools in understanding their patients.

Ze’ev Hochberg, MD, PhD Series Editor

Thirty years after completing my pediatric residency, I discover that Pediatric Nephrology has become a sophisticated specialty with solid scientific background, of which I know so little. I would still refer my patients to a specialist with many of the diagnoses, symptoms and signs discussed here. But, with the help of this outstanding algorithms and text, I would refer them after an educated initial workup, and would be better equipped to follow the specialist’s management.

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2

Introduction

3

understanding of the physiology and pathophysiology of renal function in health and disease. Hence, special emphasis has been given in this book to the novel knowledge that has accumulated on the molecular pathophysiology and molecular genetics of various kidney diseases and urinary tract abnormalities, in order to deepen and strengthen the practical approach to common problems occurring in pediatric nephrology. Indeed, many of the algorithms in this book, written by leading investigators in the area of pediatric nephrology, incorporate and exemplify this ‘bench to In the past decade, remarkable prog- patient’ approach which has become a ress has been made in our understanding characteristic of modern medicine. of the molecular pathogenesis of hereditary kidney diseases and congenital urinary It is the Editors’ hope that the algorithtract abnormalities. Studies in molecular mic, logical and stepwise approach to the genetics and molecular biology have led to diagnosis and management of various hethe identification of numerous kidney dis- reditary and acquired kidney diseases, ease-causing mutations, provided impor- fluid and electrolyte abnormalities, aberratant insights into the defective molecular tions in mineral balance, and other impairmechanisms underlying various kidney ments in kidney function, will equip the diseases and structural abnormalities of practitioner, inexperienced in the field of the kidney, and have greatly increased our pediatric nephrology, with the tools and ability to successfully confront and manage, at least at their initial stages, clinical problems which have always been notorious for their complexity and which have been left, from the outset, to specialists in the area.

During the production process of this book, it has been our privilege to interact and work with some of the leading clinicians and teachers in the field of pediatric nephrology in the world. It has been a very enriching and gratifying experience for us, the editors, for which we thank all the authors. A final note – we have been very saddened by the recent passing of Prof. Gianfranco Rizzoni, a prominent pediatric nephrologist from Rome, Italy, who contributed several excellent algorithms to this book. We send our deep condolences to his family and friends. Israel Zelikovic, MD Israel Eisenstein, MD

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Practical Algorithms in Pediatric Nephrology is a pragmatic text which classifies common clinical symptoms, signs, laboratory abnormalities and issues of management as they present themselves in daily practice. Aimed at an audience of general and family practitioners, pediatricians and trainees who are not exposed to pediatric nephrology problems on a day-today basis, it provides a rational, stepwise and as noninvasive as possible approach from which they can profit and acquire medical reasoning.

A.L. Friedman · S. Turi

Glomerular and vascular disease

Hematuria

Hematuria

/

4 Macroscopic (gross) hematuria

Microscopic hematuria 0

Exclude myo-/hemoglobinuria or red urine without hematuria 3

Persistent 2

(–) Nephritic syndrome 4

(+) Nephritic syndrome :

Hx

PHE

Laboratory/imaging

Hx

PHE

Laboratory

Urinary symptoms Stones/urinary sediment Abdominal/loin pain Weight loss Hearing impairment Eye anomalies (+)Family Hx of stones/ hearing impairment/hematuria/ bleeding disorder/ hypercoagulability

Edema, fever Abdominal/loin mass or tenderness Eye/ear examination Diaper/underwear sediment Bruises/hematomas

Urine: microscopy, culture, protein, metabolic profile of stones Serum: creatinine and BUN, electrolytes, Ca2+, phosporus, uric acid, CBC + reticulocytes, blood gases, LDH, C3, C4, ANA, ANCA Hepatitis B, C serology Imaging: plain abdominal film, renal/abdominal Doppler US, abdominal CT, angiography, kidney biopsy

Recurrent/new onset ? Postinfectious Rash, arthritis/arthralgia Hemoptysis Respiratory symptoms Weight loss, fever Drugs (NSAID, antibiotics)

Blood pressure, respiratory rate, pallor, edema, rash, petechia, arthritis/arthralgia, lung examination

Urine: microscopy, protein, eosinophils Serum: CBC + reticulocytes, creatinine, BUN, electrolytes, AST, ALT, albumin, hepatitis B, C serology, C3, C4, ANA, ANCA Kidney biopsy

Fever Strenuous exercise

Glomerular disease 5 Alport syndrome Benign familial hematuria IgA nephropathy Postinfectious glomerulonephritis Persistent asymptomatic hematuria Anatomic malformation 6 Hydronephrosis Polycystic kidney disease Tumors 7 Wilms’ tumor Neuroblastoma Rhabdomyosarcoma

Urinary tract diseases 8 Urinary tract infection Nephro-/urolithiasis Hypercalciuria Loin pain hematuria syndrome Hematologic diseases 9 Coagulopathies Renal vein thrombosis Sickle cell disease Nutcracker syndrome AV malformation Trauma

Immune-mediated disease ; Postinfectious glomerulonephritis Other glomerulonephritides (shunt GN, SBE, cryoglobulinemia) MPGN IgA nephropathy Lupus nephritis Anti-GBM glomerulopathy (Goodpasture syndrome)

Miscellaneous = Vasculitides < RPGN HSP HUS Wegner's granulomatosis TIN Churg-Strauss syndrome Microscopic polyangiitis (microscopic PAN) Polyarteritis nodosa (classic PAN)

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Transient 1

– RBCs in the urine.

2 – Microscopic hematuria is defined as >2–3 RBCs/high power field or >5 RBCs/µl. 3 – Transient hematuria is observed in children with intercurrent infection (which is the most common cause of microscopic hematuria in children) and during strenuous exercise. This type of hematuria is asymptomatic, resolves within a few days and does not warrant further evaluation. 4 – The presence of RBCs in 3 consecutive urine samples obtained over a 3-week period is defined as persistent hematuria. 5 – Damage to muscle tissue or RBCs causes a release of myoglobin or hemoglobin, respectively. Both molecules are filtered in the glomerulus and lead to red, blood-like urine, with a positive heme test on dipstick but no RBCs on urinary microscopy. Various drugs and food derivatives can cause red-colored urine without hematuria.

– The differential diagnosis of gross hematuria includes conditions with or without features of nephritic syndrome (see below). It is important to emphasize that most conditions outlined below (sections 7–11) can lead to gross as well as microhematuria. The workup of the child with hematuria should be rational, sequential, disease-oriented and as noninvasive as possible. 6

5

7 – Glomerular diseases can cause a spectrum of clinical manifestations ranging from asymptomatic microscopic hematuria to rapidly progressive glomerulonephritis and severe renal impairment. Alport syndrome is an inherited x-linked, autosomalrecessive, or rarely autosomal-dominant disorder, which is caused by a defect in collagen type IV, an essential component of the basement membrane. The clinical picture of Alport syndrome includes hearing impairment, eye abnormalities and renal disease manifested as hematuria, (microscopic or recurrent macroscopic), progressive proteinuria and deteriorating GFR culminating in ESRD. Benign familial hematuria (‘thin basement membrane’ disease) is another genetically transmitted disease that is caused by alterations in collagen type IV. The cardinal manifestation of this

Glomerular and vascular disease

mostly benign disease is asymptomatic microscopic hematuria. Although the clinical presentation of IgA nephropathy and postinfectious glomerulonephritis can be asymptomatic microscopic hematuria, these diseases are more likely to present with macroscopic hematuria with or without nephritic syndrome (see below). Persistent asymptomatic hematuria, a clinically insignificant condition, is a diagnosis made after excluding all other causes of hematuria.

12 – Nephritic syndrome is a condition characterized by gross hematuria with urinary casts (RBCs, granular), proteinuria, hypertension and variable degrees of decreased renal function.

8 – Anatomic malformations can cause hematuria, which is either microscopic or macroscopic. The features of polycystic kidney disease (either autosomal dominant or autosomal recessive), a leading cause of ESRD, include (among other manifestations) hematuria (see ‘Cystic kidneys’).

14 – Vasculitides, a group of disorders that cause inflammation of blood vessels, usually presents with gross hematuria. See appropriate algorithms.

9 – Tumors of the kidneys or the urinary tract will cause either microhematuria or, more commonly, gross hematuria. 10 – Urinary tract infections may lead (in addition to the typical urinary manifestations) to microhematuria. Hemorrhagic cystitis, a condition caused by viral infections (mostly adenovirus), radiation or cyclophosphamide administration will manifest with gross hematuria. Hypercalciuria, the most common cause of nephrolithiasis/urolithiasis in children, can cause either isolated microscopic hematuria or gross hematuria. Most of these children will have idiopathic hypercalciuria (see ‘Hypercalciuria’). Loin pain hematuria syndrome is a rare and enigmatic disorder, observed mostly in young women (see ‘Loin pain with hematuria’). 11 – Hematologic disorders will manifest usually with microscopic hematuria without urinary symptoms. Conditions that increase the risk of renal vein thrombosis include intravascular volume depletion and hypercoagulability. It is also observed in infants of diabetic mothers. Nutcracker syndrome is a condition caused by a compression of the left renal vein between the abdominal aorta and superior mesenteric artery leading to intermittent gross hematuria and left flank pain. Diagnosis is made by abdominal Doppler sonogram or angiography. Sickle cell disease can result in glomerulopathy leading to microscopic hematuria or renal papillary necrosis which will cause gross hematuria.

A.L. Friedman · S. Turi

13 – Immune-mediated GN comprises the majority of diseases that cause nephritic syndrome in children, and usually present with gross hematuria. For details, see appropriate algorithms.

15 – RPGN, or crescentic GN, usually manifest with gross hematuria in addition to the rapid decline in GFR (for details, see appropriate algorithms). Hemolytic uremic syndrome (HUS) and tubulointerstitial nephritis are additional important causes of gross hematuria (see appropriate algorithms).

Selected reading Bergstein J, Leiser J, Andreoli S: The clinical significance of asymptomatic gross and microscopic hematuria in children. Arch Pediatr Adolesc Med 2005;159:353–355. Diven SC, Travis LB: A practical primary care approach to hematuria in children. Pediatr Nephrol 2000;14:65–72. Hudson BG, Tryggvason K , Sundaramoorthy M, Neilson EG: Alport’s syndrome, Goodpasture’s syndrome, and type IV collagen. N Engl J Med 2003;348:2543–2556. Pan CG: Evaluation of gross hematuria. Pediatr Clin North Am 2006;53:401–412. Shin JI, Park JM, Lee SM, Shin YH, Kim JH, Lee JS, Kim MJ: Factors affecting spontaneous resolution of hematuria in childhood nutcracker syndrome. Pediatr Nephrol 2005;20:609–613. Yadin O: Hematuria in children. Pediatr Ann 1994;23: 474–478, 481–485. Youn T, Trachtman H, Gauthier B: Clinical spectrum of gross hematuria in pediatric patients. Clin Pediatr 2006;45:135–141.

Hematuria

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1

Glomerular and vascular disease

F. Santos · S.P. Makker

Acute nephritic syndrome

Acute nephritic syndrome

/

– Macroscopic hematuria, oliguria, acute renal failure, salt retention (hypertension and edema), proteinuria

Initial diagnostic work-up 0 History and physical examination Culture of throat and/or cutaneous lesion Serum creatinine, BUN, electrolytes and albumin levels Urinalysis + microscopy Serum C3, C4 levels, antistreptolysin O titers, hepatitis B and C serology, ANA levels Renal ultrasound, chest X-ray

6

Hypocomplementemia 1

Acute postinfectious GN 2

Antibiotics, if indicated

Rapidly declining renal function

Persistent 3

Renal biopsy

Renal biopsy

Membranoproliferative GN 4 Lupus nephritis Endocarditis

IgA GN 5 HSP Polyarteritis nodosa

RPGN 7

Supportive treatment (regardless of etiology) 6 Salt, potassium, fluid restriction Furosemide Antihypertensive drugs ± Dialysis therapy

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Transient

Normocomplementemia 3

2 – Initial diagnostic approach to a child who presents with manifestations suggestive of ANS should focus on: (a) confirmation of ANS by measuring GFR and amount of protein lost in urine as well as potential detection of RBC casts in urine sediment; (b) search for evidence of infectious causal agent, mainly group A beta-hemolytic streptococcus, by cultures of throat and skin lesions, if any, and serum determination of antistreptolysin O titer; (c) exclusion of systemic diseases, such as HSP syndrome, systemic lupus erythematosus, endocarditis or idiopathic GN (MPGN, IgA nephropathy) by detailed anamnesis, meticulous physical examination and laboratory tests which include serum C3 and C4 levels, hepatitis B and C serology and levels of ANA. No specific findings of ANS may be found in renal ultrasound which usually will show a loss of the normal corticomedullary differentiation; however, the absence of other abnormal findings is useful to rule out chronic nephro-urologic disorders; if respiratory symptoms are present, a chest X-ray film is mandatory since pulmonary edema may be a presenting manifestation of ANS. 3 – Measurement of serum C3 levels is important in the evaluation of the child presenting with ANS. Hypocomplementemia is a major diagnostic criteria of postinfectious acute GN. Serum levels of C3 are usually markedly depressed when clinical and biochemical manifestations of ANS become apparent. The degree of depression of C3 does not correlate with the severity of the disease or have any prognostic significance. Serum C3 concentrations tend to normalize progressively and persistence of hypocomplementemia beyond 8 weeks after presentation should alert the clinician to the possibility of MPGN or lupus nephritis.

7

4 – Poststreptococcal GN is representative of a larger group of postinfectious GNs in which acute glomerular injury results from immune events triggered by a variety of bacterial, viral, and protozoal infections. Poststreptococcal GN predominantly affects children between 2 and 10 years and usually follows a benign course with full recovery being the rule. Kidney biopsy, which is not indicated in typical cases, will show diffuse GN with endocapillary proliferation and

Glomerular and vascular disease

abundance of polymorphonuclear cells, positive immunoflorescence for C3 and IgG and subepithelial electron-dense deposits or ‘humps’. Poststreptococcal acute GN must be treated with penicillin as though an active infection by group A streptococcus is present. 5 – The finding of normal serum C3 concentrations or persistent hypocomplementemia must raise the suspicion of other diagnostic options mentioned above and lead to kidney biopsy. 6 – MPGN is a chronic GN rarely seen before 10 years of age. This entity is divided into 3 subtypes by histopathologic features termed MPGN I, II and III. MPGN can be idiopathic or associated with systemic diseases (suppurative infections, hepatitis B and C infection, cryoglobulinemia and malignancies). Lupus nephritis is more often found in adolescent girls with elevated titers of antinuclear antibodies and multisystemic involvement. The renal lesions are divided into 5 types based on the WHO classification of histologic findings: type 1– normal glomeruli; type 2 – mesangial changes; type 3 – focal proliferative GN; type 4 – diffuse proliferative GN (the most common and most severe form), and type 5 – membranous GN. Long-term prognosis of the severe forms of lupus nephritis (types 3 and 4) is poor and, therefore, treatment regimens are aggressive and include IV pulses of methylprednisolone and cyclophosphamide.

Selected reading 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, Wurzner R, Zipfel PF: Membranoproliferative glomerulonephritis type II (dense deposit disease): an update. J Am Soc Nephrol 2005;16:1392–1403. Delos Santos NM, Wyatt RJ: Pediatric IgA nephropathies: clinical aspects and therapeutic approaches. Semin Nephrol 2004; 24:269–286. Hricik DE, Chung-Park M, Sedor J: Glomerulonephritis. N Engl J Med 1998;339:888–889. Jucos LI: Intrarenal mechanisms of salt and water retention in the nephritic syndrome. Kidney Int 2002;61:1182–1195. Kurtzman NA: Nephritic edema. Semin Nephrol 2001;21:257–261. Lee BS, Cho HY, Kim EJ, Kang HG, Ha IS, Cheong HI, Kim JG, Lee HS, Choi Y: Clinical outcomes of childhood lupus nephritis: a single center’s experience. Pediatr Nephrol 2007;22:222–231. Madaio MP, Harrington JT: The diagnosis of glomerular diseases: acute glomerulonephritis and the nephrotic syndrome. Arch Intern Med 2001;161:25–34.

7 – IgAN is the most common GN worldwide with especially high prevalence in certain areas (south-east Asia, Pacific rim) in contrast to low rates among blacks. Although the exact etiology is unknown, there are certain predisposing genetic and environmental factors that are associated with IgAN. The pathogenesis of IgAN is complex and it involves mesangial deposition of IgA molecules, circulating IgA complexes as well as abnormal IgA glycosylation. The typical histological findings include mesangial proliferation with mesangial IgA staining on immunofluorescence. Although the longterm prognosis is usually good, hypertension, heavy proteinuria and/or reduced GFR are bad prognostic factors and aggressive therapy should be instituted which includes combinations of steroids, fish-oil, azathioprine, dipyridamole and heparin/warfarin. Vasculitis can lead to ANS with normocomplementemia. This picture is especially seen in HSP and polyarthritis nodosa. 8 – Patients with ANS require close monitoring to prevent complications. Physical activity as well as salt, potassium, and fluid intake must be restricted during the acute period of the disease. Oral or intravenous furosemide is often needed for a few days to treat oliguria and hypertension. Other drugs used to treat hypertension include calcium channel blockers, ␣- and ␤-blockers, various vasodilators, and, occasionally, ACE inhibitors. 9 – RPGN is diagnosed by an abrupt and progressive deterioration of glomerular filtration rate along with the presence of epithelial crescents in more than 60% of glomeruli. For details, see ‘Rapidly progressive glomerulonephritis’.

F. Santos · S.P. Makker

Acute nephritic syndrome

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1 – Acute GN often manifests as an ANS. The main features of this syndrome are: (a) hematuria, usually gross hematuria of sudden onset; it is sometimes associated with the presence of RBC casts in urinary sediment, which is diagnostic of glomerular bleeding; (b) oliguric acute renal failure of variable severity; oliguria is defined as urine volume less than 12–14 ml/m2/h in children and below 0.6– 0.8 ml/kg/h in neonates and infants; (c) hypertension and edema are mainly produced by salt retention that is not only secondary to decreased glomerular filtration rate but also to increased reabsorption of sodium chloride in the collecting duct. This tubular hyperabsorption of sodium chloride probably results from hyperactivity of the Na+/K+ ATPase pump located on the basolateral membrane of the collecting duct cells; (d) proteinuria of variable intensity; although urinary protein excretion in children with ANS is characteristically below the nephrotic range.

F. Santos · S.P. Makker

Glomerular and vascular disease

Proteinuria

Proteinuria

/

8 Persistent 1

Glomerular 4

Tubular

Isolated 4

Tubular disorders 2

No additional studies No treatment

Overload proteinuria 3

Nephritic syndrome 5

Associated with

Nephrotic syndrome 5

Chronic renal disease 6

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Transient 0

2 – Prevalence of proteinuria in a single urine specimen in children varies between 5% and 15%. Transient proteinuria is not indicative of underlying renal disease. This type of proteinuria is often found in association with fever, exercise, stress or dehydration and the only study required is to confirm its disappearance once the intercurrent factor has worn off. Orthostatic proteinuria is diagnosed when urinary protein is elevated when the subject is upright but normalizes during recumbency. It occurs most commonly in school-aged children, its intensity is usually below the nephrotic range, and its outcome is generally considered to be benign, so no additional diagnostic studies or therapeutic measures are necessary.

– Proteinuria detected in repeated urine samples over time is always an index of renal or systemic abnormality and should be further investigated. 3

9

4 – Decreased reabsorption of normally filtered low-molecular-weight proteins (molecular weight below 40,000 Da) by the renal proximal tubules leads to tubular proteinuria. Dipstick testing is less sensitive to detect tubular proteins than albumin. ␤2-Microglobulin and retinol-binding protein are the low-molecularweight proteins measured most frequently. Normal reference values for these proteins in children beyond 6 months of age and adults are as follows: urinary ␤2-microglobulin = 6.0–40.7 µg/mmol creatinine; plasma ␤2-microglobulin 1.0–2.4 mg/l; urinary retinol-binding protein ~1–24.5 µg/mmol creatinine. In infants, these concentrations tend to be higher. Measurement

Glomerular and vascular disease

of ␤2-microglobulin requires monitoring of urine pH because of its instability in samples with pH below 6.5. From the diagnostic point of view, the finding of tubular proteinuria is seen in the setting of a more generalized proximal tubular disorder, usually congenital or primary, that produces aminoaciduria, phosphaturia, glucosuria and/or bicarbonaturia, or as an acquired alteration secondary to interstitial nephropathy (acute pyelonephritis, reflux nephropathy, obstructive nephropathy, administration of aminoglycosides, etc.) 5 – Systemic overproduction of low-molecularweight proteins may give rise to proteinuria because of excessive amounts of these proteins in the glomerular filtrate which overwhelms the maximum reabsorptive capacity of the tubule. Thus, low-molecularweight proteinuria may be a manifestation of multiple myeloma (light chains), leukemia (lysozyme), rhabdomyolysis (myoglobin) or hemolysis (hemoglobin). 6 – With a negative personal history of renal disease, persistent glomerular proteinuria even under the nephrotic range (between 4 and 40 mg/m2/h) requires clinical evaluation (family and personal history, edema, blood pressure) laboratory work-up (urinalysis, renal function, serum lipid profile, serum complement, antinuclear antibodies, hepatitis and HIV diagnostic tests) and abdominal ultrasound to rule out associated renal dysfunction. If these complementary studies are normal, renal biopsy to identify the underlying kidney lesion may be necessary.

Selected reading Adelman RD, Restaino IG, Alon US, Blowey DL: Proteinuria and focal segmental glomerulosclerosis in severely obese adolescents. J Pediatr 2001;138: 481–485. Chandar J, Abitbol C, Montane B, Zilleruelo G: Angiotensin blockade as sole treatment for proteinuric kidney disease in children. Nephrol Dial Transplant 2007;22:1332–1337. Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A, Ingelfinger J: Evaluation and management of proteinuria and nephrotic syndrome in children: recommendations from a pediatric nephrology panel established at the National Kidney Foundation conference on proteinuria, albuminuria, risk, assessment, detection, and elimination (PARADE). Pediatrics 2000;105:1242–1249. Litwin M, Grenda R, Sladowska J, Antoniewicz J: Add-on therapy with angiotensin II receptor 1 blocker in children with chronic kidney disease already treated with angiotensin-converting enzyme inhibitors. Pediatr Nephrol 2006;21: 1716–1722. Tomlinson PA: Low molecular weight proteins in children with renal disease. Pediatr Nephrol 1992;6:565–571.

7 – For details on nephritic and nephrotic syndromes, see corresponding algorithms. 8 – High pressure and glomerular hyperfiltration in chronic renal disease may lead to proteinuria induced by glomerulosclerosis as found in diabetic nephropathy, reduced functioning renal mass, arterial hypertension, severe obesity, etc. 9 – ACE inhibitors and angiotensin II receptor antagonists are increasingly used in adult patients with chronic renal disease because of their potential renoprotective, antihypertensive and antiproteinuric actions. Although few data are available in children, accumulating evidence seems to confirm the beneficial effect of these therapies on proteinuria of pediatric patients with different types of chronic renal disease.

F. Santos · S.P. Makker

Proteinuria

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1 – Minimal amounts of proteins can be physiologically found in urine. Pathologic proteinuria can be detected by dipstick, which is especially sensitive to albumin. A rough estimation of the intensity of proteinuria may be drawn from the dipstick: trace, 1+, 2+, 3+, 4+ approximately correspond to 10–15, 30, 100, 300 and >1,000–2,000 mg/dl, respectively. A more accurate quantitation of proteinuria requires timed urine collection of measurement of the protein (mg/dl)/creatinine (mg/dl) ratio in an isolated urine sample, preferably the first one of the morning. A urinary protein to creatinine ratio 60.2 in children beyond infancy is considered abnormal. In infants, higher ratios (up to 0.5) are still considered normal. The 24-hour urine collection is the best test for the estimation of protein excretion. Values above 4 mg/m2/h are pathologic and values above 40 mg/m2/h are in the nephrotic range.

F. Santos · S.P. Makker

Glomerular and vascular disease

Nephrotic syndrome in the first year of life

Nephrotic syndrome in the first year of life

/

10 Congenital NS 0

Infantile NS 0

Finnish type NS 1

Secondary NS 2

DMS 3

FSGS 4

Particularly frequent in Finns Early-onset massive proteinuria Prematurity and large placenta No renal insufficiency Microcystic kidneys Mutations in NPHS1 gene

Intrauterine infections Congenital syphilis Toxoplasmosis Rubella CMV HIV

Isolated or Denys-Drash syndrome Early progression to renal failure Characteristic renal pathology Mutations in WT1 gene

Resistant to immunomodulatory drugs Early progression to renal failure Usually podocin gene mutations

Others 5

MCD MGN SLE

Supportive therapy 6 Nutritional supplementation Albumin infusions + furosemide Thyroid hormone replacement Anticoagulation Aggressive treatment of infections Antiproteinuric agents

Treatment of primary disease Immunomodulatory treatment

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Nephrectomy 7 Dialysis Early transplantation

2 – The term congenital NS is classically used to describe a NS of onset within the first 3 months of life (and has become synonymous with Finnish type NS). Infantile NS usually applies to NS of later onset, until 1 year of age. 3 – Finnish-type NS may be found worldwide although it is more frequent in Finland where its incidence is approximately 1/10,000 newborns. A typical clinical picture includes premature delivery, placenta weighing more than 25% of the birth weight, development of generalized edema, massive proteinuria and hypoalbuminemia at birth or within the first days of life. In untreated cases, the natural course of the disease leads to early death secondary to infection and/or malnutrition in the presence of normal glomerular filtration rate. Proteinuria may be detected prenatally by increased concentrations of alfa-fetoprotein in amniotic fluid. Microscopically, NS of Finnish type is characterized by irregular pseudocystic dilatation of proximal tubules which is typically seen after the first 3–6 months of life. The disease follows an autosomalrecessive transmission and is caused by mutations in the gene NPHS1. The gene is localized to 19q13.1 and encodes a protein named nephrin which is essential in the formation of the normal zipper-looking structure in the slit diaphragm that joins the interdigitating processes of podoctytes. Abnormal nephrin results in a massive leak of proteins through the glomerular basal membrane.

11

4 – Neonatal infections, such as syphilis and less frequently toxoplasmosis, cytomegalovirus or hepatitis can cause nephrotic syndrome. These causes must be excluded by the associated clinical manifestations and proper immunologic or serologic tests. In these cases, specific treatment of the primary disorder usually leads to remission of the NS. 5 – DMS is responsible for early-onset NS either as an isolated disease or as part of Denys-Drash syndrome in which DMS is associated with male

Glomerular and vascular disease

pseudohermaphroditism and Wilms tumor. Incomplete forms of the syndrome have been reported. DMS causes ESRD in the first 2 years of life. The pathological picture is characteristic and consists of mesangial matrix expansion, thickened glomerular basal membrane, tuft contraction and tubular dilatation. Mutations in the WT1 gene, which is expressed in podocytes and epithelial cells of the Bowman’s capsule of postnatal kidney, have been found in nearly all patients affected with Denys-Drash syndrome and in many cases of isolated DMS. 6 – Although FSGS is usually diagnosed in older children or adults, it can present in the first year of life. These cases are usually due to mutations in the gene encoding podocin, a protein which is essential in the formation and structure of the slit diaphragm. Two additional genes encoding the proteins alfa-actinin-4 and TRPC6 are known to cause FSGS when mutated, usually in older children. These genetic defects do not respond to treatment with glucocorticoids or other immunomodulatory drugs and no disease recurrence after transplantation (which is common in idiopathic FSGS) is expected.

Selected reading Holmberg C, Tryggvason K, Kestila MK, Jalanko HJ: Congenital nephrotic syndrome; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott-Williams & Wilkins, 2004, pp 503–516. Kestila M, lenkkeri U, Mannikko N, Lamerdin J, Mc Cready P, Putaaala H, Ruotsalinen V, Morita T, Nissinen M, Herva R, Kashtan DE, Peltonen L, Holmberg C, Olsen A, Tryggvason K: Positionally cloned gene for a novel glomerular protein – nephrin – is mutated in congenital nephrotic syndrome. Mol Cell 1998;1:575–582. Niaudet P, Gubler MC: WT1 and glomerular diseases. Pediatr Nephrol 2006;21:1653–1660. Tryggvason K, Patrakka J, Wartiovaara J: Hereditary proteinuria syndromes and mechanisms of proteinuria. N Engl J Med 2006;354:1387–1401.

7 – NS in infants younger than 1 year may be secondary to SLE, minimal-change nephropathy or membranous nephropathy. These cases are rare and for details on these disorders, see the appropriate algorithms. 8 – The management of an infant with persistent NS is complex and must be done in a highly specialized children’s hospital. It includes active nutritional support, control of edema by repeated administration of intravenous albumin in association with furosemide, hormone replacement, prevention of thromboembolic complications, and prompt and aggressive treatment of infections. Administration of indomethacin, ACE inhibitors, angiotensin II-type I receptor blockers to reduce glomerular filtration rate, and, subsequently, proteinuria may facilitate the control of the patient. 9 – In spite of the above measures, infants with massive proteinuria often require early nephrectomy and dialysis to place the patient in proper metabolic and nutritional conditions for a successful renal transplantation. Bilateral nephrectomy and chronic peritoneal dialysis have been recommended in Finnish type NS when the infant weighs 7 kg. The effectiveness of unilateral nephrectomy in association with antiproteinuric drugs is a matter of controversy.

F. Santos · S.P. Makker

Nephrotic syndrome in the first year of life

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1 – NS is characterized by massive proteinuria, estimated by urinary protein elimination equal to or greater than 40 mg/m2/h and/or urinary protein/creatinine ratio >2–3 mg/mg, resulting in hypoalbuminemia of less than 3 g/dl, edema and hyperlipidemia. Although minimal change nephropathy is by far the leading cause of NS in childhood, when NS presents in the first year of life, other underlying diseases must be considered.

S.P. Makker · F. Santos

Glomerular and vascular disease

Nephrotic syndrome in the child and adolescent

Nephrotic syndrome in the child and adolescent

/

History 01 Physical examination Laboratory tests

12

Gross hematuria (–) 2 Microhematuria (±) BP-N GFR-N C3, C4-N ANA (–)

Gross hematuria (+) BPM or N, GFR–mor N MASLO mC3, C4-N ANA (–) Group A B-streptococcus in throat or skin (±)

Microhematuria (+) BPM or N GFR–m or N ANA (+) C3, C4–m

Microhematuria (+) BPMor N GFR–mor N C3, C4-N

Microhematuria (+) BPM or N GFR–mor N ASLO-N mC3 C4–mor N (–) ANA

Microhematuria (±) BPM or N GFR–mor N C3, Cr-N, occasionallym ANA (–) ASLO-N

Anti DsDNA (+)

Possibly FSGS, MGN

Most likely PSGN

SLE

IgAGN 8: MGN FSGS Other chronic GN Including HSP, RPGN

Renal biopsy

Renal biopsy

Renal biopsy

Steroids and Cyclophosphamide/ Azathioprine/MMF 78

Steroids 78 Other immunosuppressive agents

Steroids 78

Supportive teatment 9

Trial with steroids 3

Urine protein (+) 6

Urine Protein (–)

MPGN

Renal biopsy

Relapse

Frequent relapses Permanent remission 4

Steroid dependent

Cyclophosphamide 5 Chlorambucil Cyclosporine A

MCD FSGS

MGN 78

Steroids Chlorambucil Cyclophosphamide Cyclosporine A FK 506

Steroids Chlorambucil Cyclosporine

HepB Abs (+)

HepC Ab(+)

ANCA (+)

HepB GN ;

HepC GN ;

Wegener's GN Polyangiitis

HIV (+) ;

Steroids and other immunosuppressive agents

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Most likely MCD

2 – History and physical examination provide important clues about the etiology of NS. Traditionally NS has been classified into primary or idiopathic and secondary types. Since the etiology in the primary type is not known, it is further classified based on histopathology into MCD, FSGS, MPGN, MGN and various proliferative glomerulonephritides including IgA nephropathy and RPGN. Secondary NS may result from infections (group A streptococci, hepatitis B and C, HIV, infected ventriculoatrial shunts, syphilis, malaria, etc.), vasculitis (SLE, HSP, Wegener’s GN and polyarteritis), systemic disorders (diabetes mellitus, amyloidosis), certain medications (captopril, penicillamine, NSAIDs), and occasionally a neoplasm (Hodgkin lymphoma). Although MCD accounts for nearly 75% of all cases of NS in children, symptoms and signs associated with conditions producing secondary NS should be elicited during history and examination. For example, antecedent of sore throat or impetigo with group A streptococci would suggest PSGN, and arthritis and facial rash would suggest SLE and a family history of Alport syndrome would suggest that as the diagnosis. Presence/ absence of hypertension provides an important clue. Blood pressure is normal in MCD but may be elevated in other entities. 3 – In the initial laboratory work-up, urine is tested for routine protein/creatinine ratio and serum for electrolytes, creatinine, BUN, total proteins, albumin, cholesterol, C3 and C4, ANA, ASLO and serology for hepatitis B, hepatitis C and HIV. In addition, a renal sonogram must be performed in every child with NS. These tests establish the diagnosis, determine if renal failure (elevated serum creatinine) is present and provide useful information about the etiology of NS.

13

4 – Gross hematuria can occur with any of the glomerular diseases producing NS but is not seen in MCD. The gross hematuria when seen is painless and brown ‘tea colored’. Microhematuria detected as occult blood on dipstick test or greater than 5 RBC/HPF on microscopic examination of urine sediment is almost always present at some time during the course of a glomerulonephritis and may be present at onset in 15–20% of patients with MCD. Persistent microhematuria, however, is not usually seen in MCD. 5 – Prednisone is given daily in a single morning dose or 3–4 divided doses at 2 mg/kg at a maximum dose of 60 mg/day. Various schedules for the continuation of prednisone after the urine

Glomerular and vascular disease

becomes negative for protein have been used but the superiority of any one schedule is not established though recent data suggest that longer treatment (6 months) may reduce the frequency of subsequent relapses. In general, the same dose is continued for 2–4 weeks and then tapered to zero over several weeks. 6 – About 15% of patients with MCD achieve a permanent remission but the remainder relapse. The relapses usually occur with common upper respiratory infections and may continue for years. Relapses are treated with prednisone as above but once urine becomes negative for protein, prednisone is given as a single dose every other morning and continued for 1–2 months and then tapered gradually to zero over the subsequent 1–2 months. Once again, several schedules for the administration of prednisone exist but the superiority of any one schedule is not established. 7 – Patients who relapse frequently, i.e. 3–4 times/year, or who become steroid-dependent, i.e. require a certain dose of prednisone at all times to stay in remission, are prone to develop side effects of prednisone (hypertension, cushigoid habitus, reduced bone mass, stunting of height, mood changes, gastrointestinal bleeding, etc.). These patients will generally achieve remission with the addition of cyclophosphamide (2.5 mg/kg) or chorambucil (0.15 mg/kg) given concurrently with the tapering down of prednisone. Blood counts are monitored weekly and the drug discontinued if the WBC count drops to ^3,500/µl. Patients receiving cyclophosphamide can develop alopecia and or hemorrhagic cystitis and should be encouraged to drink plenty of fluids. Although these two drugs appear safe at the above-recommended doses, the long-term safety for gonadal toxicity and possible future malignancy is not established and, therefore, these drugs should only be used with the full consent of the patient. In children in whom cytotoxic drugs are to be avoided (puberty) or in those who continue to relapse, cyclosporine should be used. See previous section for details. 8 – Patients who continue to have proteinuria after a course of 4–8 weeks of daily prednisone are considered steroid resistant. Some of these patients show a partial response in that the quantitative proteinuria decreases and some improvement may also be noted in serum albumin concentration and edema. Steroid-resistant NS showing MCD or FSGS on renal biopsies may also be treated with cyclophosphamide or chlorambucil, and some patients may respond by going into a complete (urine negative for protein) or an incomplete (urine positive for protein but reduction of proteinuria and improvement or resolution of edema) remission. Cyclosporine or tacrolimus may also achieve similar results in some patients; however, the exact dosages and duration of treatment are not yet established. Doses of 150–200 mg/m2/day or 4–6 mg/kg/day of cyclosporine have been used successfully. Both cyclosporine and tacrolimus are nephrotoxic. In general, patients who show a partial response to the initial course of steroids are more likely to benefit further with any of the above than those who showed no response at all to steroids.

S.P. Makker · F. Santos

9 – All other glomerulonephrides producing NS are generally first treated with prednisone which is usually started at 2 mg/kg/day (maximum 60 mg) dose. Usually after 4–6 weeks, the dose is switched to every other morning dose to reduce the side effects of prednisone. The durations of daily and alternate day prednisone administration are quite variable and not established. Various immunosuppressive agents some old (azathioprine, cyclophosphamide, chlorambucil) and some newer (cyclosporine, tacrolimus, mycophenolate motetil, sirolimus) have been and are being used in conjunction with prednisone, but there is little control data in children for specific recommendations. 10 – ACE inhibitors and angiotensin II receptor antagonists can be used in all NS associated with chronic glomerular diseases except steroid-responsive MCD and/or PSGN for their renoprotective effects. Also, lipid-lowering drugs (statins) may be used in such patients with chronic hyperlipidemia for their lipid lowering and renoprotective effects. 11 – NS associated with PSGN resolves on its own, and supportive therapy is sufficient. Generally, progressive improvement over days is seen in NS, hypertension and renal failure. 12 – Patients with NS secondary to IgA nephropathy are occasionally treated additionally with fish oil (Max FPA) 2–4 g three times a day. 13 – Hepatitis-associated NS, particularly with MPGN or MGN histology, may resolve spontaneously. Patients in whom the renal disease does not resolve may be treated with interferon-␣ or antiviral agents (lamivudine). HIV is treated with standard antiviral and protease inhibitors.

Selected reading Eddy AA, Symons JM: Nephrotic syndrome in childhood. Lancet 2003;23:629–639. Filler G, Young E, Geier P, Carpenter B, Drukker A, Feber J: Is there really an increase in non-minimal change nephrotic syndrome in children? Am J Kidney Dis 2003;42:1107–1113. Gipson DS, Gibson K, Gipson PE, Watkins S, Moxey-Mims M: Therapeutic approach to FSGS in children. Pediatr Nephrol 2007;22:28–36. Grimbert P, Audard V, Remy P, Lang P, Sahali D: Recent approaches to the pathogenesis of minimal-change nephrotic syndrome. Nephrol Dial Transplant 2003;18:245–248. Niaudet P: Steroid-resistant nephrotic syndrome in children; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott-Williams & Wilkins, 2004, pp 557–574. Niaudet P: Steroid-sensitive nephrotic syndrome in children; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott-Williams & Wilkins, 2004, pp 543–556. Ray PE, Xu L, Rakusan T, Liu XH: A 20-year history of childhood HIV-associated nephropathy. Pediatr Nephrol 2004;19:1075–1092.

Nephrotic syndrome in the child and adolescent

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1 – NS is a clinical condition that consists of edema, heavy proteinuria, hypoalbuminemia and hyperlipidemia with or without the accompanying hypertension and/or renal failure. Nephrotic range (heavy) proteinuria is defined as protein excretion of 640 mg/h/m2 obtained on a timed urine collection. It is usually evident on a routine urinalysis with dipstick test as 3 to 64 (300 to 61,000) mg/dl protein. A random spot urine tested for protein and creatinine often will show a protein/creatinine ratio of 1 or greater and ratios of 10 or greater are not uncommon in NS.

S.P. Makker · F. Santos

Glomerular and vascular disease

Rapidly progressive glomerulonephritis

Rapidly progressive glomerulonephritis

/0

Renal biopsy

14

Immunofluorescence microscopy 1

Linear staining for IgG along the GBM 2 Negative staining for albumin

No staining or minimal staining 3

Granular staining along capillary loops and/or mesangium 4

ANA (–), C3, C4–Nm Immune deposit-mediated GN Serum for anti-GBM Ab, lung hemorrhage Pauci-immune GN Group A B-streptococci, ANA, C3, C4, ANCA Anti-GBM disease

Lung hemorrhage (+) Anti-GBM Ab (±)

Lung hemorrhage (–) Anti-GBM Ab ±

Goodpasture syndrome

Steroids 5 Immunosuppressive agents Plasmapheresis

Throat/skin culture (+) for group A B-streptococci ASLOM, anti-DNAaseBM

ANA (+), C3, C4– mor N

ANA (–), C3–m C4–mor N ANCA (–)

ANA (–) C3, C4–N ANCA (–)

Necrotizing glomerulonephritis Wegener's granulomatosis Churg-Strauss syndrome Miscoscopic polyangiitis

Renal biopsy consistent with PSGN

Renal biopsy consistent with SLE

Renal biopsy consistent with MPGN

Renal biopsy consistent with IgAGN, HSP, Chronic GN

Steroids 5 Immunosuppressive agents ± plasmapheresis

Supportive treatment 5

ANCA (+)

ANCA (–)

Steroids 5 Immunosuppressive agents

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ANCA

2 – History and physical examination can provide valuable clues towards the type of RPGN. By definition these patients have hematuria, proteinuria, abnormal cellular casts in urine sediment, and renal failure (elevated serum creatinine). Frequently, they also have gross hematuria (brown tea color urine) and/or hypertension and/or NS. These clinical and laboratory features by themselves are not very helpful in uncovering the underlying etiology of RPGN. Previous throat or skin infection (impetigo) with group A ␤-streptococci, typical rash of HSP, clinical features of SLE (joint pain, skin rash, fever, etc.), hemoptysis (Goodpasture syndrome), and chronic sinusitis (Wegener’s) are helpful leading clues. 3 – A renal biopsy is performed and the tissue is processed for histology using HE, PAS, and Jones stains for light microscopy, and for immunofluorescence and transmission electron microscopy. For immunofluoresence, frozen sections are stained with fluorescein-labeled antibodies to human immunoglobulins (IgG, IgM, IgA), complement components (C3, C4 C1q), fibrinogen and albumin. All these studies are necessary for making an accurate diagnosis. Additional laboratory tests including serum ANA, ANCA, AGBMAb, C3 and C4 complement, and tests for group A ␤-streptococcal infection provide useful leads into the etiology of RPGN.

15

4 – Anti-GBM disease is a rare disorder, especially in children. It is caused by circulating antibodies (mainly IgG) against GBM in the lungs and kidney glomeruli. Clinical features include RPGN with or without pulmonary hemorrhage (called in the past Goodpasture syndrome and Goodpasture disease, respectively). Typical laboratory findings include reduced renal function, anemia and serum anti-GBM antibodies. Renal biopsy reveals crescentic GN with linear staining for IgG along the GBM. For treatment

Glomerular and vascular disease

modalities, see section (6). The prognosis, which was devastating before the plasmapheresis era, has improved dramatically but still the rates of chronic renal sequelae, ESRD and mortality are high. 5 – A subset of children and adults with RPGN will not show either immune deposits or anti-GBM antibodies on renal biopsy. This entity, termed pauciimmune GN, will be accompanied in approximately 80–90% of the cases by a positive test for ANCA in their sera. ANCA(+) RPGN may be associated with small vessel vasculitidies (Wegener’s granulomatosis, Churg-Strauss syndrome and microscopic polyangiitis) or may be idiopathic with neocrotizing glomerulonephritis on biopsy. The antigen specificity of ANCA may be for proteinase 3 or myeloperoxidase. The former produces C-ANCA and the latter P-ANCA staining. 80–90% of ANCA found in Wegener’s granulomatosis are C-ANCA. P-ANCA are more often seen in necrotizing glomerulonephritis and polyangiitis. For treatment modalities, see section (5). 6 – RPGN resulting from PSGN, despite its severity, resolves spontaneously and does not require immunosuppressive agents or plasmapheresis. Patients with PSGN, however, may require dialysis for a few days. For details on other immune-mediated diseases leading to RPGN (SLE, MPGN, IgAN, HSP, etc.), see the appropriate algorithms.

are continued until these antibodies disappear from the serum. In most cases of pauci-immune RPGN, plasmapheresis is added to the treatment regimen. The value of plasmapheresis in immune-mediated RPGN is not certain, but it is often used as a last effort in refractory cases.

Selected reading Dillon MJ: Crescentic glomerulonephritis; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 655–662. Fischer EG, Lager DJ: Anti-glomerular basement membrane glomerulonephritis: a morphologic study of 80 cases. Am J Clin Pathol 2006;125: 445–450. Jennette JC, Thomas DB: Crescentic glomerulonephritis. Nephrol Dial Transplant 2001;16 (suppl 6):80–82. Kallenberg CG: Antineutrophil cytoplasmic autoantibody-associated small-vessel vasculitis. Curr Opin Rheumatol 2007;19:17–24. Morgan MD, Harper L, Williams J, Savage C: Anti-neutrophil cytoplasm-associated glomerulonephritis. J Am Soc Nephrol 2006;17:1224–1234.

7 – Immunosuppression is generally started with a high dose of intravenous methyl prednisolone (pulse therapy). Common dosages are 15–30 mg/kg (maximum 1,000 mg) given once a day as an infusion in 50–100 ml of 5% dextrose over 1–2 h. Usually, 3 doses are given but 5–6 doses have also been given safely. This is followed by 2 mg/kg/day oral prednisone given in 3–4 divided doses. Cyclophosphamide may be added as an adjunct to therapy and can be given orally at a dosage of 2 mg/kg/day or intravenously at a dose of 500 mg/m2 according to the schedule used by the NIH to treat diffuse proliferative glomerulonephritis of SLE. The duration of prednisone and cyclophosphamide therapy is variable and is often individualized depending on the initial response. Plasmapheresis is generally added to the regimen of the above immunosuppression in RPGN resulting from anti-GBM disease particularly if autoantibodies to the GBM are present in serum. In general, the plasmapheresis treatments

S.P. Makker · F. Santos

Rapidly progressive glomerulonephritis

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1 – RPGN is a term used to describe proliferative glomerulonephritides with rapidly deteriorating renal function and renal biopsy findings showing diffuse epithelial crescents in greater than 60% of the glomeruli. Because of the presence of crescents, this entity is also called crescentic glomerulonephritis. Of note, several renal disorders can lead to a clinical picture similar to RPGN but without the typical histologic findings. These disorders include conditions such as tubulointerstitial nephritis and acute tubular necrosis.

S.P. Makker · F. Santos

Glomerular and vascular disease

Chronic nephritic syndrome

Chronic nephritic syndrome

/

History and examination 0

16

Laboratory tests 1

Urinalysis, urinalysis on family members, C3, C4, ANA, ANCA, HepCAb, HepBsAg, HIV, renal US

Hematuria/proteinuria in family members

ANA (+) C3, C4m

ANA (–) C3, C4– N ANCA (–) Hep B and C (–)

ANA (–) C3–mN, C4–m ANCA (–)

ANA (–) ANCA (–) C3, C4– Nm

ds DNA Ab (+)

SLE

IgAGN HSP MGN Chronic GN

MPGN

Hearing test Ophthalmologic exam Bone film (in nail-patella syndrome)

Renal biopsy (WHO classification)

Renal biopsy

Renal biopsy (types I, II, III)

Hep BsAg (+)

Hep C ab (+)

HIV (+)

Renal biopsy

Renal biopsy Steroids Immunosuppressive agents2

Interferon 2

Antiviral agents 2

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Alport syndrome Thin basement membrane disease Nail-patella syndrome

1 – Chronic nephritic syndrome is defined as a clinical condition resulting from a chronic GN that consists of persistent hematuria, proteinuria and abnormal cellular casts in urine sediment with or without accompanying hypertension and/or renal failure. Hematuria without proteinuria may be present in some patients and occasionally (particularly in IgA nephropathy) the hematuria may be intermittent. Renal failure may include the presence of edema and chronic nephritic syndrome may coexist with NS. 2 – All entities other than MCD and FSGS listed in the algorithm for NS and those listed in the algorithm for RPGN can produce chronic nephritic syndrome. Other conditions to be considered in the differential diagnosis of chronic GN include: Alport syndrome, thin basement membrane disease, nail-patella syndrome, subacute bacterial endocarditis, hemolytic uremic syndrome, chronic renal transplant rejection, other collagen vascular diseases besides SLE, and other infections such as filaria, leprosy and schistosomiasis. Symptoms and signs associated with the above conditions and those mentioned in the NS algorithm should be elicited during history and physical examination and would be helpful in guiding towards the etiology. Painless gross hematuria (brown, tea color) is common in chronic nephritic syndrome and is frequently precipitated by upper respiratory infections including a sore throat with group A streptococci. A helpful feature differentiating chronic nephritic syndrome from acute PSGN is the fact that in chronic nephritic syndrome the gross hematuria occurs in the classic case at the time of sore throat but in PSGN it occurs after a lag period of 1–2 weeks.

3 – Initial laboratory tests to be obtained in all patients with chronic GN are urinalysis including urine sediment examination, spot urine for protein/creatinine ratio, serum electrolytes, BUN, creatinine, total protein, albumin, serum complement C3, C4, ANA, ANCA and serologic tests for hepatitis B, hepatitis C and HIV. Hematuria, proteinuria and RBC casts in the urine sediment essentially clinch the diagnosis of glomerulonephritis. If hereditary disorder is suspected (positive family history, hearing impairment, skeletal pathology, etc.) and/or other etiologies are not apparent, urines on all immediate family members should be tested and hearing test, ophthalmologic examination and bone film should be performed.

Selected reading Balow JE: Clinical presentation and monitoring of lupus nephritis. Lupus 2005;14:25–30. Barratt J, Feehally J: Treatment of IgA nephropathy. Kidney Int 2006;69:1934–1938. Bongers EM, Gubler MC, Knoers NV: Nail-patella syndrome: overview on clinical and molecular findings. Pediatr Nephrol 2002;17:703–712. Kashtan CE: Familial hematurias: what we know and what we don’t. Pediatr Nephrol 2005;20:1027–1035.

4 – For details on therapy, see ‘Nephrotic syndrome’, ‘Rapidly progressive glomerulonephritis’, and ‘Acute nephritic syndrome’.

Glomerular and vascular disease

S.P. Makker · F. Santos

Chronic nephritic syndrome

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17

W. Proesmans · U.S. Alon

Glomerular and vascular disease

Vasculitis

Vasculitis

/ Exclude systemic lupus erythematosus 0 Modified Chapel Hill Classification 1

Large vessel vasculitis

Medium vessel vasculitis

Small vessel vasculitis

Angiography

Cardiac US, angiography, skin biopsy

Complement, ANCA, renal biopsy incl. IF

Stenoses of aorta and branches

Coronary artery aneurysm

Hepatic, renal artery aneurysms

Skin nodules

Granulomatous

Other vasculitides ;

Nongranulomatous

cANCA (+) Pauci-immune deposits

asthma ANCA (+) Eosinophilia

ANCA (–) IgA (+) Compl nl

pANCA (+)

ANCA (–) Compl low

Takayasu arteritis 2

Kawasaki syndrome 3

PAN 4

CPA 5

Wegener’s granulomatosis 6

Churg-Strauss syndrome 7

HSP 8

MPA 9

HUV :

Steroids Methotrexate Stenting TAP Surgery

Aspirin IVIG

Steroids CYP

Steroids NSAID iloprost

Steroids CYP AZA methotrexate

Steroids CYP

Steroids? CYP?

Steroids CYP AZA MMF

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18

2 – SLE is not a vasculitis strictly speaking but an autoimmune systemic disorder that mimics any rheumatic disease and has similarities with many forms of vasculitis. SLE is a chronic, remitting and relapsing inflammatory, febrile, multisystem disorder. It involves skin, joints, kidneys and serosal membranes. Characteristic hematological anomalies are leukopenia, thrombocytopenia, hemolytic anemia and increased ESR. Except for a few patients with drug-induced SLE, the etiology is unknown. The pathophysiology is thought to be a failure of the regulatory mechanisms of the autoimmune system that sustain self-tolerance. There are a series of autoantibodies present especially antibodies against double-stranded DNA which are pathognomonic. Furthermore, serum total complement and C3 levels are decreased and gammaglobulins increased.

– Classification of the vasculitides is difficult, arbitrary and not completely satisfactory. The Chapel Hill nomenclature is based on the size of the vessels involved. From a pediatric perspective, it has proved unsatisfactory. Therefore, an attempt was recently made to develop a general classification for vasculitis as seen in children. A consensus was reached at an international conference held in Vienna in June 2005. It was decided to modify the Chapel Hill classification and this document is based on this modified classification. 3

4 – Takayasu arteritis is characterized by inflammation followed by progressive obliteration and stenosis of the aorta and its branches. Clinical findings depend on the artery involved: lesions of the carotid arteries leads to ischemia of the brain (syncope, transient hemiplegia, retinal atrophy), of the subclavian arteries to loss of pulses in the arm(s), of the renal arteries to macroscopic hematuria and flank pain and renal infarction with arterial hypertension and eventually renal failure, and of the distal aorta to claudication. Angiography – conventional, CT or MRI – shows irregular vessel walls and/or narrowing of the aorta and its branches. The etiology is unknown but in some parts of the world, tuberculosis is believed to play a role.

19

5 – Kawasaki syndrome (mucocutaneous lymph node disease): this possibly (post)infectious disease is seen mainly in children below the age of 5 years and is characterized by high fever for at least 5 days, bilateral conjunctival injection, changes of the lips, the oral or pharyngeal mucosa, cervical adenopathies and a polymorphous exanthema followed by desquamation of the fingers and the toes. The main complication is aneurysms of the coronary arteries.

Glomerular and vascular disease

6 – PAN (also known as macroscopic polyangiitis) is a form of systemic, necrotizing vasculitis involving the medium-sized arteries with signs and symptoms resulting from infarction and scarring of the affected organ(s). The following findings are hallmarks of the disease: skin rash, purpura and nodules (which correspond to affected peripheral arteries), myalgia, systemic hypertension, neuropathy and arthralgia. The vasculitis leads to arterial aneurysms or occlusion. Angiography of the abdominal great vessels shows characteristic aneurysms located at the bifurcation points of the hepatic and renal arteries. Patchy renal lesions can sometimes be documented by DMSA scanning. Laboratory investigation shows anemia, signs of inflammation and circulating immune complexes. The etiology is unknown; the association with hepatitis B is common mainly in adult patients. 7 – CPA is a more benign form of polyarteritis with limited involvement of the skin, the joints and the muscles. It is a chronic, relapsing disorder and there is frequently an association with streptococcal infections. The skin has red, painful, edematous nodules at the extremities and the trunk and fever is frequent. Fingers and toes can display ischemia, the Raynaud phenomenon and, exceptionally, gangrene. Biopsies show small and mediumsized vessels with fibrinoid necrosis. 8 – Wegener’s granulomatosis is a multisystem disease characterized by necrotizing granulomatous vasculitis involving the upper and lower respiratory tract, the lungs and the kidneys. The diagnosis requires three of the following six manifestations: (1) granulomas on biopsy material, (2) naso-sinus inflammation, (3) subglottis or tracheal stenosis, (4) abnormal chest X-ray, (5) renal manifestations such as hematuria, proteinuria and decreased GFR, and (6) presence of c-ANCA, mainly anti-PR3. Renal biopsy typically shows crescentic glomerulonephritis with pauci-immune deposits. 9 – Churg-Strauss syndrome is a rare form of systemic necrotizing vasculitis characterized by asthma, hypereosinophilia and extravascular granulomas. It affects lungs, skin, peripheral nerves, gut, heart and kidneys. Laboratory findings consist of leukocytosis with eosinophilia, elevated ESR and in the majority of patients ANCA are positive mostly of the anti-MPO type. Renal involvement is not the rule but not exceptional either and consists of glomerulonephritis with hypertension and renal insufficiency. 10 – HSP is the most common vasculitis in childhood. It is a form of nonthrombocytopenic purpura due to leukoclastic vasculitis of unknown origin. The hallmarks are diffuse abdominal pain, arthralgia and arthritis, palpable purpura concentrated mainly on the buttocks and the ankles and renal manifestations (hematuria, proteinuria, hypertension, renal failure). Skin and renal biopsies show IgA deposits. The disease is self-limiting and only a small percentage of HSP patients develop serious renal complications.

W. Proesmans · U.S. Alon

11 – Microscopic polyangiitis is another systemic disease with many similarities to Wegener’s granulomatosis and polyarteritis nodosa. It differs from Wegener’s granulomatosis by the presence of P-ANCA, mainly anti-MPO and the absence of granuloma formation of the respiratory tract despite pulmonary hemorrhage. It differs from PAN by the presence of extensive glomerular involvement. MPA invariably affects the kidneys. Renal abnormalities vary but rapidly progressive glomerulonephritis is the most serious complication. 12 – HUV vasculitis is a rare form of vasculitis that is often misdiagnosed as HSP; the more so since skin biopsy shows leukoclastic vasculitis. The main characteristics are skin manifestations – urticaria, angioedema – associated with arthritis and arthralgia. Serum total complement as well as C1q, C3 and C4 levels are low due to complement activation via the classical pathway. In 50% of the patients there is glomerulonephritis – membranoproliferative or crescentic – and obstructive lung disease is equally frequent. 13 – In a number of patients, vasculitis cannot be ascribed to any of the above-mentioned categories. It is the case for, among others, malignancy-associated vasculitis and drug-related hypersensitivity as well as isolated vasculitis of the central nervous system. Finally, there is Behçet disease, a special form of vasculitis. It is a chronic inflammatory disorder involving the small blood vessels and is of unknown origin. It is characterized by recurrent aphthous ulceration of the oral and pharyngeal mucous membranes and the genitalia, skin lesions, uveitis and retinal vasculitis and sometimes optic atrophy. It frequently also involves the joints, gut and central nervous system.

Selected reading Bakkakoglu M: Takayasu arteritis in children: preliminary experience with cyclophosphamide induction and corticosteroids followed by methotrexate. J Pediatr 2007;150:72–76. Copo R, Andrulli S, Amore A, Gianoglio B, Conti G, Peruzzi L, Licatelli F, Cagnoli L: Predictors of outcome in Henoch-Schönlein nephritis in children and adults. Am J Kidney Dis 2006;47: 993–1003. Dillon MJ, Ozen S: A new international classification of childhood vasculitis. Pediatr Nephrol 2006;21:1219–1222. Hattori M, Kurayama H, Koitabashi Y, Japanese Society for Pediatric Nephrology: Antineutrophil cytoplasmatic autoantibodyassociated glomerulonephritis in children. J Am Soc Nephrol 2001;12:1493–1500. Savage COS, Harper L, Adu D: Primary systemic vasculitis. Lancet 1997;349:553–558.

Vasculitis

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1 – Systemic vasculitides are a heterogeneous group of disorders that are relatively rare in childhood. They are characterized by inflammation, necrosis and thrombosis of blood vessel walls with deposition of fibrin and platelets. Microvasculitis is often the dominant feature which affects the skin, the articulations, the kidneys, the lungs and the gut.

W. Proesmans · U.S. Alon

Glomerular and vascular disease

Hemolytic uremic syndrome

Hemolytic uremic syndrome

/

20 Diarrhea 0

No diarrhea 3

Stx (–) 2

S. dysenteriae EHEC C. Freundii

Yersinia Campylobacter Salmonella

Classical Typical HUS

Supportive

Stx (–) 4

Pneumococci 5

HIV/AIDS 6

Cancer 7

Glomerulonephritis 8

HUS ?

Pneumonia Meningitis

HIVN

Drugs TBI BMT

Acute Chronic

Supportive

Antibiotics Exchange transfusion

Specific drugs

Supportive

Supportive

Inf. (–) Cancer (–) GN (–)

Complement dysregulation

vWF protease deficiency

S-homocysteineM U-methylmalonic acidM

Familial HUS / TTP

Pregnancy Puerperium

Quinine OKT3 Calcineurin inhibitor

None

FH/FI/MCP deficient HUS 9

TTP :

Genetic cobalamin C defect ;

Autosomal-recessive, autosomal-dominant HUS <

PP-associated HUS =

Drug-associated HUS >

Unclassified HUS ?

Plasma PE

Plasma PE

Vitamin B12

PE

Supportive

Stop drug

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Stx (+) 1

2 – Diarrhea-associated HUS (D(+)HUS). In the great majority of children with HUS, there is prodromal diarrhea with the characteristics of colitis, i.e. mucous diarrhea often with blood in the stool. This postcolitis HUS is called ‘classical’ or ‘typical’ or ‘D(+)HUS’. 3 – Classical HUS is caused by Shigella dysenteriae in developing countries and by members of the enterohemorrhagic Escherichia coli family and Citrobacter freundii in industrialized parts of the world. The most frequent Stx-producing serotype is E. coli O157H7; other strains are O26, O111 and O103. Two shigatoxins have been well defined in terms of structure and biological activity: Stx1 and Stx2. HUS is mostly caused by Stx2-producing strains. There are several techniques to diagnose Stx-associated HUS (but none are 100% percent sensitive and specific): (1) bacterial culture of S. dysenteriae, Stx-producing E. coli and Citrobacter, (2) isolation of Stx from the stools, and (3) serum antibodies to specific species known to produce Stx. It is noteworthy that diarrhea can be absent in patients with proven Stx-associated HUS. Therapy in all types of D(+)HUS is supportive.

– Several case reports mention D(+)HUS with Yersinia enterocolitica, Campylobacter jejuni or Salmonella and without isolation of Stx. There is, however, no proof of a causal relationship. 4

5 – HUS not associated with diarrhea (D(–)HUS). In a minority of children and a majority of adults with HUS, there is no prodromal diarrhea. To distinguish it from classical HUS, the term D(–)HUS has been introduced. The term comprises an extremely heterogeneous group of rare disorders for many of which specific causes have recently been established.

21

6 – The association of D(–) and Stx(–)HUS necessitates thorough investigation for specific causes of HUS such as pneumococci-associated, HIV-associated, cancer-associated HUS and HUS superimposed on several forms of glomerulonephritis. 7 – Streptococcus pneumoniae-associated HUS can be observed in patients with pneumonia or meningitis. Typical features are febrile illness, respiratory or neurological signs and symptoms and a positive Coombs’ test. The traditional pathophysiological hypothesis is that neuraminidase secreted by pneumococci exposes the TFA on erythrocytes, platelets and glomerular structures,

Glomerular and vascular disease

resulting in features common to all forms of HUS. Early recognition is crucial for prognosis. Antibiotics and exchange transfusion are indicated but the administration of fresh plasma containing anti-TFA antibodies is contraindicated. The outcome is worse than in classical D(+)HUS both in terms of acute mortality and long-term renal function. – HIV positivity and AIDS are risk factors for renal complications, referred to as HIVN. HUS is part of the spectrum of HIVN. It is assumed that the virus directly affects the endothelium. In the largest study published so far, it occurred in one third of HIV-infected adult patients and was the most frequent cause of rapidly progressive renal failure. 8

9 – Cancer-associated HUS is rare especially in children. There are several ways in which cancer can lead to HUS: besides some drugs (such as mitomycin), total body irradiation and bone marrow transplantation have been implicated. There is no accepted therapy and the outcome is poor. 10 – Children as well as adults with acute or chronic forms of GN – more specifically acute poststreptococcal GN and membranoproliferative GN – have been described with hemolysis, thrombocytopenia and accelerated hypertension. This exceptional condition is known as ‘HUS superimposed on GN’.

– Abnormalities of the complement system have been found in a relatively large number of patients with D(–), familial or recurrent HUS. Complement dysfunction is mainly genetic in origin. Mutations in the genes of FH, FI and MCP – also known as CD46– have been documented to be associated with HUS. FH is a potent regulator of complement activation and FI is its co-factor. MCP, a membranebound regulator is a co-factor for FI and is expressed in glomerular endothelium. The diagnosis of complement dysregulation requires special expertise. Low plasma levels of C3, FH and FI are diagnostic but are present only in a minority of patients. In exceptional patients, complement dysregulation is acquired due to autoantibodies to FH. 11

12 – TTP which is mainly seen in adults has many similarities with HUS. Hemolysis and thrombocytopenia are accompanied by fever and varying neurological manifestations whereas renal involvement is rather limited. Diffuse platelet-rich microthrombi elicited by large multimeric forms of vWF in the circulation, are present in small blood vessels of several organs. TTP is a relapsing disorder caused by a deficiency of vWF-cleaving protease, ADAMTS13. The inherited forms of TTP are caused by mutations in the ADAMTS13 gene, the acquired nonfamilial TTP is due to autoantibodies inhibiting the protease. In some patients this acquired TTP is associated with the platelet inhibitors ticlopedine or clopidogrel. 13 – A very rare autosomal-recessive and life-threatening condition with elements of HUS is caused by defects in the intracellular cobalamine metabolism. It has been observed mainly in

W. Proesmans · U.S. Alon

newborns and young infants with systemic manifestations including central nervous system, cardiac and respiratory signs and symptoms. It is characterized biochemically by increased plasma levels of homocysteine and urinary methylmalonic aciduria. Early recognition and treatment with vitamin B12 can be life-saving. 14 – In some families, no defects in the above-mentioned genetic defects can be found. In their absence, the diagnosis of either dominant or recessive forms of HUS can be made. New underlying genetic defects are likely to be detected in the years to come. 15 – Pregnancy and/or puerperium-associated HUS is a quite common disorder in the literature. It has been speculated that hormonal disturbances are at its origin. The precise mechanism, however, needs to be elicited. 16 – Several drugs are suspected to be implicated in the development of HUS/TTP. Besides the already mentioned mitomycin and the platelet inhibitors ticlopedine and clopidrogel, there is evidence for a role for some immunosuppressive drugs of the calcineurin inhibitors family used after solid organ transplantation such as ciclosporin A and tacrolimus but OKT3 has also been implicated. Quinine is another suspected culprit as are several contraceptive hormonal preparations. 17 – In large series of D(–)HUS patients, no etiology can be found at present. Therefore, there is a need for a temporary category of ‘unclassified HUS’ patients.

Selected reading Besbas N, Karpman D, Landau D, et al: A classification of hemolytic uremic syndrome and thrombotic thrombocytopenic purpura and related disorders. Kidney Int 2006;70:423–431. Dragon-Durey MA, Frémaux-Bacchi V, Loirat C, et al: Heterozygous and homozygous factor H deficiencies associated with hemolytic uremic syndrome or membranoproliferative glomerulonephritis: report and genetic analysis of 16 cases. J Am Soc Nephrol 2004;15:787–795. Furlan M, Robles R, Galbusera M, et al: von Willebrand factor cleaving protease in thrombotic thrombocytopenic purpura and the hemolytic uremic syndrome. N Engl J Med 1998;339: 1578–1584. George JN: Thrombotic thrombocytopenic purpura. N Engl J Med 2006;354:1927–1935. Moake JL: Thrombotic microangiopathies. N Engl J Med 2002;347:589–600. Zimmerhackl LB, Besbas N, Jungraithmayer T, et al: Epidemiology, clinical presentation and pathophysiology of atypical and recurrent hemolytic uremic syndrome. Semin Thromb Hemost 2006;32:113–120.

Hemolytic uremic syndrome

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1 – The diagnostic term HUS represents a heterogeneous group of disorders with variable etiology, clinical expression and severity. Common features are acute, acquired hemolytic anemia, thrombocytopenia and renal dysfunction. Renal manifestations can range from a mild disease consisting of only minimal urinary findings (hematuria and proteinuria) to acute renal failure with oligoanuria and arterial hypertension necessitating dialysis. The histological substrate is referred to as thrombotic microangiopathy. HUS is among the most frequent causes of acute renal failure in childhood. The outcome depends on the severity and the causative agent.

Urinary tract disease/tubulointerstitial nephropathy

R. Adelman · S. Hulton

Urinary tract infection

Urinary tract infection 22 History, signs, symptoms /

Urinalysis 0

LE, nitrate negative

LE, nitrate positive

Pyuria

Bacteriuria

Bacteriuria and pyuria

Send urine culture 1

Culture negative 2

Culture positive

Evaluation 6

Treatment

Asymptomatic bacteriuria 3

Uncomplicated UTI 3

Complicated UTI 4

Adjunctive therapy 5

U/S 7

VCUG 8

Radionuclide scan 9

IVP :

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Nonspecific pyuria False negative Trauma Tuberculosis

– A urinalysis that demonstrates pyuria or is positive for leukocyte esterase or nitrite probably indicates a UTI. However, a positive dipstick with or without microscopic pyuria has a sensitivity of only 80%; in 20% of UTI, these tests are negative. The presence of bacteriuria in an unspun urine specimen is associated with a high likelihood of greater than 105 colony counts in urine culture.

5 – An uncomplicated UTI is acute cystitis or asymptomatic bacteriuria. Acute cystitis may be treated with amoxicillin and clavulanate, cefixime, sulfonamide, TMP/SMX, usually for a duration of 5–7 days. Asymptomatic bacteriuria is not treated in the older child unless the patient has usually developed symptomatic infections in such settings. 6 – Complicated infections include neonatal UTI, pyelonephritis, and urinary tract obstruction. These patients are usually treated with intravenous antibiotics and, when afebrile and stable, changed to a narrow spectrum oral antibiotic to which the organism is sensitive. The duration of therapy is usually 10 days. In stable children acute pyelonephritis may also be treated successfully with oral antibiotics.

2

3 – The diagnosis of UTI depends upon documentation of significant bacteriuria, i.e. greater than 105/ml, usually of a single organism in a midstream specimen, >103/ml, usually of a single organism in a catheterized specimen, and any growth in a suprapubic specimen. Escherichia coli is the most common organism. Urine cultures from urinary bags are frequently contaminated. A negative culture from a bag sample is reliable as a screening test but false-positive results have been recorded in up to about 40% of samples taken from infants. Remember, one may have pyuria without a UTI and UTI without pyuria. Adolescents with the triad of dysuria, frequency and pyuria may have colony counts 6 months: nitrofurantoin 2 mg/kg/day (in 2 doses) or cotrimoxazole as above 4 – Whether to recommend VCUG in all infants with persistent postnatal hydronephrosis remains controversial. We recommend performing a VCUG in these conditions: RPD above 10 mm, significant antenatal hydronephrosis, a thick-walled bladder or ureteric dilatation, and in cases of bilateral hydronephrosis.

27

5 – VUR is detected postnatally in ~10% of neonates with antenatal hydronephrosis. VUR is most severe and most frequent in males (3–4 M:1 F). In males, renal scarring (dysgenesis) is often present at birth. In patients with VUR, antibiotic prophylaxis should be continued as well as serial renal sonogram follow-up. For further details, see appropriate algorithm.

Urinary tract disease/tubulointerstitial nephropathy

6 – After ruling out VUR, radiotracers such as MAG3, DTPA or hippuran can be used to investigate the dilated urinary tract. Estimation of drainage of the urinary tract and differential renal function will indicate the severity of the obstruction. Re-ascent of the radioactive agent from bladder to kidney may indirectly suggest the presence of VUR. Unilateral renal function 6 mm at 20 weeks; >8 mm at 20–30 weeks and >10 mm at >30 weeks of gestation. While antenatal resolution of hydronephrosis may occur, the patient must still undergo postnatal investigation as the hydronephrosis can recur. The overall incidence of prenatal hydronephrosis is 1:100 to 1:500 of maternal-fetal US studies.

Urinary tract disease/tubulointerstitial nephropathy

R. Adelman · S. Hulton

Vesicourethral reflux

VUR

/

28

Evaluation 0

Treatment 2

US, repeat VCUG, or indirect CUG – DTPA or MAG3 1

Positive

Age 5

Antibiotic prophylaxis 1

Continue prophylaxis

Review 0

Consider surgery 3 (reimplantation of ureters or deflux injection) for Bilateral grade IV–V plus Severe, recurrent pyelonephritis or Severe loin pain

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Negative

1 – Approximately 35% of patients with UTI have VUR. The incidence is lower, however, amongst African-Americans. Approximately 30% of patients with VUR develop renal scars, placing them at greater risk for developing hypertension and, less commonly, ESRD. These complications are greater with severe VUR. 2 – VUR tends to clear with time. Most mild VUR (grades 1–2) will cease within 5 years of diagnosis. Even with severe VUR (grades 3–5), up to 50% will have cleared completely upon 10 years of follow-up. 3 – Repeated VCUG should be done in patients with VUR every 18–24 months. When VUR has disappeared or the patient is 5 years or older, prophylaxis can be stopped. VUR can be assessed by either contrast VCUG or a radionuclide VCUG (indirect CUG), which is less invasive and associated with lower radiation exposure. 4 – Children under the age of 5, especially under age 2, with VUR are at greatest risk for scarring associated with acute urinary infections. Infections should be diagnosed and treated promptly; scarring is more likely with delayed therapy. Most experts recommend use of prophylactic antibiotics, TMP/SMX (TMP 2 mg/ kg + SMX 10 mg/kg at night) or nitrofurantoin (1–2 mg/ kg at night) until reflux clears or the patient reaches 5 years of age when new scarring is uncommon.

Selected reading Canning DA: Deflux for vesicoureteral reflux: pro – the case for endoscopic correction. Urology 2006;68:239–241. Gil Rushton H Jr: Urinary tract infection; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 1027–1048. Greenbaum LA, Mesrobian HG: Vesicoureteral reflux. Pediatr Clin North Am 2006;53:413–427. Lorenzo AJ, Khoury AE: Endoscopic treatment of reflux: management pros and cons. Curr Opin Urol 2006;16:299–304. Perez-Brayfield M, Kirsch AJ, Hensle TW, Koyle MA, Furness P, Scherz HC: Endoscopic treatment with dextranomer/hyaluronic acid for complex cases of vesicoureteral reflux. J Urol 2004;172:1614–1616. Smellie JM, Jodal U, Lax H, Mobius TT, Hirche H, Olbing H; Writing Committee, International Reflux Study in Children (European Branch): Outcome at 10 years of severe vesicoureteric reflux managed medically: Report of the International Reflux Study in Children. J Pediatr 2001;139:656–663.

5 – Surgery of VUR, with ureteral reimplantation, is rarely indicated with mild-to-moderate VUR. Surgery for severe VUR, grade 3–5, is usually successful in curing reflux. However, antireflux surgery has not been shown to be better than conservative medical management in such outcomes as renal scarring, renal growth, renal function or incidence of secondary complications such as hypertension and chronic renal failure. Surgery may be indicated in isolated cases of recurrent severe pyelonephritis or severe loin pain or parental concerns about medical management such as long-term use of antibiotics. An alternative surgical approach is the STING procedure, injection of deflux at the vesicoureteral junction.

Urinary tract disease/tubulointerstitial nephropathy

R. Adelman · S. Hulton

VUR

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29

Urinary tract disease/tubulointerstitial nephropathy

S. Hulton · R. Adelman

Dysfunctional voiding

Dysfunctional voiding

/

30

Urine dipstix Serum creatinine Renal US

Clinical history 0

Detailed voiding history and 3-day-frequency voiding diary 1

Physical examination 2

Problems in infancy Age of toilet training Family history Psychological stress Exclude organic factors (e.g. epilepsy, diabetes)

UTI Urinary incontinence Frequency, urgency Dysuria Infrequent voiding Incomplete emptying Voiding maneuver (squat, crossed legs) Constipation, soiling

Growth Blood pressure Abdomen for loaded colon Lower back/spine – hair tufts, dimple, lipoma, sinus Neurology – lower limb reflexes, anal reflex Genitalia

Primary nocturnal enuresis*

UTI 3

Continuous incontinence/drip 4

Giggle/stress incontinence 5

Urge/frequency/incomplete/ delayed bladder emptying

Constipation >

Lazy bladder

VCUG

IVP

Pelvic floor exercises

U/S (renal/bladder) and urodynamic flow rates 6

Laxatives

A -Blocker (Prazocin) <

Follow protocol (30% have VUR)

Ectopic ureter

No

Incomplete bladder emptying

Overactive bladder 7

Double voiding

Bladder training 9 Chemoprophylaxis TMP or nitrofurantin 1–2mg/kg nocte x 3–6 months

Anticholinergic drugs : Oxybutynin 0.4 mg/kg/day, b.d. or t.d.s.

Lazy bladder 8

Ongoing biofeedback training ;

Response

No response

Review Review at 8 weeks

Video urodynamics

Non-neuropathic ‘neuropathic’ bladder (Hinman) = Stop antibiotics

Yes

Intermittent bladder catheterization Mitroffanoff – last resort

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Response

– The majority of children have acquired an adult voiding pattern by 4–5 years of age and investigations for dysfunctional voiding should not be undertaken in children under 5 years. 2

3 – The 3-day frequency voiding diary is particularly helpful to provide more detailed information about the child’s voiding pattern. The information does not have to cover consecutive days, and weekends may give better opportunity for the parent to document the information. The diary must include the record of bowel action.

– Inspection of the genitalia in boys should exclude a meatal stenosis and in girls look for labial adhesions, which can impede urinary flow. Voiding dysfunction and urinary symptoms have been described with sexual abuse and attention needs to be directed towards examination of the genitalia for any scarring, tearing or signs of trauma. This obviously needs to be performed carefully and sensitively. 4

5 – Children with dysfunctional voiding are at risk of recurrent UTIs. Both reflux and UTIs are observed in 30–40% of children at the time of dysfunctional voiding and resolve with the attainment of a normal voiding pattern. Bladder instability with high intravesical pressures are observed in children with VUR. High voiding detrusor pressures have also been observed in infants presenting with symptomatic urinary tract infections who do not have VUR. 6 – A history of continuous urinary incontinence, particularly in a young girl, is suggestive of an ectopic ureter. If intravenous urogram fails to demonstrate this, careful examination of the introitus by a trained urologist may identify the opening of the ectopic ureter.

31

7 – Giggling and laughter associated with embarrassing wetting episodes is more commonly seen in girls and is usually self-limiting. Anticholinergic agents may be helpful. Postvoid dribbling may occur in girls (commonly obese) where the urine accumulates in the lower vagina. 8 – US is very useful to image the upper urinary tract to demonstrate abnormalities such as duplex kidney, dilatation of the collecting system and gross reflux. A thickened bladder wall with trabeculation may be observed. This will depend on the expertise of the ultrasonographer. Postmicturition bladder volumes are considered significant when they represent, on repeated occasions, volumes of >20 ml

or more than 10% of the normal bladder capacity for age. Noninvasive urodynamics, using a graphic recording of urinary flow rate during voiding, is becoming a more standard office procedure. Flow patterns and rates need to be consistent to allow for appropriate evaluation and sometimes several recordings are necessary. Invasive procedures should only be done following the results of the noninvasive tests where there is a suspicion of a neuropathic bladder sphincter dysfunction and should only be performed in specialist centers. 9 – Common between 5 and 7 years of age, present with hyperactivity or instability of the bladder, with urgency and small frequent voids. This may follow an initial episode of painful voiding, e.g. following UTI or urethritis. 10 – Characterized by large capacity hypotonic bladder with infrequent voiding every 8–12 h and incontinence between voiding. Sensation of bladder fullness is reduced. Incontinence is due to overflow and the urinary stream is poor with incomplete voiding. Such bladder decompensation may occur as a result of previous posterior urethral valves in infancy and can be associated with myogenic detrusor failure. 11 – Bladder training involves frequent voiding, initially 2 hourly, later 4 hourly on a regular basis with advice to relax the pelvic floor when voiding, e.g. by whistling. Low-dose prophylactic antibiotics are useful in children who have a history of urinary tract infections without reflux. The antibiotics can be used for a short period of time, usually not longer than 6 months. 12 – Oxybutynin is the most commonly used anti-cholinergic drug. It is usually initiated at a low dose once or twice daily and is gradually titrated to a maximum dose over 6–8 weeks. Side effects are common and include facial flushing, constipation and dry mouth. Occasionally headache and palpitations are reported. Approximately 20% of patients have to stop medication because of these side effects. The management of constipation is essential and needs particular vigilance in patients on anticholinergic treatment. 13 – Biofeedback training is very useful in children over 8 years of age. This involves psychological support, learning to void using a flowmeter, ultrasound scanning to check for complete bladder emptying, the use of alarms to detect wetness and regular charting of voiding activities. Follow-up by a dedicated incontinence adviser is essential. Such behavior modification programmes will cure 50% of children within 6 months and 75% within 1 year. Pharmacological intervention may speed up this process for some patients but good voiding behavior is the key to success. 14 – Alpha-adrenergic blockade may be useful to improve bladder emptying in some patients. Prazosin or Doxazosin 0.45–1 mg at night may be used. Treatment is generally well tolerated but hypotension may be observed.

Urinary tract disease/tubulointerstitial nephropathy

S. Hulton · R. Adelman

15 – Non-neuropathic bladder (Hinman syndrome) represents the extreme of the spectrum and will only be diagnosed by exclusion of all other identifiable treatable conditions. MRI scanning of the lumbar spine is necessary to exclude an underlying undiagnosed neurological disorder. In Hinman syndrome there is no physical neurological deficit; however, the bladder behaves in a neuropathic fashion. This occurs primarily in boys as an acquired voiding disorder characterised by inappropriate voluntary contraction of the striated urinary sphincter during the process of micturition. This results in functional urinary obstruction that over time is associated with urinary tract infection, myogenic bladder failure, hydronephrosis and even renal insufficiency. Ochoa syndrome has the same clinical features at Hinman syndrome but is known as urofacial syndrome because of facial grimace instead of smile and is inherited in an autosomal-dominant pattern. If the patient is not found to have Hinman syndrome but is still not responding to treatment one must consider other conditions such as congenital bladder neck insufficiency or ectopic ureteroceles. 16 – The management of constipation is imperative in all patients. It is due to the inability to relax the pelvic floor musculature.

* Primary nocturnal enuresis is a prevalent disorder with a complex mode of inheritance. It appears to be associated with a deficiency of inhibitory signal processing in the brain stem which underlies the deficient pre-path inhibition of micturition, as well as the inability to inhibit micturition at night. A low nocturnal arginine vasopressin production may be present, and the role of melatonin in this, as well as the regulation of sleep/wake cycle, is currently under review. These children may respond to Desmopressin (DDAVP 20–40 µg intranasally). This should not be used for prolonged periods as water intoxication is a serious adverse side effect. DDAVP should be used along with other treatment modalities, such as bed wetting alarms, dry bed training and behavioural treatment. It is important to distinguish nocturnal enuresis from diurnal enuresis or daytime wetting. It is not uncommon for bed wetters to wet their underclothes during the day or for day wetters to wet the bed. They should be viewed as two separate problems. Diurnal enuresis is linked with the term ‘dysfunctional voiding’. Dysfunctional voiders exhibit poor co-ordination between the bladder and bladder outlet which results in inefficient bladder emptying and is termed ‘dyssynergia’.

Selected reading Akbal C, Genc Y, Burgu B, Ozden E, Tekgul S: Dysfunctional voiding and incontinence scoring system: quantitative evaluation of incontinence symptoms in pediatric population. Urol 2005;173:969–973. Austen PF, Ritchey ML: Dysfunctional voiding. Paediatr Rev 2000;21:336–340. Feldman AS, Bauer SB: Diagnosis and management of dysfunctional voiding. Curr Opin Pediatr 2006;18:139–147. Nørgaard JP, van Gool JD, Hjalmas K, Djurhuus JC: Standardization and definitions in lower urinary tract dysfunction in children. Br J Urol 1998;81(suppl 3):1–16. Schulman SL: Voiding dysfunction in children. Urol Clin North Am 2004;31:481–490.

Dysfunctional voiding

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1 – Enuresis is defined as normal voiding, occurring at an inappropriate time, or involuntarily in a socially unacceptable setting. Enuresis is most commonly nocturnal, although it is not uncommon for nocturnal enuretics to have episodes of diurnal enuresis. Diurnal enuresis is usually linked with the term dysfunctional voiding which can be categorised into neuropathic and non-neuropathic voiding disorders. Functional neuropathic voiding disorders include spina bifida, transverse myelitis and spinal cord trauma. This review focuses on the non-neuropathic voiding dysfunction.

Urinary tract disease/tubulointerstitial nephropathy

J. Smith · F.B. Stapleton

Loin pain with hematuria

Loin pain with hematuria

/

History and physical examination

32

Urinalysis

Red blood cells No casts

White blood cells Bacteria Urine culture

Red blood cell casts Protein

Crystals

Pyelonephritis

Glomerulonephritis

Consider urolithiasis

Blood tests including electrolytes, calcium, BUN, creatinine, blood gases

Renal angiogram

Normal Normal Ultrasound of kidneys and bladder with Doppler 0

Normal

Abnormal Urolithiasis Obstructive uropathy Polycystic kidney disease Pyelonephritis Renal vein thrombosis Tumor Nutcracker syndrome

Abnormal Glomerulopathy (e.g. IgA nephropathy) Hypercalcemia (e.g. hyperparathyroidism) Renal tubular acidosis

Renal biopsy 4

Normal Intravenous pyelogram 2

Normal

Further urine evaluation 1 24-hour collection of calcium, protein, sodium, citrate, cystine, oxalate, uric acid, creatinine

Abnormal Medullary sponge kidney Tumor Cyst

Abnormal Renal arteriovenous fistula Nutcracker syndrome

Abnormal Glomerulopathy (e.g. IgA nephropathy) Thin basement membrane disease

Loin pain hematuria syndrome 5

Cystoscopy 3 Abnormal Proteinuria Hypercalciuria Hypocitraturia Cystinuria Hyperoxaluria Hyperuricosuria

Normal

Abnormal Bladder lesion

Psychiatric evaluation 6

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Normal

1 – Evaluation of loin pain associated with hematuria (microscopic or gross) is best approached in a staged manner depending on the duration and severity of symptoms. 2 – Ultrasound of kidneys and Doppler is recommended to exclude possible etiologies of loin pain and hematuria including urolithiasis, obstructive uropathy, polycystic kidney disease, pyelonephritis, renal vein thrombosis, tumor, or evidence of nutcracker syndrome (left renal vein entrapment). 3 – Urinary concentrations of protein, calcium, uric acid, oxalate and cystine are typically normal in loin pain hematuria syndrome. Normal urinary values for school-age children: calcium 100 µmol/g creatinine), but less than the stone-forming range (>1,200 µmol/g creatinine), the child has inherited two dominant SLC 7A9 mutations. By contrast, the SLC3A1 gene encodes a subunit of the transporter and is transmitted as a recessive urinary phenotype. If both parents excrete cystine in the normal range, the child has most likely

Selected reading Goodyer PR, Saadi J, Ong P, Elkas G, Rozen R: Cystinuria subtype and the rest of nephrolithiasis. Kidney Int 1998;54:56–61. International Cystinuria Consortium: Functional analysis of mutations in SLC7A9, and genotype/ phenotype correlation in non-type I cystinuria. Hum Mol Genet 2001;10:305–316. Palacin M, Goodyer P, Nunes V, Gasparini P: Cystinuria; in Scriver C, Beaudet A, Sly W, Valle D (eds): The Metabolic and Molecular Basis of Inherited Disease. New York, McGraw-Hill, 2001, vol III, pp 4909–4932. Rogers A, Kalakish S, Desai RA, Assimos DG: Management of cystinuria. Urol Clin North Am 2007;34:347–362. Zelikovic I: Aminoaciduria and glycosuria; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 701–728.

Tubular disease

P. Goodyer · I. Eisenstein · I. Zelikovic

Cystinuria

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57

I. Eisenstein · P. Goodyer · I. Zelikovic

Tubular disease

Glycosuria

Glycosuria

/

58 Hereditary renal glycosuria 2

Generalized proximal tubular dysfunction

Fanconi syndrome Extreme prematurity 1

ISHG 3

Glucose-galactose malabsorption 4

Fanconi-Bickel syndrome 5

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Hyperglycemia 0

1 – Under normal conditions, the reabsorption of filtered glucose by the renal tubule is almost complete. Most filtered glucose is reabsorbed in the proximal convoluted tubule and the rest by proximal straight tubule, the loop of Henle, and, to some extent, by the collecting duct. Reabsorption of glucose across the proximal tubular cells occurs by an active, carriermediated, Na+-dependent process in the apical membrane and a Na+-independent, facilitated glucose transporter resides in the basolateral membrane. The evaluation of glycosuria should include determination of blood glucose levels and the evaluation of proximal tubular dysfunction (see algorithms on Fancony syndrome and Renal tubular acidosis). 2 – The human kidney is characterized by a limited capacity to reabsorb D-glucose. Beyond a certain level of blood glucose level, a maximal rate of renal glucose reabsorption is achieved and glucose will appear in the urine. Thus, glycosuria is seen in any condition leading to hyperglycemia such as diabetes mellitus, stress-induced and drug-induced hyperglycemia. 3 – Glycosuria is observed in generalized proximal tubular dysfunction (Fanconi syndrome). For details see appropriate algorithm. Glycosuria is often seen in premature newborn infants because of the immaturity of the tubular transport mechanisms.

5 – ISHG is a benign condition in which the glycosuria is the only abnormality, and there is no increase in the urinary excretion of other sugars. This disorder is caused by a genetic defect in the SGLT2- a Na+-glucose cotransporter which is located in the luminal membrane of the proximal convoluted tubule. ISHG is transmitted in an autosomally recessive fashion. Of note, some of these children have massive aminoaciduria in addition to the renal glycosuria. 6 – Glucose-galactose malabsorption is an autosomal-recessive genetic disease which is potentially lethal. The disorder is caused by a genetic defect in SGLT1, another Na+-glucose cotransporter, which is found in the intestine and kidney. The typical clinical picture of glucose-galactose malabsorption is severe watery diarrhea starting in the neonatal period. The diarrhea ceases once glucose and galactose are removed from the diet. 7 – Fanconi-Bickel syndrome is an autosomalrecessive disorder characterized by Fanconi syndrome and hepatomegaly due to glycogenesis of the liver and kidneys. The disease is caused by mutation in the gene encoding the facilitated glucose transporter GLUT2. Glycosuria is a prominent feature of this disorder but unlike the disorders outlined above, it is not the sole renal manifestation, and other proximal tubular dysfunctions exist.

Selected reading Bergeron M, Goodyer PR, Gougoux A, et al: Pathophysiology of renal hyperaminoacidurias and glucosuria; in Seldin DW, Giebisch G (eds): The Kidney: Physiology and Pathophysiology, ed 3. Philadelphia, Lippincott Williams & Wilkins, 2000, pp 2211–2233. Kleta R, Stuart C, Gill FA, Gahl WA: Renal glucosuria due to SGLT2 mutations. Mol Genet Metab 2004;82:56–58. Magen D, Sprecher E, Zelikovic I, Skorecki K: A novel missense mutation in SLC5A2 encoding SGLT2 underlies autosomal-recessive renal glucosuria and aminoaciduria. Kidney Int 2005;67:34–41. Wright EM, Turk E, Martin MG: Molecular basis for glucose-galactose malabsorption. Cell Biochem Biophys 2002;36:115–121. Zelikovic I: Aminoaciduria and glycosuria; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 701–729.

4 – Hereditary renal glycosuria is an abnormality in which variable amounts of glucose are excreted in the urine at normal blood glucose concentration. Several genetic disorders are known to cause this abnormality (see below).

Tubular disease

I. Eisenstein · P. Goodyer · I. Zelikovic

Glycosuria

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59

I. Eisenstein · P. Goodyer · I. Zelikovic

Tubular disease

Renal tubular acidosis

Renal tubular acidosis

/

History and physical examination 0 Serum creatinine, Na+, K+, Ca2+, P, HCO–3, plasma aldosterone, renin Urine-urinalysis, osmolarity, Cl–, Na+, K+, Ca2+, pH Renal US

60

Positive urinary anion gap 13 [Cl– 5.5

Urine pH Na+ + K+] Urine pH Na+ + K+) signifies normal ammonium production/secretion whereas a positive urinary anion gap (Cl– < Na+ + K+) represents decreased ammonium production/ secretion.

61

4 – HCMA accompanied by negative urinary anion gap represents an intact distal acidification mechanism. Besides gastrointestinal bicarbonate loss due to diarrhea, PRTA, also known as RTA type 2, is the most common cause of HCMA with a negative urinary anion gap. In addition to negative urinary anion gap, PRTA is characterized by hypokalemia and urinary pH < 5.5 in the face of systemic acidosis. PRTA can be isolated or can be a part of generalized proximal tubulopathy (Fanconi syndrome) which leads to hypophospatemic rickets, hypouricemia, glycosuria and aminoaciduria. For details on Fanconi syndrome, see appropriate algorithm. Major causes of PRTA/Fanconi syndrome include: hereditary disorders (cystinosis, galactosemia, tyrosinemia, hereditary fructose intolerance, mitochondrial cytopathies and Wilson disease), drugs (aminoglycosides, ifosfamide, outdated tetracyclines and carbonic anhydrase inhibitors) and heavy metal poisoning. Several genetic defects in specific proximal tubule

Tubular disease

transporters leading to primary isolated RTA have been recognized in the last years. Autosomal-recessive PRTA associated with ocular abnormalities, short stature and mental retardation is caused by a genetic defect in the Na+/HCO 3– cotransporter NBC1 located in the basolateral membrane of the proximal tubular cell. An additional entity leading to autosomal-recessive PRTA and osteopetrosis is due to mutations in the gene encoding carbonic anhydrase II, a cytoplasmatic enzyme responsible for the generation of HCO 3– and H+ from H2O and CO2. The genetic defect in this enzyme, which operates in both the proximal and distal tubule, can lead to combined distal and proximal RTA (previously known as RTA type 3). 5 – RTA types 1 and 4 are characterized by a positive urinary anion gap which is due to impaired tubular NH+4 production or secretion. 6 – DRTA is characterized by an impaired distal H+ secretion and, hence, a failure to lower urine pH in the presence of acidosis. Several different mechanisms are responsible for this type of RTA: • Secretory defect – a defect in the H+-ATPase pump of the ␣ intercalated cell in the CCD. This abnormality can be a primary-genetic disorder, or secondary to autoimmune diseases (SLE, Sjogren syndrome). • Gradient defect – an increase in membrane permeability causing backleak of luminal H+ in CCD cells. This condition is observed for example in children treated with amphotericin B. • Voltage-dependent defect – a reduction in CCD Na+ reabsorption which diminishes the luminal electronegativity, thus impairing the ability to secrete H+. This type of DRTA is accompanied by hyperkalemia and is seen in markedly volume-depleted children and secondary to amiloride treatment. A cardinal feature of DRTA is nephrolithiasis/nephrocalcinosis caused by calcium- phosphate complexes. The reason for this abnormality is the combination of the acidic urine and hypocitraturia promoting Ca-phosphorus precipitation. Mutations in the gene encoding the anion exchanger AE1 located in the ␣-intercalated cells in the CCD lead to both autosomal-dominant and autosomal-recessive DRTA. In the milder, autosomal-dominant type, the disease can manifest as mild metabolic acidosis in older children or even adults, whereas in the recessive type, which is seen mainly in the southeast Asian population, the clinical picture includes DRTA with hemolytic anemia. Autosomal-recessive DRTA coupled with sensorineural hearing loss is caused by a genetic defect in the B1 subunit of the H+-ATPase transporter.

sterone biosynthesis called CMO deficiency types I and II. Adrenal cortical failure is observed in Addison disease and in adrenoleukodystrophy, which is very rare in children. Hyporeninemic hypoaldosteronism is observed in patients with diabetic nephropathy or chronic tubolointerstitial disorders. Although considered rare in children, hyporeninemic hypoaldosteronism is probably more common in this age group than previously thought. Gordon syndrome, also called pseudohypoaldosteronism type 2, is a hereditary, autosomal-dominant disorder caused by ‘gain of function’ mutations in the genes encoding WNK1 or WNK4 kinases. The consequence of the mutation is increased NaCl reabsorption in the distal convoluted tubule which results in hypervolemia, hypertension, hyporeninemic hypoaldosteronism, hyperkalemia and type 4 RTA. Aldosterone resistance with elevated plasma levels of aldosterone, is observed in PHA 1. This hereditary disorder presents clinically with renal sodium wasting, hyperkalemia and metabolic acidosis. There are two forms of PHA 1: in the renal, autosomal-dominant form, the aldosterone resistance is limited to the kidney and is due to mutations in the gene encoding the mineralocorticoid receptor. In the autosomal-recessive multiple-end-organ form, the aldosterone resistance is present in many organs (kidney, colon, lung, sweat and salivary glands) and is due to mutations in one of the ␣-, ␤-, or ␥-subunits of the epithelial Na+ channel. There is also a secondary form of aldosterone resistance, called PHA type 3, frequently observed in infants with obstructive uropathy and/or urinary tract infection.

Selected reading Fry AC, Karet FE: Inherited renal acidosis. Physiology 2007;22: 202–211. Herrin TH: Renal tubular acidosis; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 757–776. Nicoletta JA, Schwartz GJ: Distal renal tubular acidosis. Curr Opin Pediatr 2004;16:194–198. Rodríguez Soriano J: Renal tubular acidosis: the clinical entity. J Am Soc Nephrol 2002;13:2160–2170. Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte Disorders, ed 5. New York, McGraw-Hill, 2001, pp 612–627. Scheinman SJ, Guay-Woodford LM, Thakker RV, Warnock DG: Genetic disorders of renal electrolyte transport. N Engl J Med 1999;340:1177–1187. Zelikovic I: Molecular pathophysiology of tubular transport disorders. Pediatr Nephrol 2001;16:919–935.

7 – The primary pathogenic mechanism of RTA type IV is aldosterone deficiency or resistance. In this type of RTA, the ability to acidify the urine is intact but NH+4 excretion and thus net acid excretion is reduced. Hyperkalemia is a main feature of this type of RTA. Low plasma aldosterone levels with elevated PRA is generally observed in endocrine disorders such as congenital adrenal hypoplasia, salt-losing forms of CAH or in rare inherited defects of aldo-

I. Eisenstein · P. Goodyer · I. Zelikovic

Renal tubular acidosis

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1 – The kidney is the major organ responsible for acid-base homeostasis. This homeostasis is maintained by the renal tubule in two ways: (1) reabsorption of the filtered HCO 3– (mainly by the proximal tubule), and (2) excretion of the H+ produced by the human body in the distal tubule. When one of these processes is defected RTA ensues. There are 3 major types of RTA: type 1 (DRTA), type 2 (PRTA) and type 4.

P. Goodyer · I. Eisenstein · I. Zelikovic

Tubular disease

Proximal tubulopathy (Fanconi syndrome)

Proximal tubulopathy (Fanconi syndrome)

/

62

Broad proximal tubular dysfunction 0

Cystinuria Lysinuric protein intolerance Hypophosphatemic rickets ISHG PRTA

Phosphaturia (TRP 3 mEq/kg/day) Aminoaciduria (quantitative urine amino acids) Tubular proteinuria (B2-microglobulinuria) Glucosuria Potassium wasting (TTKG >12) Salt wasting (FENa >1% with elevated renin)

Drugs 1 Chemotherapy (cisplatin/ifosfamide) Valproic acid Outdated tetracyclines Glue sniffing Heavy metal poisoning Aminoglycosides

Inherited causes 2 Cystinosis Dent disease Mitochondriopathies Fanconi-Bickel glycogenosis Tyrosinemia Wilson disease Lowe syndrome Galactosemia Hereditary fructose intolerance Idiopathic Fanconi syndrome

Hyperparathyroidism 3

Therapeutic strategies 4 Fluids, NaCl, KCl, NaHCO3 , PO4 , calcitrol, carnitine, specific therapy, organic solute replacement unnecessary

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Isolated transport defect /

63

2 – In the early 1930s, Fanconi (Switzerland), DeToni (Italy) and Debre (France) described a renal tubular syndrome in children characterized by massive urinary wasting of electrolytes, glucosuria and proteinuria, causing acidosis, rickets and severe failure to thrive. In retrospect, it is evident that these patients had cystinosis (see below) and exhibited broad dysfunction of the proximal tubule. The defect in phosphate reabsorption may be assessed by calculating the tubular reabsorption of phosphate: 1 – (urine PO4/ serum PO4) × (serum creatinine/urine creatinine); values of less than 0.85, in the face of hypophosphatemia, demonstrate the defect. proximal tubular losses of bicarbonate may be massive with acidosis requiring replacement of 10–20 mEq/kg/day; losses of this magnitude in the face of a nonanion gap acidosis indicate proximal RTA. Aminoaciduria may be quantified on an automated analyzer and normalized for urine creatinine; all amino acid transport systems are affected. LMW proteins are normally filtered through the glomerulus and reabsorbed (>95%) by endocytosis; in Fanconi syndrome there may be several grams of LMW protein excreted per day; this is best proven by measuring the 24-hour excretion of ␤2-microglobulin or retinol binding protein. Glucosuria may be detected by standard dipsticks or by direct quantification. There is no simple test for salt wasting which distinguishes a proximal tubular defect from dysfunction at more distal sites, but Fanconi syndrome is associated with NaCl losses of >1% of the filtered load in the face of volume contraction: fractional excretion of sodium = (urine Na/serum Na) × (serum creatinine/urine creatinine) × 100%. Potassium wasting is identified by calculating the trans-tubular potassium gradient (TTKG) >12. TTKG = (urine K) × 300/urine osmolarity); normal range = 4–6. Some of the patients with Fanconi syndrome also have hypercalciuria. 3 – In adults, the most common cause of Fanconi syndrome is drug toxicity and this should also be considered in children; it may be noted following chemo-

Tubular disease

therapy with ifosfamide or cisplatin. Heavy metal poisoning, glue sniffing, and other drugs have also been reported to cause proximal tubular dysfunction. 4 – Most pediatric referrals for Fanconi syndrome involve a hereditary disease; proximal tubular dysfunction may involve all transport mechanisms or may affect only a few (‘partial Fanconi syndrome’). Cystinosis nearly always causes a complete Fanconi syndrome and the diagnosis is confirmed by measurement of leukocyte cystine on an automated amino acid analyzer or by slip lamp identification of corneal crystals. Cystinosis is due to mutations of the cystinosin gene on chromosome 17p13, encoding a lysosomal membrane protein which selectively permits cystine to exit from the lysosome into the cytoplasm. Mechanical disruption of lysosomes or interference with the endocytotic membrane recycling pathway causes a broad, severe disturbance of proximal tubule transport functions. Dent disease is X-linked and caused by mutations of a chloride channel gene (CLCN5) which disrupts normal endocyctotic mechanisms; most patients with Dent disease are characterized by hypercalciuria, massive LMW proteinuria and chronic renal failure. Proximal tubule dysfunction is quite variable depending on the mutation. Mitochondriopathies are occasionally associated with lactic acidosis and may be maternally inherited (mitochondrial genes) or due to autosomal-recessive (nuclear genes) defects in the electron transport chain. The mitochondriopathies often have neuromuscular manifestations, may have episodes of rapid deterioration during intercurrent illness and usually require tissue diagnosis. In FanconiBickel syndrome, children present with hepatomegaly due to glycogenosis of the liver and kidneys; The syndrome is caused by mutations in the facilitated GLUT2. Massive glucosuria is a prominent feature in addition to other proximal tubule dysfunctions. Proximal tubule dysfunction is often incomplete in Wilson disease and tyrosinemia where it can fluctuate with metabolic crisis. In glactosemia, hereditary fructose intolerance and Lowe syndrome there are usually characteristic extrarenal features which bring the patient to medical attention. 5 – Aminoaciduria and phosphaturia may be seen in hyperparathyroidism states, but this is uncommon in children. 6 – In general, the strategy for supportive therapy of Fanconi syndrome is to replace fluid and the inorganic solutes lost in the urine. Amino acids, LMW

P. Goodyer · I. Eisenstein · I. Zelikovic

proteins and glucose do not usually deplete metabolic pools as long as adequate nutrition is maintained. On the other hand, NaCl supplementation (2–8 mEq/kg/ day) to avoid chronic volume contraction often improves growth failure. Dose may be titrated to plasma renin if there is no growth improvement. The bicarbonate requirement may vary from 2 to 20 mEq/kg/day depending on the severity of tubular dysfunction; this may also be conveniently supplied as Na/K citrate (citrate consumes H+ when metabolized in the Krebs cycle). Oral phosphate supplements (25–100 mg elemental phosphate/kg divided in 3–4 doses/day) are adjusted to assure that serum phosphate comes into the normal range 45–60 min after each dose. The aim is to provide adequate serum phosphate for bone mineralization and linear growth. However, phosphate serves as an oral calcium binder, stimulating PTH release. Since proximal tubular synthesis of 1,25(OH)2 vitamin D may also be affected, oral calcitriol 10–40 ng/kg/day in 2 divided doses is usually needed to avoid hyperparathyroidism, under close monitoring of urine calcium levels, and periodic renal sonogram to prevent hypercalciuria and nephrolithiasis. Depending on the underlying disease, specific therapy (such as cystamine in cystinosis) is indicated.

Selected reading Fanconi G: Die nicht diabetischen Glykosurien und Hyperglykämien des älteren Kindes. Jahrb Kinderheilk 1931;133:257–300. Forman JW: Cystinosis and Fanconi syndrome; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004, pp 789–806. Gahl WA, Theoene JG, Schneider J: Cystinosis. N Engl J Med 2002;347:111–121. Hsu SY, Tsai IJ, Tsau YK: Comparison of growth in primary Fanconi syndrome and proximal renal tubular acidosis. Pediatr Nephrol 2005;20:460–464. Kuwertz-Broking E, Koch HG, Marquardt T, Rossi R, Helmchen U, Muller-Hocker J, Harms E, Bulla M: Renal Fanconi syndrome: first sign of partial respiratory chain complex IV deficiency. Pediatr Nephrol 2000;14:495–498. Santer R, Steinmann B, Schaub J: Fanconi-Bickel syndrome: a congenital defect of facilitative glucose transport. Curr Mol Med 2002;2:213–227.

Proximal tubulopathy (Fanconi syndrome)

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1 – Fanconi syndrome should always be distinguished from diseases associated with an isolated defect in renal proximal tubular transport. In cystinuria, amino acid wasting is restricted to cystine, ornithine, lysine and artinine. In hereditary hypophosphatemia, proximal tubular reabsorption of phosphate is depressed but aminoaciduria is absent. For details, see algorithms on Rickets and Hypophosphatemia. ISHG, a relatively benign condition, is caused by a genetic defect in the Na+-glucose cotransporter, SGLT2.

P. Goodyer · I. Eisenstein · I. Zelikovic

Tubular disease

Polyuria

Polyuria

/

64 Renal salt wasting

Renal free water loss 3

FENa+ >1% Urine osm = 200–400 mosm/l

FENa+