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Practical

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

56 graphs, 1 figure and 10 tables, 2008

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

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Contents
1 Contributors Urinary tract disease/tubulointerstitial Hypertension
II
nephropathy 50 Neonatal hypertension
2 Preface 22 Urinary tract infection S. Turi; A.L. Friedman
Z. Hochberg R. Adelman; S. Hulton
52 Pediatric hypertension
3 Introduction 24 Dilated/obstructed urinary tract S. Turi; A.L. Friedman
I. Zelikovic; I. Eisenstein S. Hulton; R. Adelman

26 Fetal hydronephrosis
Tubular disease
J.-P. Guignard; R.N. Fine
Glomerular and vascular disease
54 Aminoaciduria
28 Vesicourethral reflux
4 Hematuria I. Eisenstein; P. Goodyer; I. Zelikovic
R. Adelman; S. Hulton
A.L. Friedman; S. Turi
30 Dysfunctional voiding 56 Cystinuria
6 Acute nephritic syndrome P. Goodyer; I. Eisenstein; I. Zelikovic
S. Hulton; R. Adelman
F. Santos; S.P. Makker
32 Loin pain with hematuria 58 Glycosuria
8 Proteinuria I. Eisenstein; P. Goodyer; I. Zelikovic
J. Smith; F.B. Stapleton
F. Santos; S.P. Makker
34 Renal trauma 60 Renal tubular acidosis
10 Nephrotic syndrome in the first year I. Eisenstein; P. Goodyer; I. Zelikovic
R. Adelman; S. Hulton
of life
36 Tubulointerstitial nephritis 62 Proximal tubulopathy
F. Santos; S.P. Makker
A.L. Friedman; S. Turi (Fanconi syndrome)
12 Nephrotic syndrome in the child and P. Goodyer; I. Eisenstein; I. Zelikovic
adolescent 64 Polyuria
S.P. Makker; F. Santos Structural/congenital abnormalities P. Goodyer; I. Eisenstein; I. Zelikovic
14 Rapidly progressive 38 Single kidney (renal agenesis) 66 Hypouricemia
glomerulonephritis G. Rizzoni ; M.A. Linshaw J. Smith; F.B. Stapleton
S.P. Makker; F. Santos
40 Renal hypoplasia-dysplasia 68 Hyperuricemia
16 Chronic nephritic syndrome G. Rizzoni ; M.A. Linshaw F.B. Stapleton; J. Smith
S.P. Makker; F. Santos
42 Nephromegaly 70 Rickets
18 Vasculitis M.A. Linshaw; G. Rizzoni G. Ariceta; B. Hoppe; C.B. Langman
W. Proesmans; U.S. Alon
44 Hyperechoic kidney
20 Hemolytic uremic syndrome M.A. Linshaw; G. Rizzoni
W. Proesmans; U.S. Alon

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

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48 Renal mass

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M.A. Linshaw; G. Rizzoni
Fluid/electrolyte/acid base balance Divalent ion metabolism Renal failure
72 Hyponatremia 92 Hypocalcemia 106 Oliguria/anuria
S. Watkins; D. Okamura; J. Rodrguez Soriano G. Ariceta; B. Hoppe; C.B. Langman J.-P. Guignard; R.N. Fine

74 Hypernatremia 94 Hypercalcemia 108 Neonatal acute renal failure


S. Watkins; D. Okamura; J. Rodrguez Soriano B. Hoppe; G. Ariceta; C.B. Langman J.-P. Guignard; R.N. Fine

76 Hypochloremia 96 Hypophosphatemia 110 Acute renal failure (child/adolescent)


J. Rodrguez Soriano; D. Okamura; S. Watkins C.B. Langman; G. Ariceta; B. Hoppe R.N. Fine; J.-P. Guignard

78 Hyperchloremia 98 Hyperphosphatemia 112 Chronic renal failure


D. Okamura; J. Rodrguez Soriano; S. Watkins C.B. Langman; G. Ariceta; B. Hoppe R.N. Fine; J.-P. Guignard

80 Hypokalemia 100 Hypomagnesemia 114 Renal osteodystrophy


D. Okamura; J. Rodrguez Soriano; S. Watkins I. Eisenstein; P. Goodyer; I. Zelikovic R.N. Fine; J.-P. Guignard

82 Hyperkalemia 102 Hypercalciuria


J. Rodrguez Soriano; D. Okamura; S. Watkins F.B. Stapleton; J. Smith
116 Index of Signs and Symptoms
84 Metabolic acidosis 104 Nephrolithiasis/urolithiasis
U.S. Alon; W. Proesmans F.B. Stapleton; J. Smith 120 Abbreviations

86 Metabolic alkalosis
U.S. Alon; W. Proesmans

88 Hypovolemia
U.S. Alon; W. Proesmans

90 Edema
W. Proesmans; U.S. Alon

III

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IV

Library of Congress Cataloging-in-Publication Data Disclaimer. The statements, options and data contained in this publi- All rights reserved. No part of this publication may be translated into
cation are solely those of the individual authors and contributors and other languages, reproduced or utilized in any form or by any means,
Practical algorithms in pediatric nephrology / editors, Israel Zelikovic, not of the publisher and the editor(s). The appearance of advertise- electronic or mechanical, including photocopying, recording, micro-
Israel Eisenstein. ments in the book is not a warranty, endorsement, or approval of the copying, or by any information storage and retrieval system, without
p. ; cm. -- (Practical algorithms in pediatrics) products or services advertised or of their effectiveness, quality or permission in writing from the publisher.
Includes bibliographical references and index. safety. The publisher and the editor(s) disclaim responsibility for any
ISBN 978-3-8055-8539-2 (soft cover : alk. paper) injury to persons or property resulting from any ideas, methods, in- Copyright 2008 by S. Karger AG, P.O. Box, CH4009 Basel
1. Pediatric nephrology--Handbooks, manuals, etc. 2. Medical structions or products referred to in the content or advertisements. (Switzerland)
protocols--Handbooks, manuals, etc. I. Zelikovic, Israel. II. Eisenstein, Printed in Switzerland on acid-free and non-aging paper (ISO 9706)
Israel, 1964- III. Series. Drug Dosage. The authors and the publisher have exerted every effort by Reinhardt Druck, Basel
[DNLM: 1. Kidney Diseases--diagnosis. 2. Adolescent. 3. Child. 4. to ensure that drug selection and dosage set forth in this text are in ISBN 9783805585392
Decision Trees. 5. Diagnosis, Differential. WS 320 P895 2008] accord with current recommendations and practice at the time of pub-
RJ476.K5P73 2008 lication. However, in view of ongoing research, changes in government
618.9261--dc22 regulations, and the constant flow of information relating to drug ther-

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2008019859 apy 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

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warnings and precautions. This is particularly important when the rec-
ommended agent is a new and/or infrequently employed drug.

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Contributors
Raymond Adelman, MD Bernd Hoppe, MD Juan Rodrguez Soriano, MD
Department of Pediatrics University Childrens Hospital Division of Pediatric Nephrology
Phoenix Childrens Hospital Division of Pediatric Nephrology Department of Pediatrics
Phoenix, AZ, USA Cologne, Germany Hospital de Cruces and Basque University
School of Medicine
Uri S. Alon, MD Sally Hulton, MD Baracaldo, Vizcaya, Spain
Section of Pediatric Nephrology Department of Pediatric Nephrology
The Childrens Mercy Hospital and Clinics The Birmingham Childrens Hospital Fernando Santos, MD
University of Missouri NHS Trust Division of Pediatric Nephrology
Kansas City, MO, USA Birmingham, United Kingdom Hospital Central de Asturias
University of Oviedo
Gema Ariceta, MD Craig B. Langman, MD Oviedo, Asturias, Spain
Division of Pediatric Nephrology Feinberg School of Medicine
Hospital de Cruces Northwestern University Jodi Smith, MD
Baracaldo, Vizcaya, Spain Kidney Diseases, Childrens Memorial Hospital Division of Pediatric Nephrology
Chicago, IL, USA Childrens Hospital and Regional Medical Center
Israel Eisenstein, MD University of Washington
Michael A. Linshaw, MD Seattle, WA, USA
Pediatric Nephrology
Rambam Medical Center Division of Pediatric Nephrology
Faculty of Medicine Technion Massachusetts General Hospital F. Bruder Stapleton, MD
Haifa, Israel Boston, MA, USA Department of Pediatrics
Childrens Hospital and Regional Medical Center
Richard N. Fine, MD Sudesh Paul Makker, MD University of Washington
Seattle, WA, USA
School of Medicine Pediatric Nephrology
State University of New York at Stony Brook UC Davis Medical Center
Stony Brook, NY, USA Sacramento, CA, USA Sandor Turi, MD
Department of Pediatrics and Child Health Center
Aaron L. Friedman, MD Daryl Okamura, MD University of Szeged
Szeged, Hungary
Department of Pediatrics Division of Pediatric Nephrology
University of Minnesota Childrens Hospital and Regional Medical Center
Minneapolis, MN, USA University of Washington Sandra Watkins, MD
Seattle, WA, USA Division of Pediatric Nephrology
Paul Goodyer, MD Childrens Hospital and Regional Medical Center
Willem Proesmans, MD University of Washington
Division of Pediatric Nephrology
Seattle, WA, USA
The Montreal Childrens Hospital Renal Unit, Department of Pediatrics
McGill University University Hospital Gasthuisberg
Montreal, Quebec, Canada Leuven, Belgium Israel Zelikovic, MD
1 Pediatric Nephrology
Jean-Pierre Guignard, MD Gianfranco Rizzoni , MD Rambam Medical Center
Faculty of Medicine Technion
Division of Pediatric Nephrology Division of Nephrology
Haifa, Israel
Department of Pediatrics Childrens Hospital and

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Lausanne University Medical School Research Institute Bambino Gesu
Lausanne, Switzerland Rome, Italy

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Preface
The term algorithm is derived from the Practical Algorithms in Pediatric Ne- This is the third in the Series of Practical
2
name of the ninth century Arabic mathe- phrology is meant as a pragmatic text to be Algorithms in Pediatrics, following Practi-
matician Algawrismi, who also gave his used at the patients bedside. The experi- cal Algorithms in Pediatric Endocrinology
name to algebra. His algorismus, indi- enced practitioner applies step-by-step and Practical Algorithms in Pediatric Hema-
cated a well-defined procedure for step-by- logical problem-solving for each patient tology-Oncology. Hopefully, this volume
step logical approach to mathematical individually. Decision trees prepared in ad- will provide residents, fellows, general pe-
problem-solving. In reading the final prod- vance have the disadvantage of unac- diatricians and family practitioners some
uct, written by some of the finest pediatric quaintedness with the individual patient. important clinical tools in understanding
nephrologists in the world and edited by Yet, for the physician who is less experi- their patients.
my friends Drs. Israel Zelikovic and Israel enced with a given problem, a prepared
Eisenstein, it is obvious that the spirit of the algorithm would provide a logical, concise,
algorismus has been utilized in its best. cost-effective approach prepared by a spe- Zeev Hochberg, MD, PhD
The algorithm input are physical symptoms cialist who is experienced with the given Series Editor
and signs, or laboratory results, which lead problem.
to a number of effective steps, and pro-
duces the diagnoses for an output. Thirty years after completing my pedi-
atric 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 af-
ter an educated initial workup, and would
be better equipped to follow the specialists
management.

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Introduction
Practical Algorithms in Pediatric Ne- understanding of the physiology and During the production process of this
phrology is a pragmatic text which classi- pathophysiology of renal function in health book, it has been our privilege to interact
fies common clinical symptoms, signs, and disease. Hence, special emphasis has and work with some of the leading clini-
laboratory abnormalities and issues of been given in this book to the novel knowl- cians and teachers in the field of pediatric
management as they present themselves edge that has accumulated on the molecu- nephrology in the world. It has been a very
in daily practice. Aimed at an audience of lar pathophysiology and molecular genet- enriching and gratifying experience for us,
general and family practitioners, pediatri- ics of various kidney diseases and urinary the editors, for which we thank all the
cians and trainees who are not exposed to tract abnormalities, in order to deepen and authors. A final note we have been very
pediatric nephrology problems on a day-to- strengthen the practical approach to com- saddened by the recent passing of Prof.
day basis, it provides a rational, stepwise mon problems occurring in pediatric ne- Gianfranco Rizzoni, a prominent pediatric
and as noninvasive as possible approach phrology. Indeed, many of the algorithms nephrologist from Rome, Italy, who con-
from which they can profit and acquire in this book, written by leading investiga- tributed several excellent algorithms to this
medical reasoning. tors in the area of pediatric nephrology, book. We send our deep condolences to
incorporate and exemplify this bench to his family and friends.
In the past decade, remarkable prog- patient approach which has become a
ress has been made in our understanding characteristic of modern medicine. Israel Zelikovic, MD
of the molecular pathogenesis of heredi- Israel Eisenstein, MD
tary kidney diseases and congenital urinary It is the Editors hope that the algorith-
tract abnormalities. Studies in molecular mic, logical and stepwise approach to the
genetics and molecular biology have led to diagnosis and management of various he-
the identification of numerous kidney dis- reditary and acquired kidney diseases,
ease-causing mutations, provided impor- fluid and electrolyte abnormalities, aberra-
tant insights into the defective molecular tions in mineral balance, and other impair-
mechanisms 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 man-
age, at least at their initial stages, clinical
problems which have always been notori-
ous for their complexity and which have
been left, from the outset, to specialists in
3
the area.

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Glomerular and vascular disease A.L. Friedman S. Turi Hematuria

/
Hematuria
4

Microscopic hematuria 0 Macroscopic (gross) hematuria

Exclude myo-/hemoglobinuria or red urine without hematuria 3

Transient 1 Persistent 2 () Nephritic syndrome 4 (+) Nephritic syndrome :

Hx PHE Laboratory/imaging Hx PHE Laboratory

Urinary symptoms Edema, fever Urine: microscopy, culture, protein, Recurrent/new onset ? Blood pressure, Urine: microscopy, protein,
Stones/urinary sediment Abdominal/loin metabolic profile of stones Postinfectious respiratory rate, eosinophils
Abdominal/loin pain mass or tenderness Serum: creatinine and BUN, electrolytes, Ca2+, Rash, arthritis/arthralgia pallor, edema, Serum: CBC + reticulocytes,
Weight loss Eye/ear examination phosporus, uric acid, CBC + reticulocytes, Hemoptysis rash, petechia, creatinine, BUN, electrolytes,
Hearing impairment Diaper/underwear blood gases, LDH, C3, C4, ANA, ANCA Respiratory symptoms arthritis/arthralgia, AST, ALT, albumin,
Eye anomalies sediment Hepatitis B, C serology Weight loss, fever lung examination hepatitis B, C serology,
(+)Family Hx of stones/ Bruises/hematomas Imaging: plain abdominal film, Drugs (NSAID, antibiotics) C3, C4, ANA, ANCA
hearing impairment/hematuria/ renal/abdominal Doppler US, Kidney biopsy
bleeding disorder/ abdominal CT, angiography, kidney biopsy
hypercoagulability

Fever Glomerular disease 5 Urinary tract diseases 8 Immune-mediated disease ; Vasculitides < Miscellaneous =
Strenuous exercise Alport syndrome Urinary tract infection Postinfectious glomerulonephritis HSP RPGN
Benign familial hematuria Nephro-/urolithiasis Other glomerulonephritides Wegner's granulomatosis HUS
IgA nephropathy Hypercalciuria (shunt GN, SBE, cryoglobulinemia) Churg-Strauss syndrome TIN
Postinfectious glomerulonephritis Loin pain hematuria syndrome MPGN Microscopic polyangiitis
Persistent asymptomatic hematuria Hematologic diseases 9 IgA nephropathy (microscopic PAN)
Anatomic malformation 6 Coagulopathies Lupus nephritis Polyarteritis nodosa (classic PAN)
Hydronephrosis Renal vein thrombosis Anti-GBM glomerulopathy
Polycystic kidney disease Sickle cell disease (Goodpasture syndrome)
Tumors 7 Nutcracker syndrome
Wilms tumor AV malformation

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1 RBCs in the urine. mostly benign disease is asymptomatic microscopic 12 Nephritic syndrome is a condition character-
hematuria. Although the clinical presentation of IgA ized by gross hematuria with urinary casts (RBCs,
2 Microscopic hematuria is defined as >23 nephropathy and postinfectious glomerulonephritis granular), proteinuria, hypertension and variable
RBCs/high power field or >5 RBCs/l. can be asymptomatic microscopic hematuria, these degrees of decreased renal function.
diseases are more likely to present with macroscopic
3 Transient hematuria is observed in children hematuria with or without nephritic syndrome (see 13 Immune-mediated GN comprises the major-
with intercurrent infection (which is the most common below). Persistent asymptomatic hematuria, a clini- ity of diseases that cause nephritic syndrome in chil-
cause of microscopic hematuria in children) and cally insignificant condition, is a diagnosis made after dren, and usually present with gross hematuria. For
during strenuous exercise. This type of hematuria is excluding all other causes of hematuria. details, see appropriate algorithms.
asymptomatic, resolves within a few days and does
not warrant further evaluation. 8 Anatomic malformations can cause hematu- 14 Vasculitides, a group of disorders that cause
ria, which is either microscopic or macroscopic. The inflammation of blood vessels, usually presents with
4 The presence of RBCs in 3 consecutive urine features of polycystic kidney disease (either autosomal gross hematuria. See appropriate algorithms.
samples obtained over a 3-week period is defined as dominant or autosomal recessive), a leading cause of
persistent hematuria. ESRD, include (among other manifestations) hematu- 15 RPGN, or crescentic GN, usually manifest
ria (see Cystic kidneys). with gross hematuria in addition to the rapid decline
5 Damage to muscle tissue or RBCs causes a in GFR (for details, see appropriate algorithms). Hemo-
release of myoglobin or hemoglobin, respectively. 9 Tumors of the kidneys or the urinary tract will lytic uremic syndrome (HUS) and tubulointerstitial
Both molecules are filtered in the glomerulus and lead cause either microhematuria or, more commonly, nephritis are additional important causes of gross
to red, blood-like urine, with a positive heme test on gross hematuria. hematuria (see appropriate algorithms).
dipstick but no RBCs on urinary microscopy. Various
drugs and food derivatives can cause red-colored 10 Urinary tract infections may lead (in addition
urine without hematuria. to the typical urinary manifestations) to microhematu- Selected reading
ria. Hemorrhagic cystitis, a condition caused by viral
6 The differential diagnosis of gross hematuria infections (mostly adenovirus), radiation or cyclophos- Bergstein J, Leiser J, Andreoli S: The clinical signifi-
includes conditions with or without features of phamide administration will manifest with gross cance of asymptomatic gross and microscopic
nephritic syndrome (see below). It is important to hematuria. Hypercalciuria, the most common cause of hematuria in children. Arch Pediatr Adolesc Med
emphasize that most conditions outlined below nephrolithiasis/urolithiasis in children, can cause either 2005;159:353355.
(sections 711) can lead to gross as well as micro- isolated microscopic hematuria or gross hematuria. Diven SC, Travis LB: A practical primary care
hematuria. The workup of the child with hematuria Most of these children will have idiopathic hyper- approach to hematuria in children. Pediatr Nephrol
should be rational, sequential, disease-oriented calciuria (see Hypercalciuria). Loin pain hematuria 2000;14:6572.
and as noninvasive as possible. syndrome is a rare and enigmatic disorder, observed Hudson BG, Tryggvason K , Sundaramoorthy M,
mostly in young women (see Loin pain with hematu- Neilson EG: Alports syndrome, Goodpastures
7 Glomerular diseases can cause a spectrum of ria). syndrome, and type IV collagen. N Engl J Med
clinical manifestations ranging from asymptomatic 2003;348:25432556.
microscopic hematuria to rapidly progressive glomer- 11 Hematologic disorders will manifest usually Pan CG: Evaluation of gross hematuria. Pediatr Clin
ulonephritis and severe renal impairment. with microscopic hematuria without urinary symp- North Am 2006;53:401412.
Alport syndrome is an inherited x-linked, autosomal- toms. Conditions that increase the risk of renal vein Shin JI, Park JM, Lee SM, Shin YH, Kim JH, Lee JS,
recessive, or rarely autosomal-dominant disorder, thrombosis include intravascular volume depletion Kim MJ: Factors affecting spontaneous resolution
which is caused by a defect in collagen type IV, an and hypercoagulability. It is also observed in infants of hematuria in childhood nutcracker syndrome.
essential component of the basement membrane. The of diabetic mothers. Nutcracker syndrome is a condi- Pediatr Nephrol 2005;20:609613.
clinical picture of Alport syndrome includes hearing tion caused by a compression of the left renal vein Yadin O: Hematuria in children. Pediatr Ann 1994;23:
impairment, eye abnormalities and renal disease man- between the abdominal aorta and superior mesenteric 474478, 481485.
ifested as hematuria, (microscopic or recurrent macro- artery leading to intermittent gross hematuria and Youn T, Trachtman H, Gauthier B: Clinical spectrum
scopic), progressive proteinuria and deteriorating GFR left flank pain. Diagnosis is made by abdominal of gross hematuria in pediatric patients. Clin Pediatr
culminating in ESRD. Benign familial hematuria (thin Doppler sonogram or angiography. Sickle cell disease 2006;45:135141.
5 can result in glomerulopathy leading to microscopic
basement membrane disease) is another genetically
transmitted disease that is caused by alterations in hematuria or renal papillary necrosis which will cause
collagen type IV. The cardinal manifestation of this gross hematuria.

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Glomerular and vascular disease A.L. Friedman S. Turi Hematuria
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

6 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

Hypocomplementemia 1 Normocomplementemia 3 Rapidly declining renal function

Transient Persistent 3

Renal biopsy Renal biopsy

Acute postinfectious GN 2 Membranoproliferative GN 4 IgA GN 5 RPGN 7


Lupus nephritis HSP
Endocarditis Polyarteritis nodosa

Antibiotics, if indicated Supportive treatment (regardless of etiology) 6 Methylprednisolone pulse therapy


Salt, potassium, fluid restriction Cytotoxic drugs
Furosemide Plasmapheresis
Antihypertensive drugs
Dialysis therapy

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1 Acute GN often manifests as an ANS. The main features of abundance of polymorphonuclear cells, positive immunoflorescence
Selected reading
this syndrome are: (a) hematuria, usually gross hematuria of sudden for C3 and IgG and subepithelial electron-dense deposits or humps.
onset; it is sometimes associated with the presence of RBC casts Poststreptococcal acute GN must be treated with penicillin as Appel GB, Cook HT, Hageman G, Jennette JC, Kashgarian M,
in urinary sediment, which is diagnostic of glomerular bleeding; though an active infection by group A streptococcus is present. Kirschfink M, Lambris JD, Lanning L, Lutz HU, Meri S, Rose NR,
(b) oliguric acute renal failure of variable severity; oliguria is defined Salant DJ, Sethi S, Smith RJ, Smoyer W, Tully HF, Tully SP,
as urine volume less than 1214 ml/m2/h in children and below 0.6 5 The finding of normal serum C3 concentrations or Walker P, Welsh M, Wurzner R, Zipfel PF: Membranoproliferative
0.8 ml/kg/h in neonates and infants; (c) hypertension and edema are persistent hypocomplementemia must raise the suspicion of other glomerulonephritis type II (dense deposit disease): an update.
mainly produced by salt retention that is not only secondary to de- diagnostic options mentioned above and lead to kidney biopsy. J Am Soc Nephrol 2005;16:13921403.
creased glomerular filtration rate but also to increased reabsorption Delos Santos NM, Wyatt RJ: Pediatric IgA nephropathies:
of sodium chloride in the collecting duct. This tubular hyperabsorp- 6 MPGN is a chronic GN rarely seen before 10 years of age. clinical aspects and therapeutic approaches. Semin Nephrol 2004;
tion of sodium chloride probably results from hyperactivity of the This entity is divided into 3 subtypes by histopathologic features 24:269286.
Na+/K+ ATPase pump located on the basolateral membrane of the termed MPGN I, II and III. MPGN can be idiopathic or associated with Hricik DE, Chung-Park M, Sedor J: Glomerulonephritis. N Engl J
collecting duct cells; (d) proteinuria of variable intensity; although systemic diseases (suppurative infections, hepatitis B and C infec- Med 1998;339:888889.
urinary protein excretion in children with ANS is characteristically tion, cryoglobulinemia and malignancies). Lupus nephritis is more Jucos LI: Intrarenal mechanisms of salt and water retention in
below the nephrotic range. often found in adolescent girls with elevated titers of antinuclear the nephritic syndrome. Kidney Int 2002;61:11821195.
antibodies and multisystemic involvement. The renal lesions are Kurtzman NA: Nephritic edema. Semin Nephrol 2001;21:257261.
2 Initial diagnostic approach to a child who presents with divided into 5 types based on the WHO classification of histologic Lee BS, Cho HY, Kim EJ, Kang HG, Ha IS, Cheong HI, Kim JG,
manifestations suggestive of ANS should focus on: (a) confirmation findings: type 1 normal glomeruli; type 2 mesangial changes; type Lee HS, Choi Y: Clinical outcomes of childhood lupus nephritis:
of ANS by measuring GFR and amount of protein lost in urine as well 3 focal proliferative GN; type 4 diffuse proliferative GN (the most a single centers experience. Pediatr Nephrol 2007;22:222231.
as potential detection of RBC casts in urine sediment; (b) search for common and most severe form), and type 5 membranous GN. Madaio MP, Harrington JT: The diagnosis of glomerular diseases:
evidence of infectious causal agent, mainly group A beta-hemolytic Long-term prognosis of the severe forms of lupus nephritis (types 3 acute glomerulonephritis and the nephrotic syndrome.
streptococcus, by cultures of throat and skin lesions, if any, and and 4) is poor and, therefore, treatment regimens are aggressive and Arch Intern Med 2001;161:2534.
serum determination of antistreptolysin O titer; (c) exclusion of sys- include IV pulses of methylprednisolone and cyclophosphamide.
temic diseases, such as HSP syndrome, systemic lupus erythemato-
sus, endocarditis or idiopathic GN (MPGN, IgA nephropathy) by 7 IgAN is the most common GN worldwide with especially
detailed anamnesis, meticulous physical examination and laboratory high prevalence in certain areas (south-east Asia, Pacific rim) in
tests which include serum C3 and C4 levels, hepatitis B and C serol- contrast to low rates among blacks. Although the exact etiology is
ogy and levels of ANA. No specific findings of ANS may be found in unknown, there are certain predisposing genetic and environmental
renal ultrasound which usually will show a loss of the normal corti- factors that are associated with IgAN. The pathogenesis of IgAN is
comedullary differentiation; however, the absence of other abnormal complex and it involves mesangial deposition of IgA molecules,
findings is useful to rule out chronic nephro-urologic disorders; if circulating IgA complexes as well as abnormal IgA glycosylation.
respiratory symptoms are present, a chest X-ray film is mandatory The typical histological findings include mesangial proliferation with
since pulmonary edema may be a presenting manifestation of ANS. mesangial IgA staining on immunofluorescence. Although the long-
term prognosis is usually good, hypertension, heavy proteinuria
3 Measurement of serum C3 levels is important in the evalua- and/or reduced GFR are bad prognostic factors and aggressive ther-
tion of the child presenting with ANS. Hypocomplementemia is a apy should be instituted which includes combinations of steroids,
major diagnostic criteria of postinfectious acute GN. Serum levels of fish-oil, azathioprine, dipyridamole and heparin/warfarin. Vasculitis
C3 are usually markedly depressed when clinical and biochemical can lead to ANS with normocomplementemia. This picture is espe-
manifestations of ANS become apparent. The degree of depression cially seen in HSP and polyarthritis nodosa.
of C3 does not correlate with the severity of the disease or have any
prognostic significance. Serum C3 concentrations tend to normalize 8 Patients with ANS require close monitoring to prevent com-
progressively and persistence of hypocomplementemia beyond 8 plications. Physical activity as well as salt, potassium, and fluid
weeks after presentation should alert the clinician to the possibility intake must be restricted during the acute period of the disease. Oral
of MPGN or lupus nephritis. or intravenous furosemide is often needed for a few days to treat
oliguria and hypertension. Other drugs used to treat hypertension
4 Poststreptococcal GN is representative of a larger group of include calcium channel blockers, - and -blockers, various vaso-
7 postinfectious GNs in which acute glomerular injury results from dilators, and, occasionally, ACE inhibitors.
immune events triggered by a variety of bacterial, viral, and proto-
zoal infections. Poststreptococcal GN predominantly affects children 9 RPGN is diagnosed by an abrupt and progressive deteriora-
between 2 and 10 years and usually follows a benign course with full tion of glomerular filtration rate along with the presence of epithelial

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recovery being the rule. Kidney biopsy, which is not indicated in typi- crescents in more than 60% of glomeruli. For details, see Rapidly
cal cases, will show diffuse GN with endocapillary proliferation and progressive glomerulonephritis.

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Glomerular and vascular disease F. Santos S.P. Makker Acute nephritic syndrome
Glomerular and vascular disease F. Santos S.P. Makker Proteinuria

/
Proteinuria
8

Transient 0 Persistent 1

Tubular Glomerular 4

Isolated 4 Associated with

Tubular disorders 2 Overload proteinuria 3 Nephritic syndrome 5 Nephrotic syndrome 5 Chronic renal disease 6

No additional studies ACE or angiotensin receptor antagonists 7


No treatment

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1 Minimal amounts of proteins can be physi- of 2-microglobulin requires monitoring of urine pH
Selected reading
ologically found in urine. Pathologic proteinuria can be because of its instability in samples with pH below 6.5.
detected by dipstick, which is especially sensitive to From the diagnostic point of view, the finding of tubu- Adelman RD, Restaino IG, Alon US, Blowey DL:
albumin. A rough estimation of the intensity of pro- lar proteinuria is seen in the setting of a more general- Proteinuria and focal segmental glomerulosclerosis
teinuria may be drawn from the dipstick: trace, 1+, 2+, ized proximal tubular disorder, usually congenital or in severely obese adolescents. J Pediatr 2001;138:
3+, 4+ approximately correspond to 1015, 30, 100, 300 primary, that produces aminoaciduria, phosphaturia, 481485.
and >1,0002,000 mg/dl, respectively. A more accurate glucosuria and/or bicarbonaturia, or as an acquired Chandar J, Abitbol C, Montane B, Zilleruelo G: An-
quantitation of proteinuria requires timed urine collec- alteration secondary to interstitial nephropathy (acute giotensin blockade as sole treatment for proteinuric
tion of measurement of the protein (mg/dl)/creatinine pyelonephritis, reflux nephropathy, obstructive kidney disease in children. Nephrol Dial Transplant
(mg/dl) ratio in an isolated urine sample, preferably the nephropathy, administration of aminoglycosides, etc.) 2007;22:13321337.
first one of the morning. A urinary protein to creatinine Hogg RJ, Portman RJ, Milliner D, Lemley KV, Eddy A,
ratio 60.2 in children beyond infancy is considered 5 Systemic overproduction of low-molecular- Ingelfinger J: Evaluation and management of
abnormal. In infants, higher ratios (up to 0.5) are still weight proteins may give rise to proteinuria because proteinuria and nephrotic syndrome in children:
considered normal. The 24-hour urine collection is of excessive amounts of these proteins in the glomeru- recommendations from a pediatric nephrology
the best test for the estimation of protein excretion. lar filtrate which overwhelms the maximum reabsorp- panel established at the National Kidney Founda-
Values above 4 mg/m2/h are pathologic and values tive capacity of the tubule. Thus, low-molecular- tion conference on proteinuria, albuminuria, risk,
above 40 mg/m2/h are in the nephrotic range. weight proteinuria may be a manifestation of multiple assessment, detection, and elimination (PARADE).
myeloma (light chains), leukemia (lysozyme), rhabdo- Pediatrics 2000;105:12421249.
2 Prevalence of proteinuria in a single urine myolysis (myoglobin) or hemolysis (hemoglobin). Litwin M, Grenda R, Sladowska J, Antoniewicz J:
specimen in children varies between 5% and 15%. Add-on therapy with angiotensin II receptor 1
Transient proteinuria is not indicative of underlying 6 With a negative personal history of renal dis- blocker in children with chronic kidney disease
renal disease. This type of proteinuria is often found in ease, persistent glomerular proteinuria even under the already treated with angiotensin-converting
association with fever, exercise, stress or dehydration nephrotic range (between 4 and 40 mg/m2/h) requires enzyme inhibitors. Pediatr Nephrol 2006;21:
and the only study required is to confirm its disappear- clinical evaluation (family and personal history, edema, 17161722.
ance once the intercurrent factor has worn off. Ortho- blood pressure) laboratory work-up (urinalysis, renal Tomlinson PA: Low molecular weight proteins in
static proteinuria is diagnosed when urinary protein function, serum lipid profile, serum complement, anti- children with renal disease. Pediatr Nephrol
is elevated when the subject is upright but normalizes nuclear antibodies, hepatitis and HIV diagnostic tests) 1992;6:565571.
during recumbency. It occurs most commonly in and abdominal ultrasound to rule out associated renal
school-aged children, its intensity is usually below the dysfunction. If these complementary studies are
nephrotic range, and its outcome is generally consid- normal, renal biopsy to identify the underlying kidney
ered to be benign, so no additional diagnostic studies lesion may be necessary.
or therapeutic measures are necessary.
7 For details on nephritic and nephrotic syn-
3 Proteinuria detected in repeated urine sam- dromes, see corresponding algorithms.
ples over time is always an index of renal or systemic
abnormality and should be further investigated. 8 High pressure and glomerular hyperfiltration
in chronic renal disease may lead to proteinuria
4 Decreased reabsorption of normally filtered induced by glomerulosclerosis as found in diabetic
low-molecular-weight proteins (molecular weight nephropathy, reduced functioning renal mass, arterial
below 40,000 Da) by the renal proximal tubules leads hypertension, severe obesity, etc.
to tubular proteinuria. Dipstick testing is less sensitive
to detect tubular proteins than albumin. 2-Microglob- 9 ACE inhibitors and angiotensin II receptor
ulin and retinol-binding protein are the low-molecular- antagonists are increasingly used in adult patients
weight proteins measured most frequently. Normal with chronic renal disease because of their potential
reference values for these proteins in children beyond renoprotective, antihypertensive and antiproteinuric
6 months of age and adults are as follows: urinary actions. Although few data are available in children,
9 2-microglobulin = 6.040.7 g/mmol creatinine; plas- accumulating evidence seems to confirm the benefi-
ma 2-microglobulin 1.02.4 mg/l; urinary retinol-bind- cial effect of these therapies on proteinuria of pediatric
ing protein ~124.5 g/mmol creatinine. In infants, patients with different types of chronic renal disease.
these concentrations tend to be higher. Measurement

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Glomerular and vascular disease F. Santos S.P. Makker Proteinuria
Glomerular and vascular disease F. Santos S.P. Makker Nephrotic syndrome in the first year of life

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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 Others 5

Particularly frequent in Finns Intrauterine infections Isolated or Denys-Drash syndrome Resistant to


Early-onset massive proteinuria Congenital syphilis Early progression to renal failure immunomodulatory drugs
Prematurity and large placenta Toxoplasmosis Characteristic renal pathology Early progression to renal failure
No renal insufficiency Rubella Mutations in WT1 gene Usually podocin gene mutations
Microcystic kidneys CMV
Mutations in NPHS1 gene HIV

MCD
MGN
SLE

Nephrectomy 7 Supportive therapy 6 Treatment of primary disease


Dialysis Nutritional supplementation Immunomodulatory treatment
Early transplantation Albumin infusions + furosemide
Thyroid hormone replacement
Anticoagulation

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Aggressive treatment of infections

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Antiproteinuric agents

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1 NS is characterized by massive proteinuria, pseudohermaphroditism and Wilms tumor. Incom-
Selected reading
estimated by urinary protein elimination equal to or plete forms of the syndrome have been reported. DMS
greater than 40 mg/m2/h and/or urinary protein/creati- causes ESRD in the first 2 years of life. The pathologi- Holmberg C, Tryggvason K, Kestila MK, Jalanko HJ:
nine ratio >23 mg/mg, resulting in hypoalbuminemia cal picture is characteristic and consists of mesangial Congenital nephrotic syndrome; in Avner ED,
of less than 3 g/dl, edema and hyperlipidemia. Al- matrix expansion, thickened glomerular basal mem- Harmon WE, Niaudet P (eds): Pediatric Nephrology,
though minimal change nephropathy is by far the lead- brane, tuft contraction and tubular dilatation. Muta- ed 5. Philadelphia, Lippincott-Williams & Wilkins,
ing cause of NS in childhood, when NS presents in the tions in the WT1 gene, which is expressed in podo- 2004, pp 503516.
first year of life, other underlying diseases must be cytes and epithelial cells of the Bowmans capsule of Kestila M, lenkkeri U, Mannikko N, Lamerdin J,
considered. postnatal kidney, have been found in nearly all Mc Cready P, Putaaala H, Ruotsalinen V, Morita T,
patients affected with Denys-Drash syndrome and in Nissinen M, Herva R, Kashtan DE, Peltonen L,
2 The term congenital NS is classically used to many cases of isolated DMS. Holmberg C, Olsen A, Tryggvason K: Positionally
describe a NS of onset within the first 3 months of life cloned gene for a novel glomerular protein neph-
(and has become synonymous with Finnish type NS). 6 Although FSGS is usually diagnosed in older rin is mutated in congenital nephrotic syndrome.
Infantile NS usually applies to NS of later onset, until children or adults, it can present in the first year of life. Mol Cell 1998;1:575582.
1 year of age. These cases are usually due to mutations in the gene Niaudet P, Gubler MC: WT1 and glomerular
encoding podocin, a protein which is essential in the diseases. Pediatr Nephrol 2006;21:16531660.
3 Finnish-type NS may be found worldwide formation and structure of the slit diaphragm. Two Tryggvason K, Patrakka J, Wartiovaara J: Hereditary
although it is more frequent in Finland where its inci- additional genes encoding the proteins alfa-actinin-4 proteinuria syndromes and mechanisms of protein-
dence is approximately 1/10,000 newborns. A typical and TRPC6 are known to cause FSGS when mutated, uria. N Engl J Med 2006;354:13871401.
clinical picture includes premature delivery, placenta usually in older children. These genetic defects do not
weighing more than 25% of the birth weight, develop- respond to treatment with glucocorticoids or other
ment of generalized edema, massive proteinuria and immunomodulatory drugs and no disease recurrence
hypoalbuminemia at birth or within the first days of after transplantation (which is common in idiopathic
life. In untreated cases, the natural course of the dis- FSGS) is expected.
ease leads to early death secondary to infection and/or
malnutrition in the presence of normal glomerular 7 NS in infants younger than 1 year may be
filtration rate. Proteinuria may be detected prenatally secondary to SLE, minimal-change nephropathy or
by increased concentrations of alfa-fetoprotein in membranous nephropathy. These cases are rare and
amniotic fluid. Microscopically, NS of Finnish type is for details on these disorders, see the appropriate
characterized by irregular pseudocystic dilatation of algorithms.
proximal tubules which is typically seen after the first
36 months of life. The disease follows an autosomal- 8 The management of an infant with persistent
recessive transmission and is caused by mutations in NS is complex and must be done in a highly special-
the gene NPHS1. The gene is localized to 19q13.1 and ized childrens hospital. It includes active nutritional
encodes a protein named nephrin which is essential in support, control of edema by repeated administration
the formation of the normal zipper-looking structure of intravenous albumin in association with furosemide,
in the slit diaphragm that joins the interdigitating pro- hormone replacement, prevention of thromboembolic
cesses of podoctytes. Abnormal nephrin results in a complications, and prompt and aggressive treatment
massive leak of proteins through the glomerular basal of infections. Administration of indomethacin, ACE
membrane. inhibitors, angiotensin II-type I receptor blockers to
reduce glomerular filtration rate, and, subsequently,
4 Neonatal infections, such as syphilis and less proteinuria may facilitate the control of the patient.
frequently toxoplasmosis, cytomegalovirus or hepati-
tis can cause nephrotic syndrome. These causes must 9 In spite of the above measures, infants with
be excluded by the associated clinical manifestations massive proteinuria often require early nephrectomy
and proper immunologic or serologic tests. In these and dialysis to place the patient in proper metabolic
11 cases, specific treatment of the primary disorder usu- and nutritional conditions for a successful renal trans-
ally leads to remission of the NS. plantation. Bilateral nephrectomy and chronic perito-
neal dialysis have been recommended in Finnish type
5 DMS is responsible for early-onset NS either NS when the infant weighs 7 kg. The effectiveness of

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as an isolated disease or as part of Denys-Drash unilateral nephrectomy in association with antiprotein-
syndrome in which DMS is associated with male uric drugs is a matter of controversy.

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Glomerular and vascular disease F. Santos S.P. Makker Nephrotic syndrome in the first year of life
Glomerular and vascular disease S.P. Makker F. Santos Nephrotic syndrome in the child and adolescent

/
Nephrotic syndrome in the child and adolescent
12 History 01
Physical examination
Laboratory tests

Gross hematuria () 2 Gross hematuria (+) Microhematuria (+) Microhematuria (+) Microhematuria (+) Microhematuria ()
Microhematuria () BPM or N, GFRmor N BPM or N BPMor N BPM or N BPM or N
BP-N MASLO GFRm or N GFRmor N GFRmor N GFRmor N
GFR-N mC3, C4-N ANA (+) C3, C4-N ASLO-N C3, Cr-N, occasionallym
C3, C4-N ANA () C3, C4m mC3 ANA ()
ANA () Group A B-streptococcus in C4mor N ASLO-N
throat or skin () () ANA

Anti DsDNA (+)

Most likely Possibly Most likely PSGN SLE IgAGN 8: MPGN


MCD FSGS, MGN MGN
FSGS
Other chronic GN
Trial with steroids 3 Supportive teatment 9 Including HSP, RPGN

Renal biopsy Renal biopsy Renal biopsy

Urine Protein () Urine protein (+) 6


Steroids and Steroids 78 Steroids 78
Cyclophosphamide/ Other immunosuppressive agents
Azathioprine/MMF 78
Relapse Renal biopsy

Permanent Frequent relapses Steroid dependent HepB Abs (+) HepC Ab(+) ANCA (+) HIV (+) ;
remission 4

MCD MGN 78 HepB GN ; HepC GN ; Wegener's GN


FSGS Polyangiitis

Cyclophosphamide 5 Steroids Steroids Steroids and


Chlorambucil Chlorambucil Chlorambucil other immunosuppressive agents

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Cyclosporine A Cyclophosphamide Cyclosporine
Cyclosporine A

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FK 506

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1 NS is a clinical condition that consists of edema, heavy pro- becomes negative for protein have been used but the superiority of 9 All other glomerulonephrides producing NS are generally
teinuria, hypoalbuminemia and hyperlipidemia with or without the any one schedule is not established though recent data suggest that first treated with prednisone which is usually started at 2 mg/kg/day
accompanying hypertension and/or renal failure. Nephrotic range longer treatment (6 months) may reduce the frequency of subse- (maximum 60 mg) dose. Usually after 46 weeks, the dose is
(heavy) proteinuria is defined as protein excretion of 640 mg/h/m2 quent relapses. In general, the same dose is continued for 24 weeks switched to every other morning dose to reduce the side effects of
obtained on a timed urine collection. It is usually evident on a routine and then tapered to zero over several weeks. prednisone. The durations of daily and alternate day prednisone
urinalysis with dipstick test as 3 to 64 (300 to 61,000) mg/dl protein. administration are quite variable and not established. Various immu-
A random spot urine tested for protein and creatinine often will show 6 About 15% of patients with MCD achieve a permanent nosuppressive agents some old (azathioprine, cyclophosphamide,
a protein/creatinine ratio of 1 or greater and ratios of 10 or greater remission but the remainder relapse. The relapses usually occur with chlorambucil) and some newer (cyclosporine, tacrolimus, mycophe-
are not uncommon in NS. common upper respiratory infections and may continue for years. nolate motetil, sirolimus) have been and are being used in conjunc-
Relapses are treated with prednisone as above but once urine tion with prednisone, but there is little control data in children for
2 History and physical examination provide important clues becomes negative for protein, prednisone is given as a single dose specific recommendations.
about the etiology of NS. Traditionally NS has been classified into every other morning and continued for 12 months and then tapered
primary or idiopathic and secondary types. Since the etiology in the gradually to zero over the subsequent 12 months. Once again, 10 ACE inhibitors and angiotensin II receptor antagonists can
primary type is not known, it is further classified based on histo- several schedules for the administration of prednisone exist but the be used in all NS associated with chronic glomerular diseases except
pathology into MCD, FSGS, MPGN, MGN and various proliferative superiority of any one schedule is not established. steroid-responsive MCD and/or PSGN for their renoprotective
glomerulonephritides including IgA nephropathy and RPGN. effects. Also, lipid-lowering drugs (statins) may be used in such
Secondary NS may result from infections (group A streptococci, 7 Patients who relapse frequently, i.e. 34 times/year, or who patients with chronic hyperlipidemia for their lipid lowering and
hepatitis B and C, HIV, infected ventriculoatrial shunts, syphilis, become steroid-dependent, i.e. require a certain dose of prednisone renoprotective effects.
malaria, etc.), vasculitis (SLE, HSP, Wegeners GN and polyarteritis), at all times to stay in remission, are prone to develop side effects of
systemic disorders (diabetes mellitus, amyloidosis), certain medi- prednisone (hypertension, cushigoid habitus, reduced bone mass, 11 NS associated with PSGN resolves on its own, and support-
cations (captopril, penicillamine, NSAIDs), and occasionally a stunting of height, mood changes, gastrointestinal bleeding, etc.). ive therapy is sufficient. Generally, progressive improvement over
neoplasm (Hodgkin lymphoma). Although MCD accounts for nearly These patients will generally achieve remission with the addition of days is seen in NS, hypertension and renal failure.
75% of all cases of NS in children, symptoms and signs associated cyclophosphamide (2.5 mg/kg) or chorambucil (0.15 mg/kg) given
with conditions producing secondary NS should be elicited during concurrently with the tapering down of prednisone. Blood counts 12 Patients with NS secondary to IgA nephropathy are occa-
history and examination. For example, antecedent of sore throat or are monitored weekly and the drug discontinued if the WBC count sionally treated additionally with fish oil (Max FPA) 24 g three times
impetigo with group A streptococci would suggest PSGN, and drops to ^3,500/l. Patients receiving cyclophosphamide can a day.
arthritis and facial rash would suggest SLE and a family history of develop alopecia and or hemorrhagic cystitis and should be encour-
Alport syndrome would suggest that as the diagnosis. Presence/ aged to drink plenty of fluids. Although these two drugs appear safe 13 Hepatitis-associated NS, particularly with MPGN or MGN
absence of hypertension provides an important clue. Blood pressure at the above-recommended doses, the long-term safety for gonadal histology, may resolve spontaneously. Patients in whom the renal
is normal in MCD but may be elevated in other entities. toxicity and possible future malignancy is not established and, disease does not resolve may be treated with interferon- or anti-
therefore, these drugs should only be used with the full consent of viral agents (lamivudine). HIV is treated with standard antiviral and
3 In the initial laboratory work-up, urine is tested for routine the patient. In children in whom cytotoxic drugs are to be avoided protease inhibitors.
protein/creatinine ratio and serum for electrolytes, creatinine, BUN, (puberty) or in those who continue to relapse, cyclosporine should
total proteins, albumin, cholesterol, C3 and C4, ANA, ASLO and be used. See previous section for details.
serology for hepatitis B, hepatitis C and HIV. In addition, a renal Selected reading
sonogram must be performed in every child with NS. These tests 8 Patients who continue to have proteinuria after a course of
establish the diagnosis, determine if renal failure (elevated serum 48 weeks of daily prednisone are considered steroid resistant. Eddy AA, Symons JM: Nephrotic syndrome in childhood.
creatinine) is present and provide useful information about the Some of these patients show a partial response in that the quantita- Lancet 2003;23:629639.
etiology of NS. tive proteinuria decreases and some improvement may also be Filler G, Young E, Geier P, Carpenter B, Drukker A, Feber J:
noted in serum albumin concentration and edema. Steroid-resistant Is there really an increase in non-minimal change nephrotic
4 Gross hematuria can occur with any of the glomerular NS showing MCD or FSGS on renal biopsies may also be treated syndrome in children? Am J Kidney Dis 2003;42:11071113.
diseases producing NS but is not seen in MCD. The gross hematuria with cyclophosphamide or chlorambucil, and some patients may Gipson DS, Gibson K, Gipson PE, Watkins S, Moxey-Mims M:
when seen is painless and brown tea colored. Microhematuria respond by going into a complete (urine negative for protein) or an Therapeutic approach to FSGS in children. Pediatr Nephrol
detected as occult blood on dipstick test or greater than 5 RBC/HPF incomplete (urine positive for protein but reduction of proteinuria 2007;22:2836.
on microscopic examination of urine sediment is almost always and improvement or resolution of edema) remission. Cyclosporine Grimbert P, Audard V, Remy P, Lang P, Sahali D: Recent
present at some time during the course of a glomerulonephritis and or tacrolimus may also achieve similar results in some patients; approaches to the pathogenesis of minimal-change nephrotic
13 however, the exact dosages and duration of treatment are not yet syndrome. Nephrol Dial Transplant 2003;18:245248.
may be present at onset in 1520% of patients with MCD. Persistent
microhematuria, however, is not usually seen in MCD. established. Doses of 150200 mg/m2/day or 46 mg/kg/day of Niaudet P: Steroid-resistant nephrotic syndrome in children; in
cyclosporine have been used successfully. Both cyclosporine and Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5.
5 Prednisone is given daily in a single morning dose or 34 tacrolimus are nephrotoxic. In general, patients who show a partial Philadelphia, Lippincott-Williams & Wilkins, 2004, pp 557574.

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divided doses at 2 mg/kg at a maximum dose of 60 mg/day. Various response to the initial course of steroids are more likely to benefit Niaudet P: Steroid-sensitive nephrotic syndrome in children; in
schedules for the continuation of prednisone after the urine further with any of the above than those who showed no response at Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5.

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all to steroids. Philadelphia, Lippincott-Williams & Wilkins, 2004, pp 543556.
Ray PE, Xu L, Rakusan T, Liu XH: A 20-year history of childhood
HIV-associated nephropathy. Pediatr Nephrol 2004;19:10751092.

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Glomerular and vascular disease S.P. Makker F. Santos Rapidly progressive glomerulonephritis

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Rapidly progressive glomerulonephritis
14 Renal biopsy

Immunofluorescence microscopy 1

Linear staining for IgG along the GBM 2 No staining or minimal staining 3 Granular staining along capillary loops
Negative staining for albumin and/or mesangium 4

ANA (), C3, C4Nm


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
ANCA

Throat/skin culture (+) ANA (+), C3, C4 ANA (), C3m ANA ()
Lung hemorrhage (+) Lung hemorrhage () for group A B-streptococci mor N C4mor N C3, C4N
Anti-GBM Ab () Anti-GBM Ab ANCA (+) ANCA () ASLOM, anti-DNAaseBM ANCA () ANCA ()

Goodpasture syndrome Necrotizing glomerulonephritis Renal biopsy Renal biopsy Renal biopsy Renal biopsy
Wegener's granulomatosis consistent with consistent with consistent with consistent with
Churg-Strauss syndrome PSGN SLE MPGN IgAGN, HSP,
Miscoscopic polyangiitis Chronic GN

Steroids 5 Steroids 5 Supportive treatment 5 Steroids 5

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Immunosuppressive agents Immunosuppressive agents Immunosuppressive agents
Plasmapheresis plasmapheresis

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1 RPGN is a term used to describe proliferative modalities, see section (6). The prognosis, which was are continued until these antibodies disappear from
glomerulonephritides with rapidly deteriorating renal devastating before the plasmapheresis era, has the serum. In most cases of pauci-immune RPGN,
function and renal biopsy findings showing diffuse improved dramatically but still the rates of chronic plasmapheresis is added to the treatment regimen.
epithelial crescents in greater than 60% of the glom- renal sequelae, ESRD and mortality are high. The value of plasmapheresis in immune-mediated
eruli. Because of the presence of crescents, this entity RPGN is not certain, but it is often used as a last effort
is also called crescentic glomerulonephritis. Of note, 5 A subset of children and adults with RPGN in refractory cases.
several renal disorders can lead to a clinical picture will not show either immune deposits or anti-GBM
similar to RPGN but without the typical histologic find- antibodies on renal biopsy. This entity, termed pauci-
ings. These disorders include conditions such as tubu- immune GN, will be accompanied in approximately Selected reading
lointerstitial nephritis and acute tubular necrosis. 8090% of the cases by a positive test for ANCA in
their sera. ANCA(+) RPGN may be associated with Dillon MJ: Crescentic glomerulonephritis; in
2 History and physical examination can pro- small vessel vasculitidies (Wegeners granulomatosis, Avner ED, Harmon WE, Niaudet P (eds): Pediatric
vide valuable clues towards the type of RPGN. By defi- Churg-Strauss syndrome and microscopic polyangi- Nephrology, ed 5. Philadelphia, Lippincott Williams
nition these patients have hematuria, proteinuria, itis) or may be idiopathic with neocrotizing glomerulo- & Wilkins, 2004, pp 655662.
abnormal cellular casts in urine sediment, and renal nephritis on biopsy. Fischer EG, Lager DJ: Anti-glomerular basement
failure (elevated serum creatinine). Frequently, they The antigen specificity of ANCA may be for proteinase membrane glomerulonephritis: a morphologic
also have gross hematuria (brown tea color urine) 3 or myeloperoxidase. The former produces C-ANCA study of 80 cases. Am J Clin Pathol 2006;125:
and/or hypertension and/or NS. These clinical and and the latter P-ANCA staining. 8090% of ANCA 445450.
laboratory features by themselves are not very helpful found in Wegeners granulomatosis are C-ANCA. Jennette JC, Thomas DB: Crescentic glomerulo-
in uncovering the underlying etiology of RPGN. P-ANCA are more often seen in necrotizing glomerulo- nephritis. Nephrol Dial Transplant 2001;16
Previous throat or skin infection (impetigo) with group nephritis and polyangiitis. For treatment modalities, (suppl 6):8082.
A -streptococci, typical rash of HSP, clinical features see section (5). Kallenberg CG: Antineutrophil cytoplasmic auto-
of SLE (joint pain, skin rash, fever, etc.), hemoptysis antibody-associated small-vessel vasculitis.
(Goodpasture syndrome), and chronic sinusitis Curr Opin Rheumatol 2007;19:1724.
6 RPGN resulting from PSGN, despite its
(Wegeners) are helpful leading clues. Morgan MD, Harper L, Williams J, Savage C:
severity, resolves spontaneously and does not require Anti-neutrophil cytoplasm-associated glomerulo-
immunosuppressive agents or plasmapheresis. nephritis. J Am Soc Nephrol 2006;17:12241234.
3 A renal biopsy is performed and the tissue is
Patients with PSGN, however, may require dialysis
processed for histology using HE, PAS, and Jones for a few days. For details on other immune-mediated
stains for light microscopy, and for immunofluores- diseases leading to RPGN (SLE, MPGN, IgAN,
cence and transmission electron microscopy. For HSP, etc.), see the appropriate algorithms.
immunofluoresence, frozen sections are stained with
fluorescein-labeled antibodies to human immuno- 7 Immunosuppression is generally started
globulins (IgG, IgM, IgA), complement components with a high dose of intravenous methyl prednisolone
(C3, C4 C1q), fibrinogen and albumin. All these studies (pulse therapy). Common dosages are 1530 mg/kg
are necessary for making an accurate diagnosis. (maximum 1,000 mg) given once a day as an infusion
Additional laboratory tests including serum ANA, in 50100 ml of 5% dextrose over 12 h. Usually, 3 dos-
ANCA, AGBMAb, C3 and C4 complement, and tests es are given but 56 doses have also been given safely.
for group A -streptococcal infection provide useful This is followed by 2 mg/kg/day oral prednisone given
leads into the etiology of RPGN. in 34 divided doses. Cyclophosphamide may be
added as an adjunct to therapy and can be given orally
4 Anti-GBM disease is a rare disorder, espe-
at a dosage of 2 mg/kg/day or intravenously at a dose
cially in children. It is caused by circulating antibodies of 500 mg/m2 according to the schedule used by the
(mainly IgG) against GBM in the lungs and kidney NIH to treat diffuse proliferative glomerulonephritis of
glomeruli. Clinical features include RPGN with or SLE. The duration of prednisone and cyclophospha-
without pulmonary hemorrhage (called in the past mide therapy is variable and is often individualized
Goodpasture syndrome and Goodpasture disease, depending on the initial response. Plasmapheresis is
15 respectively). Typical laboratory findings include generally added to the regimen of the above immuno-
reduced renal function, anemia and serum anti-GBM suppression in RPGN resulting from anti-GBM disease
antibodies. Renal biopsy reveals crescentic GN with particularly if autoantibodies to the GBM are present
linear staining for IgG along the GBM. For treatment in serum. In general, the plasmapheresis treatments

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Glomerular and vascular disease S.P. Makker F. Santos Rapidly progressive glomerulonephritis
Glomerular and vascular disease S.P. Makker F. Santos Chronic nephritic syndrome

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Chronic nephritic syndrome
16 History and examination 0

Laboratory tests 1

Urinalysis, urinalysis on family members, C3, C4,


ANA, ANCA, HepCAb, HepBsAg, HIV, renal US

Hematuria/proteinuria ANA (+) ANA () ANA () ANA ()


in family members C3, C4m C3, C4 N C3mN, C4m ANCA ()
ANCA () ANCA () C3, C4 Nm
Hep B and C ()

ds DNA Ab (+)

Alport syndrome SLE IgAGN MPGN Hep BsAg (+) Hep C ab (+) HIV (+)
Thin basement membrane disease HSP
Nail-patella syndrome MGN
Chronic GN

Hearing test Renal biopsy Renal biopsy Renal biopsy (types I, II, III) Renal biopsy
Ophthalmologic exam (WHO classification)
Bone film (in nail-patella syndrome)

Renal biopsy

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Steroids Interferon 2 Antiviral agents 2

Univ. of California San Diego


Immunosuppressive agents2

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1 Chronic nephritic syndrome is defined as a 3 Initial laboratory tests to be obtained in all
Selected reading
clinical condition resulting from a chronic GN that con- patients with chronic GN are urinalysis including urine
sists of persistent hematuria, proteinuria and abnor- sediment examination, spot urine for protein/creati- Balow JE: Clinical presentation and monitoring of
mal cellular casts in urine sediment with or without nine ratio, serum electrolytes, BUN, creatinine, total lupus nephritis. Lupus 2005;14:2530.
accompanying hypertension and/or renal failure. He- protein, albumin, serum complement C3, C4, ANA, Barratt J, Feehally J: Treatment of IgA nephropathy.
maturia without proteinuria may be present in some ANCA and serologic tests for hepatitis B, hepatitis C Kidney Int 2006;69:19341938.
patients and occasionally (particularly in IgA nephrop- and HIV. Hematuria, proteinuria and RBC casts in the Bongers EM, Gubler MC, Knoers NV: Nail-patella
athy) the hematuria may be intermittent. Renal failure urine sediment essentially clinch the diagnosis of glo- syndrome: overview on clinical and molecular
may include the presence of edema and chronic ne- merulonephritis. If hereditary disorder is suspected findings. Pediatr Nephrol 2002;17:703712.
phritic syndrome may coexist with NS. (positive family history, hearing impairment, skeletal Kashtan CE: Familial hematurias: what we know and
pathology, etc.) and/or other etiologies are not appar- what we dont. Pediatr Nephrol 2005;20:10271035.
2 All entities other than MCD and FSGS listed ent, urines on all immediate family members should
in the algorithm for NS and those listed in the algo- be tested and hearing test, ophthalmologic examina-
rithm for RPGN can produce chronic nephritic syn- tion and bone film should be performed.
drome. Other conditions to be considered in the differ-
ential diagnosis of chronic GN include: Alport syn-
drome, thin basement membrane disease, nail-patella 4 For details on therapy, see Nephrotic syn-
syndrome, subacute bacterial endocarditis, hemolytic drome, Rapidly progressive glomerulonephritis, and
uremic syndrome, chronic renal transplant rejection, Acute nephritic syndrome.
other collagen vascular diseases besides SLE, and oth-
er infections such as filaria, leprosy and schistosomia-
sis. Symptoms and signs associated with the above
conditions and those mentioned in the NS algorithm
should be elicited during history and physical exami-
nation and would be helpful in guiding towards the
etiology. Painless gross hematuria (brown, tea color) is
common in chronic nephritic syndrome and is fre-
quently precipitated by upper respiratory infections
including a sore throat with group A streptococci.
A helpful feature differentiating chronic nephritic syn-
drome 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 12 weeks.

17

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Univ. of California San Diego
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Glomerular and vascular disease S.P. Makker F. Santos Chronic nephritic syndrome
Glomerular and vascular disease W. Proesmans U.S. Alon Vasculitis

/
Vasculitis
Exclude systemic lupus erythematosus 0

18 Modified Chapel Hill Classification 1

Large vessel vasculitis Medium vessel vasculitis Small vessel vasculitis Other vasculitides ;

Angiography Cardiac US, angiography, skin biopsy Complement, ANCA, renal biopsy incl. IF

Stenoses of aorta Coronary artery Hepatic, renal Skin nodules Granulomatous Nongranulomatous
and branches aneurysm artery aneurysms

cANCA (+) asthma ANCA () pANCA (+) ANCA ()


Pauci-immune ANCA (+) IgA (+) Compl low
deposits Eosinophilia Compl nl

Takayasu arteritis 2 Kawasaki syndrome 3 PAN 4 CPA 5 Wegeners Churg-Strauss HSP 8 MPA 9 HUV :
granulomatosis 6 syndrome 7

Steroids Aspirin Steroids Steroids Steroids Steroids Steroids? Steroids Steroids


Methotrexate IVIG CYP NSAID CYP CYP CYP? CYP CYP
Stenting iloprost AZA AZA IVIG
TAP methotrexate MMF
Surgery

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Univ. of California San Diego
Downloaded by:
1 Systemic vasculitides are a heterogeneous group of disor- 6 PAN (also known as macroscopic polyangiitis) is a form of 11 Microscopic polyangiitis is another systemic disease with
ders that are relatively rare in childhood. They are characterized by systemic, necrotizing vasculitis involving the medium-sized arteries many similarities to Wegeners granulomatosis and polyarteritis
inflammation, necrosis and thrombosis of blood vessel walls with with signs and symptoms resulting from infarction and scarring of nodosa. It differs from Wegeners granulomatosis by the presence of
deposition of fibrin and platelets. Microvasculitis is often the domi- the affected organ(s). The following findings are hallmarks of the dis- P-ANCA, mainly anti-MPO and the absence of granuloma formation
nant feature which affects the skin, the articulations, the kidneys, the ease: skin rash, purpura and nodules (which correspond to affected of the respiratory tract despite pulmonary hemorrhage. It differs
lungs and the gut. peripheral arteries), myalgia, systemic hypertension, neuropathy from PAN by the presence of extensive glomerular involvement.
and arthralgia. The vasculitis leads to arterial aneurysms or occlu- MPA invariably affects the kidneys. Renal abnormalities vary but
2 SLE is not a vasculitis strictly speaking but an autoimmune sion. Angiography of the abdominal great vessels shows character- rapidly progressive glomerulonephritis is the most serious complica-
systemic disorder that mimics any rheumatic disease and has simi- istic aneurysms located at the bifurcation points of the hepatic and tion.
larities with many forms of vasculitis. SLE is a chronic, remitting and renal arteries. Patchy renal lesions can sometimes be documented
relapsing inflammatory, febrile, multisystem disorder. It involves by DMSA scanning. Laboratory investigation shows anemia, signs of 12 HUV vasculitis is a rare form of vasculitis that is often mis-
skin, joints, kidneys and serosal membranes. Characteristic hemato- inflammation and circulating immune complexes. The etiology is diagnosed as HSP; the more so since skin biopsy shows leukoclastic
logical anomalies are leukopenia, thrombocytopenia, hemolytic ane- unknown; the association with hepatitis B is common mainly in adult vasculitis. The main characteristics are skin manifestations urti-
mia and increased ESR. Except for a few patients with drug-induced patients. caria, angioedema associated with arthritis and arthralgia. Serum
SLE, the etiology is unknown. The pathophysiology is thought to total complement as well as C1q, C3 and C4 levels are low due to
be a failure of the regulatory mechanisms of the autoimmune sys- 7 CPA is a more benign form of polyarteritis with limited complement activation via the classical pathway. In 50% of the
tem that sustain self-tolerance. There are a series of autoantibodies involvement of the skin, the joints and the muscles. It is a chronic, patients there is glomerulonephritis membranoproliferative or
present especially antibodies against double-stranded DNA which relapsing disorder and there is frequently an association with crescentic and obstructive lung disease is equally frequent.
are pathognomonic. Furthermore, serum total complement and C3 streptococcal infections. The skin has red, painful, edematous
levels are decreased and gammaglobulins increased. nodules at the extremities and the trunk and fever is frequent. 13 In a number of patients, vasculitis cannot be ascribed to
Fingers and toes can display ischemia, the Raynaud phenomenon any of the above-mentioned categories. It is the case for, among
3 Classification of the vasculitides is difficult, arbitrary and and, exceptionally, gangrene. Biopsies show small and medium- others, malignancy-associated vasculitis and drug-related hyper-
not completely satisfactory. The Chapel Hill nomenclature is based sized vessels with fibrinoid necrosis. sensitivity as well as isolated vasculitis of the central nervous sys-
on the size of the vessels involved. From a pediatric perspective, it tem. Finally, there is Behet disease, a special form of vasculitis. It is
has proved unsatisfactory. Therefore, an attempt was recently made 8 Wegeners granulomatosis is a multisystem disease a chronic inflammatory disorder involving the small blood vessels
to develop a general classification for vasculitis as seen in children. characterized by necrotizing granulomatous vasculitis involving and is of unknown origin. It is characterized by recurrent aphthous
A consensus was reached at an international conference held in the upper and lower respiratory tract, the lungs and the kidneys. ulceration of the oral and pharyngeal mucous membranes and the
Vienna in June 2005. It was decided to modify the Chapel Hill classifi- The diagnosis requires three of the following six manifestations: genitalia, skin lesions, uveitis and retinal vasculitis and sometimes
cation and this document is based on this modified classification. (1) granulomas on biopsy material, (2) naso-sinus inflammation, optic atrophy. It frequently also involves the joints, gut and central
(3) subglottis or tracheal stenosis, (4) abnormal chest X-ray, (5) renal nervous system.
4 Takayasu arteritis is characterized by inflammation fol- manifestations such as hematuria, proteinuria and decreased GFR,
lowed by progressive obliteration and stenosis of the aorta and its and (6) presence of c-ANCA, mainly anti-PR3. Renal biopsy typically
branches. Clinical findings depend on the artery involved: lesions of shows crescentic glomerulonephritis with pauci-immune deposits. Selected reading
the carotid arteries leads to ischemia of the brain (syncope, transient
hemiplegia, retinal atrophy), of the subclavian arteries to loss of puls- Bakkakoglu M: Takayasu arteritis in children: preliminary
9 Churg-Strauss syndrome is a rare form of systemic necro-
es in the arm(s), of the renal arteries to macroscopic hematuria and experience with cyclophosphamide induction and corticosteroids
tizing vasculitis characterized by asthma, hypereosinophilia and
flank pain and renal infarction with arterial hypertension and eventu- followed by methotrexate. J Pediatr 2007;150:7276.
extravascular granulomas. It affects lungs, skin, peripheral nerves,
ally renal failure, and of the distal aorta to claudication. Angiography Copo R, Andrulli S, Amore A, Gianoglio B, Conti G, Peruzzi L,
gut, heart and kidneys. Laboratory findings consist of leukocytosis
conventional, CT or MRI shows irregular vessel walls and/or nar- Licatelli F, Cagnoli L: Predictors of outcome in Henoch-Schnlein
with eosinophilia, elevated ESR and in the majority of patients ANCA
rowing of the aorta and its branches. The etiology is unknown but in nephritis in children and adults. Am J Kidney Dis 2006;47:
are positive mostly of the anti-MPO type. Renal involvement is not
some parts of the world, tuberculosis is believed to play a role. 9931003.
the rule but not exceptional either and consists of glomerulonephri-
Dillon MJ, Ozen S: A new international classification of childhood
tis with hypertension and renal insufficiency.
vasculitis. Pediatr Nephrol 2006;21:12191222.
5 Kawasaki syndrome (mucocutaneous lymph node disease):
Hattori M, Kurayama H, Koitabashi Y, Japanese Society for
this possibly (post)infectious disease is seen mainly in children 10 HSP is the most common vasculitis in childhood. It is a form Pediatric Nephrology: Antineutrophil cytoplasmatic autoantibody-
below the age of 5 years and is characterized by high fever for at of nonthrombocytopenic purpura due to leukoclastic vasculitis of
19 associated glomerulonephritis in children. J Am Soc Nephrol
least 5 days, bilateral conjunctival injection, changes of the lips, the unknown origin. The hallmarks are diffuse abdominal pain, arthral- 2001;12:14931500.
oral or pharyngeal mucosa, cervical adenopathies and a polymor- gia and arthritis, palpable purpura concentrated mainly on the Savage COS, Harper L, Adu D: Primary systemic vasculitis.
phous exanthema followed by desquamation of the fingers and the buttocks and the ankles and renal manifestations (hematuria, pro- Lancet 1997;349:553558.
toes. The main complication is aneurysms of the coronary arteries. teinuria, hypertension, renal failure). Skin and renal biopsies show

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IgA deposits. The disease is self-limiting and only a small percent-

Univ. of California San Diego


age of HSP patients develop serious renal complications.

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Glomerular and vascular disease W. Proesmans U.S. Alon Vasculitis
Glomerular and vascular disease W. Proesmans U.S. Alon Hemolytic uremic syndrome

/
Hemolytic uremic syndrome
20
Diarrhea 0 No diarrhea 3

Stx (+) 1 Stx () 2 Stx () 4

S. dysenteriae Yersinia
EHEC Campylobacter
Pneumococci 5 HIV/AIDS 6 Cancer 7 Glomerulonephritis 8 Inf. ()
C. Freundii Salmonella
Cancer ()
GN ()

Classical HUS ? Pneumonia HIVN Drugs Acute


Typical Meningitis TBI Chronic
HUS BMT

Supportive Supportive Antibiotics Specific drugs Supportive Supportive


Exchange transfusion

Complement vWF protease S-homocysteineM Familial Pregnancy Quinine None


dysregulation deficiency U-methylmalonic acidM HUS / TTP Puerperium OKT3
Calcineurin inhibitor

FH/FI/MCP deficient TTP : Genetic cobalamin C Autosomal-recessive, PP-associated Drug-associated Unclassified


HUS 9 defect ; autosomal-dominant HUS = HUS > HUS ?
HUS <

Plasma Plasma Vitamin B12 PE Supportive Stop drug

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PE PE

Univ. of California San Diego


Downloaded by:
1 The diagnostic term HUS represents a heterogeneous resulting in features common to all forms of HUS. Early recognition newborns and young infants with systemic manifestations including
group of disorders with variable etiology, clinical expression and is crucial for prognosis. Antibiotics and exchange transfusion are central nervous system, cardiac and respiratory signs and symp-
severity. Common features are acute, acquired hemolytic anemia, indicated but the administration of fresh plasma containing anti-TFA toms. It is characterized biochemically by increased plasma levels of
thrombocytopenia and renal dysfunction. Renal manifestations antibodies is contraindicated. The outcome is worse than in homocysteine and urinary methylmalonic aciduria. Early recognition
can range from a mild disease consisting of only minimal urinary classical D(+)HUS both in terms of acute mortality and long-term and treatment with vitamin B12 can be life-saving.
findings (hematuria and proteinuria) to acute renal failure with oligo- renal function.
anuria and arterial hypertension necessitating dialysis. The histo- 14 In some families, no defects in the above-mentioned
logical substrate is referred to as thrombotic microangiopathy. HUS 8 HIV positivity and AIDS are risk factors for renal complica- genetic defects can be found. In their absence, the diagnosis of either
is among the most frequent causes of acute renal failure in child- tions, referred to as HIVN. HUS is part of the spectrum of HIVN. It is dominant or recessive forms of HUS can be made. New underlying
hood. The outcome depends on the severity and the causative agent. assumed that the virus directly affects the endothelium. In the genetic defects are likely to be detected in the years to come.
largest study published so far, it occurred in one third of HIV-infected
2 Diarrhea-associated HUS (D(+)HUS). In the great majority of adult patients and was the most frequent cause of rapidly progres- 15 Pregnancy and/or puerperium-associated HUS is a quite
children with HUS, there is prodromal diarrhea with the characteris- sive renal failure. common disorder in the literature. It has been speculated that
tics of colitis, i.e. mucous diarrhea often with blood in the stool. This hormonal disturbances are at its origin. The precise mechanism,
postcolitis HUS is called classical or typical or D(+)HUS. 9 Cancer-associated HUS is rare especially in children. There however, needs to be elicited.
are several ways in which cancer can lead to HUS: besides some
3 Classical HUS is caused by Shigella dysenteriae in develop- drugs (such as mitomycin), total body irradiation and bone marrow 16 Several drugs are suspected to be implicated in the devel-
ing countries and by members of the enterohemorrhagic Escherichia transplantation have been implicated. There is no accepted therapy opment of HUS/TTP. Besides the already mentioned mitomycin and
coli family and Citrobacter freundii in industrialized parts of the world. and the outcome is poor. the platelet inhibitors ticlopedine and clopidrogel, there is evidence
The most frequent Stx-producing serotype is E. coli O157H7; other for a role for some immunosuppressive drugs of the calcineurin
strains are O26, O111 and O103. Two shigatoxins have been well 10 Children as well as adults with acute or chronic forms of inhibitors family used after solid organ transplantation such as ciclo-
defined in terms of structure and biological activity: Stx1 and Stx2. GN more specifically acute poststreptococcal GN and membrano- sporin A and tacrolimus but OKT3 has also been implicated. Quinine
HUS is mostly caused by Stx2-producing strains. There are several proliferative GN have been described with hemolysis, thrombo- is another suspected culprit as are several contraceptive hormonal
techniques to diagnose Stx-associated HUS (but none are 100% cytopenia and accelerated hypertension. This exceptional condition preparations.
percent sensitive and specific): (1) bacterial culture of S. dysenteriae, is known as HUS superimposed on GN.
Stx-producing E. coli and Citrobacter, (2) isolation of Stx from the 17 In large series of D()HUS patients, no etiology can be
stools, and (3) serum antibodies to specific species known to pro- 11 Abnormalities of the complement system have been found found at present. Therefore, there is a need for a temporary category
duce Stx. It is noteworthy that diarrhea can be absent in patients in a relatively large number of patients with D(), familial or recurrent of unclassified HUS patients.
with proven Stx-associated HUS. Therapy in all types of D(+)HUS is HUS. Complement dysfunction is mainly genetic in origin. Mutations
supportive. 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 Selected reading
4 Several case reports mention D(+)HUS with Yersinia entero- complement activation and FI is its co-factor. MCP, a membrane-
colitica, Campylobacter jejuni or Salmonella and without isolation of bound regulator is a co-factor for FI and is expressed in glomerular Besbas N, Karpman D, Landau D, et al: A classification of hemo-
Stx. There is, however, no proof of a causal relationship. endothelium. The diagnosis of complement dysregulation requires lytic uremic syndrome and thrombotic thrombocytopenic purpura
special expertise. Low plasma levels of C3, FH and FI are diagnostic and related disorders. Kidney Int 2006;70:423431.
5 HUS not associated with diarrhea (D()HUS). In a minority but are present only in a minority of patients. In exceptional patients, Dragon-Durey MA, Frmaux-Bacchi V, Loirat C, et al: Heterozygous
of children and a majority of adults with HUS, there is no prodromal complement dysregulation is acquired due to autoantibodies to FH. and homozygous factor H deficiencies associated with hemolytic
diarrhea. To distinguish it from classical HUS, the term D()HUS has uremic syndrome or membranoproliferative glomerulonephritis:
been introduced. The term comprises an extremely heterogeneous 12 TTP which is mainly seen in adults has many similarities report and genetic analysis of 16 cases. J Am Soc Nephrol
group of rare disorders for many of which specific causes have with HUS. Hemolysis and thrombocytopenia are accompanied by 2004;15:787795.
recently been established. fever and varying neurological manifestations whereas renal Furlan M, Robles R, Galbusera M, et al: von Willebrand factor
involvement is rather limited. Diffuse platelet-rich microthrombi elic- cleaving protease in thrombotic thrombocytopenic purpura
6 The association of D() and Stx()HUS necessitates ited by large multimeric forms of vWF in the circulation, are present and the hemolytic uremic syndrome. N Engl J Med 1998;339:
thorough investigation for specific causes of HUS such as pneumo- in small blood vessels of several organs. TTP is a relapsing disorder 15781584.
cocci-associated, HIV-associated, cancer-associated HUS and caused by a deficiency of vWF-cleaving protease, ADAMTS13. The George JN: Thrombotic thrombocytopenic purpura. N Engl J Med
HUS superimposed on several forms of glomerulonephritis. inherited forms of TTP are caused by mutations in the ADAMTS13 2006;354:19271935.
21 gene, the acquired nonfamilial TTP is due to autoantibodies inhibit- Moake JL: Thrombotic microangiopathies. N Engl J Med
7 Streptococcus pneumoniae-associated HUS can be ob- ing the protease. In some patients this acquired TTP is associated 2002;347:589600.
served in patients with pneumonia or meningitis. Typical features with the platelet inhibitors ticlopedine or clopidogrel. Zimmerhackl LB, Besbas N, Jungraithmayer T, et al: Epidemiology,
are febrile illness, respiratory or neurological signs and symptoms clinical presentation and pathophysiology of atypical and

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and a positive Coombs test. The traditional pathophysiological 13 A very rare autosomal-recessive and life-threatening recurrent hemolytic uremic syndrome. Semin Thromb Hemost
hypothesis is that neuraminidase secreted by pneumococci exposes condition with elements of HUS is caused by defects in the intra- 2006;32:113120.

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the TFA on erythrocytes, platelets and glomerular structures, cellular cobalamine metabolism. It has been observed mainly in

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Glomerular and vascular disease W. Proesmans U.S. Alon Hemolytic uremic syndrome
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

Treatment Evaluation 6

Nonspecific pyuria
False negative
Trauma
Tuberculosis

Asymptomatic Uncomplicated UTI 3 Complicated UTI 4 Adjunctive U/S 7 VCUG 8 Radionuclide IVP :

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bacteriuria 3 therapy 5 scan 9

Univ. of California San Diego


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1 The clinical manifestations of UTI vary 5 An uncomplicated UTI is acute cystitis or 11 Radionuclide scan is the most reliable meth-
according to the age of the child. In infants under 2 asymptomatic bacteriuria. Acute cystitis may be treat- od for detecting acute pyelonephritis and renal scars.
years of age, UTI may present with failure to thrive, ed with amoxicillin and clavulanate, cefixime, sulfon- The detection of renal scars is important because of
feeding problems, screaming, irritability, diarrhea, amide, TMP/SMX, usually for a duration of 57 days. the association between unilateral and bilateral renal
vomiting, and fever. In children older than 2 years, UTI Asymptomatic bacteriuria is not treated in the older scars and the development of hypertension; vesico-
may present with fever, frequency, dysuria, enuresis, child unless the patient has usually developed symp- ureteral reflux alone without scars is associated with a
acute urinary retention, and abdominal or flank pain. tomatic infections in such settings. low incidence of hypertension. Studies using DMSA
Similarly, the physical findings might be none, tender- scanning show little or no risk of renal scars develop-
ness in the flank, suprapubic or abdominal area, fever, 6 Complicated infections include neonatal UTI, ing in children age 4 years or older.
pallor, enlargement of the bladder or kidneys, a meatal pyelonephritis, and urinary tract obstruction. These
abnormality, abnormal stream, and hypertension. patients are usually treated with intravenous antibiot- 12 Intravenous pyelogram is rarely indicated in
Often unrecognized is the association of palpable fecal ics and, when afebrile and stable, changed to a narrow the evaluation of UTI unless one is looking for a duplex
masses reflecting constipation, especially in children spectrum oral antibiotic to which the organism is sen- kidney or a small ureteral calculus.
with recurrent UTI. Except in the first 6 months of life, sitive. The duration of therapy is usually 10 days. In
UTIs are much more common in females. stable children acute pyelonephritis may also be treat-
ed successfully with oral antibiotics. Selected reading
2 A urinalysis that demonstrates pyuria or is
positive for leukocyte esterase or nitrite probably indi- 7 Nonpharmacologic therapy may be helpful in Bachur R, Harper MB: Reliability of the urinalysis for
cates a UTI. However, a positive dipstick with or with- the patient with UTI, including encouragement to take predicting urinary tract infections in young febrile
out microscopic pyuria has a sensitivity of only 80%; fluids to assist in bladder emptying. Acidifying agents, children. Arch Pediatr Adolesc Med 2001;155:6065.
in 20% of UTI, these tests are negative. The presence such as cranberry juice, may be helpful. A patient Chang SL, Shortliffe LD: Pediatric urinary tract
of bacteriuria in an unspun urine specimen is associ- should be encouraged to empty his bladder complete- infections. Pediatr Clin North Am 2006;53:379400.
ated with a high likelihood of greater than 105 colony ly, often using double voiding techniques. Constipa- Hansson S, Jodal U: Urinary tract infection; in
counts in urine culture. tion, if present, should be vigorously treated. Both Avner ED, Harmon WE, Niaudet P (eds): Pediatric
mechanical and chemical urethral trauma should be Nephrology, ed 5. Philadelphia, Lippincott Williams
3 The diagnosis of UTI depends upon docu- avoided. Children should avoid bubble bath and chem- & Wilkins, 2004, pp 10071026.
mentation of significant bacteriuria, i.e. greater than ical irritants and should be counseled on avoiding self- Mahant S, Friedman J, MacArthur C: Renal
105/ml, usually of a single organism in a midstream injury. Therapeutic delay increases the incidence of ultrasound findings and vesicoureteral reflux in
specimen, >103/ml, usually of a single organism in a renal scaring significantly; patients with UTI should be children hospitalised with urinary tract infection.
catheterized specimen, and any growth in a suprapu- treated promptly. Arch Dis Child 2002;86:419420.
bic specimen. Escherichia coli is the most common Smellie JM, Barratt TM, Chantler C, Gordon I,
organism. Urine cultures from urinary bags are fre- 8 The evaluation of UTI would include a renal Prescod NP, Ransley PG, Woolf AS: Medical versus
quently contaminated. A negative culture from a bag and bladder ultrasound, cystorethrogram, a radio- surgical treatment in children with severe bilateral
sample is reliable as a screening test but false-positive nuclide scan (DMSA), or intravenous pyelogram. The vesicoureteric reflux and bilateral nephropathy:
results have been recorded in up to about 40% of sam- indications for such studies include pyelonephritis, a a randomized trial. Lancet 2001;357:13291333.
ples taken from infants. Remember, one may have py- first UTI in a boy, a first UTI in a girl <5 years of age, or Verrier Jones K: Time to review the value of imaging
uria without a UTI and UTI without pyuria. Adoles- a first UTI in a child with an abnormal voiding pattern, after urinary tract infection in infants. Arch Dis Child
cents with the triad of dysuria, frequency and pyuria hypertension, poor growth or a family history of UTI or 2005;90:663664.
may have colony counts <105. structural abnormality of the urinary tract. Walsh TJ, Hsieh S, Grady R, Mueller BA: Antenatal
hydronephrosis and the risk of pyelonephritis
4 When a urine culture is negative in a patient 9 Renal ultrasound is easy to perform and is hospitalization during the first year of life. Urology
with UTI symptoms, it is important to rule out false- used in detecting obstructions, masses, calculi, and 2007;69:970974.
negatives due to dilute urine specimens, prior use renal swelling, but has a low sensitivity for scars.
of antibiotic therapy, tuberculosis, or, rarely, acute Renal ultrasound is not an adequate method for the
obstruction. With dysuria and frequency in the pres- detection of vesicoureteral reflux, even severe reflux.
ence of a negative culture, one must consider chemi-
23 cal or mechanical trauma to the urethra which may 10 Voiding cystorethrogram is used to evaluate
include child abuse. for vesicoureteral reflux, which, when severe, tends to
be associated with secondary complications such as
scarring and hypertension. Mild-to-moderate vesico-

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ureteral reflux tends to resolve over time. Severe reflux
has about a 50% chance of resolving over 510 years.

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Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton Urinary tract infection
Urinary tract disease/tubulointerstitial nephropathy S. Hulton R. Adelman Dilated/obstructed urinary tract

/
Dilated/obstructed urinary tract
24 Abnormal US

Infants 0 Older children 0

VCUG If thick-walled UTI/female


bladder consider
PUV 6

VCUG

VUR VUR Mild dilatation Moderate/severe dilatation


No UTI

Yes No Yes No MAG3/ DTPA renal scan 2

MAG3/DTPA renal scan 2


Obstructed 3
Obstructed 3

No Yes
No Yes

If severe, drainage

Prophylactic Repeat US Consider surgical relief 5 Suprapubic/urethral Prophylactic antibiotics Repeat US If severe, drainage
antibiotics 36 months 4 catheter drainage 36 months 4

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DMSA renal scan 1 Cystourethroscopy and valve DMSA renal scan 1 Consider surgical

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fulguration/ablation relief 5

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1 Dilatation of the urinary tract is considered 4 A dynamic renal scan using radiotracers such
Selected reading
when there is dilatation of the renal pelvis (hydrone- as MAG3 or DTPA in conjunction with a diuretic agent,
phrosis) with or without a dilated ureter. The clinical e.g. intravenous furosemide, is the preferred test to Belarmino JM, Kogan BA: Management of neonatal
features of a dilated/obstructed urinary tract depend investigate the dilated urinary tract. Estimation of hydronephrosis. Early Hum Dev 2006;82:914.
upon whether the obstruction is acute or chronic, drainage of the urinary tract and differential renal Fefer S, Ellsworth P: Prenatal hydronephrosis.
partial or complete, and on whether complications function will indicate the severity of the obstruction. Pediatr Clin North Am 2006;53:429447.
such as infection are present. The two commonest This scan, however, is best performed after the first Greenbaum LA, Mesrobian HG: Vesicoureteral
causes of dilatation of the urinary tract are VUR and month of life, when renal function is more mature. reflux. Pediatr Clin North Am 2006;53:413427.
obstruction. VUR presents usually with UTI or it can be Hubert KC, Palmer JS: Current diagnosis and
asymptomatic. A history of oligohydramnios (occa- 5 Causes of obstruction: management of fetal genitourinary abnormalities.
sionally polyhydramnios) during pregnancy may be Urol Clin North Am 2007;34:89101.
UPJ/UVJ obstruction Onen A, Jayanthi VR, Koff SA: Long-term follow up
noted. Acute obstruction usually presents with pain,
Intrinsic of prenatally detected severe bilateral newborn
depending on the site of the obstruction. Hematuria is
External compression hydronephrosis initially managed nonoperatively.
present when calculi are found. Hypertension can
Prolapsing ureterocoele (female) J Urol 2002;168:11181120.
occur in patients with acute obstruction. Polyuria due
Hydrocolpos (female) Piepsz A, Ham HR: Pediatric applications of renal
to the inability to concentrate the urine may result
Pelvic mass (e.g. Wilms tumor, abscess, nuclear medicine. Semin Nucl Med 2006;36:1635.
from acute bilateral partial obstruction.
ectopic kidney)
In chronic obstruction, a full bladder or enlarged kid-
UPJ obstruction is seen more commonly than UVJ
ney may be palpable. The inability to conserve sodium
obstruction.
is a common feature and may lead to salt wasting
and hyponatremia. In the case of severe obstruction, Bladder outlet obstruction
once satisfactory drainage has been established, it is Posterior urethral valves (male)
imperative to send the urine for culture and to treat Stone
infection aggressively. Monitoring of body weight, se- Rhabdomyosarcoma
rum electrolytes levels, acid base and fluid balance is Meatal polyp/stenosis
required. Hyperkalemic acidosis is commonly noted Prolapsed ureterocele
and close attention must be paid to postobstructive External compression
diuresis. Pelvic tumor
Spinal tumor
2 The management of a child with a dilated uri-
nary tract depends on the age of the child, the degree 6 If renal function is stable and the child is
of dilatation, the presence or absence of a dilated asymptomatic, observation of the child is appropriate.
ureter and whether there is a history of UTI. Age is an Progression of the hydronephrosis on ultrasound may
additional important factor in determining how to indicate a repeat diuretic renogram to demonstrate
proceed with the evaluation. In infants, females and, increasing obstruction.
in the case of UTI, a VCUG is usually the first test. In
older children, the degree of hydronephrosis and the 7 There is considerable debate about the indi-
parenchymal appearance dictates if a renal scan is cations for and timing of surgery for UPJ obstruction.
needed. Proponents of early surgery claim that pyeloplasty
should be performed before function is allowed to
3 DMSA radionuclide scan is the most reliable deteriorate. There is evidence, however, that many
test for detecting renal scars. The detection of renal neonates managed conservatively will demonstrate
scars is important because of the association between improvement in function without intervention.
unilateral and bilateral renal scars and the develop-
ment of hypertension and renal failure later in life. It is 8 Posterior urethral valves are the commonest
indicated in children with UTI and high-grade VUR and cause of lower urinary tract obstruction in male in-
25
if the renal US shows signs of renal injury (small or fants. 3040% of children presenting with posterior
hyperechogenic kidneys). urethral valves will also have renal dysplasia. Cystic
dysplastic changes in an individual kidney may be
associated with ipsilateral VUR.

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Univ. of California San Diego
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Urinary tract disease/tubulointerstitial nephropathy S. Hulton R. Adelman Dilated/obstructed urinary tract
Urinary tract disease/tubulointerstitial nephropathy J.-P. Guignard R.N. Fine Fetal hydronephrosis

Fetal hydronephrosis
26 Antenatal US /

US at 37 days

Urinary tract dilatation 0

RPD <10 mm RPD 10 mm

US at 1 month Antibiotic prophylaxis 1

RPD <5 mm RPD 5 mm VCUG at 1 month 2

No reflux

Dynamic renal scan at 6 weeks 4

VUR 3 Obstructive uropathy 5

Notify pediatric urologist and nephrologist

US at 1 year Antibiotic prophylaxis, serial US

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Univ. of California San Diego
Conservative treatment 5 Surgery

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1 Most renal abnormalities are detected at 6 After ruling out VUR, radiotracers such as
Selected reading
1820 weeks. Persistent postnatal abnormalities are MAG3, DTPA or hippuran can be used to investigate
usually seen when the RPD is >6 mm at 20 weeks; the dilated urinary tract. Estimation of drainage of the Asku N, Yavascan O, Kangin M, Kara OD, Avdin Y,
>8 mm at 2030 weeks and >10 mm at >30 weeks of urinary tract and differential renal function will indi- Erdogan H,Tuncel TC, Cetinkaya E,Ozbay E,
gestation. While antenatal resolution of hydronephro- cate the severity of the obstruction. Re-ascent of the Sandikcioglu TG: Postnatal management of infants
sis may occur, the patient must still undergo postnatal radioactive agent from bladder to kidney may indirect- with antenatally detected hydronephrosis.
investigation as the hydronephrosis can recur. The ly suggest the presence of VUR. Unilateral renal func- Pediatr Nephrol 2005;20:12531259.
overall incidence of prenatal hydronephrosis is 1:100 tion <35% of total bilateral function suggests that the De Bruyn R, Gordon I: Postnatal investigation of fetal
to 1:500 of maternal-fetal US studies. kidney may be at risk of obstructive damage. Whether renal disease. Prenat Diagn 2001;21:984991.
such a kidney will benefit from early relief of obstruc- Ismaili K, Avni FE, Wissing KM, Hall M; Brussels
2 At birth, hydronephrosis is defined by a tion is still debated. Dynamic renal scan is best per- Free University Perinatal Nephrology Study Group:
RPD >5 mm. RPD 510 mm: mild hydronephrosis; RPD formed after the first month of life, when renal func- Long-term clinical outcome of infants with mild and
1020 mm: moderate hydronephrosis; RPD >20 mm: tion is more mature. moderate fetal pyelectasis: validation of neonatal
severe hydronephrosis. As much as 50% of renal ultrasound as a screening tool to detect significant
abnormalities detected in utero disappear after birth. 7 The obstruction of the urinary tract can be nephrouropathies. J Pediatr 2004;144:759765.
Obstructive and nonobstructive conditions can dilate located at the UPJ junction, the UVJ or in the urethra Lee RS, Cendron M, Kinnamon DD, Nguyen HT:
the urinary tract. Obstructive causes include: obstruc- (posterior urethral valves). Antenatal hydronephrosis as a predictor of
tion of the UPJ (45%) and of the UVJ (20%), posterior UPJ obstruction: Conservative management of UPJ postnatal outcome: a meta-analysis. Pediatrics
urethral valves (10%) or ureterocele/ureteral ectopia. anomalies is justified in most infants, provided that 2006;118:586593.
Nonobstructive causes include VUR (15%), transient the pelvic dilatation does not increase on repeated US, Martini S, Guignard JP: Diagnostic et prise en
hydronephrosis and physiological hydronephrosis. and that on isotopic studies the relative function of the charge des dilatations des voies urinaires dpistes
affected kidney does not deteriorate. The indication in intero. Rev Med Suisse Rom 2002;122:619624.
3 Prophylaxis should be started if significant and the best time for pyeloplasty remains ill-defined. Woodward M, Frank D: Postnatal management of
hydronephrosis (RPD >10 mm) is seen on renal US. UVJ obstruction: Megaureters are the results of abnor- antenatal hydronephrosis. BJU Int 2002;89:149156.
Drugs commonly used include: mal or dysfunctional UVJ. Spontaneous improvement
First month of life: of megaureters is common, so that conservative
amoxycillin 1030 mg/kg/day (in 2 doses) management is recommended when renal function
16 months: and dilatation remains stable. Ureteric reimplantation
cotrimoxazole 34 mg/kg/day (in 2 doses) may be performed when dilatation increases and
>6 months: renal function deteriorates.
nitrofurantoin 2 mg/kg/day (in 2 doses) or Posterior urethral valves: The most common cause of
cotrimoxazole as above congenital bladder outlet obstruction, occurring only
in males; its incidence is approximately 1:8,000. The
4 Whether to recommend VCUG in all infants bladder outlet obstruction leads to a trabeculated,
with persistent postnatal hydronephrosis remains thick-walled bladder, and to damage to the renal
controversial. We recommend performing a VCUG in parenchyma. Clinical presentation can range from
these conditions: RPD above 10 mm, significant ante- severe obstruction in utero leading to fetal demise, to
natal hydronephrosis, a thick-walled bladder or ure- hydronephrosis with normal kidney function diag-
teric dilatation, and in cases of bilateral hydronephro- nosed in late childhood. Transurethral incision of the
sis. valves is the treatment of choice.
Ureterocele: Occurs in 1:5,000 neonates with M:F ratio
5 VUR is detected postnatally in ~10% of neo- of 1:35. Ureteroceles are frequently associated with
nates with antenatal hydronephrosis. VUR is most duplicated collecting system (8090%), are bilateral in
severe and most frequent in males (34 M:1 F). In 1020% of patients, and associated with ectopic inser-
males, renal scarring (dysgenesis) is often present at tion of the ureter into bladder in up to 75% of cases.
birth. In patients with VUR, antibiotic prophylaxis A large ureterocele may result in bilateral ureteral
27 should be continued as well as serial renal sonogram obstruction. Transurethral endoscopic punction of the
follow-up. For further details, see appropriate algo- ureterocele is often used as an initial intervention.
rithm.

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Urinary tract disease/tubulointerstitial nephropathy J.-P. Guignard R.N. Fine Fetal hydronephrosis
Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton VUR

/
Vesicourethral reflux
28

Evaluation 0 Treatment 2

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

Negative Positive

Age <5 Age >5

Continue prophylaxis Antibiotic prophylaxis 1

Review 0 Consider surgery 3


(reimplantation of ureters or deflux injection) for
Bilateral grade IVV
plus

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Severe, recurrent pyelonephritis or
Severe loin pain

Univ. of California San Diego


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1 Approximately 35% of patients with UTI have
Selected reading
VUR. The incidence is lower, however, amongst Afri-
can-Americans. Approximately 30% of patients with Canning DA: Deflux for vesicoureteral reflux:
VUR develop renal scars, placing them at greater risk pro the case for endoscopic correction. Urology
for developing hypertension and, less commonly, 2006;68:239241.
ESRD. These complications are greater with severe Gil Rushton H Jr: Urinary tract infection; in Avner ED,
VUR. Harmon WE, Niaudet P (eds): Pediatric Nephrology,
ed 5. Philadelphia, Lippincott Williams & Wilkins,
2 VUR tends to clear with time. Most mild VUR 2004, pp 10271048.
(grades 12) will cease within 5 years of diagnosis. Greenbaum LA, Mesrobian HG: Vesicoureteral
Even with severe VUR (grades 35), up to 50% will reflux. Pediatr Clin North Am 2006;53:413427.
have cleared completely upon 10 years of follow-up. Lorenzo AJ, Khoury AE: Endoscopic treatment of
reflux: management pros and cons. Curr Opin Urol
3 Repeated VCUG should be done in patients 2006;16:299304.
with VUR every 1824 months. When VUR has disap- Perez-Brayfield M, Kirsch AJ, Hensle TW, Koyle MA,
peared or the patient is 5 years or older, prophylaxis Furness P, Scherz HC: Endoscopic treatment with
can be stopped. VUR can be assessed by either con- dextranomer/hyaluronic acid for complex cases of
trast VCUG or a radionuclide VCUG (indirect CUG), vesicoureteral reflux. J Urol 2004;172:16141616.
which is less invasive and associated with lower radia- Smellie JM, Jodal U, Lax H, Mobius TT, Hirche H,
tion exposure. Olbing H; Writing Committee, International Reflux
Study in Children (European Branch): Outcome at
4 Children under the age of 5, especially under 10 years of severe vesicoureteric reflux managed
age 2, with VUR are at greatest risk for scarring associ- medically: Report of the International Reflux Study
ated with acute urinary infections. Infections should in Children. J Pediatr 2001;139:656663.
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 (12 mg/
kg at night) until reflux clears or the patient reaches 5
years of age when new scarring is uncommon.

5 Surgery of VUR, with ureteral reimplantation,


is rarely indicated with mild-to-moderate VUR. Sur-
gery for severe VUR, grade 35, 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, re-
nal 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.
29

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Univ. of California San Diego
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Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton VUR
Urinary tract disease/tubulointerstitial nephropathy S. Hulton R. Adelman Dysfunctional voiding

/
Dysfunctional voiding
30
Detailed voiding history and Physical examination 2 Urine dipstix
Clinical history 0
3-day-frequency voiding diary 1 Serum creatinine
Renal US

Problems in infancy UTI Growth


Age of toilet training Urinary incontinence Blood pressure
Family history Frequency, urgency Abdomen for loaded colon
Psychological stress Dysuria Lower back/spine hair tufts, dimple, lipoma, sinus
Exclude organic factors Infrequent voiding Neurology lower limb reflexes, anal reflex
(e.g. epilepsy, diabetes) Incomplete emptying Genitalia
Voiding maneuver (squat, crossed legs)
Constipation, soiling

Primary nocturnal enuresis*

UTI 3 Continuous Giggle/stress Urge/frequency/incomplete/ Constipation > Lazy bladder


incontinence/drip 4 incontinence 5 delayed bladder emptying

VCUG IVP Pelvic floor exercises U/S (renal/bladder) and Laxatives A -Blocker
urodynamic flow rates 6 No (Prazocin) <

Follow protocol Ectopic ureter


(30% have VUR) Anticholinergic drugs :
Incomplete bladder Overactive bladder 7 Lazy bladder 8 Oxybutynin 0.4 mg/kg/day, b.d. or t.d.s.
emptying

Ongoing biofeedback training ;


Double voiding Bladder training 9
Chemoprophylaxis
TMP or nitrofurantin 12mg/kg
nocte x 36 months Response No response
Review
Review at 8 weeks Video urodynamics

Response
Non-neuropathic Intermittent bladder
neuropathic bladder catheterization

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(Hinman) =

Univ. of California San Diego


Stop antibiotics Yes
Mitroffanoff last resort

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1 Enuresis is defined as normal voiding, occurring at an inap- or more than 10% of the normal bladder capacity for age. Noninva- 15 Non-neuropathic bladder (Hinman syndrome) represents
propriate time, or involuntarily in a socially unacceptable setting. sive urodynamics, using a graphic recording of urinary flow rate dur- the extreme of the spectrum and will only be diagnosed by exclusion
Enuresis is most commonly nocturnal, although it is not uncommon ing voiding, is becoming a more standard office procedure. Flow pat- of all other identifiable treatable conditions. MRI scanning of the lum-
for nocturnal enuretics to have episodes of diurnal enuresis. terns and rates need to be consistent to allow for appropriate evalua- bar spine is necessary to exclude an underlying undiagnosed neuro-
Diurnal enuresis is usually linked with the term dysfunctional voiding tion and sometimes several recordings are necessary. Invasive proce- logical disorder. In Hinman syndrome there is no physical neurologi-
which can be categorised into neuropathic and non-neuropathic dures should only be done following the results of the noninvasive cal deficit; however, the bladder behaves in a neuropathic fashion.
voiding disorders. Functional neuropathic voiding disorders include tests where there is a suspicion of a neuropathic bladder sphincter This occurs primarily in boys as an acquired voiding disorder charac-
spina bifida, transverse myelitis and spinal cord trauma. This review dysfunction and should only be performed in specialist centers. terised by inappropriate voluntary contraction of the striated urinary
focuses on the non-neuropathic voiding dysfunction. sphincter during the process of micturition. This results in functional
9 Common between 5 and 7 years of age, present with urinary obstruction that over time is associated with urinary tract
2 The majority of children have acquired an adult voiding pat- hyperactivity or instability of the bladder, with urgency and small infection, myogenic bladder failure, hydronephrosis and even renal
tern by 45 years of age and investigations for dysfunctional voiding frequent voids. This may follow an initial episode of painful voiding, insufficiency. Ochoa syndrome has the same clinical features at
should not be undertaken in children under 5 years. e.g. following UTI or urethritis. Hinman syndrome but is known as urofacial syndrome because of
facial grimace instead of smile and is inherited in an autosomal-dom-
3 The 3-day frequency voiding diary is particularly helpful to 10 Characterized by large capacity hypotonic bladder with inant pattern. If the patient is not found to have Hinman syndrome
provide more detailed information about the childs voiding pattern. infrequent voiding every 812 h and incontinence between voiding. but is still not responding to treatment one must consider other con-
The information does not have to cover consecutive days, and week- Sensation of bladder fullness is reduced. Incontinence is due to ditions such as congenital bladder neck insufficiency or ectopic ure-
ends may give better opportunity for the parent to document the overflow and the urinary stream is poor with incomplete voiding. teroceles.
information. The diary must include the record of bowel action. Such bladder decompensation may occur as a result of previous
posterior urethral valves in infancy and can be associated with 16 The management of constipation is imperative in all
4 Inspection of the genitalia in boys should exclude a meatal myogenic detrusor failure. patients. It is due to the inability to relax the pelvic floor musculature.
stenosis and in girls look for labial adhesions, which can impede
urinary flow. Voiding dysfunction and urinary symptoms have been 11 Bladder training involves frequent voiding, initially 2 hourly, * Primary nocturnal enuresis is a prevalent disorder with a complex mode of
inheritance. It appears to be associated with a deficiency of inhibitory signal
described with sexual abuse and attention needs to be directed later 4 hourly on a regular basis with advice to relax the pelvic floor
processing in the brain stem which underlies the deficient pre-path inhibition of
towards examination of the genitalia for any scarring, tearing or when voiding, e.g. by whistling. Low-dose prophylactic antibiotics micturition, as well as the inability to inhibit micturition at night. A low nocturnal
signs of trauma. This obviously needs to be performed carefully and are useful in children who have a history of urinary tract infections arginine vasopressin production may be present, and the role of melatonin in this,
sensitively. without reflux. The antibiotics can be used for a short period of time, as well as the regulation of sleep/wake cycle, is currently under review. These
usually not longer than 6 months. children may respond to Desmopressin (DDAVP 2040 g intranasally). This
should not be used for prolonged periods as water intoxication is a serious
5 Children with dysfunctional voiding are at risk of recurrent
adverse side effect. DDAVP should be used along with other treatment modalities,
UTIs. Both reflux and UTIs are observed in 3040% of children at the 12 Oxybutynin is the most commonly used anti-cholinergic
such as bed wetting alarms, dry bed training and behavioural treatment. It is
time of dysfunctional voiding and resolve with the attainment of a drug. It is usually initiated at a low dose once or twice daily and is important to distinguish nocturnal enuresis from diurnal enuresis or daytime
normal voiding pattern. Bladder instability with high intravesical gradually titrated to a maximum dose over 68 weeks. Side effects wetting. It is not uncommon for bed wetters to wet their underclothes during the
pressures are observed in children with VUR. High voiding detrusor are common and include facial flushing, constipation and dry mouth. 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.
pressures have also been observed in infants presenting with symp- Occasionally headache and palpitations are reported. Approximately
Dysfunctional voiders exhibit poor co-ordination between the bladder and
tomatic urinary tract infections who do not have VUR. 20% of patients have to stop medication because of these side bladder outlet which results in inefficient bladder emptying and is termed
effects. The management of constipation is essential and needs dyssynergia.
6 A history of continuous urinary incontinence, particularly in particular vigilance in patients on anticholinergic treatment.
a young girl, is suggestive of an ectopic ureter. If intravenous uro-
gram fails to demonstrate this, careful examination of the introitus by 13 Biofeedback training is very useful in children over 8 years
Selected reading
a trained urologist may identify the opening of the ectopic ureter. of age. This involves psychological support, learning to void using
a flowmeter, ultrasound scanning to check for complete bladder Akbal C, Genc Y, Burgu B, Ozden E, Tekgul S: Dysfunctional voiding
7 Giggling and laughter associated with embarrassing wet- emptying, the use of alarms to detect wetness and regular charting and incontinence scoring system: quantitative evaluation of incon-
ting episodes is more commonly seen in girls and is usually self-lim- of voiding activities. Follow-up by a dedicated incontinence adviser tinence symptoms in pediatric population. Urol 2005;173:969973.
iting. Anticholinergic agents may be helpful. Postvoid dribbling may is essential. Such behavior modification programmes will cure 50% Austen PF, Ritchey ML: Dysfunctional voiding. Paediatr Rev
occur in girls (commonly obese) where the urine accumulates in the of children within 6 months and 75% within 1 year. Pharmacological 2000;21:336340.
lower vagina. intervention may speed up this process for some patients but good Feldman AS, Bauer SB: Diagnosis and management of dysfunc-
31 voiding behavior is the key to success. tional voiding. Curr Opin Pediatr 2006;18:139147.
8 US is very useful to image the upper urinary tract to demon- Nrgaard JP, van Gool JD, Hjalmas K, Djurhuus JC: Standardiza-
strate abnormalities such as duplex kidney, dilatation of the collecting 14 Alpha-adrenergic blockade may be useful to improve tion and definitions in lower urinary tract dysfunction in children.
system and gross reflux. A thickened bladder wall with trabeculation bladder emptying in some patients. Prazosin or Doxazosin 0.451 mg Br J Urol 1998;81(suppl 3):116.

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may be observed. This will depend on the expertise of the ultraso- at night may be used. Treatment is generally well tolerated but hypo- Schulman SL: Voiding dysfunction in children. Urol Clin North Am
nographer. Postmicturition bladder volumes are considered signifi- tension may be observed. 2004;31:481490.

Univ. of California San Diego


cant when they represent, on repeated occasions, volumes of >20 ml

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Urinary tract disease/tubulointerstitial nephropathy S. Hulton R. Adelman Dysfunctional voiding
Urinary tract disease/tubulointerstitial nephropathy J. Smith F.B. Stapleton Loin pain with hematuria

/
Loin pain with hematuria
32 History and physical examination

Urinalysis

Red blood cells White blood cells Red blood cell casts Crystals Blood tests including Renal angiogram
No casts Bacteria Protein electrolytes, calcium, BUN,
Urine culture creatinine, blood gases

Normal Abnormal
Pyelonephritis Glomerulonephritis Consider urolithiasis Renal arteriovenous fistula
Normal Abnormal Nutcracker syndrome
Ultrasound of kidneys and bladder with Doppler 0 Glomerulopathy
(e.g. IgA nephropathy)
Hypercalcemia
(e.g. hyperparathyroidism) Renal biopsy 4
Normal Abnormal Renal tubular acidosis
Urolithiasis
Obstructive uropathy
Polycystic kidney disease Normal Abnormal
Pyelonephritis Intravenous pyelogram 2 Glomerulopathy
Renal vein thrombosis (e.g. IgA nephropathy)
Tumor Thin basement membrane disease
Nutcracker syndrome
Normal Abnormal
Medullary sponge kidney
Tumor
Further urine evaluation 1 Cyst Loin pain hematuria syndrome 5
24-hour collection of calcium, protein, sodium, citrate,
cystine, oxalate, uric acid, creatinine

Cystoscopy 3

Normal Abnormal
Proteinuria
Hypercalciuria Normal Abnormal Psychiatric evaluation 6
Hypocitraturia Bladder lesion
Cystinuria
Hyperoxaluria

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Hyperuricosuria

Univ. of California San Diego


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1 Evaluation of loin pain associated with 6 To exclude significant pathology, such as
Selected reading
hematuria (microscopic or gross) is best approached IgA nephropathy or thin basement membrane disease,
in a staged manner depending on the duration and a renal biopsy is recommended. Descriptions of renal Burke JR, Hardie IR: Loin pain haematuria syndrome.
severity of symptoms. pathology in loin pain hematuria syndrome (see Pediatr Nephrol 1996;10:216220.
below) vary markedly. Reported abnormalities include Chin JL, Kloth D, Paulter SE, Mulligan M: Renal
2 Ultrasound of kidneys and Doppler is recom- mesangial proliferation, interstitial fibrosis, and arte- autotransplantation for the loin pain-hematuria
mended to exclude possible etiologies of loin pain and riolar and arterial hyalinosis. Immunofluorescence syndrome: long-term follow-up of 26 cases. J Urol
hematuria including urolithiasis, obstructive uropathy, may show arteriolar C3 deposits as well as IgM and 1998;160:12321235.
polycystic kidney disease, pyelonephritis, renal IgA in the mesangium. Hebert LA, Betts JA, Sedmark DD, Cosio FG,
vein thrombosis, tumor, or evidence of nutcracker Bay WH, Carlson S: Loin pain-hematuria syndrome
syndrome (left renal vein entrapment). 7 The definition of loin pain hematuria syn- associated with thin glomerular basement
drome is based upon hematuria, gross or microscopic, membrane and hemorrhage into renal tubules.
3 Urinary concentrations of protein, calcium, associated with recurrent episodes of loin pain, unilat- Kidney Int 1996;49:168173.
uric acid, oxalate and cystine are typically normal in eral or bilateral. Pain may radiate across the abdomen Weisburg LS, Bloom PB, Simmons RL, Viner ED:
loin pain hematuria syndrome. Normal urinary values or toward the groin. Patients are mainly young women Loin pain haematuria syndrome. Am J Nephrol
for school-age children: calcium <4 mg/kg/day or and older children. Diagnosis of loin pain hematuria 1993;13:229237.
calcium/creatinine (mg/mg) <0.2; citrate >400 mg/g is a diagnosis of exclusion. Patients must have normal Winearls CG, Bass C: The loin pain hematuria
creatinine; uric acid <0.56 mg/dl GFR; oxalate <50 mg/ renal function and a normal genito-urinary system. syndrome. Nephrol Dial Transplant 1994;9:
1.73 m2/day; cystine <60 mg/1.73 m2/day. There must be no evidence of infection, malignancy, 15371539.
calculi or hypercalciuria. Management of loin pain syn-
4 Depending on severity and duration of symp- drome presents a challenge and is best addressed by
toms, further investigations are indicated. An IVP can a multidisciplinary team. Analgesic therapy is the
identify the uncommon diagnoses, medullary sponge mainstay of therapy. Most patients inevitably require
kidney which can lead to pain, and hematuria due to narcotic analgesia for pain relief. A variety of other
the passage of microcalculi. interventions have been reported including biofeed-
back, transcutaneous nerve stimulation and regional
5 Cystoscopy should be performed to deter- nerve blocks. Renal auto-transplantation has been the
mine if hematuria is unilateral or bilateral and to most successful surgical intervention.
exclude a bladder lesion that could be causing pain
and hematuria. 8 Evaluation should include a detailed psychi-
atric examination including patients perception of
pain, history of physical or sexual abuse, and family
psychiatric history. There is a strong correlation with
somatoform pain disorder. The possibility of factitious
disorder should also be considered.

33

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Univ. of California San Diego
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Urinary tract disease/tubulointerstitial nephropathy J. Smith F.B. Stapleton Loin pain with hematuria
Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton Renal trauma

/01
Renal trauma
34

Gross hematuria or microscopic hematuria with No gross hematuria or microscopic hematuria with
RBC >20/HPF RBC <20/HPF

CT scan 2
(usually CT angio)

Renal contusion Diagnosis unclear (ex. neoplasm)


Mild-to-moderate laceration 345 Severe renal bleeding
Pedicle injury
Ureteropelvic avulsion
Large or pulsatile retroperitoneal hematoma
Bladder rupture 6

Observe Surgery Observe

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Univ. of California San Diego
Downloaded by:
1 The kidney is the most commonly injured
Selected reading
abdominal organ as well as the most often injured part
of the genitourinary system. Buckley JC, McAninch JW: The diagnosis,
management, and outcomes of pediatric renal
2 Blunt trauma accounts for 90% of renal injuries. Urol Clin North Am 2006;33:3340.
injuries. Christensen R: Invasive radiology for pediatric
trauma. Semin Pediatr Surg 2001;10:711.
3 Physical findings compatible with renal Heyns CF: Renal trauma: indications for imaging and
trauma include an abdominal mass or tenderness, surgical exploration. BJU Int. 2004;93:11651170.
flank tenderness or ecchymoses, rib fracture, Patel HP, Bissler JJ: Hematuria in children.
abdominal distention, hypertension or hypotension. Pediatr Clin North Am 2001;48:15191537.
Puig S, Schaefer-Prokop C, Mang T, Prokop M:
4 Computerized tomography (usually a CT Single- and multi-slice spiral computed tomography
angio) is the imaging of choice and indicated for rapid of the paediatric kidney. Eur J Radiol 2002;43:
deceleration injury such as a fall or motor vehicle 139145.
accident, a penetrating injury, presence of physical
findings, gross hematuria, or microscopic hematuria
>20 RBCs/HPF.

5 Most renal injuries are contusions which


require no therapy.

6 Most renal lacerations, even those that


are moderate to severe, heal with nonoperative
intervention.

7 Pre-existing renal anomalies occur in


1520% of children presenting with renal trauma and
hematuria.

8 Bladder rupture is diagnosed with a cysto-


urethrogram. It is frequently associated with gross
hematuria, pelvic fracture, but may be seen in
child abuse. Most extraperitoneal rupture responds
to bladder drainage; otherwise, surgery is usually
indicated.

35

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Urinary tract disease/tubulointerstitial nephropathy R. Adelman S. Hulton Renal trauma
Urinary tract disease/tubulointerstitial nephropathy A.L. Friedman S. Turi Tubulointerstitial nephritis

/
Tubulointerstitial nephritis
36 Renal insufficiency/ failure
Tubular dysfunction

Fever, hematuria (gross/microscopic) Polyuria, polydipsia, metabolic acidosis glycosuria,


proteinuria, pyuria, eosinopholia, eosinophiluria, flank pain, rash, high urine pH, sterile pyuria, non-nephrotic range proteinuria,
arthralgia, polyuria, eye symptoms, history of recent drug intake insidious onset (months to years)

AIN Chronic TIN 6

Urine: microscopy, eosinophils 0 , culture Urine: microscopy, pH, osmolarity, electrolytes,


Serum: CBC + reticulocytes, creatinine, BUN, protein electrophoresis, organic acids
electrolytes, bicarbonate, ASLO, ANA Serum: creatinine, BUN, electrolytes, bicarbonate, CBC, ANA,
Imaging: renal US, ophthalmologic examination ceruloplasmin, WBC cystine
Renal biopsy 1 Imaging: renal US, VCUG, nuclear scan
Renal biopsy 7

Immune-mediated 2 Infectious 3 Idiopathic 4 Anatomic malformation 8 Inflammatory 9 Hereditary/metabolic : Hematologic


Drug-induced Direct infection Reflux nephropathy SLE Cystinosis Sickle cell disease
SLE, other GN Reactive TIN Obstructive nephropathy Vasculitis Wilson
TINU Dysplasia/hypoplasia Other GN Hyperoxaluria

Therapy 5

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1 The interstitium gives structural support for 5 A host of infectious agents including bacteria,
Selected reading
the nephrons and the renal vascular bed. The tubulo- viruses, fungi as well as rickettsia can lead to AIN
interstitium comprises approximately 80% of the renal either due to a direct invasion of the pathogen to the Alon US: Tubulointerstitial nephritis; in Avner ED,
parenchyma. TIN is a distinct entity that should not be interstitium, or secondary to a reactive immunologic Harmon WE, Niaudet P (eds): Pediatric Nephrology,
confused with GN. process during which no infectious agent is isolated ed 5. Philadelphia, Lippincott Williams & Wilkins,
from the renal parenchyma. 2004, pp 817831.
2 The presence of more than 1% eosinophils of Clarkson MR, Giblin L, OConnell FP, OKelly P,
the total WBC in the urine is considered significant and 6 Idiopathic AIN is a diagnosis of exclusion and Walshe JJ, Conlon P, DAmico G, Ferrario F,
it is a sensitive (although not specific) marker of AIN. it is rarely seen in children. Rastaldi MP: Tubulointerstitial damage in glomerular
diseases: its role in the progression of renal dam-
3 Findings on renal biopsy typical of AIN 7 The data for the use of glucocorticoids in AIN age. Am J Kidney Dis 1995;26:124132.
include interstitial edema and cellular infiltrate as well is primarily anecdotal. Pulse methylprednisolone or Krause I, Cleper R, Eisenstein B, Davidovits M:
as tubulitis. Renal biopsy, when indicated, is essential brief oral courses of glucocorticoids in patients whose Acute renal failure, associated with non-steroidal
in distinguishing glomerular from tubulointerstitial renal function fails to improve within 13 weeks after anti-inflammatory drugs in healthy children.
injury. stopping presumed inciting agent may be of benefit. Pediatr Nephrol 2005;20:12951298.
OMeara Y, Dormon A, Campbell E, Donohoe J:
8 The differential diagnosis of CTIN is broad. Acute interstitial nephritis: clinical features and
4 Immune-mediated conditions are the leading
AIN from any cause, may lead to CTIN. response to corticosteroid therapy. Nephrol Dial
cause of AIN in children. Drugs/toxins associated with
Transplant. 2004;19:27782783.
AIN include, for example:
9 The main histologic findings of CTIN include: Vohra S, Eddy A, Levin AV, Taylor G, Laxer RM:
Penicillins (methicillin, ampicillin, penicillin G)
interstitial fibrosis, tubular atrophy, mild lymphocyte Tubulointerstitial nephritis and uveitis in children
Ciprofloxacin
infiltrate and glomerular drop-out. Potential findings and adolescents: four new cases and a review of
Sulfonamide
depending on underlying etiology include: tubular the literature. Pediatr Nephrol 1999;13:426432.
Rifampin
NSAID including aspirin pigment, casts, crystals, inclusion, etc.
Phenytoin
10 CTIN due to congenital anatomic malforma-
Furosemide
Allopurinol tion is the leading cause of end stage renal disease
H2 blockers in children. These malformations include: obstructive
nephropathy (the most common cause of CTIN in
Combinations of the above-listed drugs appear to lead children), aplastic/hypoplastic/dysplastic kidneys or
to more significant toxicity or greater likelihood of reflux nephropathy.
developing AIN. SLE may lead to AIN with or without
11 All types of GN, if severe and prolonged, may
GN. The AIN in SLE patients is due to immune depos-
its found in the tubulointerstitium. In general, any lead to tubulointerstitial damage and CTIN.
condition leading to GN can be associated with tubu-
12 Hereditary disorders causing either tubular
lointerstitial involvement. TINU is a rare disorder of
unknown etiology seen mostly in adolescent females. and/or interstitial damage may lead to CTIN. Both Wil-
Causes of this disorder include infections, drugs son disease and cystinosis lead to Fanconi syndrome
(NSAID) and auto-immune disorders. The renal (see algorithm), and when the metabolic abnormalities
disease in TINU usually resolves spontaneously of these disorders are uncontrolled and long-lasting,
whereas the uveitis requires aggressive immuno- they will lead to chronic and irreversible interstitial
suppressive therapy. damage as well. Primary hyperoxaluria (see algorithm
on Nephrolithiasis) is another genetically transmitted
disease in which excessive production of oxalate leads
to accumulation of calcium oxalate stones in the renal
37 tubulointerstitium.

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Urinary tract disease/tubulointerstitial nephropathy A.L. Friedman S. Turi Tubulointerstitial nephritis
Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Single kidney (renal agenesis)

/
Single kidney (renal agenesis)
38
Association of nonurological malformations 0

Clinical evaluation 1
US 2
VCUG 3
DMSA renal scan 4

Single kidney compensatory hypertrophy Urinary tract abnormalities 3


Normal urinary tract

Annual follow-up in outpatient clinic 5 Investigations and treatment according to


the specific malformation found

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Univ. of California San Diego
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1 Absence of a kidney is usually asymptomatic: 5 Unilateral renal agenesis may be the end
Selected reading
this condition is discovered incidentally on prenatal result of regression of a multicystic dysplastic kidney
ultrasound, during evaluation of UTI, during screening during gestation. Associated urological anomalies Dursun H, Bayazit AK, Buyukcelik M, Soran M,
for hip luxation or for associated congenital abnor- have been found in approximately 3545% of these Noyan A, Anarat A: Associated anomalies in
malities, or in adult during work-up for a possible cases. The majority of these malformations are VUR children with congenital solitary functioning kidney.
donation of a kidney. (hence, voiding cystourethrography is recommended Pediatr Surg Int 2005;21:456459.
in infants with single kidney), but ureteropelvic junc- Johnson B, Christensen C, Dirusso S, Choudhury M,
2 Genital, skeletal, cardiac, gastrointestinal and tion stenosis and ureterovesical junction obstruction Franco I: A need for reevaluation of sports participa-
chromosomal abnormalities have been found to be are also found. tion recommendations for children with a solitary
more frequent in children with single kidney than in kidney. J Urol 2005;174:686689.
the general population. In addition, maternal use of 6 DMSA renal scan should be done to check Matsukura H, Toyoshima S, Inaba S, Miyanaki T,
cocaine and maternal diabetes can lead to renal agen- the function of the kidney and to confirm that there is Miyamoto M: Vesicoureteral junction obstruction
esis. no ectopic functioning renal tissue, possibly missed by associated with unilateral renal agenesis. Urol Int
US. 2003;71:329330.
3 Clinical evaluation is aimed to exclude the Parikh CR, McCall D, Engelman C, Schrier RW:
presence of hypertension and/or UTI and to ascertain 7 Renal sonogram should be periodically Congenital renal agenesis: case-control analysis of
that the single kidney has normal glomerular filtration performed to follow the hypertrophic growth of the birth characteristics. Am J Kidney Dis 2002;39:
rate, concentrating capacity and microalbuminuria kidney. If no UTI occurs, no microalbuminuria appears 689694.
excretion. and BP is normal, it is not necessary to monitor GFR Woolf AS, Hillman KA: Unilateral renal agenesis
and concentrating capacity closely. Follow-up exami- and the congenital solitary functioning kidney:
4 Sonogram of the urinary tract should aim to nation should include an annual measurement of BP developmental, genetic and clinical perspectives.
exclude direct or indirect signs of other urinary tract and urinalysis. Periodic measurements of urinary BJU Int 2007;99:1721.
malformations, to ascertain that the single kidney is protein excretion and GFR are also indicated because,
clearly hypertrophied (calculated with the centiles), in the long term, these patients may have an increased
and to check whether the renal parenchyma is nor- incidence of proteinuria, hypertension and renal
mally and uniformly thick with normal echogenicity. insufficiency. Although the American Academy of
Pediatrics recommended in the past that children with
a solitary kidney do not participate in contact sports,
recent studies show that there is no increased risk for
a major renal trauma for children engaging in these
activities.

39

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Univ. of California San Diego
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Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Single kidney (renal agenesis)
Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Renal hypoplasia-dysplasia

/
Renal hypoplasia-dysplasia
40 Assessment of renal function 0
US
VCUG
DMSA renal scan

Multicystic dysplasia 1 Hypoplasia/dysplasia with Hypoplasia-dysplasia without Oligomeganephronia 3


urinary tract malformation 2 urinary tract malformation 2

Appropriate decisions according to


the urinary tract malformations
found in the contralateral kidney

Nephrological follow-up

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Univ. of California San Diego
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1 True renal hypoplasia is defined as a reduc- 3 A MCDK represents the most common
Selected reading
tion in the number of nephrons that have developed expression of renal dysplasia: the overall structure of
and differentiated normally. Pure hypoplasia is rare. the kidney is abnormal, no pelvis and no typical lobar Dziarmaga A, Quinlan J, Goodyer P: Renal
Approximately 2.5% of the childrens autopsies show organization is recognized. Microscopically, only hypoplasia: lessons from Pax2. Pediatr Nephrol
the presence of small kidneys without evident clinical dysplastic tissue is present, without normal nephronic 2006;21:2631.
problems. The majority of hypoplastic kidneys are also structures. Only a few primitive glomeruli may be Hubert KC, Palmer JS: Current diagnosis and
dysplastic because their parenchyma is structurally present. In most cases, the associated ureter is atretic management of fetal genitourinary abnormalities.
disorganized and contains undifferentiated tissue, and renal function is absent. The incidence of MCDK is Urol Clin North Am 2007;34:89101.
with primitive ducts and/or focal areas of cartilaginous about 1 in 4,300 livebirths. The diagnosis of MCDK is Kalyoussef E, Hwang J, Prasad V, Barone J:
metaplasia of the blastema. Other features like cysts done antenatally by the finding of a unilateral flank Segmental multicystic dysplastic kidney in children.
and primitive tubules and ductules may be present. mass in a newborn or, by chance, in coincidence with Urology 2006;68:1121.
For this reason, a reliable diagnosis of renal dysplasia an abdominal US. Palmer LS: Pediatric urologic imaging. Urol Clin
is dependent on histological examination. From the North Am 2006;33:409423.
practical point of view, renal hypoplasia and dysplasia 4 Hypoplasia can be unilateral (1 in 500 adults) Salomon R, Tellier AL, Attie-Bitach T, Amiel J,
always mean a reduction in the number of functioning or bilateral. In unilateral hypoplasia, if the controlateral Vekemans M, Lyonnet S, Dureau P, Niaudet P,
nephrons. The entity of this reduction cannot, how- kidney is normal it must be clearly hypertrophic. In Gubler MC, Broyer M: PAX2 mutations in oligome-
ever, be precisely assessed by standard examinations this case, the renal prognosis is good and only the risk ganephronia. Kidney Int 2001;59:457462.
such as US because the renal volume in this case is of hypertension and proteinuria over time should be
not necessarily proportional to the number of func- kept in mind; if the contralateral kidney is not hypertro-
tioning nephrons. phic, it probably means that both kidneys are, to a dif-
ferent degree, abnormal. If hypoplasia is bilateral, the Selected reading for Nephromegaly,
2 The kidney and urinary tract contralateral to a possibility of the development of chronic renal failure pages 42 and 43
hypoplastic-dysplastic kidney may be abnormal in a must be kept in mind.
Ahmed HU, Arya M, Levitt G, Duffy PG, Mushtaq I,
substantial proportion of patients (2075%). For this
Sebire NJ: Part I. Primary malignant non-Wilms
reason, US and VCUG should always be performed to 5 Oligomeganephronic renal dysplasia is
renal tumours in children. Lancet Oncol 2007;8:
evaluate the degree of compensatory hypertrophy of characterized by a low number of nephrons (2025%
730737.
the healthy kidney and to ascertain or exclude the of normal), very enlarged glomeruli (twice the normal
Becker A, Baum M: Obstructive uropathy. Early Hum
presence of urinary tract malformations. In addition, volume) and hypertrophic tubules as well as by the
Dev 2006;82:1522.
DMSA renal scan should be done to assess renal func- absence of urinary tract malformations. At the histo-
Chou JY, Matern D, Mansfield BC, Chen YT:
tion. Renal function (glomerular filtration rate, concen- logical level, the precocious arrest of the development
Type I glycogen storage diseases: disorders of the
trating capacity, microalbuminuria and proteinuria) of the metanephric renal blastema is the most likely
glucose-6-phosphatase complex. Curr Mol Med
must be carefully evaluated and checked periodically. cause of oligomeganephronia. The majority of report-
2002;2:121143.
ed cases are not associated with a genetic disorder.
Driscoll K, Isakoff M, Ferrer F: Update on pediatric
genitourinary oncology. Curr Opin Urol 2007;17:
281286.
Karadeniz C, Oguz A, Ataoglu O, Citak C, Buyan N,
Pinarli G, Ozkaya O, Kapucu O: Primary renal lym-
phoma and xanthogranulomatous pyelonephritis
in childhood. J Nephrol 2002;15:597600.
Zugor V, Schott GE, Labanaris AP: Xanthogranulo-
matous pyelonephritis in childhood: a critical
analysis of 10 cases and of the literature. Urology
2007;70:157160.

41

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Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Renal hypoplasia-dysplasia
Structural/congenital abnormalities M.A. Linshaw G. Rizzoni Nephromegaly

/
Nephromegaly
42
Normal/minor anomaly Pathological Pseudoenlargement, transient nephromegaly 1
Physiological response 0

Hypertrophy Tamm-Horsfall protein


Duplex kidney Pararenal mass
Column of Bertin Splenic compression
Fetal lobulation Perirenal urinoma
Perirenal hematoma
Renal angioplasty
After lithotripsy
Pseudotumor-sarcoid

Obstructive 2 Cystic 3 Metabolic 4 Inflammatory, Hematologic 6 Oncologic 7 Miscellaneous


toxic, anoxic 5

With hydronephrosis Diabetes mellitus Sickle cell Beckwith-Weidemann


Ureteropelvic junction obstruction Glycogen storage disease Thalassemia Congenital hemihypertrophy
Ureterovesical junction obstruction type 1 Hemophilia Sjogren
Posterior urethral valves Hereditary tyrosinemia Myelofibrosis Renal amyloidosis
Vesicoureteral reflux Fabrys disease RVT Radiocontrast nephropathy
Prune belly syndrome Acromegaly
Polycystic kidney disease Acute tubulointerstitial nephritis Wilms tumor
Other (stone, tumor, clot)
Autosomal dominant Glomerulonephritis Nephroblastomatosis
Without hydronephrosis
Autosomal recessive Pyelonephritis Mesoblastic nephroma
Myoglobinuria
Glomerulocystic kidney disease Abscess-intra-/perirenal Clear cell sarcoma
Hemoglobinuria
Tuberous sclerosis Renal malakoplakia Neuroblastoma
Acute urate nephropathy
Multicystic dysplastic kidney Nephrotic syndrome Malignant rhabdoid
Acute tubular necrosis Cystic nephroma
Acute lymphoblastic leukemia
Hodgkin/non-Hodgkin lymphoma
Angiomyolipoma

US, MAG-3 diuretic scan, US, CT, syndromic Specific labs Urinalysis, culture, CBC, smear, Radiographic study; Specific syndromes,
VCUG, CT, cystoscopy, IVP findings, tissue CBC, urine eosinophils, Hb electrophoresis, bone marrow or tissue, history, labs
Urine-pigmented casts, urinary protein, bone marrow, tissue for diagnosis

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myoglobin, uric acid crystals renal function, lipids, coagulation, US, CT,
Blood-hemolysis, CPK, reticulocytes biopsy as needed, proteinuria, fibrin products

Univ. of California San Diego


BUN, creatinine, uric acid

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1 Nephromegaly is noted by palpation of an abdominal/flank 5 ARPKD may present in utero with large, hyperechoic kidneys, scess). Nephromegaly is usually not palpable and resolves about 2
mass or by radiographic study. The degree of renomegaly is unrelated oligohydramnios, no bladder visualization and negative family history. weeks after starting therapy. In renal malakoplakia/xanthogranuloma-
to disease severity, histological pattern or prognosis. History and phys- Most affected children progress to renal failure in childhood, but mild tous pyelonephritis, a form of chronic interstitial nephritis, patients
ical examination with laboratory and radiological studies may allow disease can be undiagnosed for years. Neonatal ADPKD can cause have recurrent UTI, sometimes massive renomegaly and a non-func-
diagnosis without biopsy/surgery. large, hyperechoic kidneys with/without visible cysts. Cysts may ini- tioning avascular mass. Destroyed renal parenchyma is replaced by
tially be unilateral. Patients can be asymptomatic early in the disease yellowish-brown soft infiltrate of bacteria, inflammatory cells, lipid-lad-
2 Renomegaly from renal hypertrophy occurs in response to with cysts noted on US performed because a parent is affected. Cysts en histiocytes and calculi. The lesion resembles malignancy and histo-
congenital/acquired solitary kidney or unilateral reduction in renal may present as abdominal pain, mass, hematuria, hypertension or UTI. logical diagnosis is needed. ATN, toxic or hypoxic, often causes reno-
function. Hypertrophy starts minutes after loss of a healthy kidney and Extrarenal problems include mitral valve prolapse, cysts in liver, ovary, megaly. By contrast, hypoxic injury causes acute cortical necrosis and
takes months to complete. Benign nephromegaly includes duplex kid- spleen and pancreas, hernias and cerebral aneurysms. MCDK, a severe renal infarction does not. This may relate to ongoing renal arterial flow
ney seen on abdominal US or CT. Two benign conditions may resemble renal dysgenesis, is the most common cause of neonatal abdominal during tubular necrosis whereas severe arterial compromise sufficient
a mass. Palpable persistent fetal lobulation in a child is clarified by US. mass. The MCDK has an atretic or non patent ureter and no identifiable to necrose glomeruli is associated with reduced renal blood flow. Cell
A prominent Bertin column is differentiated from tumor by US (with renal sinus or functioning renal parenchyma. Contralateral anomalies, swelling and consequent renomegaly are unlikely if blood flow is insuf-
agents to enhance vascularity) or CT. e.g. VUR, UPJ obstruction, are common. VCUG and nuclear scan can ficient to deliver more fluid into the kidney.
confirm lack of VUR and function. Tuberous sclerosis (autosomal-domi-
3 Pseudo-renal enlargement may reflect splenic left renal com- nant neurocutaneous hamartomatosis) affects skin, heart, retina, cen- 8 Sickle cell disease may induce renomegaly by sickling of red
pression, posterior pararenal mass, perirenal hematoma or urinoma. tral nervous system and kidney. Renal lesions include angiomyolipo- blood cells, oxidative stress, medullary congestion and vaso-occlusive
Traumatic intra-/extrarenal hematoma and traumatic/obstructive urin- mas (~50% of patients) that are often bilateral and best evaluated with disease. A similar process may occur in thalassemia. RVT causes neph-
oma are seen by US or CT. Transient renomegaly may follow angio- CT, and large cysts (~20% of patients) resembling ADPKD. GCKD in- romegaly and gross hematuria. In older nephrotic children, CT may
plasty for renal artery stenosis or ESWL and occurs with sarcoid granu- cludes entities with glomerular (not tubular) cysts that are typically di- show renal vein or inferior vena caval thrombus, pericapsular venous
lomatous infiltration that distorts renal contour and mimics tumor. A lated Bowmans capsules with an aborted/primitive glomerulus. Cysts collaterals or opacification of renal parenchyma. In neonates or older
notable cause in neonates/older children, Tamm-Horsfall proteinuria, are cortical, not medullary, in contrast to other cystic diseases. Infants infants, look for diffusely enlarged, hyperechoic kidneys with ill-de-
may present as renal masses. US shows large, hyperechoic kidneys may have abdominal masses (cystic kidneys by US) and renal insuf- fined central-echo complexes and poor venous Doppler flow. Inferior
resembling ARPKD, RVT, dysplasia or intrarenal obstruction. Oliguria ficiency. Mild disease can present later in life with hypertension or flank vena caval or main renal vein thrombus is usually absent.
and ARF may occur, but usually reverse in a few days or weeks. pain.
9 Wilms tumor (nephroblastoma) is the most common tumor
4 Urinary tract obstruction may present as a flank/abdominal 6 In diabetes mellitus, renomegaly becomes prominent in pu- causing renomegaly in children. Work-up includes laboratory data, US,
mass or distended bladder in infancy or may be found at evaluation of berty, especially with reduced renal function. Glomerular hypertrophy, chest film, skeletal survey, abdominal/chest CT. Radiological study may
UTI, abdominal/flank pain or hematuria. UPJ obstruction, the most proximal tubular hyperplasia and hypertrophy may relate to increased miss contralateral renal tumors and renal surgical exploration may be
common cause of hydronephrosis/renomegaly in newborns, can be growth hormone and insulin-like growth factor. Careful glycemic con- needed. Nephroblastomatosis (residual metanephrogenic tissue in a
seen antenatally by US, can present as an abdominal mass and often trol reduces renal hyperfiltration and high GFR, but may not reduce mature kidney) causes renomegaly. This can regress to fibrous tissue,
resolves spontaneously in 612 months. Other causes of hydronephro- renomegaly. Glycogen storage disease type 1 can present at 34 mature to glomeruli and tubules, or become malignant (e.g. Wilms tu-
sis/renomegaly include UVJ obstruction, VUR and PUV. PUV, mucosal months of age with hepatomegaly or hypoglycemic seizures when mor), but the usual course of nephroblastomatosis is regression before
cusps that appose during voiding, can obstruct urine flow. If mild, they food intake decreases (acute illness or night feeding is stopped). Renal malignancy. Other renal tumors are usually unilateral and solid. Con-
may present after many years with incontinence, polyuria, nocturia or problems include renomegaly from accumulated glycogen, hyperfiltra- genital mesoblastic nephroma (leiomyomatous hamartoma) is usually
UTI. If severe, infants have an enlarged, trabeculated bladder, weak tion, proteinuria, FSGS, nephrocalcinosis, stones and Fanconi-like syn- benign and tends to present in infants <3 months of age. Neuroblas-
stream, renal dysplasia, severe hydronephrosis and hydroureter (not drome. Hereditary tyrosinemia type 1 causes liver and renal tubular toma is usually solid, may have calcifications or cysts and must be dif-
always bilateral) and may have urosepsis. Diagnosis is best made by dysfunction with renomegaly and uniform thickness of renal cortex. ferentiated from primary renal tumor. Clear-cell sarcoma typically pres-
VCUG. If hydroureter/nephrosis is unilateral, check for urethral obstruc- Fabrys disease shows nephromegaly in the 3rd decade from accumu- ents in a 3- to 5-year-old child, tends to metastasize to bone and brain
tion as well as high ureteral lesions with IVP or antegrade pyelogram. lation of glycosphingolipid. Acromegaly causes nephromegaly prob- and has a poor prognosis. Work-up includes brain MRI, bone scan, skel-
In Prune-Belly syndrome (mostly in males), in utero prostatic urethral ably from increased tubule mass rather than increased glomerular size. etal survey and abdominal/chest CT. Malignant rhabdoid tumor is usu-
obstruction or urethral hypoplasia may be causative in many cases. Other causes of renomegaly include Perlman, Sjogren, Beckwith- ally large, originates in the central hilar area, replaces the whole kidney,
Features include oligohydramnios, hydronephrosis, renomegaly, di- Wiedemann syndromes, renal amyloidosis, intravenous hyperalimen- metastasizes to lung, brain, liver and has median presenting age at
lated prostatic urethra and ureters, VUR, bilateral cryptorchidism, lax/ tation/protein loading (usually bilateral and reversible) and in convales- around 11 months. Abdominal and chest CT and brain MRI are needed.
wrinkled nonresistant abdominal wall (hypoplastic lower abdominal cent burn patients, perhaps from higher renal workload (high therapeu- Multilocular cystic nephroma usually presents from 3 to 24 months of
muscles) and renal dysplasia and is suspected by finding cystomegaly tic salt/fluid/protein intake and catabolism). age as benign multilocular cyst or as cystic lesion with stroma contain-
on US as early as 1214 weeks gestation. Nephrolithiasis is the most ing partially differentiated blastema cells. The latter may have Wilms
43 common acquired cause of childhood hydronephrosis/renomegaly. 7 Nephromegaly may occur with acute postinfectious or vascu- tumor nodules and is indistinguishable from cystic Wilms tumor with-
Intrarenal obstruction with no hydronephrosis occurs when pigmented litic glomerulonephritis (can be unilateral with flank pain) and with NS out biopsy. Hematologic malignancies, e.g. acute lymphoblastic leuke-
casts/crystals occlude tubule lumens. With dehydration and acidic (with no relation to histology or steroid response). Loin pain may relate mia or lymphoma, cause diffuse unilateral or bilateral nephromegaly
urine, hemoglobinuria/myoglobinuria and hyperuricosuria can cause to fluid retention and a response to diuretics often relieves pain. Pa- from renal infiltration or discrete intrarenal/hilar mass lesions. Rare
ARF and large, echoic kidneys, resembling ARPKD, RVT or dysplasia, tients with acute TIN typically have renal tenderness, pyuria, urinary causes of renomegaly include renal adenomatosis, histiocytic medul-

198.143.33.65 - 8/6/2015 3:20:59 PM


but this usually reverses in days to weeks (prognosis of large echoic WBC casts and renomegaly on US. Acute bacterial infections with re- lary reticulosis, Castleman disease and renal cell carcinoma.
kidneys is not always bad). nomegaly may be intrarenal (pyelonephritis, abscess) or perirenal (ab-

Univ. of California San Diego


Selected reading, see page 41.

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Structural/congenital abnormalities M.A. Linshaw G. Rizzoni Nephromegaly
Structural/congenital abnormalities M.A. Linshaw G. Rizzoni Hyperechoic kidney

/
Hyperechoic kidney
44

Cortical 0 Medullary 0

Diffuse 1 Focal 4 Nephrocalcinosis 5

Large kidney 2 Small-normal size kidney 3

Cystic kidney diseases Chronic renal failure Pyelonephritis Hypercalciuria Cushing syndrome 6
Interstitial nephritis Nephronophthisis Tumors Hyperoxaluria Corticosteroid therapy
Acute tubular necrosis Dysplasia with hypoplasia Xanthinuria Fat deposition
Acute glomerulonephritis Ischemia Medullary sponge kidney Renal candidiasis
Nephrotic syndrome Cortical necrosis Vascular congestion
Malignancy Chronic glomerulonephritis Urate nephropathy
Infections Tamm-Horsfall protein precipitation
Metabolic storage diseases
Renal vein thrombosis

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Neonatal hyperechoic kidney with normal GFR

Univ. of California San Diego


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1 Kidneys on US are normally hypoechoic GN and NS (especially in congenital nephrotic syn- are furosemide toxicity, particularly in premature or
compared to the liver and spleen. In neonates, the kid- drome) may cause hyperechoic renal enlargement. newborn infants, distal renal tubular acidosis, vitamin
neys are generally isoechoic to these organs, but not Infiltrative diseases such as leukemia, infectious pro- D and A toxicity and hyperparathyroidism. In medul-
hyperechoic. The relative increase in echotexture of cess (candida, tuberculosis), glycogen storage disease lary sponge kidney, hypercalciuria is not typical, but
the infant kidney cortex has been ascribed to the rela- type 1 (Von Gierke) and tyrosinemia may lead to large does occur. In general, nephrocalcinosis occurs with
tively increased density of glomeruli/cortical area. Glo- hyperechogenic kidneys. hypercalciuria or hypercalcemia in the presence of
merulogenesis ceases after 3436 weeks of gestation. RVT causes a large congested, hemorrhagic, edema- factors favoring urinary or tissue Ca precipitation.
Thereafter, although there is increase in glomerular tous, echogenic kidney that may calcify. Edema and Medullary calcification usually starts in the fornices at
size, increase in cortical mass is largely a reflection of hemorrhage give an early hyperechoic appearance the tip of the pyramid and then spreads throughout the
tubular growth. Echogenicity decreases as tubular and cause nephromegaly. pyramid. Hyperechoic pyramids with calcifications are
growth expands, more filtrate fills the larger tubules, We occasionally see large hyperechoic kidneys in ill brighter than other causes of hyperechogenicity.
tubules further separate glomeruli, and tissue inter- neonates without renal dysfunction that normalize
faces that reflect sound waves become more spread over several weeks to months by sonography. Thus, 8 Medullary hyperechogenicity not related to
apart. Echogenicity gradually decreases until ~6 it is appropriate to be patient and avoid immediate nephrocalcinosis is seen with Cushing syndrome and
months of age at which point virtually all normal kid- prediction of future renal problems to parents. steroid therapy, from fat deposition, renal candidiasis,
neys are hypoechoic to liver and spleen except for the vascular congestion (papillary necrosis, sickle-cell
renal sinus area. Fat is normally echogenic. In contrast 5 In general, hyperechoic small kidneys are anemia), medullary infection and fibrosis. Urate
to the adult, the neonatal central renal sinus has little scarred and fibrotic. Diseases include chronic glomer- nephropathy causes hyperechoic kidneys with distal
fat and its area of echogenicity is much smaller. The ulonephritis or pyelonephritis, Alport syndrome, cysti- nephron urate deposition, but echogenicity is not
medullary pyramids are hypoechoic, prominent in the nosis, nail-patella syndrome, nephronophthisis, HUS, limited to the medulla. A non-nephrocalcinotic cause
newborn kidney and help define corticomedullary renal dysplasia, and ESRD. Clinical history or physical of medullary hyperechogenicity is precipitation of
differentiation. or laboratory findings help define the diagnosis. Corti- Tamm-Horsfall protein, usually in dehydrated neo-
The appearance of pathologic hyperechogenicity on cal necrosis and malignant hypertension may lead to a nates. Acute renal insufficiency may occur, but is
renal US reflects a temporary or permanent patho- small, hyperechoic kidney. In the infant, small hyper- usually quickly reversible (as is the hyperechogenicity)
logic state, but the echoic pattern is not diagnostic of echoic kidneys are seen in dysplastic renal disease and not likely to require dialysis or cause renal dam-
any specific disease. associated with hypoplasia and in renal ischemic corti- age. Echogenic kidneys with urate or Tamm-Horsfall
cal and medullary necrosis. Cortical echogenicity does protein deposition are usually enlarged.
2 The hyperechoic kidney requires follow-up of not correlate with the severity or type of glomerular
renal structure and function with therapy directed lesions on biopsy, but does correlate with the severity
toward the specific illness. History and physical exam of interstitial lesions. Selected reading
usually point to the diagnosis. Hyperechoic kidneys
may be small, normal-sized or large. In addition, 6 Focal areas of cortical hyperechogenicity Cheidde L, Ajzen SA, Tamer Langen CH,
hyperechogenicity may be cortical or medullary and may occur with tumors (e.g. angiomyolipoma, Christophalo D, Pfeferman Heilberg I: A critical
can be focal or diffuse. Edematous, infectious and mesoblastic nephroma, rhabdoid tumor of kidney) or appraisal of the radiological evaluation of
infiltrative states should improve with specific therapy, infection (pyelonephritis). nephrocalcinosis. Nephron Clin Pract 2007;106:
but hyperechoic kidneys due to scarring/fibrosis will c119c124.
not recover. 7 Diffusely hyperechogenic renal pyramids Karlowicz MG, Adelman RD: What are the possible
generally indicate medullary nephrocalcinosis. Nor- causes of neonatal nephrocalcinosis? Semin
3 Diffuse cortical hyperechogenicity, in con- mal size and corticomedullary architecture is usually Nephrol 1998;18:364367.
trast to medullary involvement, is rare in infants, but maintained in these kidneys. Ultrasonography is more Kasap B, Soylu A, Turkmen M, Kavukcu S:
not uncommon in older children. It can be categorized sensitive than plain film radiography for detecting Relationship of increased renal cortical echogenicity
by kidney size (large or small-to-normal). renal calcifications and nephrocalcinosis. High-resolu- with clinical and laboratory findings in pediatric
tion computed tomography without contrast is even renal disease. J Clin Ultrasound 2006;34:339342.
4 Large hyperechoic kidneys in the infant occur more sensitive than sonography. Karlowicz and Adel- Makhoul IR, Soudack M, Smolkin T, Sujov P,
with autosomal recessive or dominant forms of poly- man provide a convenient way to categorize nephro- Epelman M, Eisenstein I, Magen D, Zelikovic I:
cystic kidney disease, glomerulocystic disease, and calcinosis in infants, depending on whether the patient Neonatal transient renal failure with renal medullary
45 is normo- or hypercalcemic and normo- or hypercal- hyperechogenicity: clinical and laboratory features.
diffuse cystic renal dysplasia. In ARPKD and medullary
cystic kidney disease, the hyperechogenicity may ciuric. Hereditary disorders leading to hypercalciuria Pediatr Nephrol 2005;20:904949.
actually be more prominent in the medulla. Large with or without hypercalcemia include William, Bartter, Marks SD, Massicotte MP, Steele BT, Matsell DG,
hyperechoic kidneys are seen in acute TIN and in acute Liddle and Lowe syndromes, primary hyperoxaluria Filler G, Shah PS, Perlman M, Rosenblum ND,

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tubular necrosis (myoglobinuria, hemoglobinuria). types 1 and 2, distal renal tubular acidosis with neuro- Shah VS: Neonatal renal venous thrombosis: clinical
Other relatively common renal diseases such as acute sensory deafness and Dents disease. Other causes outcomes and prevalence of prothrombotic

Univ. of California San Diego


disorders. J Pediatr 2005;146:811816.

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Structural/congenital abnormalities M.A. Linshaw G. Rizzoni Hyperechoic kidney
Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Cystic kidneys

/
Cystic kidneys
46

Polycystic kidney disease 0 Glomerulocystic kidney disease 3 Hereditary Medullary cystic disease
malformation syndrome 6

Autosomal-dominant Autosomal-recessive Non syndromal 4 With malformation syndrome 5 Juvenile nephronophthisis Medullary sponge
polycystic kidney disease 1 polycystic kidney disease 2 Medullary cystic disease 7 kidney 8

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Univ. of California San Diego
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1 Cystic kidneys may be found in numerous clinicopathologi- antenatal ultrasound can show enlarged hyperechogenic kidneys which is an autosomal dominant disorder with chronic interstitial
cal entities which are very different from each other. Once cystic with oligo- or anhydramnios. Cysts are normally very small (<2 mm) nephritis, medullary cysts, marked thickening of tubular basement
kidneys are found, usually by sonography, the following information but, with increasing age, may become larger, usually <2 cm. Portal membrane, was mapped. This gene encodes to the uromodulin pro-
and clinical data must be carefully obtained: complete family and fibrosis is always present and, with time, may lead to the clinical pic- tein. Mutations in this gene lead to FJHN as well as to MCKD2 and to
personal history; physical examination and BP measurement; renal ture of portal hypertension. The gene responsible for ARPKD called GCKD with hyperuricemia and isosthenuria. In fact, it is now sug-
function (glomerular and tubular) evaluation; renal and liver US in PKHD1, identified on chromosome 6 p 21, encodes fibrocystin, a gested that FJHN and MCKD type 2 are facets of the same disease.
the child and in the parents. The most important renal cystic disor- transmembrane protein. Severe cases (neonatal and infantile form)
ders are PKD, GCKD, cystic kidneys with a hereditary malformation map to the same region as milder forms who survive; the major 10 MSK consists of the dilatation of collecting ducts (sponge-
and medullary cystic disease. It is often difficult to distinguish problems are declining renal function, severe arterial hypertension like appearance). Most cases are sporadic and the prevalence in the
between the various cystic disorders, especially if family history is and portal hypertension. general population, although unknown, is estimated to be from
unremarkable and US is normal in the parents. Multiple large bilat- 1:5,000 to 1:20,000. MSK is often an asymptomatic and benign condi-
eral cysts will orientate toward ADPKD; very enlarged hyperecho- 5 Bilateral GCKD is a rare disorder characterized by glomeru- tion, but hematuria, urinary tract infection and nephrolithiasis may
genic kidneys in an infant with chronic renal failure and/or arterial lar cysts, i.e. dilated Bowmans spaces with normal tubules; GCKD is be present. Concentrating and acidification defects and hypercalci-
hypertension will suggest ARPKD; a significant concentrating defect a heterogeneous group of entities which may be isolated (nonsyn- uria may be present. MSK can be diagnosed by intravenous pyelog-
with or without chronic renal failure with non enlarged kidneys and dromal) or associated with malformation syndromes. The diagnosis raphy which shows dilated collecting tubules (brush-like pattern).
no hypertension may be suggestive of GCKD or of medullary cystic can only be obtained histologically.
disease.
6 Primary, nonsyndromic GCKD can be transmitted as an
Selected reading
2 PKD is an inheritable cystic disorder involving both kidneys autosomal-dominant disease or can be sporadic. There are two
and without dysplasia. Both ADPKD and ARPKD can be found in genetically transmitted entities that lead to GCKD: the renal cysts Gambaro G, Feltrin GP, Lupo A, Bonfante L, DAngelo A,
infants and children; clinical presentation may often be very similar and diabetes syndrome that is associated with mutations in the Antonello A: Medullary sponge kidney (Lenarduzzi-Cacchi-Ricci
and, therefore, it may not be easy to differentiate the two entities hepatocyte nuclear factor-1b gene, and GCKD with hyperuricemia disease): a Padua Medical School discovery in the 1930s.
especially if no renal or liver abnormalities are found in the parents and isosthenuria caused by mutations in the gene encoding uro- Kidney Int 2006;69:663670.
or grandparents. In this case, liver or kidney histology should be modulin also known as Tamm-Horsfall glycoprotein. Lens XM, Banet JF, Outeda P, Barrio-Luca V: Novel pattern of
examined. An exact diagnosis is also important for an appropriate mutation in uromodulin disorders: autosomal dominant medullary
genetic counseling. 7 GCKD can be syndromal and part of syndromes such as cystic kidney disease type 2, familial juvenile hyperuricemic
Zellweger, short rib polydactyly, oral-facial-digital type I, trisomy 13, nephropathy, and autosomal dominant glomerulocystic kidney
3 In ADPKD, cysts arise from all segments of the nephron and brachymesomelia. disease. Am J Kidney Dis 2005;46:5257.
their size is often >2 cm. Renal involvement may be asymmetrical. Rossetti S, Harris PC: Genotype-phenotype correlations in
The prevalence is very high (1/200 to 1/1,000). Two genes are involved 8 Cystic kidneys may be found frequently in the presence of autosomal dominant and autosomal recessive polycystic kidney
in ADPKD: PKD1, which encodes for the polycystin-1 protein, is tuberous sclerosis, Jeune asphyxiating thoracic dysplasia, von disease. J Am Soc Nephrol 2007;18:13741380.
responsible for approximately 85% of cases. PKD2 encodes for poly- Hippel-Lindau syndrome and in those syndromes already mentioned Simons M, Walz G: Polycystic kidney disease: cell division without
cystin-2. ADPKD due to mutation in PKD2 show a milder clinical for GCKD. a c(l)ue? Kidney Int 2006;70:854864.
picture with later onset. Prenatal ultrasound can show, in a minority Wilson PD: Polycystic kidney disease. N Engl J Med 2004;350:
of cases, enlarged hyperechogenic kidneys, with or without cysts. 9 In medullary cystic disease cysts are exclusively situated in 151164.
Postnatally, in rare cases, there is severe clinical involvement at birth the medulla and, especially, at the corticomedullary junction and
or in infancy; most often, ADPKD is suspected when bilateral renal arise from the convoluted distal and collecting tubules. Despite the
cysts are found on US in an asymptomatic child. Extrarenal manifes- name, in many cases cysts may not be found on ultrasound or may
tations (liver, pancreas or ovarian cysts, cardiac valvular abnormali- only be detected later in life. The nephronophthisis-medullary cystic
ties, cerebral aneurysms) are very rare in the pediatric age. If renal disease (NPH-MCKD) complex is characterized by polyuria, polydip-
and liver ultrasound in the parents (older than 30) is normal, the pos- sia, anemia, growth retardation, chronic renal failure, corticomedul-
sibility of ADPKD due to a de-novo mutation should be considered lary cysts as well as interstitial fibrosis with thickening and thinning
(this is the case in approximately 5% of the patients with ADPKD). of the tubular basement membrane. Juvenile NPH is an autosomal
Asymptomatic children should be checked annually (physical exami- recessive disease and can occur with ocular, liver, skeletal and cer-
nation, blood pressure measurement, urinalysis) keeping in mind the ebellar abnormalities; it is due to mutations in at least three different
possible complications of urinary tract infectious and renal calculi. loci: NPHP1 in chromosome 2, NPHP2 in chromosome 9 and NPHP3
47 in chromosome 3 (adolescent NPH). MCKD is inherited as an autoso-
4 In ARPKD, renal cysts arise only from the collecting ducts; a mal-dominant trait, causes chronic renal failure at a later age (3060
varying degree of periportal fibrosis and biliary dysgenesis is always years of age) and may be associated with hyperuricemia and gout.
present. The great majority of cases are diagnosed in the pediatric Two separate genes, MCKD1-MCKD2, on chromosome 1 and chro-

198.143.33.65 - 8/6/2015 3:20:59 PM


age but a very small proportion can also be found in adults. ARPKD mosome 16, respectively, can cause the disease. Renal histology is
is much rarer than APKD (1:10,000 to 1:40,000). In very severe forms, indistinguishable from that in NPH. Recently, the gene for FJHN

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Structural/congenital abnormalities G. Rizzoni M.A. Linshaw Cystic kidneys
Structural/congenital abnormalities M.A. Linshaw G. Rizzoni Renal mass

/
Renal mass
48

Normal/physiological 0 Fluid collection, infection 1 Renal anomaly Renal anomaly Tumor 4 Cystic lesion 5
no hydronephrosis 2 hydronephrosis 3

Prominent fetal lobulation Abscess (intrarenal/extrarenal) Duplex kidney UPJ obstruction Wilms ARPKD
Column of Bertin Hematoma Horseshoe kidney UVJ obstruction Mesoblastic nephroma ADPKD
Renal hypertrophy Urinoma Pelvic kidney PUV Malignant rhabdoid MCDK
Xanthogranulomatous/ Crossed, ectopia Prune-belly syndrome Clear-cell sarcoma Cystic nephroma
renal malakoplakia Angiomyolipoma GCKD
Renal cell carcinoma Lymphangiectasis

Confirm: US or CT US, CT, culture, antibiotics, Abdominal CT; US, VCUG, MAG-3 diuretic Radiographic study; Abdominal CT, DMSA
surgery, fluid (creatinine), nuclide scan to confirm and DMSA scans, CT abdomen/chest, scan for function, tissue
tissue, observation as needed ectopic kidney; VCUG for UTI antegrade pyelogram; brain MRI, abdominal US, for accurate diagnosis
or later hydronephrosis cystoscopy, IVP IVP, bone scan skeletal survey;

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tissue diagnosis

Univ. of California San Diego


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1 Renal mass is noted by palpation of an abdominal/flank mass 5 Urinary tract obstruction may present as a flank/abdominal such as acute lymphoblastic leukemia and lymphoma may lead to dif-
or by radiographic study. Most renal masses cause renomegaly and mass or distended bladder in an infant or may be found at evaluation fuse unilateral or bilateral nephromegaly from renal infiltration or dis-
are easier to feel in infants. History and physical examination with labo- for UTI, abdominal or flank pain or hematuria. UPJ obstruction is the crete intrarenal or hilar mass lesions. Rare causes of renomegaly in-
ratory and radiological studies may allow diagnosis without biopsy/ most common cause of hydronephrosis and nephromegaly in the new- clude renal adenomatosis, histiocytic medullary reticulosis, Castleman
surgery in many cases. Radiographic studies include renal/bladder US, born. It can be seen antenatally by US, usually presents as a palpable disease and renal cell carcinoma.
CT, MRI, VCUG, nuclear scan-MAG-3 with/without furosemide and abdominal mass and often resolves spontaneously in 612 months.
DMSA. IVP and magnetic resonance urography help define complex Other etiologies leading to hydronephrosis with nephromegaly in chil- 7 Renomegaly occurs in several cystic diseases. ARPKD may
anatomic problems associated with tumors, anomalies or obstruction. dren include ureterovesical junction obstruction; VUR and posterior present in utero with large, hyperechoic kidneys, oligohydramnios, no
IVP is still useful when one needs to limit radiation exposure from CT. urethral valves. Prune-belly syndrome occurs mostly in males. In utero bladder visualization and negative family history. Most affected chil-
US shows if the mass is unilateral or bilateral, cystic or solid, and if re- prostatic urethral obstruction or urethral hypoplasia may be causative dren progress to renal failure in childhood although mild disease can
nal contour is normal or distorted. A MAG-3 furosemide scan with ure- in a majority of cases. Features include oligohydramnios, hydronephro- be undiagnosed for years. Neonatal ADPKD can cause large, hyper-
thral catheter helps identify functional obstruction. VCUG is used to sis, renomegaly, dilated and tortuous ureters, dilated prostatic urethra, echoic kidneys with/without visible cysts. Cysts may initially be unilat-
view bladder and urethral anatomy and VUR. VUR, bilateral cryptorchidism and hypoplastic lower abdominal mus- eral. Patients are often asymptomatic early in the disease with cysts
cles. Bladder is large and atonic and abdominal wall lax, wrinkled and noted on an US done because a parent is affected. Cysts may present
2 Renomegaly from renal hypertrophy occurs in response to offers no resistance to palpation. The syndrome is suspected antena- as abdominal pain, mass, hematuria, hypertension or UTI. Extrarenal
congenital/acquired solitary kidney or unilateral reduction in renal tally by finding cystomegaly on US as early as 1214 weeks of gesta- problems include mitral valve prolapse, cysts in liver, ovary, spleen and
function. Hypertrophy starts minutes after loss of a healthy kidney and tion. Renal dysplasia is common. Nephrolithiasis is the most common pancreas, hernias and cerebral aneurysms. MCDK, a severe renal dys-
takes months to complete. Two benign conditions may resemble a acquired condition leading to hydronephrosis and renomegaly in chil- genesis, is the most common cause of neonatal abdominal mass. In
mass. Palpable persistent fetal lobulation in a child is clarified by US. dren. Intrarenal obstruction without hydronephrosis occurs when pig- MCDK, there is no renal sinus or functioning parenchyma and there is
A prominent Bertin column is differentiated from tumor by US (with mented casts or crystals occlude tubule lumens. With dehydration and an atretic or nonpatent ureter. Contralateral anomalies, e.g. VUR and
agents to enhance vascularity) or CT. acidic urine, hemoglobinuria, myoglobinuria and hyperuricosuria all UPJ, are common. VCUG and nuclear scan can confirm lack of VUR and
can cause acute renal failure and renomegaly. Work-up is designed to function. Tuberous sclerosis, an autosomal-dominant neurocutaneous
3 Acute bacterial infections with nephromegaly may be classi- look for functional obstruction and VUR. It is important to check for hamartomatosis, involves skin, heart, retina, central nervous system
fied as intrarenal (pyelonephritis, abscess) or perirenal (abscess). Acute posterior urethral valves that can cause unilateral hydroureter and hy- and kidney. Renal lesions include angiomyolipomas (~50% of patients)
renal infection may be classified from CT findings as (1) pyelonephritis dronephrosis and to rule out higher, unsuspected ureteral lesions with with fat, smooth muscle, and abnormal vessels that are often bilateral
(large kidney with global decreased parenchymal enhancement), (2) IVP or antegrade pyelogram. and best evaluated with CT, and large cysts (~20% of patients) resem-
bacterial nephritis (striated or wedge-shaped zones or ill-defined areas bling ADPKD. Glomerulocystic disease includes entities with glomeru-
of low attenuation), or (3) renal abscess (well-defined noncystic area of 6 Renal mass is common in tumors. Wilms tumor (nephroblas- lar (not tubular) cysts that are typically dilated Bowmans capsules with
low attenuation that may have a fibrous capsule). All may be unilateral toma), ~85% of renal tumors, is the most common tumor leading to an aborted/primitive glomerulus. Cysts are cortical, not medullary, a
or bilateral. One expects a good response to antibiotics for acute pyelo- nephromegaly in children. In addition to laboratory data, work-up in- finding differentiating this from other cystic diseases. Infants may pre-
nephritis or type A bacterial nephritis. Bacterial nephritis type B is likely cludes US, chest film, skeletal survey and abdominal/chest CT. sent with abdominal masses (cystic kidneys by US) and renal insuf-
to be associated with a protracted response to antibiotics and may lead Radiological study may miss contralateral renal tumors. Thus, surgical ficiency. The disease can be sporadic or inherited and mild or present
to abscess formation. A renal/perirenal abscess will likely require surgi- exploration of contralateral kidney may be needed. Nephroblastomato- later in life with hypertension or flank pain.
cal drainage. In renal malakoplakia/xanthogranulomatous pyelonephri- sis (residual metanephrogenic tissue in a mature kidney) causes reno-
tis, a form of chronic interstitial nephritis, patients have recurrent UTI, megaly. These can regress to fibrous tissue, mature to tubules and
sometimes massive renomegaly and a nonfunctioning avascular mass. glomeruli, or become malignant (e.g. Wilms tumor) although the usual Selected reading
Destroyed renal parenchyma is replaced by yellowish-brown soft infil- course of nephroblastomatosis is regression before malignancy. Other
trate of bacteria, inflammatory cells, lipid-laden histiocytes and calculi. renal tumors are usually unilateral and solid. Congenital mesoblastic Ahmed HU, Arya M, Levitt G, Duffy PG, Mushtaq I, Sebire NJ:
Clinical findings include fever, night sweats, loin pain, abdominal mass, nephroma (leiomyomatous hamartoma), the most common solid tu- Part I: Primary malignant non-Wilms renal tumours in children. Lan-
fatigue, weight loss, anemia, hematuria, and leukocytosis. US shows mor of newborns, is usually benign and tends to present in infants un- cet Oncol 2007;8:730737.
multiple anechoic or hypoechoic corticomedullary masses and der 3 months of age. Neuroblastoma is usually solid, may have calcifi- Avner ED, Sweeney WE Jr: Renal cystic disease: new insights for the
contracted renal pelvis. CT may reveal a staghorn calculus obscured cations or cysts and must be differentiated from primary renal tumor. clinician.
sonographically by peripelvic fibrosis. The lesion can be diffuse, Clear-cell sarcoma typically presents in a 3- to 5-year-old child, has a Becker A, Baum M: Obstructive uropathy. Early Hum Dev 2006;
segmental or focal. Surgery is often needed as the lesion resembles poor prognosis and tends to metastasize to bone and brain. Work-up 82:1522. Curr Opin Urol 2007;17:281286.
malignancy and histological diagnosis is essential. includes brain MRI, bone scan, skeletal survey and abdominal/chest CT. Driscoll K, Isakoff M, Ferrer F: Update on pediatric genitourinary on-
Malignant rhabdoid tumor is usually large, originates in the central hilar cology. J Nephrol 2002;15:597600.
4 Anomalies that may present as a mass and are generally not area, replaces the whole kidney, metastasizes mainly to lung, brain, liv- Karadeniz C, Oguz A, Ataoglu O, Citak C, Buyan N, Pinarli G,
49 associated with hydronephrosis include duplex kidney, horseshoe kid- er and has median presenting age ~11 months. Chest/abdominal CT Ozkaya O, Kapucu O: Primary renal lymphoma and xanthogranulo-
ney, pelvic kidney and crossed (fused or nonfused) ectopic kidney. and brain MRI are needed. Multilocular cystic nephroma presents as matous pyelonephritis in childhood. Pediatr Clin North Am
These conditions are seen on abdominal US or CT. While they are usu- benign multilocular cyst or as a cystic lesion with stroma containing 2006;53:889909.
ally benign, problems such as abdominal/pelvic discomfort, UTI, partially differentiated blastema cells. The latter may have Wilms tu- Zugor V, Schott GE, Labanaris AP: Xanthogranulomatous
kinked ureter or hydronephrosis can occur over time and periodic im- mor nodules and is indistinguishable from cystic Wilms tumor without pyelonephritis in childhood: a critical analysis of 10 cases and of the

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aging with US is useful. biopsy. Most children present these tumors from 324 months of age. literature. Urology 2007;70:157160.
In addition to the tumors mentioned above, hematologic malignancies

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Structural/congenital abnormalities M.A. Linshaw G. Rizzoni Renal mass
Hypertension S. Turi A.L. Friedman Neonatal hypertension

/0
Neonatal hypertension
50 Clinical Features

Accutely ill neonate Less acutely ill neonate


Congestive heart failure Unexplained irritability
Cardiogenic shock Failure to thrive 5
Intracranial hemorrhage
Life-threatening conditions

History Physical examination


Case and family histories Dysmorphic features, heart murmur, cyanosis, dyspnea/tachypnea,
Medical procedures (e.g. umbilical artery catheterization) tachycardia, hepatosplenomegaly

Generally useful Useful in selected infants


Serum: CBC, BUN, creatinine, electrolytes, calcium Serum: PRA, cortisol, thyroid studies, aldosterone
Urine: urinalysis ( culture) Urine: catecholamines
Imaging: chest X-ray, echocardiogram renal sonogram and Doppler study Imaging: abdominal/pelvic sonogram, voiding cystourethrography,
CT angiogram, nuclear scan (DTPA/Mag-3/DMSA)

Renal Renovascular 1 Cardio-pulmonary 2 Endocrine Drugs 3 Neurologic 4 Tumors Miscellaneous

Congenital Thromboembolism Coarctation of aorta Congenital adrenal Glucocorticoids Pain Wilms tumor TPN
PKD (AD, AR) Renal artery stenosis BPD hyperplasia Theophylline Elevated intracranial Mesoblastic Hypercalcemia
MCDK Mid-aortic coarctation Hyperthyroidism Caffeine pressure (intracranial nephroma Postclosure of
Obstructive uropathy RVT Gordon syndrome Vitamin D intoxication hemorrhage, Neuroblastoma abdominal wall defect
Acquired Congenital rubella syndrome Maternal drug abuse hydrocephalus, etc.) ECMO
Acute tubular necrosis (cocaine, heroin) Seizures

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Cortical necrosis
HUS

Univ. of California San Diego


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1 BP is low at birth. It increases with age, by 90 Upper 95% CI
80 Selected reading
1 mm Hg per day within the period of 38 days. It rises

Systolic BP (mm Hg)


70
by about 1 mm Hg per week between ages 5 and 6 Brewer ED: Evaluation of hypertension in childhood
60
weeks. At a later age, systolic BP is around 95 10 mm diseases; in Avner ED, Harmon WE, Niaudet P (eds):
50
Hg. Hypertension is a rare condition in the neonate. 40 Lower 95% CI
Pediatric Nephrology, ed 5. Philadelphia, Lippincott
Neonates with hypertension are at a high risk of devel- 30 Williams & Wilkins, 2004, pp 11791198.
oping cardiorespiratory failure and cerebral distress. 20 Cordero L, Timan CJ, Waters HH, Sachs LA: Mean
In a neonate or infant, the BP is considered to be 10 arterial pressures during the first 24 hours of life in
elevated if it is above the 95th percentile for infants of 0 < or = 600-gram birth weight infants. J Perinatol
similar gestational or postconceptual age and size. 22 24 26 28 30 32 34 36 38 40 42 2002;22:348353.
For older infants (112 months), hypertension could be Gestational age (weeks) Flynn JT: Neonatal hypertension: diagnosis and
defined as blood pressure elevation above the 95th 70 management. Pediatr Nephrol 2000;14:332341.
percentile for infants of similar age, size and gender. 60 Upper 95% CI
Friedman AL, Hustead VA: Hypertension in babies

Diastolic BP (mm Hg)


50
following discharge from a neonatal intensive care
2 The actual incidence of hypertension in unit. Pediatr. Nephrol 1987;1:3034.
40
neonates is between 0.2 and 3%. As opposed to older Lee J, Rajadurai VS, Tan KW: Blood pressure
30 standards for very low birth weight infants during
children in whom hypertension is most commonly Lower 95% CI
caused by renal or endocrine disorders, in neonates 20 the first day of life. Arch Dis Child Fetal Neonatal Ed
the common causes of hypertension are renovascular 10 1999;81:168170.
disease, cardiac malformations, as well as broncho- 0 Zubrow AB, Hulman S, Kushmer H, Falkner B:
pulmonary dysplasia. 22 24 26 28 30 32 34 36 38 40 42 Determinants of blood pressure in infants admitted
Gestational age (weeks) to neonatal intensive care units: a prospective
3 Umbilical artery catheter is the most com- multicenter study. J Perinatol 1995;15:470479.
mon cause of hypertension in neonates. The catheter
may lead to thrombus formation. The thrombi may
embolize to the kidneys, causing areas of infarction
and increased release of renin, which, in turn, elevates
blood pressure. RVT is a relatively common cause of
hypertension in asphyxiated or hypovolemic infants, Table. Commonly used drugs for the treatment of neonatal hypertension
infants with coagulopathies, as well as in infants of
Drug Class Dose Route Comments
diabetic mothers.
Diazoxide vasodilator 25 mg/kg per dose rapid bolus injection slow injection ineffective, duration
4 Coarctation of the aorta is the most common (arteriolar) unpredictable, use with caution, may cause
rapid hypotension
heart malformation that leads to hypertension in neo-
nates. The hypertension in this condition is found in Enalaprilat ACE inhibitor 528 g/kg/day i.v. injection over may cause prolonged hypotension and
the upper extremities. 510 min acute renal insufficiency
The etiology of hypertension in BPD is probably
multifactorial and includes prolonged glucocorticoid
Esmolol -blocker drip: 100300 g/kg i.v. infusion very short-acting constant infusion
administration and chronic hypoxia. per min necessary

Hydralazine vasodilator bolus: 0.150.6 mg/kg i.v. bolus or tachycardia frequent side effect;
5 Various drugs may cause hypertension in (arteriolar) per dose infusion must administer q 4 h when given i.v. bolus
neonates, either by direct administration to the sick drip: 0.755.0 g/kg
neonate (glucocorticoids, theophylline), or due to per min
maternal drug abuse that leads to hypertension in their
Labetalol - and -blocker 1.203.0 mg/kg per h i.v. bolus or heart failure, BPD relative contraindications
infant child (e.g. heroin, cocaine).
constant infusion
51
6 A common cause of hypertension in prema- Nicardipine Ca2+ channel blocker 13 g/kg per min constant infusion may cause reflex tachycardia
ture infants is intracranial hemorrhage.
Sodium vasodilator 0.510 g/kg per min constant infusion thiocyanate toxicity can occur with

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nitroprusside (arteriolar and prolonged (>72 h) use or in renal failure
venous)

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Hypertension S. Turi A.L. Friedman Neonatal hypertension
Hypertension S. Turi A.L. Friedman Pediatric hypertension

/0
Pediatric hypertension
Evaluation 1
52

Hx and physical examination, ABPM 2


Urinalysis, CBC, serum creatinine and BUN
Serum electrolytes, Ca2+, bicarbonate and uric acid
Renal sonogram, ECG, ophthalmologic examination

Renal 3 Renovascular 4 Endocrine/metabolic 5 Cardiac 6 CNS 7 Drugs Essential 8

Renal sonogram PRA Serum: aldosterone, cortisol, ECG, Echocardiogram Fundus examination Positive family Hx
Voiding cystourethrography Renal Doppler sonogram PRA, TSH, FT4 Cardiac catheterization Brain CT/MRI Normal physical examination
Renal nuclear scan CT angio./angiography Urine: cathecholamines, cortisol Lumbar puncture and workup
(DTPA/MAG-3, DMSA) Imaging: abdominal sonogram,
Renal biopsy MIBG scan

PRAM

Anatomic malformations RVT Low plasma renin Coarctation of aorta Brain trauma Glucocorticoids Positive genetic analysis
Reflux/obstructive Renal artery stenosis Cushing syndrome Brain tumor Vitamin D (in selected cases)
nephropathy (fibromuscular dysplasia, Primary hyperaldosteronism CNS bleeding Cyclosporin A
Renal trauma neurofibromatosis, etc.) Liddle syndrome Pseudotumor cerebri Oral contraceptives
Renal tumors Umbilical artery catheter Gordon syndrome Guillain-Barr syndrome Sympathomimetics
No anatomic malformations (in neonate) Apparent mineralocorticoid excess Familial dysautonomia Amphetamines
Pyelonephritis Takayasu arteritis Glucocorticoid-remediable aldosteronism Cocaine
Hemolytic-uremic syndrome Moyamoya disease Congenital adrenal hyperplasia Heavy metal poisoning
Glomerulonephritides (hypertensive forms)
Vasculitides Normal plasma renin
Pheochromcytoma
Hyperthyroidism
Hypercalcemia

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Treatment 9

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1 Hypertension in children is an overlooked and relatively 4 ABPM is the measurement of BP values over a 24-hour pe- 11 For children and adolescents with essential hypertension,
common condition. Its prevalence is riod preferably at home while the child maintains his ordinary activi- nonpharmacologic therapies (diet, salt restrictions and physical ac-
1.213% depending on the studied population of children. Pediatric ties. ABPM is recommended when there are large fluctuations in BP tivity) are usually effective in reducing BP. However, because of ei-
hypertension is a leading risk factor for cardiovascular disease, renal values, for follow-up after changes in treatment, or when white-coat ther end-organ involvement (particularly left ventricular hypertro-
disease, and stroke later in life. hypertension is suspected. phy) or unwillingness to change lifestyle, antihypertensive medica-
Blood pressure values in children are defined and classified as fol- tions are often needed. Severe hypertension should be promptly
lows: 5 Renal diseases are the most common causes of secondary treated, pharmacologically or later, if indicated, surgically. Blood
Normal BP: Average systolic or diastolic BP below the 90th percentile hypertension in children (see appropriate algorithms for details). pressure should not be normalized immediately but initially lowered
for age, gender, and height. to a safe level.
Borderline hypertension: Average systolic or diastolic BP between 6 The combination of elevated BP with the laboratory find- The therapy of secondary hypertension includes the treatment of the
the 90th and 95th percentiles for age, gender, and height. ings of hypokalemia, metabolic alkalosis, and elevated plasma renin basic disease as well as the hypertension itself. Often multiple class-
Hypertension: Average systolic or diastolic BP greater than the 95th and aldosterone levels in children is most commonly due to renovas- es of drugs must be used. Major classes of antihypertensive drugs
percentile for age, gender, and height. cular disease. The most common etiologies of renovascular diseases commonly used in children include: calcium channel blockers, diuret-
Hypertensive emergency: Markedly elevated BP accompanied by are renovascular changes secondary to umbilical artery catheter in ics, -blockers, vasodilators and ACE inhibitors. For dosage, side ef-
acute end-organ damage (seizures, encephalopathy, heart failure, newborn infants and fibromuscular dysplasia in older children. Other fects and contraindications see Selected reading.
etc.). less common causes of renovascular hypertension are listed in this
White-coat hypertension: Elevated BP measurements in the presence algorithm. Selected reading
of health care professionals but normotension at other times.
For BP values by age, gender and height see reference below [Pediat- 7 Endocrine/metabolic disorders leading to hypertension are Bender UJ, Bonilla-Felix MA, Portman RJ: Epidemiology of hyper-
rics 2004;114:555576]. subclassified according to PRA and serum aldosterone levels. For tension; in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Ne-
BP should be routinely measured in high-risk infants from birth, and detailed discussion, see algorithms on Hypokalemia, Hypochlore- phrology, ed 5. Philadelphia, Lippincott Williams & Wilkins, 2004,
in all children from age 3 years on. Measurement of BP should be mia and Metabolic alkalosis. Pheochromocytoma is a (usually be- pp 11251152.
performed by a trained person on a quiet, relaxed child, using an ap- nign) tumor of the chromaffin cells in the adrenal gland or the sym- Ingelfinger JR: The molecular basis of pediatric hypertension. Pe-
propriate-size cuff. The fifth Korotkoff phase should be used for de- pathetic nervous system which secretes excessive amounts of cat- diatr Clin North Am 2006;53:
termination of diastolic BP. Repeated BP measurements in the office echolamines and can lead to severe hypertensive attacks. 10111028.
and at home are necessary to confirm the diagnosis of systemic hy- Lifton RP, Gharavi AG, Geller DS: Molecular mechanisms of human
pertension. 8 Coarctation of aorta is the most common heart malforma- hypertension. Cell 2001;23:545556.
tion that leads to hypertension in children. The hypertension in this Pappadis SL, Somers MJG: Hypertension in adolescents: a review
2 It is beyond the scope of this text to elaborate on all causes condition is found in the upper extremities. of diagnosis and management. Curr Opin Pediatr 2003;15:370378.
of hypertension in children. Hence, only selected diseases will be Soergel M, Kirschstein M, Busch C, Danne T, Gellermann J, Holl R,
discussed. For discussion of other disorders, see the appropriate al- 9 Any condition leading to increased intracranial pressure Krull F, Reusz GS, Rascher W: Oscillometric twenty-four hour am-
gorithms. Of note, the younger the child and the higher the BP, the will cause systemic hypertension, sometimes accompanied by bra- bulatory BP values in healthy children and adolescents: a multi-
more likely a secondary cause will be found and an earlier and more dycardia and widened pulse pressure (Cushing triad). center trial including. J Pediatr 1997;130:178184.
extensive evaluation should be pursued. Stephens SE, Dillon MJ: The investigation and management of hy-
10 It is increasingly believed that essential (primary) hyperten- pertension. Curr Paediatr 2002; 12:561568.
3 History and physical examination of the child with hyper- sion, the most common cause of hypertension in adolescents and The 4th Report on the Diagnosis, Evaluation, and Treatment of High
tension should include the following systems: Cardiovascular: Palpa- adults, has its roots in early childhood. Family studies have demon- Blood Pressure in Children and Adolescents: National High Blood
tion of femoral pulses, auscultation of murmurs and search for evi- strated that about 2040% of the BP variance observed in the popula- Pressure Education Program Working Group on High Blood Pres-
dence of congestive heart failure. BP must be measured in all 4 ex- tion is determined genetically. However, in most cases, the segrega- sure in Children and Adolescents. Pediatrics 2004;114:555576.
tremities to rule out coarctation of the aorta. tion of BP in families does not follow a Mendelian or single-gene pat- Yagil Y, Yagil C: The search for the genetic basis of hypertension.
Abdomen: The presence of enlarged kidneys, masses or bruits. tern, but it seems to be under the influence of a variety of genetic, Curr Opin Nephrol Hypertens 2005; 14:141147.
Endocrine: Flushing, sweating, weight changes; physical examination demographic, and environmental factors. Several genes have been
should search for thyromegaly, virilization or cushingoid habitus. shown to affect BP (angiotensinogen, renin, ACE, AT1 receptor, nitric
Cutaneous: The presence of caf-au-lait spots, rash, purpura or neu- oxide synthase genes, etc.). The significance and the contribution of
rofibromas. specific polymorphisms as well as variations in function of each of
The workup of the child with hypertension should be rational, se- these genes to final regulation of BP are the subject of current re-
53
quential, disease- oriented and as noninvasive as possible. The initial search.
evaluation of the hypertensive child should include all the tests out-
lined in this section. Additional tests should be reserved for the sub-
sequent evaluation depending on the suspected condition (as out-

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lined in the algorithm).

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Hypertension S. Turi A.L. Friedman Pediatric hypertension
Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Aminoaciduria

/
Aminoaciduria
54

Generalized AA 0 Overflow AA 0 Isolated hereditary AA 1

Cationic AA 2 Neutral AA 3 Imminoaciduria and Dicarboxylic AA 5


glycinuria 4

Fanconi syndrome Inborn errors of Classic cystinuria (types I, II, III) Hartnup disease Imminoglycinuria Dicarboxylic AA
Prematurity amino acid metabolism Lysinuric protein intolerance Methioninuria Isolated glycinuria
Isolated cystinuria Histidinuria
Hyperdibasic AA type I
Isolated lysinuria

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1 Free amino acids circulating in the blood are 5 Hartnup disease, the most common disorder
Selected reading
derived from dietary protein hydrolization, intracellular of the neutral AA group, is an autosomally recessive
peptides catabolism and from de novo synthesis with- inherited disease. It is characterized by intestinal mal- Bergeron M, Goodyer PR, Gougoux A, et al:
in cells. These free amino acids are filtered through the absorption, and massive hyperexcretion of the neutral Pathophysiology of renal hyperaminoacidurias and
renal glomeruli and, under normal conditions, more monoamino monocarboxylic amino acids (alanine, glucosuria; in Seldin DW, Giebisch G (eds): The
than 99% are reabsorbed by the renal tubule, mainly in phenylalanine, serine, theronine, valine, leucine, iso- Kidney: Physiology and Pathophysiology, ed 5.
the proximal tubule (PT). There are several amino ac- leucine, tryptophan, tyrosine, histidine, glutamine and Philadelphia, Lippincott Williams & Wilkins, 2000:
ids transport mechanism in the PT that are character- asparagine). Clinical features usually appear in adoles- 22112233.
ized by their Na+ dependency vs. independency, by the cence or adulthood and they resemble those of pella- Broer A, Cavanaugh JA, Rasko JE, Broer S:
electroneutrality of the transport mechanism or by gra (photosensitive rash, ataxia and psychiatric mani- The molecular basis of neutral aminoacidurias.
their specificity to certain amino acids. festations). The disease is caused by mutations in the Pflugers Arch 2006;451:511517.
gene SLC6A19 which encodes a sodium-dependent Palacin M, Bertran J, Chillaron J, Estevez R,
2 Generalized AA is seen in Fanconi syndrome neutral amino acid transporter, expressed in kidneys Zorzano A: Lysinuric protein intolerance: mecha-
(see appropriate algorithm) and in the urine of prema- and intestine. Methioninuria and histidinuria are ex- nisms of pathophysiology. Mol Genet Metab
ture newborn infants because of the immaturity of the tremely rare disorders reported in very few cases 2004;81(suppl 1):S2737.
tubular transport mechanisms. In addition, overflow worldwide. Seow HF, Broer S, Broer A, Bailey CG, Potter SJ,
AA is due to inborn errors of amino acid metabolism. Cavanaugh JA, Rasko JE: Hartnup disorder is
6 Imminoglycinuria is a benign, autosomal- caused by mutations in the gene encoding the
3 Hereditary AAs are a group of disorders in recessive disorder characterized by urinary excretion neutral amino acid transporter SLC6A19. Nat Genet
which a single or a group of amino acids are excreted of excessive amounts of proline, hydroxyproline and 2004;36:10031007.
in excessive amounts in the urine. These disorders are glycine. Its incidence is 1:15,000 live births. Patients Zelikovic I: Aminoaciduria and glycosuria; in
categorized into 5 major groups according to the trans- are usually asymptomatic. The genetic defect has not Avner ED, Harmon WE, Niaudet P (eds): Pediatric
port pathway affected. Of note, in the algorithm only 4 been identified yet but it is believed to involve the Nephrology, ed 5. Philadelphia, Lippincott
groups are depicts. The fifth, -AA, is found only in transport system, located on the brush-border mem- Williams & Wilkins, 2004, pp 701729.
animals. brane of the proximal tubule that is responsible for the
reabsorption of the amino acids proline, hydroxypro-
4 Cationic AA is divided into 5 disorders. The line and glycine. Isolated glycinuria is an extremely
most common disease, classic cystinuria, is discussed rare condition described in only a few patients so far.
in detail in the appropriate algorithm.
In LPI, a rare autosomal-recessive disorder, excessive 7 Dicarboxylic AA is another benign, autoso-
urinary excretion of dibasic amino acids (especially mal-recessive disorder caused by hyperexcretion in
lysine) is accompanied by poor intestinal absorption of the urine of glutamate and aspartate. The incidence of
these amino acids. Typical clinical pictures of children this disorder is 1:29,000 live births and although be-
with LPI include protein malnutrition, FTT, vomiting, nign in nature, there are rare reports of hypoglycemia
diarrhea, hepatosplenomegaly, hyperammonemia, in patients with dicarboxylic AA, which is corrected by
hypotony and seizures. LPI is caused by a defect in the the administration of glutamate and aspartate. The
gene encoding one of the subunits of system y+L, re- genetic defect is not known but the candidate gene is
sponsible for the efflux of dibasic amino acids from the gene encoding EAAC1, an anionic amino acid
the tubular cells to the blood. Treatment of patients transporter expressed in the kidney and the intestine.
with LPI includes protein restriction as well as oral
supplements of arginine, ornithine and citrulline.
Isolated cystinuria, isolated lysinuria and hyperdibasic
AA type I are very rare disorders. Each one of these
diseases has been reported in only few children world-
wide.
55

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Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Aminoaciduria
Tubular disease P. Goodyer I. Eisenstein I. Zelikovic Cystinuria

/
Cystinuria
(hexagonal crystals in urine; urine cystine >100 mol/g creatinine)

56

Broad aminoaciduria Elevated cystine, ornithine, arginine and lysine 0

Age >2 years Newborn

Persistent cystinuria Partial resolution


>1,200 mol/g creatinine <1,200 mol/g creatinine

Fanconi syndrome Recessive/recessive Dominant/dominant 1 Mixed type Heterozygote (dominant/N)

Nephrolithiasis 2

Passage of stone Persistent stone Multiple stones Obstructive stones

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Conservative measures MPG or penicillamine
(high fluid intake) Lithotripsy, endoscopic surgery

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(urinary alkalinization)

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1 Children with cystinuria may be identified in inherited two mutant SLC3A1 genes. Both types of
Selected reading
screening programs, during evaluation of familial cystinuria have a high risk of recurrent nephrolithiasis
nephrolithiasis or when they present with renal calculi. and usually excrete cystine in the range of 2,5005,000 Goodyer PR, Saadi J, Ong P, Elkas G, Rozen R:
The incidence of cystinuria worldwide is estimated to mol/g creatinine. High fluid intake (about 2.5 l/m2) Cystinuria subtype and the rest of nephrolithiasis.
be about 1:10,000 but may be higher in specific popu- should be advised; this can be individualized by mea- Kidney Int 1998;54:5661.
lations (1:2,000 among newborns in England, 1:2,500 suring the amount of cystine excreted per day and cal- International Cystinuria Consortium: Functional
in Libyan Jews). Normally, >98% of filtered amino culating the amount of fluid needed to dilute the cys- analysis of mutations in SLC7A9, and genotype/
acids is reabsorbed by transport mechanisms in the tine to <1,200 mol/l. Patients who frequently exceed phenotype correlation in non-type I cystinuria.
luminal membrane of proximal tubular cells. However, this theoretic limit of urinary cystine solubility in acidic Hum Mol Genet 2001;10:305316.
in patients who inherit one or more of the cystinuria urine should take 0.52.0 mEq/kg/day of NaHCO3 or Palacin M, Goodyer P, Nunes V, Gasparini P:
genes, the specific transport mechanism shared by potassium citrate to bring urine pH to >7.5, especially Cystinuria; in Scriver C, Beaudet A, Sly W, Valle D
cystine, artinine, ornithine and lysine is defective. The overnight when urine is most concentrated and acidic. (eds): The Metabolic and Molecular Basis of
only clinical consequence is cystine nephrolithiasis. Yearly ulrasonography is warranted after age 5 years. Inherited Disease. New York, McGraw-Hill, 2001,
Cystinuria should be distinguished from a broader On the other hand, children who inherit one recessive vol III, pp 49094932.
Fanconi pattern of aminoaciduria, accompanied and one dominant gene from their parents have the Rogers A, Kalakish S, Desai RA, Assimos DG:
by variable degrees of glucosuria, proteinuria and mixed type of cystinuria and have much lower risk of Management of cystinuria. Urol Clin North Am
phosphaturia. stone formation, requiring less intense monitoring. 2007;34:347362.
Zelikovic I: Aminoaciduria and glycosuria; in
2 At birth, renal tubular reabsorption of amino 4 Pure cystine calculi are radio-opaque and Avner ED, Harmon WE, Niaudet P (eds): Pediatric
acids is not fully mature. There is little effect on nor- often incorporate variable amounts of calcium; they Nephrology, ed 5. Philadelphia, Lippincott
mal infants but children who are carriers of one par- may be identified by ordinary radiography or by ultra- Williams & Wilkins, 2004, pp 701728.
tially dominant (type II or type III) cystinuria gene may sonography. About 4050% of stones recovered from
excrete cystine at exaggerated levels, appearing to be cystinuria patients contain substantial amounts of
homozygotes. Final diagnosis should be delayed; calcium. Prior to starting an alkalinizing agent, hyper-
urine cystine quantification should be repeated at calciuria should be ruled out. Individual risk of nephro-
about 2 years of age. lithiasis cannot be predicted by urine cystine level
alone. If multiple or obstructive stones are identified,
3 Cystinuria has now been attributed to two cystine chelating agents such as MPG (1015 mg/kg/
principal genes. SLC 7A9 encodes the luminal cystine day) or penicillamine (30 mg/kg/day) may be intro-
transporter, itself, and is transmitted as a dominant duced, monitoring carefully for side effects such as
urinary phenotype. If both parents excrete cystine fever, rash, elevation of liver enzymes and proteinuria.
above the normal range (>100 mol/g creatinine), but Partial dissolution may allow the stone to pass, but
less than the stone-forming range (>1,200 mol/g cre- most will require lithotripsy or surgical stone removal.
atinine), the child has inherited two dominant SLC 7A9 Long-term prophylaxis with these agents (vs. high
mutations. By contrast, the SLC3A1 gene encodes a fluid intake plus urinary alkalinization) should be indi-
subunit of the transporter and is transmitted as a vidualized based on compliance, drug tolerance and
recessive urinary phenotype. If both parents excrete severity of recurrent stone disease.
cystine in the normal range, the child has most likely

57

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Tubular disease P. Goodyer I. Eisenstein I. Zelikovic Cystinuria
Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Glycosuria

/
Glycosuria
58

Hyperglycemia 0 Generalized proximal tubular dysfunction Hereditary renal glycosuria 2

Fanconi syndrome ISHG 3 Glucose-galactose malabsorption 4 Fanconi-Bickel syndrome 5


Extreme prematurity 1

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1 Under normal conditions, the reabsorption of 5 ISHG is a benign condition in which the
Selected reading
filtered glucose by the renal tubule is almost complete. glycosuria is the only abnormality, and there is no
Most filtered glucose is reabsorbed in the proximal increase in the urinary excretion of other sugars. This Bergeron M, Goodyer PR, Gougoux A, et al:
convoluted tubule and the rest by proximal straight disorder is caused by a genetic defect in the SGLT2- a Pathophysiology of renal hyperaminoacidurias and
tubule, the loop of Henle, and, to some extent, by the Na+-glucose cotransporter which is located in the glucosuria; in Seldin DW, Giebisch G (eds): The
collecting duct. Reabsorption of glucose across the luminal membrane of the proximal convoluted tubule. Kidney: Physiology and Pathophysiology, ed 3.
proximal tubular cells occurs by an active, carrier- ISHG is transmitted in an autosomally recessive Philadelphia, Lippincott Williams & Wilkins, 2000,
mediated, Na+-dependent process in the apical mem- fashion. Of note, some of these children have massive pp 22112233.
brane and a Na+-independent, facilitated glucose aminoaciduria in addition to the renal glycosuria. Kleta R, Stuart C, Gill FA, Gahl WA: Renal glucosuria
transporter resides in the basolateral membrane. The due to SGLT2 mutations. Mol Genet Metab
evaluation of glycosuria should include determination 6 Glucose-galactose malabsorption is an auto- 2004;82:5658.
of blood glucose levels and the evaluation of proximal somal-recessive genetic disease which is potentially Magen D, Sprecher E, Zelikovic I, Skorecki K: A novel
tubular dysfunction (see algorithms on Fancony syn- lethal. The disorder is caused by a genetic defect in missense mutation in SLC5A2 encoding SGLT2
drome and Renal tubular acidosis). SGLT1, another Na+-glucose cotransporter, which is underlies autosomal-recessive renal glucosuria and
found in the intestine and kidney. The typical clinical aminoaciduria. Kidney Int 2005;67:3441.
2 The human kidney is characterized by a lim- picture of glucose-galactose malabsorption is severe Wright EM, Turk E, Martin MG: Molecular basis for
ited capacity to reabsorb D-glucose. Beyond a certain watery diarrhea starting in the neonatal period. The glucose-galactose malabsorption. Cell Biochem
level of blood glucose level, a maximal rate of renal diarrhea ceases once glucose and galactose are Biophys 2002;36:115121.
glucose reabsorption is achieved and glucose will removed from the diet. Zelikovic I: Aminoaciduria and glycosuria;
appear in the urine. Thus, glycosuria is seen in any in Avner ED, Harmon WE, Niaudet P (eds):
condition leading to hyperglycemia such as diabetes 7 Fanconi-Bickel syndrome is an autosomal- Pediatric Nephrology, ed 5. Philadelphia, Lippincott
mellitus, stress-induced and drug-induced hyperglyce- recessive disorder characterized by Fanconi syndrome Williams & Wilkins, 2004, pp 701729.
mia. and hepatomegaly due to glycogenesis of the liver and
kidneys. The disease is caused by mutation in the
3 Glycosuria is observed in generalized proxi- gene encoding the facilitated glucose transporter
mal tubular dysfunction (Fanconi syndrome). For GLUT2. Glycosuria is a prominent feature of this disor-
details see appropriate algorithm. Glycosuria is often der but unlike the disorders outlined above, it is not
seen in premature newborn infants because of the the sole renal manifestation, and other proximal tubu-
immaturity of the tubular transport mechanisms. lar dysfunctions exist.

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).

59

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Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Glycosuria
Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Renal tubular acidosis

/
Renal tubular acidosis
60 History and physical examination 0
Serum creatinine, Na+, K+, Ca2+, P, HCO3, plasma aldosterone, renin
Urine-urinalysis, osmolarity, Cl, Na+, K+, Ca2+, pH
Renal US

Negative urinary anion gap 1 Positive urinary anion gap 13


[Cl >Na+ + K+] [Cl <Na+ + K+]
Urine pH <5.5
Hypokalemia

Urine pH >5.5 Urine pH <5.5


Hyperkalemia

RTA type 2 (PRTA) 2 RTA type 1 (DRTA) 4 RTA type 4 5

Hypokalemia Hyperkalemia

Inherited causes Secretory or gradient defect Voltage-dependent defect Aldosterone deficiency


Cystinosis Inherited causes Obstructive uropathy Addison disease
Dent disease Marfan syndrome Sickle cell disease Congenital adrenal hypoplasia
Mitochondriopathies Ehlers-Danlos syndrome SLE CAH (salt-losing types)
Fanconi-Bickel glycogenosis Wilson disease Marked volume depletion CMO deficiency type I and II
Tyrosinemia Primary-genetic Amiloride administration Hyporeninemic hypoaldosteronism
Wilson disease Autoimmune disorders Diabetes mellitus
Lowe syndrome Sjogren syndrome Interstitial nephritis
Galactosemia SLE Gordon syndrome (PHA type II)
Hereditary fructose intolerance Chronic active hepatitis Aldosterone resistant
Glycogen storage disease type 1 Primary biliary cirrhosis Pseudohypoaldosteronism
Primary-genetic Rheumatoid arthritis Obstructive uropathy
Drugs Drugs Chronic tubulointerstitial damage
Chemotherapy (cisplatin/ifosfamide) Amphotericin B Drugs (spironolactone, cyclosporin, heparin, amiloride)
Valoproic acid Ifosfamide
Outdated tetracyclines Lithium
Glue sniffing Toluene
Heavy metal poisoning Analgesic abuse
Aminoglycosides

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Disorders of calcium metabolism

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Hyperparathyroidism
Vitamin D deficiency

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1 The kidney is the major organ responsible for acid-base transporters leading to primary isolated RTA have been recognized sterone biosynthesis called CMO deficiency types I and II. Adrenal
homeostasis. This homeostasis is maintained by the renal tubule in in the last years. Autosomal-recessive PRTA associated with ocular cortical failure is observed in Addison disease and in adrenoleuko-
two ways: (1) reabsorption of the filtered HCO 3 (mainly by the proxi- abnormalities, short stature and mental retardation is caused by a dystrophy, which is very rare in children.
mal tubule), and (2) excretion of the H+ produced by the human body genetic defect in the Na+/HCO 3 cotransporter NBC1 located in the Hyporeninemic hypoaldosteronism is observed in patients with dia-
in the distal tubule. When one of these processes is defected RTA basolateral membrane of the proximal tubular cell. An additional betic nephropathy or chronic tubolointerstitial disorders. Although
ensues. There are 3 major types of RTA: type 1 (DRTA), type 2 (PRTA) entity leading to autosomal-recessive PRTA and osteopetrosis is due considered rare in children, hyporeninemic hypoaldosteronism is
and type 4. to mutations in the gene encoding carbonic anhydrase II, a cyto- probably more common in this age group than previously thought.
plasmatic enzyme responsible for the generation of HCO 3 and H+ Gordon syndrome, also called pseudohypoaldosteronism type 2, is a
2 The evaluation of the child with RTA includes obtaining his- from H2O and CO2. The genetic defect in this enzyme, which operates hereditary, autosomal-dominant disorder caused by gain of function
tory regarding abnormal growth pattern, polyuria, recurrent vomit- in both the proximal and distal tubule, can lead to combined distal mutations in the genes encoding WNK1 or WNK4 kinases. The con-
ing, pathologic fractures, psychomental retardation, family history of and proximal RTA (previously known as RTA type 3). sequence of the mutation is increased NaCl reabsorption in the distal
genetic diseases, intrauterine fetal demise or fetal uropathy and drug convoluted tubule which results in hypervolemia, hypertension,
administration. Physical examination includes weight and height 5 RTA types 1 and 4 are characterized by a positive urinary hyporeninemic hypoaldosteronism, hyperkalemia and type 4 RTA.
measurement, signs of rickets (bowing, frontal bossing, etc.), dys- anion gap which is due to impaired tubular NH+4 production or Aldosterone resistance with elevated plasma levels of aldosterone, is
morphic features and signs of hepato-/splenomegaly. Laboratory secretion. observed in PHA 1. This hereditary disorder presents clinically with
evaluation includes serum levels of creatinine, BUN, electrolyte lev- renal sodium wasting, hyperkalemia and metabolic acidosis. There
els, calcium, inorganic phosphorus, bicarbonate as well as plasma 6 DRTA is characterized by an impaired distal H+ secretion and, are two forms of PHA 1: in the renal, autosomal-dominant form, the
aldosterone levels and PRA. Urine should be obtained for urinalysis, hence, a failure to lower urine pH in the presence of acidosis. Several aldosterone resistance is limited to the kidney and is due to muta-
pH, osmolarity, Ca2+ and electrolyte levels (Cl , Na+ and K+). In addi- different mechanisms are responsible for this type of RTA: tions in the gene encoding the mineralocorticoid receptor. In the
tion, renal US should be performed in every child with suspected Secretory defect a defect in the H+-ATPase pump of the inter- autosomal-recessive multiple-end-organ form, the aldosterone
RTA. calated cell in the CCD. This abnormality can be a primary-genetic resistance is present in many organs (kidney, colon, lung, sweat and
disorder, or secondary to autoimmune diseases (SLE, Sjogren salivary glands) and is due to mutations in one of the -, -, or -sub-
3 A primary means by which the renal tubule handles an acid syndrome). units of the epithelial Na+ channel. There is also a secondary form
load is by production of ammonia (NH3). When combined with H+ in Gradient defect an increase in membrane permeability causing of aldosterone resistance, called PHA type 3, frequently observed in
the distal tubular lumen, NH3 is converted to ammonium ion (NH4+) backleak of luminal H+ in CCD cells. This condition is observed for infants with obstructive uropathy and/or urinary tract infection.
which is lipid-insoluble and therefore cannot be reabsorbed. example in children treated with amphotericin B.
Because a direct measurement of urinary ammonium excretion is Voltage-dependent defect a reduction in CCD Na+ reabsorption
cumbersome, urinary anion gap [Na+ + K+ Cl] serves as an indirect which diminishes the luminal electronegativity, thus impairing the Selected reading
index of urinary ammonium excretion and hence of distal acidifica- ability to secrete H+. This type of DRTA is accompanied by hyperka-
tion ability. This index is based on the fact that any change in urinary lemia and is seen in markedly volume-depleted children and sec- Fry AC, Karet FE: Inherited renal acidosis. Physiology 2007;22:
ammonium excretion will be accompanied by a parallel change ondary to amiloride treatment. 202211.
in urinary chloride excretion in order to maintain electroneutrality. A cardinal feature of DRTA is nephrolithiasis/nephrocalcinosis Herrin TH: Renal tubular acidosis; in Avner ED, Harmon WE,
A negative urinary anion gap (Cl > Na+ + K+) signifies normal caused by calcium- phosphate complexes. The reason for this abnor- Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia,
ammonium production/secretion whereas a positive urinary anion mality is the combination of the acidic urine and hypocitraturia pro- Lippincott Williams & Wilkins, 2004, pp 757776.
gap (Cl < Na+ + K+) represents decreased ammonium production/ moting Ca-phosphorus precipitation. Mutations in the gene encod- Nicoletta JA, Schwartz GJ: Distal renal tubular acidosis. Curr Opin
secretion. ing the anion exchanger AE1 located in the -intercalated cells in the Pediatr 2004;16:194198.
CCD lead to both autosomal-dominant and autosomal-recessive Rodrguez Soriano J: Renal tubular acidosis: the clinical entity.
4 HCMA accompanied by negative urinary anion gap repre- DRTA. In the milder, autosomal-dominant type, the disease can man- J Am Soc Nephrol 2002;13:21602170.
sents an intact distal acidification mechanism. Besides gastrointesti- ifest as mild metabolic acidosis in older children or even adults, Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte
nal bicarbonate loss due to diarrhea, PRTA, also known as RTA type whereas in the recessive type, which is seen mainly in the southeast Disorders, ed 5. New York, McGraw-Hill, 2001, pp 612627.
2, is the most common cause of HCMA with a negative urinary anion Asian population, the clinical picture includes DRTA with hemolytic Scheinman SJ, Guay-Woodford LM, Thakker RV, Warnock DG:
gap. In addition to negative urinary anion gap, PRTA is characterized anemia. Autosomal-recessive DRTA coupled with sensorineural Genetic disorders of renal electrolyte transport. N Engl J Med
by hypokalemia and urinary pH < 5.5 in the face of systemic acidosis. hearing loss is caused by a genetic defect in the B1 subunit of the 1999;340:11771187.
PRTA can be isolated or can be a part of generalized proximal tubu- H+-ATPase transporter. Zelikovic I: Molecular pathophysiology of tubular transport
lopathy (Fanconi syndrome) which leads to hypophospatemic rickets, disorders. Pediatr Nephrol 2001;16:919935.
hypouricemia, glycosuria and aminoaciduria. For details on Fanconi 7 The primary pathogenic mechanism of RTA type IV is
61 aldosterone deficiency or resistance. In this type of RTA, the ability
syndrome, see appropriate algorithm. Major causes of PRTA/Fanconi
syndrome include: hereditary disorders (cystinosis, galactosemia, to acidify the urine is intact but NH+4 excretion and thus net acid
tyrosinemia, hereditary fructose intolerance, mitochondrial cytopa- excretion is reduced. Hyperkalemia is a main feature of this type of
thies and Wilson disease), drugs (aminoglycosides, ifosfamide, out- RTA. Low plasma aldosterone levels with elevated PRA is generally

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dated tetracyclines and carbonic anhydrase inhibitors) and heavy observed in endocrine disorders such as congenital adrenal hypo-
metal poisoning. Several genetic defects in specific proximal tubule plasia, salt-losing forms of CAH or in rare inherited defects of aldo-

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Tubular disease I. Eisenstein P. Goodyer I. Zelikovic Renal tubular acidosis
Tubular disease P. Goodyer I. Eisenstein I. Zelikovic Proximal tubulopathy (Fanconi syndrome)

/
Proximal tubulopathy (Fanconi syndrome)
62

Isolated transport defect / Broad proximal tubular dysfunction 0

Cystinuria Phosphaturia (TRP <85% with low serum PO4)


Lysinuric protein intolerance PRTA (bicarbonate therapy >3 mEq/kg/day)
Hypophosphatemic rickets Aminoaciduria (quantitative urine amino acids)
ISHG Tubular proteinuria (B2-microglobulinuria)
PRTA Glucosuria
Potassium wasting (TTKG >12)
Salt wasting (FENa >1% with elevated renin)

Drugs 1 Inherited causes 2 Hyperparathyroidism 3


Chemotherapy (cisplatin/ifosfamide) Cystinosis
Valproic acid Dent disease
Outdated tetracyclines Mitochondriopathies
Glue sniffing Fanconi-Bickel glycogenosis
Heavy metal poisoning Tyrosinemia
Aminoglycosides Wilson disease
Lowe syndrome
Galactosemia
Hereditary fructose intolerance
Idiopathic Fanconi syndrome

Therapeutic strategies 4
Fluids, NaCl, KCl, NaHCO3 , PO4 , calcitrol, carnitine, specific therapy,

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organic solute replacement unnecessary

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1 Fanconi syndrome should always be distin- therapy with ifosfamide or cisplatin. Heavy metal proteins and glucose do not usually deplete metabolic
guished from diseases associated with an isolated poisoning, glue sniffing, and other drugs have also pools as long as adequate nutrition is maintained. On
defect in renal proximal tubular transport. In cystinuria, been reported to cause proximal tubular dysfunction. the other hand, NaCl supplementation (28 mEq/kg/
amino acid wasting is restricted to cystine, ornithine, day) to avoid chronic volume contraction often im-
lysine and artinine. In hereditary hypophosphatemia, 4 Most pediatric referrals for Fanconi syn- proves growth failure. Dose may be titrated to plasma
proximal tubular reabsorption of phosphate is de- drome involve a hereditary disease; proximal tubular renin if there is no growth improvement. The bicar-
pressed but aminoaciduria is absent. For details, see dysfunction may involve all transport mechanisms or bonate requirement may vary from 2 to 20 mEq/kg/day
algorithms on Rickets and Hypophosphatemia. ISHG, may affect only a few (partial Fanconi syndrome). depending on the severity of tubular dysfunction; this
a relatively benign condition, is caused by a genetic Cystinosis nearly always causes a complete Fanconi may also be conveniently supplied as Na/K citrate (ci-
defect in the Na+-glucose cotransporter, SGLT2. syndrome and the diagnosis is confirmed by measure- trate consumes H+ when metabolized in the Krebs cy-
ment of leukocyte cystine on an automated amino acid cle). Oral phosphate supplements (25100 mg elemen-
2 In the early 1930s, Fanconi (Switzerland), analyzer or by slip lamp identification of corneal crys- tal phosphate/kg divided in 34 doses/day) are adjust-
DeToni (Italy) and Debre (France) described a renal tals. Cystinosis is due to mutations of the cystinosin ed to assure that serum phosphate comes into the nor-
tubular syndrome in children characterized by massive gene on chromosome 17p13, encoding a lysosomal mal range 4560 min after each dose. The aim is to
urinary wasting of electrolytes, glucosuria and pro- membrane protein which selectively permits cystine provide adequate serum phosphate for bone mineral-
teinuria, causing acidosis, rickets and severe failure to to exit from the lysosome into the cytoplasm. Mechan- ization and linear growth. However, phosphate serves
thrive. In retrospect, it is evident that these patients ical disruption of lysosomes or interference with the as an oral calcium binder, stimulating PTH release.
had cystinosis (see below) and exhibited broad dys- endocytotic membrane recycling pathway causes a Since proximal tubular synthesis of 1,25(OH)2 vitamin
function of the proximal tubule. The defect in phos- broad, severe disturbance of proximal tubule transport D may also be affected, oral calcitriol 1040 ng/kg/day
phate reabsorption may be assessed by calculating functions. Dent disease is X-linked and caused by mu- in 2 divided doses is usually needed to avoid hyper-
the tubular reabsorption of phosphate: 1 (urine PO4/ tations of a chloride channel gene (CLCN5) which dis- parathyroidism, under close monitoring of urine cal-
serum PO4) (serum creatinine/urine creatinine); val- rupts normal endocyctotic mechanisms; most patients cium levels, and periodic renal sonogram to prevent
ues of less than 0.85, in the face of hypophosphatemia, with Dent disease are characterized by hypercalciuria, hypercalciuria and nephrolithiasis. Depending on the
demonstrate the defect. proximal tubular losses of massive LMW proteinuria and chronic renal failure. underlying disease, specific therapy (such as cysta-
bicarbonate may be massive with acidosis requiring Proximal tubule dysfunction is quite variable depend- mine in cystinosis) is indicated.
replacement of 1020 mEq/kg/day; losses of this mag- ing on the mutation. Mitochondriopathies are occa-
nitude in the face of a nonanion gap acidosis indicate sionally associated with lactic acidosis and may be
proximal RTA. Aminoaciduria may be quantified on an maternally inherited (mitochondrial genes) or due to
automated analyzer and normalized for urine creati- autosomal-recessive (nuclear genes) defects in the Selected reading
nine; all amino acid transport systems are affected. electron transport chain. The mitochondriopathies
LMW proteins are normally filtered through the glom- often have neuromuscular manifestations, may have Fanconi G: Die nicht diabetischen Glykosurien und
erulus and reabsorbed (>95%) by endocytosis; in Fan- episodes of rapid deterioration during intercurrent ill- Hyperglykmien des lteren Kindes. Jahrb Kinder-
coni syndrome there may be several grams of LMW ness and usually require tissue diagnosis. In Fanconi- heilk 1931;133:257300.
protein excreted per day; this is best proven by mea- Bickel syndrome, children present with hepatomegaly Forman JW: Cystinosis and Fanconi syndrome;
suring the 24-hour excretion of 2-microglobulin or due to glycogenosis of the liver and kidneys; The syn- in Avner ED, Harmon WE, Niaudet P (eds): Pediatric
retinol binding protein. Glucosuria may be detected by drome is caused by mutations in the facilitated GLUT2. Nephrology, ed 5. Philadelphia, Lippincott
standard dipsticks or by direct quantification. There is Massive glucosuria is a prominent feature in addition Williams & Wilkins, 2004, pp 789806.
no simple test for salt wasting which distinguishes a to other proximal tubule dysfunctions. Proximal tubule Gahl WA, Theoene JG, Schneider J: Cystinosis.
proximal tubular defect from dysfunction at more dysfunction is often incomplete in Wilson disease and N Engl J Med 2002;347:111121.
distal sites, but Fanconi syndrome is associated with tyrosinemia where it can fluctuate with metabolic cri- Hsu SY, Tsai IJ, Tsau YK: Comparison of growth in
NaCl losses of >1% of the filtered load in the face of sis. In glactosemia, hereditary fructose intolerance primary Fanconi syndrome and proximal renal
volume contraction: fractional excretion of sodium = and Lowe syndrome there are usually characteristic tubular acidosis. Pediatr Nephrol 2005;20:460464.
(urine Na/serum Na) (serum creatinine/urine creati- extrarenal features which bring the patient to medical Kuwertz-Broking E, Koch HG, Marquardt T, Rossi R,
nine) 100%. Potassium wasting is identified by cal- attention. Helmchen U, Muller-Hocker J, Harms E, Bulla M:
culating the trans-tubular potassium gradient (TTKG) Renal Fanconi syndrome: first sign of partial
>12. TTKG = (urine K) 300/urine osmolarity); normal 5 Aminoaciduria and phosphaturia may be respiratory chain complex IV deficiency. Pediatr
63 seen in hyperparathyroidism states, but this is uncom- Nephrol 2000;14:495498.
range = 46. Some of the patients with Fanconi syn-
drome also have hypercalciuria. mon in children. Santer R, Steinmann B, Schaub J: Fanconi-Bickel
syndrome: a congenital defect of facilitative glucose
3 In adults, the most common cause of Fanconi 6 In general, the strategy for supportive thera- transport. Curr Mol Med 2002;2:213227.

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syndrome is drug toxicity and this should also be con- py of Fanconi syndrome is to replace fluid and the
sidered in children; it may be noted following chemo- inorganic solutes lost in the urine. Amino acids, LMW

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Tubular disease P. Goodyer I. Eisenstein I. Zelikovic Proximal tubulopathy (Fanconi syndrome)
Tubular disease P. Goodyer I. Eisenstein I. Zelikovic Polyuria

/
Polyuria
64

Renal salt wasting Renal free water loss 3

FENa+ >1% FENa+ <1%


Urine osm = 200400 mosm/l Urine osm <200 mosm/l

Fanconi syndrome 0 Primary NDI Central DI


salt-losing states 1

Urinary tract obstruction X-linked Congenital


Nephronophthisis Autosomal recessive Acquired
Bartter syndrome Drug-induced
Gitelman syndrome Hypercalcemia
Pseudohypoaldosteronism Hypokalemia
Adrenogenital syndrome

Salt and water replacement 2 Water replacement 4 DDAVP

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1 Polyuria is divided into conditions where high 4 In many of the conditions associated with naprosyn (510 mg/kg/day in divided doses) may then
urine volume reflects renal tubular salt wasting and salt wasting, the principal of therapy is replacement of be used to blunt the compensatory production of
those in which there is primary free water loss. To fluids and electrolyte losses in the urine. renal prostaglandin. The combination of these effects
make this distinction, the patient must be in a state of enhances proximal tubular fluid reabsorption. Con-
relative volume contraction (may be confirmed by el- 5 Children who present with polyuria due to versely, the use of a diuretic in Bartter syndrome may
evated plasma renin; avoid assessment during rapid renal free water losses, must first be distinguished be life-threatening, since marked volume contraction
intravenous fluid infusions). Under these conditions, from those with psychogenic polydipsia. Since any already exists. The strategy here is to introduce
a fractional excretion of sodium (FENa+) >1% indicates form of chronic polyuria washes out the renal medul- naprosyn plus oral salt supplements (48 mEq/kg/day);
a salt-losing state. FENa+ = [Urine sodium/serum lary concentrating gradient, the initial response to naprosyn again blunts prostaglandin production, re-
sodium] [serum creatinine/urine creatinine] 100%. water deprivation or vasopressin may be blunted; ducing intraglomerular pressure and, thus, the filtered
If FENa+ is <1% under these conditions, the next goal is most fluid restriction daily intranasal or subcutane- load of salt. Doses are adjusted to bring plasma renin
to determine whether polyuria is due to an osmotic ous DDAVP (0.52 g) for 23 days may sometimes be to 23 times normal. Therapy of other conditions in
solute such as glucose or mannitol; urine osmolarity needed to demonstrate a completely normal renal this algorithm involves additional considerations, but
less than 150 mosm/l suggests dysfunction of the col- response. Classical NDI is an X-linked disease (females replacement of salt or free water is important in each
lecting duct and free water loss. are asymptomatic or mildly affected) caused by inacti- one.
vating mutations of the vasopressin receptor in the
2 Children with polyuria due to the renal Fan- renal collecting duct. A rare autosomal-recessive form
coni syndrome are readily identified by tests of proxi- of NDI is due to mutations of the aquaporin II gene, Selected reading
mal tubular dysfunction (tubular reabsorption of phos- preventing water flux through the collecting tubule.
phate, proximal RTA, aminoaciduria, LMW proteinuria, Important conditions leading to secondary NDI include Bichet DG, Fijiwara TM: Nephrogenic diabetes
etc.). For details, see algorithm on Faconi syndrome. hypercalcemia, hypokalemia, sickle cell disease, insipidus; in Sciver C, Beaudet A, Sly W, Valle D
chronic renal failure and drugs (lithium, demeclocy- (eds): The Metabolic and Molecular Bases of Inher-
3 Obstructive uropathy damages the distal cline). In infant males, polyuria and urine osmolarity of ited Disease. New York, McGraw-Hill, 2001, vol III,
nephron causing polyuria from defective reabsorption 50100 mosm/l are evident in the first days of life, but pp 49094932.
of both salt and water in collecting duct. Polyuria is water loss increases rapidly in the postnatal period Pinelli JM, Symington AJ, Cunningham KA, Paes BA:
also characteristic of several inherited salt-losing con- and should be diagnosed as quickly as possible to Case report and review of the prenatal implications
ditions (exposure to diuretic drugs should be excluded avoid brain injury from dehydration. Whenever pos- of maternal lithium use. Am J Obstet Gynecol 2002;
by history). Nephronophthisis (medullary cystic dis- sible, urgent molecular diagnosis is advisable. A short 187:245249.
ease complex) is a group of autosomal-recessive dis- water deprivation test is also diagnostic, but great care Robben JH, Knoers NV, Deen PM: Cell biological
eases caused by mutations in several genes. In over must be taken to avoid excessive dehydration; body aspects of the vasopressin type-2 receptor and
90% of the cases of juvenile nephronophthisis (NPHS1) weights are taken every 30 min. Water is withheld until aquaporin 2 water channel in nephrogenic diabetes
polyuria is noted in childhood well before progressive urine osmolarity reaches a plateau as indicated by an insipidus. Am J Physiol Renal Physiol 2006;291:
renal insufficiency becomes evident between 10 and hourly increase of <30 mosm/l for 3 successive hours F257F270.
20 years. In Europe, NPH1 accounts for 1015% of chil- or until body weight drops by 3%. DDAVP (0.52 g) is Saunier S, Salomon R, Antignac C: Nephronoph-
dren with ESRD. While FENa+ may reflect salt-wasting, then administered subcutaneously and urine osmolar- thisis. Curr Opin Genet Dev 2005;15:324331.
urine is usually dilute, implying that polyuria may also ity is measured 60 minutes afterward. In children with Saxena A, Hanukogulu I, Saxena D, Thompson RJ,
reflect free water losses from collecting duct dysfunc- CDI, urine osmolarity is low (<200 mosm/l) but rises by Gardiner RM, Hanukoglu A: Novel mutations
tion associated with characteristic medullary cysts >50% following DDAVP. CDI may be congenital or responsible for autosomal recessive multisystem
and interstitial disease. Bartter syndrome is caused by secondary to pituitary ablation by trauma or tumors. pseudohypoaldosteronism and sequence variants
mutations in various genes involved in salt reabsorp- In children with inherited NDI, urine osmolarity is in epithelial sodium channel alpha-, beta-, and
tion by the thick ascending limb of the loop of Henle; also low (50150 mosm/l) and there is no significant gamma-subunit genes. J Clin Endocrinol Metab
the syndrome is mimicked by furosemide and associ- increase (<20%) after DDAVP. Intermediate results may 2002;87:33443350.
ated with striking hypercalciuria. In Gitelman syn- reflect partial CDI or mild NDI mutations. Zelikovic I: Hypokalaemic salt-losing tubulopathies:
drome, the gene for sodium/chloride reabsorption in an evolving story. Nephrol Dial Transplant 2003;
the distal convoluted is mutated, but salt losses are 6 The distinction between salt-wasting states 18:16961700.
modest and often only mild polyuria exists; hypocalci- and diabetes insipidus is crucial since the approaches
65 to therapy are quite different. In NDI, the strategy is to
uria is a characteristic finding. Pseudohypoaldosteron-
ism and adrenogenital syndrome are easily distin- create mild volume contraction with hydrochlorothia-
guished by the presence of acidosis and/or hyperkale- zide (12 mg/kg/day) and restricted renal solute load;
mia.

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Tubular disease P. Goodyer I. Eisenstein I. Zelikovic Polyuria
Tubular disease J. Smith F.B. Stapleton Hypouricemia

Hypouricemia
66 Serum uric acid <2 mg/dl

Determine urinary uric acid excretion /

Normal or decreased uric acid excretion Increased uric acid excretion


(urinary uric acid <0.34 mg/dl GFR*) (urinary uric acid >0.57 mg/dl GFR**)
* Mean uric acid excretion for children older than 2 years ** Mean +2 SD for children older than 2 years

Medications 0 Medications 3
Ex. allopurinol Idiopathic renal hypouricemia 4
Metabolic disorders 1 Generalized proximal tubular defect 5
Xanthinuria 2 SIADH, extracellular volume expansion 6

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Diabetes mellitus 7

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1 Urinary uric acid concentration is determined 5 Hypouricemia and uric acid stones may
Selected reading
by glomerular filtration of uric acid as well as by a develop due to administration of drugs that inhibit
complex array of reabsorption and secretion process- tubular reabsorption or increase tubular secretion of Baldree LA, Stapleton FB: Uric acid metabolism in
es of this substance in the renal tubule. Uric acid uric acid (table). children. Pediatr Clin N Am 1990;37:391418.
excretion (in a urine sample) is expressed as uric acid Cameron JS, Moro F, Simmonds HA: Gout, uric acid
(Ua) excretion per deciliter of GFR which is calculated 6 Idiopathic renal hypouricemia is an inherited and purine metabolism in paediatric nephrology.
according to the formula (UUa SCr/UCr), where Cr is disorder caused by a defect in the proximal tubular Pediatr Nephrol 1993;7:105118.
creatinine and U and S are concentrations in mg/dl in urate/anion exchanger URAT1 which leads to renal Hediger MA, Johnson RJ, Miyazaki H, Endou H:
urine and serum, respectively. urate wasting. The disease is characterized by exer- Molecular physiology of urate transport. Physiology
cise-induced acute renal failure and nephrolithiasis. 2005;20:125133.
2 The table lists some of the medications that Icihida K, Hosoyamada M, Hisatome I, Enomoto A,
are associated with hypouricemia. Allopurinol, a com- 7 Generalized defects in proximal tubular func- Hikita M, Endou H, Hosoya T: Clinical and molecular
petitive inhibitor of the enzyme xanthine oxidase, is tion may lead to renal urate wasting. Examples include analysis of patients with renal hypouricemia in
the most commonly implicated medication which idiopathic Fanconi syndrome, cystinosis, Wilson dis- Japan: influence of URAT1 gene on urinary urate
leads to hypouricemia by decreased uric acid produc- ease and galactosemia. Hodgkin disease and paren- excretion. J Am Soc Nephrol 2004;15:164173.
tion. teral alimentation are also associated with uricosuria Stapleton FB, Linshaw MA, Hassansein K: Uric acid
and hypouricemia. excretion in normal children. J Pediatr 1978;92:911.
3 Persistent hypouricemia has been associated
with deficiencies of enzymes such as nucleoside phos- 8 In SIADH, antidiuresis results in expansion of
phorylase and PP-ribose-P-synthetase. the extracellular fluid compartment, which then leads
to increased urinary excretion of uric acid.
4 Xanthinuria is an autosomal-recessive dis-
order caused by a deficiency of the enzyme xanthine 9 The development of hyperglycemia, glucos-
dehydrogenase (and, in some cases, also aldehyde uria and osmotic diuresis is associated with decreased
oxidase) and characterized by xanthine urolithiasis, urate reabsorption in the proximal tubule.
myopathy, and polyarthritis.

Table. Selected medications associated with hypouricemia

Decreased uric acid production


Allopurinol
Azouridine
Orotic acid
Oxypurinol
Increased uric acid secretion
Ascorbic acid (high dose)
Citrate
Dicumarol
Most diuretics (acutely, before extracellular volume contraction)
Estrogens
Glycerol guaiacholate
Glycine
Halofenate
Outdated tetracyclines (Fanconi syndrome)
Iopanoic acid (radiocontrast agent)
67 Meglumine iodipamide
Phenylbutazone
Phenol sulfophthalein
p-Nitrophenylbutazone
Probenecid

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Salicylates (high dose)
Sodium diatrizoate (radiocontrast agent)

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Tubular disease J. Smith F.B. Stapleton Hypouricemia
Tubular disease F.B. Stapleton J. Smith Hyperuricemia

/
Hyperuricemia
68
Elevated serum uric acid level (table 1)

Complete medical and family history

Positive medication history / Negative family history Positive family history


(e.g. diuretics)

Examine extracellular fluid volume status

Normal ECF volume Increased ECF volume Decreased ECF volume Increased uric acid excretion* Decreased uric acid excretion*

Cell lysis Acute renal failure 4 Diarrhea 5 Genetic diseases 2 Uromodulim disorders 3
Hemolysis Congestive heart failure Nephrogenic diabetes insipidus HGPRT deficiency FJHN
Polycythemia (Lesch-Nyhan syndrome) MCKD2
Leukemia/lymphoma PRPS overactivity GCKD
Tumor lysis syndrome G6P deficiency
Exercise, acidosis/alkalosis 0 (glycogen storage disease type 1)
Hypertension 1
Hereditary/metabolic conditions 23
Miscellaneous conditions
Hypothyroidism
Hypoparathyroidism
Psoriasis
Sarcoidosis
Obesity
Starvation
Down syndrome

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* see Hypouricemia, for values of urinary acid excretion

Downloaded by:
1 There are numerous medications that alter disease type 1) is an autosomal-recessive enzymatic
Selected reading
the metabolism of uric acid. Diuretics are the class of defect. Patients usually display hyperuricemia during
drugs most commonly associated with hyperuricemia infancy and gout later in life. In this disease there is Baldree LA, Stapleton FB: Uric acid metabolism in
(table 2). They initially cause a uricosuric response increased uric acid production due to depletion of children. Pediatr Clin N Am 1990;37:391418.
which is followed by decreased renal urate excretion. intracellular high energy phosphates and diffusion of Cameron JS, Moro F, Simmonds HA: Gout, uric acid
The antiuricosuric response is due to the extracellular adenosine out of the cell. and purine metabolism in paediatric nephrology.
fluid volume depletion induced by the diuretics and Pediatr Nephrol 1993;7:105118.
can be abolished by replacing urinary sodium losses. 5 FJHN, autosomal-dominant medullary cystic Cameron JS, Simmonds HA: Hereditary hyperurice-
kidney disease type 2 (MCKD2) and autosomal-domi- mia and renal disease. Semin Nephrol 2005;25:918.
2 The lactic acidemia induced by exercise nant GCKD constitute a group of hereditary renal dis- Scolari F, Caridi G, Rampoldi L, et al: Uromodulin
reduces uric acid excretion. Respiratory acidosis and eases that share an autosomal dominant pattern of storage diseases: clinical aspects and mechanisms.
diabetic ketoacidosis have been associated with transmission as well as hyperuricemia/gout and pro- Am J Kidney Dis 2004;44:987999.
reduced uric acid excretion. Metabolic alkalosis (espe- gressive renal damage that may cause end-stage renal Stapleton FB, Linshaw MA, Hassansein K: Uric acid
cially if associated with extracellular volume contrac- disease. Histologically, FJHN and MCKD2 are charac- excretion in normal children. J Pediatr 1978;92:911.
tion) can promote uric acid retention. terized by chronic interstitial nephritis with thickening
of the tubular basement membrane and corticomedul-
3 Hyperuricemia is a common finding in lary cysts, while GCKD is characterized by diffuse glo-
untreated hypertensive patients. It has been shown merular cysts caused by marked dilatation of Bowman
that uric acid affects vascular smooth muscle cells space in most glomeruli. These three diseases are
and endothelial cell proliferation and hyperuricemia caused by mutations in the gene encoding uromodu-
has been implicated in the pathogenesis of hyper- lim (Tamm-Horsfall protein), a protein which is exclu-
tension and vascular disease. sively expressed in the thick ascending limb of the
loop of Henle and the distal convoluted tubule. Lack of
4 These are examples of genetic diseases uromodulim function is associated with impairment of
which are associated with hyperuricemia. HGPRT defi- the urine-concentrating process, resulting in water
ciency (Lesch-Nyan syndrome) is an X-linked reces- depletion and hyperuricemia.
sive disorder in males. It is characterized by clinical
gout, hyperuricemia, nephrolithiasis, and a neurologic 6 In acute renal failure, there is a decrease in
syndrome of cerebral palsy, mental retardation, and the filtered load of uric acid presented to the renal Table 2. Selected medications associated with hyperuricemia
obsessive destructive and self-mutilating behavior. tubules. In addition, there may be increased uric acid
The disease can be diagnosed by demonstrating low synthesis secondary to catabolism. Increase uric acid production
Vitamin B12 (acute administration)
HGPRT level in erythrocytes of affected patients. PRPS Cytotoxic drugs
overactivity disorder is a heterogeneous X-linked 7 Diarrhea-induced volume contraction Ethanol
disorder associated with hyperuricemia, gout and diminishes urinary uric acid excretion and leads to 2-Ethylamoni-1,3,4-thiadiazole
nephrolithiasis frequently presenting in children less hyperuricemia. Fructose
than 10 years of age. G6P deficiency (glycogen storage Nicotinic acid
Pancreatic extract

Decrease uric acid excretion


Diuretics (indirectly when ECF volume is diminished)
Acetazolamide
Amiloride
Chlorthalidone
Furosemide
Organomercurials
Thiazides
Triamterene
Ethambutol
69 Table 1. Normal serum values (mean + SD) for uric acid in neonates and children Ethanol
Laxative abuse (alkalosis)
2933 weeks 3437 weeks 3840 weeks Male Female Male Female Male Female Levodopa
34 years 34 years 59 years 59 years 1014 years 1014 years Methoxyflurane
Nicotinic acid

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Serum uric acid, 7.71 + 2.65 6.04 + 2.19 5.19 + 2.65 3.45 + 1.01 3.44 + 0.80 3.63 + 1.04 3.71 + 0.92 4.28 + 1.19 4.09 + 1.20 Pyrazinamide
mg/dl Salicylates (low dose)

Univ. of California San Diego


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Tubular disease F.B. Stapleton J. Smith Hyperuricemia
Tubular disease G. Ariceta B. Hoppe C.B. Langman Rickets

/
Rickets
70 Serum total [Ca] 0

Normal Elevated Lowered

PTH 1 Jansen syndrome @ PTH 1


Vitamin D intoxication
Malignancy

Elevated Normal Normal Elevated

25(OH)D 2 Serum [P] 9 25(OH)D 2

Lowered Normal Normal Lowered Lowered Elevated

1,25(OH)2D 2

Vitamin D depletion 3 Chronic kidney disease 6 Pseudorickets : X-linked hypophosphatemic Disease not Vitamin D depletion 3 Lowered Elevated
Malabsorption 4 Early vitamin D treatment 7 rickets ; identified yet 8 Malabsorption 4
Liver diseases 5 Disease not identified yet 8 Autosomal dominant Liver diseases 5
hypophosphatemic rickets <
Tumor-induced osteomalacia = Chronic kidney Vitamin D-resistant
Hypophosphatemic rickets with disease 6 rickets B
hypercalciuria > 1A-Hydroxylase Dietary Ca deficiency

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Fanconi syndrome/chronic deficiency A

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metabolic acidosis ?

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1 Rickets is the clinical expression of undermineralization of 8 CKD refers to declining glomerular filtration rates, and is tions in the gene encoding NaPi IIc, a Na-P cotransporter of the proxi-
osteoid, produced at the epiphysis of growing bones, leading to disor- staged from 1 to 5. The inability to produce 1,25(OH)2D may appear in mal tubule. Any patient with hereditary hypophosphatemic rickets
dered endochondral bone formation. It represents not a single disease, CKD advanced stages (4 and 5) from the absence of sufficient kidney should be referred to an experienced center or practitioner in the nu-
but a process with wide heterogeneity. Clinical expression may occur mass, or related to hyperphosphatemia. In earlier CKD stages (2, 3) ances of its care.
in the skull, chest, pelvis, upper and lower extremities, with palpable, children may suffer metabolic acidosis that suppresses 1,25(OH)2D pro-
17 Children with idiopathic, or syndromic Fanconi syndrome
knobby-like enlargements. Skeletal deformity may result in a knock- duction also.
kneed or bowed appearance of the lower extremities. Dental develop- (see specific Algorithm chapter) commonly present with rickets. Fac-
ment may be impaired in primary and secondary dentition as well. Ra- 9 During vitamin D repletion, there are dys-synchronous tem- tors for its presence include chronic metabolic acidosis, hypophospha-
diographically, the most characteristic changes are in the epiphyses, poral changes with elevation of PTH remaining for several weeks to temia with insufficient production of 1,25(OH)2D, and/or CKD (see foot-
with widening, and an irregular, frayed, and cupped appearance. The months after restoration of circulating levels of 25(OH)D. note 14).
cortices are thin, and the bone appears with reduced density.
10 Disease not identified yet (DNIY). The clinician should be criti- 18 These diseases may resemble rickets. For details see algo-
2 Serum total calcium [Ca] is an easy differential point to begin cal in these circumstances. While new diseases, or explanations for rithm on Hypercalemia.
the evaluation of rickets. Normal ranges have been established for age. existing diseases, arise continually, it is often misleading information,
19 Autosomal-recessive, inherited absence of the proximal tu-
Its value may be lowered with concomitant hypoalbuminemia, or or misguided assays, that result in the disease not indentified yet clas-
raised with concomitant hyperproteinemia. Thus blood ionized calcium sification. bule 25-hydroxyvitamin D-1-hydroxylase has been referred to previ-
indicates if there is a real calcium disturbance. ously as vitamin D-dependent rickets, type 1. Currently this disease
11 Serum phosphorus (P) varies with age, time of day, and state entity should be referred as 1-hydroxylase deficiency. It responds to
3 Serum PTH refers to an immunometric assay measurement of acid-base balance. Normative values have been established. Re- physiologic replacement doses of the active hormone, 1,25(OH)2D.
to detect 1-84 PTH. While controversy exists as to the meaning of first duced P interpretation needs concomitant evaluation of P kidney han-
20 End-organ resistance to 1,25(OH)2D may occur in presence of
generation assays that may detect other N-terminal fragments, and dling (see algorithm for Hypophosphatemia).
thereby elevate the total PTH level, it is not clear that the newer assays mutated intracellular vitamin D receptor (VDR) resulting in a hypofunc-
offer better discrimination for rachitic diseases. PTH value must be in- 12 Pseudorickets refers to other metabolic, genetic, or structural tional or absent receptor. The disease has been called vitamin D-de-
terpreted with respect to either serum total Ca or ionized Ca. diseases in which the radiographic appearance more commonly than pendent rickets, type 2 in the past. The highest blood levels of
the clinical appearance resembles rickets. They include intrinsic bone 1,25(OH)2D in humans are seen here, with values often above 400 pg/ml
4 Measurement of circulating vitamin D metabolites is useful in disorders (chondrodysplasias), mucopolysaccharidoses, sex steroid (normal, 1580). Any patient with this disorder should be referred to an
the differential diagnosis. 25(OH)D is produced in the liver, and repre- hormonal insufficiency disorders, vitamin C deficiency, osteogenesis experienced center or practitioner in the nuances of its care.
sents the major substrate of the vitamin D. Its level defines sufficiency imperfecta, hypophosphatasia, osteopetrosis, craniometaphyseal dys-
21 Primary dietary calcium deficiency may produce a picture of
of the vitamin. Despite some ethnic differences 25(OH)D levels <5 ng/ plasia, and others.
ml are considered deficient. Values between 5 and 15 ng/ml should be rickets in the presence of adequate vitamin D. This picture has been
interpreted carefully with respect to the presence or absence of rickets. 13 X-linked hypophosphatemic rickets (XLH) is an X-linked, described in preterm neonates, and young infants and older children in
Circulating levels of 1,25(OH)2D, produced in the kidney proximal tu- dominant disease caused by Phex gene (Phosphate regulating with rural South Africa.
bule, but with some minor extrarenal production too, are often prob- Homologies to Endopeptidases on the X chromosome) mutations. The
lematic to interpret, except in the few circumstances noted in this algo- condition is associated with inappropriate phosphaturia. Levels of
rithm. The normal range is 2080 pg/ml. 1,25(OH)2D, that should be stimulated by hypophosphatemia, are often Selected reading
in the normal range, suggesting a second defect in the vitamin D
5 Vitamin D depletion is a common cause of rickets. Depletion
Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y: A clinical and
system too. Phenotype-genotype relationships await clarification.
molecular genetic study of hypophosphatemic rickets in children.
is caused by a dietary lack of the parent compound, and/or insufficient
Pediatr Res 2005;58:329333.
sunlight exposure to have dermal conversion of precursors into vita- 14 XLH expression is mimicked by autosomal-dominant hypo-
Hochberg Z: Vitamin-D-dependent rickets type 2. Horm Res 2002;
min D. After restoration of body vitamin D stores the rachitic bone phosphatemic rickets, produced by mutations in the gene encoding
58:297302.
heals completely with no long-term consequences generally. FGF-23, a potent phosphaturic agent.
Holick MF: Resurrection of vitamin D deficiency and rickets.
6 Malabsorption may produce functional vitamin D deficiency 15 Some primitive, ectodermally derived tumors may produce a
J Clin Invest. 2006;116:20622072.
Klein GL, Soriano H, Shulman RJ, Levy M, Jones G, Langman CB:
due to its solubility. Processes that impair fat absorption (sprue, inflam- substance leading to inappropriate phosphaturia, hypophosphatemia,
Hepatic osteodystrophy in chronic cholestasis: evidence for a
matory bowel diseases, cystic fibrosis, etc.) will lead to lowered vita- and rickets (in children) or osteomalacia (in adults). Hence, tumor-in-
multifactorial etiology. Pediatr Transplant 2002;6:136140.
min D body stores and reduced conversion to the 25(OH)D substrate. duced osteomalacia denomination has been applied to both conditions.
Langman CB: Disorders of phosphorus, calcium and vitamin D;
Removal of the tumor results in complete correction of the rachitic
71 7 25(OH)D is produced in hepatocytes by a cytosolic mixed in Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5.
state, although the presence of the tumor may be difficult to demon-
Philadelphia, Lippincott Williams & Wilkins, 2004, pp 237254.
function P450 enzyme, whose gene has been cloned and sequenced. Al- strate.
Thacher TD, Fischer PR, Pettifor JM: Rickets: vitamin D and calcium
terations in hepatic production leading to substrate deficiency include
deficiency. J Bone Miner Res 2007;22:638.
hepatic mass reduction, alterations in P450 enzyme activity, xenobiotics 16 Two inheritance patterns, autosomal dominant or recessive,

198.143.33.65 - 8/6/2015 3:21:41 PM


(antibiotics, anti-epileptics, etc.), or enterohepatic circulation (cystic have been described for hereditary hypophosphatemia with renal hy-
fibrosis), since nearly 80% of daily production of 25(OH)D is salvaged percalciuria. In both, the hypophosphatemia is accompanied by supra-

Univ. of California San Diego


by this route. To date, there are no well-described cases of absence of physiologic levels of 1,25(OH)2D. The genetic abnormality in hereditary
the hepatic vitamin-D-25-hydroxylase enzyme in a child with rickets. hypophosphatemia with renal hypercalciuria (HHRH) is due to muta-

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Tubular disease G. Ariceta B. Hoppe C.B. Langman Rickets
Fluid/electrolyte/acid base balance S. Watkins D. Okamura J. Rodrguez Soriano Hyponatremia

/
Hyponatremia
(Serum Na+ <130 mEq/l)

72
Exclude pseudohyponatremia or hypertonic hyponatremia /

Hypovolemia 01 Euvolemia/mild volume excess 01 Hypervolemia 01

Urine sodium (mEq/l) Urine Sodium (mEq/l) Urine sodium (mEq/l)

Variable 8
[Na+] >20 [Na+] <20 [Na+] <20 29 [Na+] >20

Renal losses 2 Extrarenal losses 67

Diuretics Vomiting Glucocorticoid deficiency Cirrhosis Renal failure 2:


Salt-losing nephropathy 3 Diarrhea Hypothyroidism Heart failure
Metabolic alkalosis 4 Burns Primary polydipsia Nephrotic syndrome
Ketonuria Pancreatitis SIADH
Osmotic diuresis Cystic fibrosis
Cerebral salt wasting 5

Sodium and water replacement ; Water restriction ; Sodium and water restriction ;

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Univ. of California San Diego
Downloaded by:
1 It is important to exclude pseudohyponatremia (secondary 9 Skin Na+ losses: Observed in the setting of cystic fibrosis
Selected reading
to hyperlipidemia or hyperproteinemia) and to exclude hypertonic and loss of skin barrier, such as burns. As with gastrointestinal
hyponatremia (elevated serum osmolality secondary to hyperglyce- losses, renal sodium avidity is high. Avner ED: Clinical disorders of water metabolism: hyponatremia
mia or mannitol infusion). and hypernatremia. Pediatr Ann 1995;24:2330.
10 The main mechanism of hyponatremia in this condition is Moritz ML, Ayus JC: Preventing neurological complications from
2 Serum sodium will be diminished in the setting of body water retention. In cortisol deficiency (primary or secondary), the dysnatremias in children. Pediatr Nephrol 2005;20:16871700.
water excess, sodium depletion or a combination of the two. A thor- hyponatremia is due to a combination of excessive ADH release and Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte
ough clinical evaluation of the child to determine his volume status is urinary Na+ losses. In hypothyroidism, hyponatremia is caused by Disorders, ed 5. New York, McGraw-Hill, 2001, pp 703712.
therefore vital in order to proceed with the work-up: (1) History: impaired water excretion due to ADH release and diminished water Sakarcan A, Bocchini J Jr: The role of fludrocortisone in a child
Changes in weight, intake and output (urinary, gastric, stool), medi- delivery to the diluting segments of the renal tubule. Primary poly- with cerebral salt wasting. Pediatr Nephrol 1998;12:769771.
cation history. (2) Examination: Weight, skin changes (edema, turgor), dipsia is rare in children and most patients will have normal levels of Trachtman H: Sodium and water; in Avner ED, Harmon WE,
fontanelle changes, blood pressure/orthostatics, mucous mem- serum sodium unless water intake significantly exceeds urine output. Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia,
branes, cardiac gallop. SIADH is a common cause of hyponatremia in children and is due to Lippincott Williams & Wilkins, 2004, pp 125145.
a combination of water excess and excessive urinary Na+ excretion
3 Once fluid status is assessed, patients work-up can be leading to the euvolemic state. SIADH can be seen in a variety of situ-
appropriately directed. Determination of urine Na+ concentration is ations including infections, neuropsychiatric diseases, neoplasms,
essential for narrowing the differential diagnosis. It should be lung diseases and secondary to drugs (table). Laboratory investiga-
emphasized that there is no correlation between urinary Na+ level tion includes: Serum and urine osmolarity, electrolytes, serum BUN,
(which is normally determined by the ECF volume status) and serum creatinine, plasma aldosterone, cortisol levels and thyroid function
Na+ concentration. tests.

4 Renal etiology: Kidney disease can cause both fluid reten- 11 The hyponatremia in hypervolemic/edematous states is
tion and excess sodium losses. characterized by high total body sodium content due to avid renal
sodium retention. In these conditions, the hyponatremia is primarily Table. Causes of SIADH
5 Salt-losing nephropathies include any form of renal disease due to water retention. In the setting of liver failure and nephrotic I. Increased hypothalmic production of ADH
that cause an impairment in sodium reabsorbtion and hence free wa- syndrome, intravascular volume depletion and hypoalbuminemia
Neuropsychiatric disorders
ter excretion. Etiologies include: Bartters syndrome and Gitelmans contribute to urinary sodium retention leading to hypervolemia. 1. Infections: meningitis (tuberculous or bacterial), encephalitis, abscess,
syndrome, renal tubular acidosis, TIN, pyelonephritis and hypo- or herpes zoster 2. Vascular: thrombosis, subarachnoid or subdural hemorrhage,
pseudohypoaldosteronism. Hypoaldosteronism (aldosterone defi- 12 In renal failure, the combination of water retention and de- cavernous sinus thrombosis, cerebrovascular accident 3. Neoplasm:
ciency) will result in high urine sodium and water losses and its main creased tubular ability to reabsorb sodium causes hyponatremia and primary or metastatic 4. Skull fracture, head injury 5. Psychosis, delirium
causes are immune-mediated diseases (polyglandular or isolated), elevated urinary sodium concentration. tremens 6. Other: Guillain-Barr syndrome, acute intermittent porphyria,
autonomic neuropathy, hypothalamic sarcoidosis, postpituitary surgery,
salt-losing forms of CAH and adrenoleukodystrophy. Pseudohypo- multiple sclerosis, epilepsy, hydrocephalus, lupus erythematosus, peripheral
aldosteronism is caused by primary or acquired diseases character- 13 Management of hyponatremia: In the stable patient, serum neuropathy, spinal cord lesions
ized by end organ resistance to aldosterone. Laboratory investiga- sodium levels should be normalized slowly to prevent central pon-
Drugs
tion of salt-losing nephropathies includes: Serum and urine osmolar- tine myelinolysis. The amount of sodium to be replaced in hypovole- 1. Intravenous cyclophosphamide (increased sensitivity may also
ity, serum BUN, creatinine, electrolytes, acid-base status, plasma mic hyponatremia can be assessed by the formula: contribute) 2. Carbamazepine (though increased sensitivity is probably
aldosterone levels, urinary electrolyte levels and renal sonogram. important) 3. Vincristine or vinblastine 4. Psychiatric drugs
Na+ deficit = (serum Na+ concentration desired 5. Bromocriptine 6. Clofibrate 7. General anesthesia 8. Narcotics, opiate
serum Na+ concentration present) TBW, derivatives
6 In metabolic alkalosis (as well as in some forms of RTA)
the hyponatremia is due to urinary losses of Na+ that accompany the where TBW (total body water) = 0.6 body weight (kg). Correction of Pulmonary disease
bicarbonaturia. serum Na+ levels should be done cautiously and should not exceed 1. Pneumonia: viral, bacterial, fungal 2. Tuberculosis 3. Lung abscess,
empyema 4. Acute respiratory failure 5. Positive pressure ventilation
10 mEq/l/day. Diuretics hypertonic saline should be only considered 6. Other: asthma, COPD, atelactasis, pneumothorax, cystic fibrosis
7 The features of cerebral salt wasting are similar to those of in the patient with neurologic changes (seizure, coma), and should
Miscellaneous
SIADH except for volume depletion which is a feature of the former. only be done in the pediatric intensive care unit setting. Of note, loop
Postoperative patient, severe nausea, pain, infection with HIV, idiopathic
Cerebral salt wasting is characterized by excessive urinary sodium diuretics, but not thiazides, should be used since the former augment
losses in patients with intracranial disease. The exact mechanism is excretion of electrolyte free water. In the setting of cortisol deficiency II. Ectopic (nonhypothalamic) production of ADH
73 or hypothyroidism, treatment with thyroid replacement or glucocor-
1. Ewing sarcoma 2. Hodgkin disease, leukemia 3. Pulmonary tuberculosis
unknown but it has been speculated that the Na+ loss is due to the
release of a natriuretic factor, probably from the injured brain. ticoid therapy is indicated. If true hypoaldosteronism or cerebral salt III. Potentiation of ADH effect
1. Chlorpropamide 2. Carbamazepine 3. Psychosis 4. Intravenous
wasting is diagnosed, treatment with mineralocorticoids is indicated.
cyclophosphamide 5. Prostaglandin synthesis inhibitors (salicylates,
8 Gastrointestinal Na+ losses: Gastrointestinal disease can NSAIDS)

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result in sodium losses with or without fluid losses, as well as fluid
IV. Exogenous administration of ADH
retention. Vomiting and diarrhea can result in losses of sodium and

Univ. of California San Diego


Vasopressin, desmopressin, oxytocin
water. In the setting of gastrointestinally driven hyponatremia, se-
rum aldosterone levels and sodium avidity of the kidneys are high.

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Fluid/electrolyte/acid base balance S. Watkins D. Okamura J. Rodrguez Soriano Hyponatremia
Fluid/electrolyte/acid base balance S. Watkins D. Okamura J. Rodrguez Soriano Hypernatremia

/
Hypernatremia
(Serum Na+ >150 mEq/l)

74

Hypovolemia / Euvolemia / Hypervolemia /

Urine Na+ (mEq/l) 0 Urine Na+ (mEq/l) 0 Urine Na+ (mEq/l) 0

[Na+] variable [Na+] >20 7

[Na+] >20 1 [Na+] <20 2 Urine osmolality (mosm/kg) 3

>800 <300

Renal losses Extrarenal losses Insensible losses DI Improperly mixed formula


Renal dysplasia Diarrhea Skin NaHCO3/NaCl administration
Postobstruction Sweating Lungs Mineralocorticoid excess
Osmotic diuresis Fever Hypodipsia
Diuretics (loop, osmotic) Burns

Water deprivation test 4


(response to DDAVP)

Yes No

CDI 5 NDI 6

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Hypotonic fluid replacement 8 Hypotonic fluid replacement 8 Water replacement 8 Water replacement 8 Water replacement 8 Water replacement 8
DDAVP Thiazide/potassium- Diuretics, dialysis

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sparing diuretics

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1 Serum sodium will be elevated in the setting of sodium ex- 8 NDI is a congenital or acquired disorder in which hypotha-
Selected reading
cess or water losses. A thorough clinical evaluation of the child to lamic function and ADH production and secretion are normal but
determine his volume status is therefore vital in order to proceed there is a lack of renal responsiveness to ADH. Congenital NDI is in- Avner ED: Clinical disorders of water metabolism: hyponatremia
with the work-up: (1) History: Information from patient/family on herited in an X-linked, autosomal-recessive or, rarely, autosomal- and hypernatremia. Pediatr Ann 1995;24:2330.
weight changes, intake and output (urinary, gastric, stool), medica- dominant fashion. The X-linked disease is due to different mutations Moritz ML, Ayus JC: Preventing neurological complications from
tion history. (2) Examination: Weight, skin changes (edema, turgor), in the ADH (V2) receptor gene. The autosomal-recessive and autoso- dysnatremias in children. Pediatr Nephrol 2005;20:16871700.
fontanelle changes, blood pressure/orthostatics, mucous mem- mal-dominant forms are caused by mutations in the H2O channel Rose BD, Post TW: Clinical Physiology of Acid-Base and Electrolyte
branes, cardiac gallop. Due to the fact that in hypernatremic dehydra- (AQP2) gene. Major causes of acquired NDI include lithium adminis- Disorders, ed 5. New York, McGraw-Hill, 2001, pp 750758.
tion the ECF volume may be preserved, the classic signs of dehydra- tration, hypercalcemia, hypokalemia and osmotic diuresis associated Trachtman H: Sodium and water; in Avner ED, Harmon WE,
tion (sunken eyes and fontanelle, reduced skin turgor, hypotension) with uncontrolled diabetes mellitus. Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia,
may be absent. Lippincott Williams & Wilkins, 2004 pp 125145.
9 Sodium excess can be due to exogenous administration of
2 Once fluid status is assessed, patients work-up can be ap- sodium (improperly mixed formulas or NaCl or NaHCO3 administra-
propriately directed. Determination of urine Na+ concentration is es- tion). Infants are especially susceptible to sodium overload. For ex-
sential for narrowing the differential diagnosis. It should be empha- ample, the administration of only 1 tablespoon of NaCl to a newborn
sized that there is no correlation between urinary Na+ level (which is infant can raise the plasma Na by as much as 70 mEq/l. Sodium ex-
normally determined by the ECF volume status), and serum Na+ con- cess can also be secondary to mineralocorticoid excess. In this con-
centration. dition, the hypernatremia is usually mild or even absent, and the
main electrolyte abnormalities are hypokalemia and hypochloremia
3 In renal conditions causing hypernatremia, there are usually (see, Hypokalemia and Hypochloremia).
both water and sodium losses, but the water losses exceed the so- Table. Causes of SIADH
dium losses. The water loss is usually secondary to the reduced uri- 10 Rapid correction of hypernatremia can induce cerebral ede- I. Increased hypothalmic production of ADH
nary concentrating ability present in these patients. ma, seizures, permanent neurologic damage and death. These com-
Neuropsychiatric disorders
plications are a result of rapid reduction in ECF osmolality causing
1. Infections: meningitis (tuberculous or bacterial), encephalitis, abscess,
4 Diarrhea is the most common cause of hypernatremic de- entry of water into cells in the brain and cerebral edema. To minimize herpes zoster 2. Vascular: thrombosis, subarachnoid or subdural hemorrhage,
hydration in children, especially in infants. Other causes of extrarenal this risk, the plasma sodium level should be slowly reduced unless cavernous sinus thrombosis, cerebrovascular accident 3. Neoplasm:
hypernatremic dehydration in children such as losses from skin are the patient has symptomatic hypernatremia. The rate at which the primary or metastatic 4. Skull fracture, head injury 5. Psychosis, delirium
much less common in children. sodium concentration should be lowered is no more than 0.5 mEq/l tremens 6. Other: Guillain-Barr syndrome, acute intermittent porphyria,
autonomic neuropathy, hypothalamic sarcoidosis, postpituitary surgery,
per hour or 12 mEq/l per day. Since most cases of hypernatremia are
multiple sclerosis, epilepsy, hydrocephalus, lupus erythematosus, peripheral
5 The normal response to the elevated plasma osmolarity is due to water loss, gradual correction requires calculation of free wa- neuropathy, spinal cord lesions
secretion of ADH resulting in renal water reabsorption and hence ter deficit [Water deficit = 0.6 weight (kg) (plasma Na/140 1)]. Fre-
Drugs
elevated urine osmolality, usually above 800 mosm/kg. Thus, in the quent monitoring of electrolyte levels is necessary to assure gradual 1. Intravenous cyclophosphamide (increased sensitivity may also
hypernatremic patient, the urine osmolality determines whether reduction of hypernatremia. In CDI, treatment involves careful use of contribute) 2. Carbamazepine (though increased sensitivity is probably
there is a urinary concentrating defect. DDAVP at minimum dose needed to maintain an adequate urine out- important) 3. Vincristine or vinblastine 4. Psychiatric drugs
put. Treatment of NDI may involve use of a thiazide diuretic (which 5. Bromocriptine 6. Clofibrate 7. General anesthesia 8. Narcotics, opiate
6 Water deprivation test should be done in a hospital setting decreases ECF volume thereby increasing H2O reabsorption) and po- derivatives
with close observation of vital signs and urine output. Monitor tassium-sparing diuretic such as amiloride. Pulmonary disease
weight, blood pressure, heart rate, electrolytes, serum and urinary 1. Pneumonia: viral, bacterial, fungal 2. Tuberculosis 3. Lung abscess,
empyema 4. Acute respiratory failure 5. Positive pressure ventilation
osmolality every hour for 4 h. Give DDAVP intranasally if patient is 6. Other: asthma, COPD, atelactasis, pneumothorax, cystic fibrosis
polyuric or urine osm/serum osm <1.5. After 1 h, if patient is still
Miscellaneous
polyuric or urine osm/serum osm <1.5, replace urine output ml for ml
Postoperative patient, severe nausea, pain, infection with HIV, idiopathic
for 2 h then recheck weight and electrolyte levels. Test is completed
after 7 h. If the patient responded to ADH with increased urine osmo- II. Ectopic (nonhypothalamic) production of ADH
1. Ewing sarcoma 2. Hodgkin disease, leukemia 3. Pulmonary tuberculosis
lality, decreased urine output and decreased serum osmolality, liber-
alize fluids cautiously. Watch input closely to avoid water intoxica- III. Potentiation of ADH effect
1. Chlorpropamide 2. Carbamazepine 3. Psychosis 4. Intravenous
tion. If patient did not respond to ADH, then patient has NDI and lib-
75 cyclophosphamide 5. Prostaglandin synthesis inhibitors (salicylates,
eralize fluids ad libitum. NSAIDS)
IV. Exogenous administration of ADH
7 CDI is caused by impaired production or secretion of ADH. Vasopressin, desmopressin, oxytocin
Common causes of CDI include craniopharyngioma, trauma, malig-

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nancies or infiltrative diseases (e.g. histiocytosis X).

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Fluid/electrolyte/acid base balance S. Watkins D. Okamura J. Rodrguez Soriano Hypernatremia
Fluid/electrolyte/acid base balance J. Rodrguez Soriano D. Okamura S. Watkins Hypochloremia

/
Hypochloremia
(Serum Cl <100 mEq/l)

76

Hypovolemia 0 Euvolemia/volume excess 0

Urine Cl 1 Hypertension
Urine Cl >10 mEq/l
PRAm6

<10 mEq/l 0 >10 mEq/l


Plasma aldosterone levels

Decreased Cl intake Renal Cl losses 5

Yes 2 No

Gastrointestinal Cl losses 3 Cutaneous Cl losses 4 Low/normal 7 High 8

Dietary chloride deficiency Vomiting Cystic fibrosis Bartter syndrome Liddle syndrome Glucocorticoid-remediable aldosteronism
in neonates (maternal vomiting) Pyloric stenosis, psychogenic Excessive sweating Gitelman syndrome AME Primary hyperaldosteronism
Prebiliary obstruction Burns Diuretics Licorice ingestion
Intracranial hypertension Gluco- or mineralocorticoid
Gastric drainage administration

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Chloride diarrhea
Congenital, sporadic

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1 Hypochloremia is usually associated with 7 Increased urinary losses of Cl are observed
Selected reading
metabolic alkalosis. It is often difficult to establish in some inherited tubular disorders such as Bartter
which of these two laboratory findings is the primary and Gitelman syndromes or following prolonged ther- Rodrguez Soriano J, Vallo A, Castillo G, Oliveros R,
phenomenon. Hypokalemia is also frequently present. apy with loop or thiazide diuretics. Cea JM, Balzategui MJ: Biochemical features of
dietary chloride deficiency syndromes: a compara-
2 Patient assessment: Hypochloremia can be 8 The combination of hypertension, hypochlo- tive study of 30 cases. J Pediatr 1982;103:209214.
accompanied by either hypovolemia or euvolemia/ remic metabolic alkalosis, urinary chloride wasting, Rodrguez Soriano J: Bartter and related syndromes:
volume excess. A thorough clinical evaluation of the hypokalemia and hyporeninemia is characteristic of The puzzle is almost solved. Pediatr Nephrol 1998;
child to determine his volume status is therefore vital hyperaldosteronism (with high plasma aldosterone 12:315327.
in order to proceed with the work-up: (1) History: Infor- levels) or pseudohyperaldosteronism (with low/nor- Rodrguez Soriano J: Tubular disorders of
mation from patient/family of weight changes, intake mal plasma aldosterone levels) . electrolyte regulation; in Avner ED, Harmon WE,
and output (urinary, gastric, stool), medication history. Niaudet P (eds): Pediatric Nephrology, ed 5.
(2) Examination: Weight, skin changes (edema, turgor), 9 Liddle syndrome is a rare hereditary autoso- Lippincott Williams & Wilkins, 2004, pp 729756.
fontanelle changes, blood pressure/orthostatics, mu- mal-dominant disease characterized by low renin level, Rose BD, Post TW: Clinical Physiology of
cous membranes, cardiac gallop. volume expansion and hypertension due to excessive Acid-Base and Electrolyte Disorders, ed 5.
and unregulated NaCl reabsorption in the distal neph- New York, McGraw-Hill, 2001, pp 555557.
3 In a hypovolemic patient, determination of ron. This situation is due to gain of function mutation Scheinman SJ, Guay-Woodford LM, Thakker RV,
urine Cl concentration is essential for narrowing the in the genes encoding the subunits or of the epithe- Warnock DG: Genetic disorders of renal electrolyte
differential diagnosis. lial Na+ channel. AME is caused by inactivating muta- transport. N Engl J Med 1999;340:11771187.
tions in the gene encoding renal 11-hydroxysteroid Sojo A, Rodrguez Soriano J, Vitoria JC, Vzquez C,
4 Decreased intake of Cl is a rare cause of dehydrogenase type 2. The defective enzyme fails to Ariceta G, Villate A: Chloride deficiency as a
hypochloremia. Dietary chloride deficiency has been inactivate cortisol, which in turn binds to the mineralo- presentation or complication of cystic fibrosis.
described in infants fed soy or regular formulas with corticoid receptor to cause Na+ retention, hyperten- Eur J Pediatr 1994;153:825828.
low Cl content due to a manufacture mistake. This sion and hypokalemia. Ingestion of licorice which Zelikovic I: Molecular pathophysiology of tubular
syndrome may be also rarely observed in breast fed inhibits 11-hydroxysteroid dehydrogenase type 2, transport disorders. Pediatr Nephrol 2001;16:
infants due to low C content of the human milk. may cause similar abnormalities. 919935.

5 Hypochloremia due to gastrointestinal Cl 10 Glucocorticoid-remediable aldosteronism is


losses is a prominent feature of persistent vomiting or an inherited, autosomal-dominant disease, which is a
gastric drainage. It is characteristically observed in result of formation of a chimeric gene that possesses
infants with pyloric stenosis, and more rarely follow- the 5-11-hydroxylase and the 3-aldosterone syn-
ing other conditions associated with persistent vomit- thase sequences. In this situation, aldosterone secre-
ing such as prebiliary obstruction, intracranial hyper- tion is under the influence of ACTH instead of angio-
tension or psychogenic vomiting. Congenital hypo- tensin II and is completely suppressed by dexametha-
chloremia of the newborn infant may occur due to pro- sone administration. The diagnosis of primary hyper-
fuse vomiting of the mother prior to delivery. Congeni- aldosteronism (Conn disease) is rarely made in chil-
tal chloride diarrhea is caused by an inherited defect of dren.
intestinal Cl transport due to mutations in the gene
encoding the intestinal Cl/HCO3 exchanger. This disor-
der should be suspected when an infant presents with
watery diarrhea since birth and a fecal Cl concentra-
tion above 90 mEq/l.

6 Increased cutaneous losses of Cl may be


caused by excessive sweating during exercise or heat
stress. This is a common phenomenon in patients with
77
cystic fibrosis. Infants with cystic fibrosis may present
with a clinical picture of failure to thrive associated
with hypochloremic and hypokalemic metabolic alka-
losis which mimics Bartter syndrome. However, a dif-

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ferential feature is the very low value of urinary Cl in
cystic fibrosis.

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Fluid/electrolyte/acid base balance J. Rodrguez Soriano D. Okamura S. Watkins Hypochloremia
Fluid/electrolyte/acid base balance D. Okamura J. Rodrguez Soriano S. Watkins Hyperchloremia

/
Hyperchloremia
(Serum Cl >110 mEq/l)

78

Metabolic acidosis (normal anion gap) /

No Yes

Urine anion gap 1


[Na+ + K+ Cl]

Negative 2 Positive 3

Bromide poisoning 0 Intestinal HCO3 losses RTA type I (distal RTA)


RTA type II (proximal RTA) RTA type IV
Acetazolamide administration
Exogenous acid administration
TPN

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Ureterosigmoidostomy

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1 Calculation of the serum anion gap [Na+ Fanconi syndrome include: hereditary disorders (cysti-
Selected reading
HCO 3 Cl] (normal value 1012 mEq/l) is essential for nosis, galactosemia, tyrosinemia, hereditary fructose
the evaluation of MA. Hyperchloremic metabolic aci- intolerance, mitochondrial cytopathies and Wilson Herrin TH: Renal tubular acidosis; in Avner ED,
dosis, in which hyperchloremia compensates for the disease), drugs (aminoglycosides, ifosfamide, outdat- Harmon WE, Niaudet P (eds): Pediatric Nephrology,
loss of bicarbonate, is therefore a normal anion gap ed tetracyclines), heavy metal poisoning, and genetic ed 5. Philadelphia, Lippincott Williams & Wilkins,
MA. In contrast, in high anion gap MA (characterized defects in specific proximal tubule transporters lead- 2004, pp 757776.
by the presence of anions other than bicarbonate), the ing to primary isolated RTA. Acetazolamide is an in- Rodrguez Soriano J: Renal tubular acidosis:
serum chloride level remains within normal limits. hibitor of carbonic anhydrase, an enzyme which has a the clinical entity. J Am Soc Nephrol. 2002;13:
major role in tubular bicarbonate regeneration. Inhibi- 21602170.
2 Bromide poisoning can lead to pseudohyper- tion of this enzyme will cause HCMA. Other causes of Rose BD, Post TW: Clinical Physiology of Acid-Base
chloremia (because standard laboratory tests can not HCMA with a negative urinary anion gap are rare in and Electrolyte Disorders, ed 5. New York,
make the distinction between these two anions) and children. McGraw-Hill, 2001, pp 612627.
negative serum anion gap. Some bromide products Scheinman SJ, Guay-Woodford LM, Thakker RV,
also cause mental status changes. 5 RTA types I and IV are characterized by a pos- Warnock DG: Genetic disorders of renal electrolyte
itive urinary anion gap which is due to impaired tubu- transport. N Engl J Med 1999;340:11771187.
3 A primary means by which the renal tubule lar NH+4 production or secretion. Zelikovic I: Renal tubular acidosis. Pediatr Ann 1995;
handles an acid load is by production of ammonia RTA type I (distal RTA) is characterized by an impaired 24:4854.
(NH3). When combined with H+ in the distal tubular distal H+ secretion and hence, a failure to lower urine
lumen, NH3 is converted to ammonium ion (NH4+) pH in the presence of acidosis. Several different mech-
which is lipid-insoluble and therefore can not be anisms are responsible for this type of RTA:
reabsorbed. Because a direct measurement of urinary Secretory defect: A defect in the H+-ATPase pump of
ammonium excretion is cumbersome, urinary anion the intercalated cell in the CCD. This abnormality
gap [Na+ + K+ Cl] serves as an indirect index of can be a primary genetic disorder, or secondary to
urinary ammonium excretion and hence of distal autoimmune diseases (SLE, Sjogren syndrome).
acidification ability. Any change in urinary ammonium Gradient defect: An increase in membrane permeabil-
excretion will be accompanied by a parallel change ity causing backleak of luminal H+ in CCD cells. This
in urinary chloride excretion in order to maintain condition is observed for example in children treated
electroneutrality. with amphotericin B.
Voltage-dependent defect: A reduction in CCD Na+
4 HCMA accompanied by negative urinary reabsorption which diminishes the luminal electro-
anion gap represents an intact distal acidification negativity, thus impairing the ability to secrete H+.
mechanism. Gastrointestinal bicarbonate loss due to This type of distal RTA is accompanied by hyperkale-
diarrhea is the most common cause of HCMA in mia and is seen in markedly volume depleted children
children. Proximal RTA (RTA type II) does not usually and secondary to amiloride treatment.
interfere with urinary ammonium excretion. Proximal The primary pathogenic mechanism of RTA type IV is
RTA can be isolated or can be a part of generalized aldosterone deficiency or resistance. In this type of
proximal tubulopathy (Fanconi syndrome) which leads RTA, the ability to acidify the urine is intact but NH+4
to hypophospatemic rickets, hypouricemia, glycosuria excretion and thus net acid excretion is reduced.
and aminoaciduria. Major causes of proximal RTA/ Hyperkalemia is a main feature of this type of RTA (for
further details, see Hyperkalemia).

79

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Fluid/electrolyte/acid base balance D. Okamura J. Rodrguez Soriano S. Watkins Hyperchloremia
Fluid/electrolyte/acid base balance D. Okamura J. Rodrguez Soriano S. Watkins Hypokalemia

/
Hypokalemia
(Plasma K+ <3.5 mEq/l)

80
Urine K+

<20 mEq/l >20 mEq/l

Decreased K+ intake Blood pressure

Yes 0 No Normal/low 4 High

PRA

Parenteral fluids
Protein-calorie malnutrition

Low 5 High 8

Plasma aldosterone level Renovascular disease


Renin-secreting tumor
Gastrointestinal K losses 1
+
Cutaneous K losses 2
+
Altered K distribution 3
+

Associated with alkalosis Cystic fibrosis Metabolic alkalosis Postobstructive diuresis Low/normal 6 High 7
Vomiting, gastric drainage Excessive sweating Insulin administration Recovery from ARF
Congenital chloride diarrhea Burns B2-Agonists administration RTA type 1
Associated with acidosis Barium poisoning Fanconi syndrome
Profuse or prolonged diarrhea Familial hypokalemic Bartter syndrome Liddle syndrome Glucocorticoid-remediable
Malabsorption, biliary/intestinal fistula periodic paralysis Gitelman syndrome AME aldosteronism
Enterostomy losses, ureterosigmoidostomy Diuretics Licorice ingestion Primary hyperaldosteronism
Unpredictable acid-base abnormality Gluco- or mineralocorticoid

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Laxative or enema abuse administration
Villous adenoma

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1 Plasma K+ level is indicative of the total intra- obstruction or recovery from ARF. It is also character-
Selected reading
cellular content of K+. The relationship between the istically observed in some inherited tubular disorders
reduction in plasma K+ and the deficit in intracellular K+ such as distal RTA, Bartter syndrome and Gitelman Kamel S, Quaggin S, Halperin ML: Disorders of
is curvilinear: when the plasma K+ decreases from syndrome or following prolonged therapy with loop or potassium homeostasis: an approach based on
3.5 to 2.5 mEq/l, the deficit in cell K+ is still small, but thiazide diuretics. pathophysiology. Am J Kidney Dis 1994;24:597613.
becomes more and more significant (up to 30%) when Rodrguez Soriano J: Bartter and related syndromes:
the plasma K+ level decreases below 2.0 mEq/l. 7 The combination of hypertension, hyperkaliu- the puzzle is almost solved. Pediatr Nephrol 1998;12:
ric hypokalemia, metabolic alkalosis and hyporenin- 315327.
2 Decreased intake of K+ is a rare cause of emia is characteristic of hyperaldosteronism (with high Rodrguez Soriano J: Potassium homeostasis and its
hypokalemia in the Western world. However, primary plasma aldosterone levels) or pseudohyperaldosteron- disturbances in children. Pediatr Nephrol 1995;9:
protein-calorie malnutrition, complicated by gastro- ism (with low/normal plasma aldosterone levels). 364374.
enteritis, is the most common cause of hypokalemia in Rodrguez Soriano J: Tubular disorders of electro-
underdeveloped countries. 8 Liddle syndrome is a rare hereditary autoso- lyte regulation; in Avner ED, Harmon WE, Niaudet P
mal-dominant disease characterized by low renin, vol- (eds): Pediatric Nephrology, ed 5. Philadelphia,
3 Gastrointestinal K+ losses may be accompa- ume expansion and hypertension due to excessive Lippincott Williams & Wilkins, 2004, pp 729756
nied by metabolic alkalosis or acidosis. Hypokalemic and unregulated NaCl reabsorption in the distal neph- Scheinman SJ, Guay-Woodford LM, Thakker RV,
metabolic alkalosis is a prominent feature of persistent ron. This situation is due to gain of function mutation Warnock DG: Genetic disorders of renal electrolyte
vomiting (as observed in pyloric stenosis), and of con- in the genes encoding the subunits or of the epithe- transport. N Engl J Med 1999;340:11771187.
genital chloride diarrhea (an entity caused by an inher- lial Na+ channel. AME is caused by inactivating muta- Zelikovic I: Molecular pathophysiology of tubular
ited defect in intestinal chloride transport). Although tions in the gene encoding renal 11-hydroxysteroid transport disorders. Pediatr Nephrol 2001;16:
there is some K+ loss via the gastrointestinal tract, dehydrogenase type 2. The defective enzyme fails to 919935.
most K+ losses in these settings are due to urinary K+ inactivate cortisol, which in turn binds to the mineralo-
losses. The kaliuria is caused by a combination of corticoid receptor to cause Na+ retention, hyperten-
hyperaldosteronism, secondary to hypovolemia, and sion and hypokalemia. Ingestion of licorice which
increased distal tubular reabsorption of Na+, which inhibits 11-hydroxysteroid dehydrogenase type 2,
accompanies the HCO3 delivered to this nephron seg- may cause similar abnormalities.
ment. Diarrhea can lead to gastrointestinal K+ losses
associated with metabolic acidosis. 9 Glucocorticoid-remediable aldosteronism is
an inherited, autosomal-dominant disease, which is a
4 Increased cutaneous losses of K+ and Cl lead- result of formation of a chimeric gene that possesses
ing to secondary hypokalemia may be caused by the 5-11-hydroxylase and the 3-aldosterone syn-
excessive sweating during exercise or heat stress. This thase sequences. In this situation, aldosterone secre-
is a common phenomenon in patients with cystic tion is under the influence of ACTH instead of angio-
fibrosis. Infants with cystic fibrosis may present with tensin II and is completely suppressed by dexametha-
a clinical picture of failure to thrive and electrolyte sone administration. The diagnosis of primary hyper-
abnormalities mimicking Bartter syndrome. aldosteronism (Conn disease) is rarely made in chil-
dren.
5 Altered K+ distribution, with a shift of K+ from
the extracellular to the intracellular compartment, is a 10 The combination of hyperkaliuric hypokale-
common cause of hypokalemia. It may occur after in- mia, metabolic alkalosis, elevated blood pressure and
sulin administration during treatment of diabetic coma, elevated plasma renin and aldosterone levels in chil-
or as a complication of bronchodilator therapy with dren is almost always due to renovascular disease.
2-agonists. Familial hypokalemic periodic paralysis Major etiologies include: renovascular changes sec-
is an inherited disorder caused by mutations in ondary to umbilical artery catheter in newborn infants,
the pore-forming 1S-subunit of the skeletal muscle arteritis secondary to Takayasu or Moyamoya disease,
T-tubule calcium-entry channel. fibromuscular dysplasia (idiopathic or secondary to
81 neurofibromatosis type I), or extrinsic compression of
6 Increased urinary losses of K+ with normo- or the renal artery due to a tumor, hematoma or fibrosis.
hypotension are often observed as a result of the mas- Renin-secreting tumor is rarely diagnosed in children.
sive polyuria that follows release of acute urinary tract

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Fluid/electrolyte/acid base balance D. Okamura J. Rodrguez Soriano S. Watkins Hypokalemia
Fluid/electrolyte/acid base balance J. Rodrguez Soriano D. Okamura S. Watkins Hypokalemia

/
Hyperkalemia
(Plasma K+ >5.2 mEq/l)

82
Exclude spurious hyperkalemia or pseudohyperkalemia 0

Urine K+

>20 mEq/l <20 mEq/l

Exogenous K+ administration Low GFR 3 Normal GFR 4

Yes 1 No Normal plasma Low plasma High plasma


aldosterone 5 aldosterone aldosterone 8

PRA

Endogenous K+ source Altered K+ distribution 2

High 6 Low 7

Acute hemolysis Metabolic acidosis Acute renal failure Defective renal secretion CAH Hyporeninemic hypoaldosteronism PHA type 1 and 3
GI bleeding Insulin deficiency Chronic renal failure Sickle cell disease, SLE, Salt-losing CAH Gordon syndrome (PHA type 2)
Rhabdomyolysis, exercise Drugs obstructive uropathy Adrenocortical failure
Infection B 2-Blockers therapy RTA type 1 (hyperkalemic form) CMO deficiency type 1 and 2
Burns Digoxin overdose Drugs
Surgery Succinylcholine Spironolactone, triamterene, amiloride,
Prematurity ACE inhibitors, heparin, cyclosporine A,
Hyperosmolality NSAID, trimethoprim
Diet Familial hyperkalemic
Oral or i.v. K+ load periodic paralysis
Transfusions

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1 Severe hyperkalemia is a life-threatening lism. In mild-to-moderate chronic renal failure, signifi- 10 Aldosterone resistance with elevated plasma
condition. An electrocardiogram must be obtained cant hyperkalemia is uncommon unless a state of levels of aldosterone, is observed in PHA type 1.
promptly to test for changes such as prolonged PR hyporeninemic hypoaldosteronism exists (see below). This hereditary disorder presents clinically with renal
interval, widened QRS complex or ventricular fibrilla- sodium wasting, hyperkalemia and metabolic acidosis.
tion. If these changes are observed, or plasma K+ con- 6 The combination of hyperkalemia, low uri- There are two forms of PHA type 1: In the renal, auto-
centration rises above 7 mEq/l, immediate therapy for nary potassium concentration and normal GFR is usu- somal-dominant form, the aldosterone resistance is
hyperkalemia should be initiated. This includes: Intra- ally the result of aldosterone deficiency or resistance. limited to the kidney and is due to mutations in the
venous (IV) administration of calcium gluconate, An estimate of aldosterone activity in the distal and gene encoding the mineralocorticoid receptor. In the
NaHCO3 and/or glucose with insulin, administration of collecting tubule is given by the so-called transtubular autosomal-recessive multiple-end-organ form, the
a 2-agonist aerosol, or dialysis therapy, if necessary. potassium gradient, as calculated by the formula: aldosterone resistance is present in many organs (kid-
Mild hypokalemia (<6 mEq/l) without EKG changes can ney, colon, lung, sweat and salivary glands) and is due
[UK /(Uosm/Posm)]
be managed by decreasing dietary K+ intake and by . Normal value 64.0. to mutations in one of the genes encoding the -, -, or
Plasma K
oral or rectal administration of a cation exchange resin -subunits of the epithelial Na+ channel. There is also a
(Kayexalate). secondary form of aldosterone resistance, called PHA
7 Defective renal secretion of K+ with normal
type 3, frequently observed in infants with obstructive
2 Spurious hyperkalemia is due to the libera-
plasma aldosterone level with or without mild renal
uropathy and/or urinary tract infection.
failure, may be observed in acute or chronic interstitial
tion of K+ from cellular elements of muscle during
nephropathies (obstructive uropathy, SLE, sickle cell
blood drawing or from erythrocytes during in vitro
disease). In the hyperkalemic form of RTA type 1 (also
hemolysis, In pseudohyperkalemia, K+ is elevated in Selected reading
known as voltage-type distal RTA), there is a reduction
serum but not in plasma due to its liberation from
in Na+ reabsorption in the cortical collecting duct, Kamel S, Quaggin S, Halperin ML: Disorders of
platelets and leukocytes during clot retraction in indi-
which diminishes the tubular lumen electronegativity, potassium homeostasis: an approach based on
viduals with thrombocytosis or leukocytosis or in a
thus impairing distal K+ secretion. Defective renal pathophysiology. Am J Kidney Dis 1994;24:597613.
rare entity called familial pseudohyerkalemia.
secretion of K+ is more frequently seen as a conse- Rodrguez Soriano J: Bartter and related syndromes:
3 Increased intake of K+ rarely induces hyperka-
quence of administration of various drugs. These the puzzle is almost solved. Pediatr Nephrol 1998;12:
drugs should be used with extreme caution in the 315327.
lemia unless there is reduced renal function, as occurs
presence of preexisting renal disease. Rodrguez Soriano J: Potassium homeostasis and its
in preterm newborn infants or in patients with chronic
renal failure. Transfusions of aged or irradiated blood disturbances in children. Pediatr Nephrol 1995;9:
8 Hypokaliuric hyperkalemia due to aldoste-
products may also induce hyperkalemia. 364374.
rone deficiency with elevated PRA is generally Rodrguez Soriano J: Tubular disorders of electro-
4 Altered K+ distribution, with release of K+
observed in endocrine disorders such as congenital lyte regulation; in Avner ED, Harmon WE, Niaudet P
adrenal hypoplasia, salt-losing forms of CAH or in rare (eds): Pediatric Nephrology, ed 5. Philadelphia,
from the intracellular to the extracellular compartment,
inherited defects of aldosterone biosynthesis called Lippincott Williams & Wilkins, 2004, pp 729756.
is not rare. In metabolic acidosis H+ moves into the
CMO deficiency types 1 and 2. Adrenal cortical failure Scheinman SJ, Guay-Woodford LM, Thakker RV,
cells, and causes shift of intracellular K+ to the extracel-
is observed in Addison disease and in adrenoleuko- Warnock DG: Genetic disorders of renal electrolyte
lular fluid. However, only very severe degree of meta-
dystrophy. transport. N Engl J Med 1999;340:11771187.
bolic acidosis due to retention of fixed acids will be
accompanied by hyperkalemia. In organic acidemia Zelikovic I: Molecular pathophysiology of tubular
9 Hyporeninemic hypoaldosteronism is ob-
(lactic acidosis, ketoacidosis, hereditary organic acido- transport disorders. Pediatr Nephrol 2001;16:
served in patients with diabetic nephropathy or chron- 919935.
sis), on the other hand, the organic anion is able to fol-
ic tubolointerstitial disorders. Although considered
low the H+ into the cells, thus alleviating the need for K+
rare in children, hyporeninemic hypoaldosteronism is
redistribution. Hyperkalemia may be seen in sick pre-
probably more common in this age group than previ-
term newborn infants even without impaired renal
ously thought. Gordon syndrome, also called pseudo-
function or metabolic acidosis and as a consequence
hypoaldosteronism type 2, is a hereditary, autosomal-
of administration of several drugs. Familial hyperkale-
dominant disorder caused by loss of function muta-
mic periodic paralysis (Garmstrop disease) is a very
tions in the gene encoding WNK4 or gain of function
rare disorder caused by mutations of the gene encod-
83 mutations in the gene encoding WNK1 kinase. The
ing the -subunit of the skeletal Na+ channel.
consequence of the mutation is increased NaCl reab-
5 Decreased excretion of K+ is frequently seen
sorption in the distal convoluted tubule which results
in hypervolemia, hypertension, hyporeninemic hy-
in both acute and chronic renal failure. Hyperkalemia
poaldosteronism, hyperkalemia and type 4 RTA.

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develops in oliguric acute renal failure even in the ab-
sence of excessive K+ intake because of tissue catabo-

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Fluid/electrolyte/acid base balance J. Rodrguez Soriano D. Okamura S. Watkins Hypokalemia
Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Metabolic acidosis

/
Metabolic acidosis
84 Renal failure 0

No Yes

Normal (1012 mEq/l) Blood anion gap 1 Increased < Blood lactate

Urine anion gap 2


Elevated Normal

Cl >Na++K+ 3 Cl <Na++K+ 4
Blood glucose

Urine pH High Normal/low

Urine ketones
>5.8 <5.8
Elevated Negative
Serum K+
RTA type 4 7
Hypoglycemic Toxicology
syndromes
Low High PRA Fasting Negative

Positive
High Low
Distal RTA Hyperkalemic
(type 1) 5 distal RTA (type 1) 6
Blood pressure
Plasma aldosterone
Diabetes mellitus Acute failure Chronic failure
High Normal Nondiabetic causes
Low High

Plasma cortisol

Renal US
Normal Low

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Univ. of California San Diego
Intestinal HCO3 losses Primary PHA type 1 8 Gordon Hyporeninemic Liver failure Salicylates Examine:
RTA type 2 (proximal RTA) hypoaldosteroidism syndrome : hypoaldosteronism ; Leukemia Ethylene glycol Carnitine (blood)

Downloaded by:
Acetazolamide administration (PHA type 2) Solid tumors Methanol Urine for reducing substances,
Exogenous acid administration Salicylates organic and amino acids
TPN Muscle hyperactivity
Ureterosigmoidostomy Tissue hypoperfusion
and hypoxia
Addison disease PHA type 3 Inherited and
Congenital adrenal (vesicoureteral reflux, obstructive uropathy, metabolic disorders
hyperplasia pyelonephritis) 9 Diabetes mellitus

1 MA is characterized by low blood HCO3 level as well as by drase, an enzyme which has a major role in tubular bicarbonate re- 12 Gordons syndrome, also called pseudohypoaldostreonism
low pCO2 level caused by compensatory hyperventilation. generation. Inhibition of this enzyme will cause HCMA. Other causes type 2, is a hereditary, autosomal-dominant disorder caused by gain
of HCMA with a negative urinary anion gap are rare in children. of function mutation in the genes encoding WNK1 or WNK4 kinases.
2 MA in renal failure is usually associated with increased se- The consequence of the mutation is increased NaCl reabsorption in
rum anion gap [Na+ HCO3 CI ] due to accumulation of acids in the 6 RTA types 1 and 4 are characterized by a positive urinary the distal convoluted tubule which results in hypervolemia, hyper-
blood. However, due to tubular damage, a component of normal an- anion gap [Cl < Na+ + K+] which is due to impaired tubular NH4+ pro- tension, hyporeninemic hypoaldosteronism, hyperkalemia and type
ion gap acidosis is often added, resulting in a mixed picture. duction or secretion. 4 RTA.

3 Calculation of the serum anion gap [Na+ HCO3 Cl ] is es- 7 RTA type 1 (distal RTA) is characterized by an impaired distal 13 Hyporeninemic hypoaldosteronism can be caused by vari-
sential for the evaluation of MA. In normal anion gap MA, hyperchlo- H+ secretion and, hence, a failure to lower urine pH in the presence of ous conditions including:
remia compensates for the loss of bicarbonate. In contrast, in high acidosis. Several different mechanisms are responsible for this type interstitial nephritis, sickle cell nephropathy, amiloride administra-
anion gap MA (characterized by the presence of anions other than of RTA: tion, diabetes mellitus, obstructive uropathy and others. Although
bicarbonate), the serum chloride level remains within normal limits. Secretory defect a defect in the H+-ATPase pump of the interca- considered rare in children, hyporeninemic hypoaldosteronism is
lated cell in the CCD. This abnormality can be a primary-genetic dis- probably more common in this age group than previously thought.
4 A primary means by which the renal tubule handles an acid order, or secondary to autoimmune diseases (SLE, Sjogren syn-
load is by production of ammonia (NH3). When combined with H+ in drome). 14 Increased serum anion gap indicates that an unmeasured
the distal tubular lumen, NH3 is converted to ammonium ion (NH4+) Gradient defect an increase in membrane permeability causing anion is added to the blood, either endogenously (lactate, ketone
which is lipid-insoluble and therefore cannot be reabsorbed. Be- backleak of luminal H+ in CCD cells. This condition is observed for bodies, organic acids) or exogenously (salicylates, ethelene glycol,
cause a direct measurement of urinary ammonium excretion is cum- example in children treated with amphotericin B. methanol). For details on the various disorders leading to high anion
bersome, urinary anion gap [Na+ + K+ Cl] serves as an indirect in- gap MA in children see appropriate references.
dex of urinary ammonium excretion and hence of distal acidification 8 Hyperkalemic distal (type 1) RTA is seen mainly in associa-
ability. Any change in urinary ammonium excretion will be accompa- tion with obstructive uropathy in markedly volume-depleted children
nied by a parallel change in urinary chloride excretion in order to and secondary to amiloride treatment. In this type of distal RTA (also Selected reading
maintain electroneutrality. Anions like ketone bodies and certain an- known as voltage-type distal RTA), there is a reduction in Na+ reab-
tibiotics may interfere with calculation of the urine anion gap. Fur- sorption in the cortical collecting duct, which diminishes the tubular Batlle D, Moorthi KM, Schlueter W, Kurtzman N: Distal renal tubular
thermore, NH4+ excretion decreases in the face of hypovolemia and lumen electronegativity, thus impairing distal H+ and K+ secretion. acidosis and the potassium enigma. Semin Nephrol 2006;26:
avid tubular Na reabsorption (urine Na <20 mEq/l). 471478.
9 RTA type 4 is characterized by hyperkalemia and decreased Hanna JD, Scheinman JI, Chan JCM: The kidney in acid-base
5 HCMA accompanied by negative urinary anion gap [Cl > ability to secrete NH4+. balance. Pediatr Clin N Am 1995;42:1365.
Na+ + K+] represents an intact distal acidification mechanism. Gastro- Herrin TH: Renal tubular acidosis; in Avner ED, Harmon WE,
intestinal bicarbonate loss due to diarrhea is the most common 10 11 PHA types 1 and 3 are characterized by hyponatremia, Niaudet P (eds): Pediatric Nephrology, ed 5. Philadelphia,
cause of HCMA in children. Proximal RTA (RTA type 2) does not usu- hypernatriuria, hyperkalemia and metabolic acidosis. There are two Lippincott Williams & Wilkins, 2004, pp 757776.
ally interfere with urinary ammonium excretion. Proximal RTA can forms of PHA 1: in the renal, autosomal-dominant form, the aldoste- Krapf R, Seldin DW, Alpern RJ: Clinical syndromes of metabolic
be isolated or can be a part of generalized proximal tubulopathy rone resistance is limited to the kidney and is due to mutations in the acidosis; in Seldin DW, Giebisch G (eds): The Kidney:
(Fanconi syndrome) which leads to hypophosphatemic rickets, gene encoding the mineralocorticoid receptor. In the autosomal-re- Physiology and Pathophysiology, ed 3. Philadelphia, Lippincott
hypouricemia, glycosuria and aminoaciduria. Major causes of proxi- cessive, multiple-end-organ form, the aldosterone resistance is Williams & Wilkins, 2000, pp 20732130.
85 mal RTA/Fanconi syndrome include: hereditary disorders (cystinosis, present in many organs (kidney, colon, lung, sweat and salivary Nicoletta JA, Schwartz GJ: Distal renal tubular acidosis.
galactosemia, tyrosinemia, hereditary fructose intolerance, mito- glands) and is due to mutations in one of the -, - or -subunits of Curr Opin Pediatr 2004;16:194198.
chondrial cytopathies and Wilson disease), drugs (aminoglycosides, the epithelial Na+ channel. There is also a secondary form of aldoste- Rodrguez Soriano J: Renal tubular acidosis: the clinical entity.
ifosfamide, outdated tetracyclines), heavy metal poisoning, and ge- rone resistance called PHA type 3, frequently observed in infants J Am Soc Nephrol 2002;13:21602170.

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netic defects in specific proximal tubule transporters leading to pri- with obstructive uropathy and/or urinary tract infection. Zelikovic I: Renal tubular acidosis. Pediatr Ann 1995; 24:4854.
mary isolated RTA. Acetazolamide is an inhibitor of carbonic anhy-

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Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Metabolic acidosis
Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Metabolic alkalosis

/
Metabolic alkalosis
86 Urine chloride

High (>20 mEq/l) 0 Variable 5 Low (<20 mEq/l) 6

Blood pressure Special diet/formula Yes

No Low Cl intake
Normal High

Chronic diuretic therapy Yes


Diuretics (recent) Plasma renin

No Loop, thiazides

Yes No 1 High 2 Low Gastric loss Yes

Plasma aldosterone No Vomiting, nasogastric suction

Diarrhea Yes
High 3 Low 4

No Congenital CI diarrhea
Colonic adenoma

Other causes of hypovolemia Yes


Hereditary potassium- Glucocorticoid-remediable Gastrocystoplasty
losing tubulopathies aldosteronism Excessive alkali administration
(Bartter, Gitelman syndrome) Primary Hypoparathyroidism
No Contraction alkalosis
hyperaldosteronism Glucose ingestion after starvation
Large dose of penicillin
Severe K or Mg depletion
Sweat test Abnormal

Loop Renal artery stenosis Liddle syndrome


Thiazides Renin-secreting tumors Apparent mineralocorticoid excess Normal Cystic fibrosis

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11A-Hydroxylase deficiency
Gluco-/mineralocorticoid administration

Univ. of California San Diego


Licorice ingestion Post hypercapnia

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1 Metabolic alkalosis is characterized by elevat- 5 Glucocorticoid-remediable aldosteronism is
Selected reading
ed serum HCO3 and pCO2 levels. The latter is caused an inherited, autosomal-dominant disease, which is a
by compensatory hypoventilation. Metabolic alkalosis result of formation of a chimeric gene that possesses Galla JH: Metabolic alkalosis. J Am Soc Nephrol
is usually associated with hypochloremia and it is of- the 5-11-hydroxylase and the 3-aldosterone syn- 2000;11:369375.
ten difficult to establish which of these two laboratory thase sequences. In this situation, aldosterone secre- Laski ME, Sabatini S: Metabolic alkalosis, bedside
findings is the primary phenomenon. Metabolic alkalo- tion is under the influence of ACTH instead of angio- and bench. Semin Nephrol 2006;26:404421.
sis can be accompanied by either hypovolemia or eu- tensin II and is completely suppressed by dexametha- Oh MS, Carroll HJ: Mechanism of chloride deficit in
volemia/volume excess. A thorough clinical evaluation sone administration. The diagnosis of primary hyper- the maintenance of metabolic alkalosis. Nephron
of the child to determine his volume status is therefore aldosteronism (Conn disease) is rarely made in chil- 2002;91:379382.
vital in order to proceed with the work-up: dren. Rodrguez Soriano J: Tubular disorders of electro-
I. History: Information from patient/family of weight lyte regulation; in Avner ED, Harmon WE, Niaudet P
changes, intake and output (urinary, gastric, stool), 6 Liddle syndrome is a rare hereditary autoso- (eds): Pediatric Nephrology, ed 5. Philadelphia,
medication history. mal-dominant disease characterized by low renin, vol- Lippincott Williams & Wilkins, 2004, pp 729756.
II. Examination: Weight, skin changes (edema, turgor), ume expansion and hypertension due to excessive Wesson DE, Alpern RJ, Seldin DW: Clinical
fontanelle changes, blood pressure/orthostatics, and unregulated NaCl reabsorption in the distal neph- syndromes of metabolic alkalosis; in Seldin DW,
mucous membranes, cardiac gallop. ron. This situation is due to gain of function mutation Giebisch G (eds): The Kidney: Physiology and
in the genes encoding the - or -subunits of the epi- Pathophysiology, ed 3. Philadelphia, Lippincott
2 Most conditions that lead to metabolic alkalo- thelial Na+ channel. AME is caused by inactivating mu- Williams & Wilkins, 2000, pp 20552072.
sis and are associated with high urine chloride level tations in the gene encoding renal 11-hydroxysteroid Zelikovic I: Molecular pathophysiology of tubular
and are regarded as chloride-resistant. dehydrogenase type 2. The defective enzyme does not transport disorders. Pediatr Nephrol 2001;16:
inactivate cortisol, which in turn binds to the mineralo- 919935.
3 As a rule of thumb, the earlier the age of pre- corticoid receptor to cause Na+ retention, hyperten-
sentation of hereditary potassium-losing nephropa- sion and hypokalemia. Ingestion of licorice which in-
thies, the more severe the presentation. When pre- hibits 11-hydroxysteroid dehydrogenase type 2, may
sented in early childhood, it is often associated with cause similar abnormalities.
severe urinary losses of Na and Cl and failure to thrive
(Bartter syndrome). In later childhood, presentation is 7 In the majority of these conditions urine chlo-
milder, at times with tetany due to hypomagnesemia/ ride level is expected to be low.
hypocalcemia (Gitelman syndrome). These syndromes
mimic the pictures seen when either loop diuretics or 8 The combination of metabolic alkalosis and
thiazides are used, with reduction in NaCl reabsorp- low urine Cl level is observed in conditions caused
tion in the loop of Henle (Bartter syndrome) or the dis- either by low chloride intake or extrarenal losses of
tal tubule (Gitelman syndrome), respectively. Bartter this ion, through the gastrointestinal tract or the skin.
syndrome is characterized by urinary calcium losses These disorders are characterized by volume depletion
whereas Gitelman syndrome by increased urinary and low urinary chloride concentration and are regard-
magnesium losses. ed as chloride responsive. For details on these condi-
tions, see sections on Hypokalemia and Hypochlore-
4 The combination of hyperkaliuric hypokale- mia.
mia, metabolic alkalosis, elevated blood pressure and
elevated plasma renin and aldosterone levels in chil-
dren is almost always due to renovascular disease.
Major etiologies include: renovascular changes sec-
ondary to umbilical artery catheter in newborn infants,
arteritis secondary to Takayasu or Moyamoya disease,
fibromuscular dysplasia (idiopathic or secondary to
neurofibromatosis type 1), or extrinsic compression of
87 the renal artery due to a tumor, hematoma or fibrosis.
Although the gold standard for the diagnosis of renal
artery stenosis is selective renal angiogram, currently
CT angiography is the preferred mode of imaging. Re-

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nin-secreting tumor is rarely diagnosed in children.

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Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Metabolic alkalosis
Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Hypovolemia

/
Hypovolemia
88 Trauma, bleeding Normal/high 9
Environmentally induced hypovolemia

Serum Na
No

Urine volume Low/normal High


(renal Na + H2O losses) (renal H2O losses)

Low 0 Glucosuria Diabetes insipidus

Response to ADH
Yes No
CNS Respiratory GI tract losses 3 Skin Third spacing

Pharmacotherapy Yes No
Toxicology
Serum albumin
Metabolic Metabolic Central Renal
alkalosis acidosis
Yes No

Low 6 Normal GFR

Ascites
Anasarca Acute Vascular Normal Low
abdomen 8 pathology

Urine protein Urinary


salt wasting Improving Stable

High Negative
Serum

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aldosterone

Univ. of California San Diego


Downloaded by:
Insensible Melena Excessive Renal Pleural Bleeding Diuretics Low Normal/high Postobstructive Chronic renal
losses 2 sweating 4 disease effusion 7 Rupture Osmotic uropathy failure
Obstruction diuresis
Blood pressure

Adipsia 1 Gastric Intestinal Insensible Malnutrition Intestinal Diabetes


Pancreatic losses 5 Malabsorption obstruction mellitus
Biliary Burns Protein-losing Pancreatitis Proximal
Normal High
enteropathy Peritonitis tubulopathy
Liver disease
Hypoaldosteronism Salt-losing Hyponatremic
Hypoadrenalism nephropathy : hypertensive
syndrome ;

1 Hypovolemia is characterized by rapid heart rate, decreased 8 Although massive proteinuria often results in hypovolemia, Selected reading
tissue perfusion and at times lowered blood pressure. A thorough some patients remain euvolemic. The volume status can be assessed
clinical evaluation of the hypovolemic child is vital in order to pro- by measuring FENa, which is very low in hypovolemic states, or in Bockenkamp B, Vyas H: Understanding and managing acute fluid
ceed with the work-up: conditions characterized by low effective circulatory volume (e.g. NS, and electrolyte disturbances. Curr Paediatr 2003;13:520528.
I. History: Information from patient/family on weight changes, intake congestive heart failure, etc.). Boluyt N, Bollen CW, Bos AP, Kok JH, Offringa M: Fluid resuscita-
and output (urinary, gastric, stool), medication history. tion in neonatal and pediatric hypovolemic shock: a Dutch
II. Examination: Weight, skin changes (edema, turgor), fontanelle 9 A large pleural effusion, especially when continuously Pediatric Society evidence-based clinical practice guideline.
changes, heart rate, blood pressure/orthostatics, mucous mem- drained, can result in hypovolemia. Intens Care Med 2006;32:9951003.
branes, cardiac gallop, capillary refill time. Finberg L: Dehydration in infancy and childhood. Pediatr Rev
10 Some of these conditions, if becoming long-standing, can 2002;23:277282.
2 Hypovolemia accompanied by low urine volume (below 1 result in hypoalbuminemia. Nicholls MG: Unilateral renal ischemia causing
ml/kg/h) usually indicates that the ability of the kidneys to conserve the hyponatremic hypertensive syndrome in children more
water is intact and that the cause of the hypovolemia is extrarenal. 11 The combination of hypovolemia with high urine output common than we think? Pediatr Nephrol 2006;21:887890.
indicates that there is an impairment in renal water reabsorption, Rose BD, Post TW: Clinical Physiology of
3 Patients with adipsia/hypodipsia often have additional CNS either due to an intrinsic renal defect or secondary to an osmotic Acid-Base and Electrolyte Disorders, ed 5.
manifestations. As some of them may also have partial ADH defi- substance in the urine that interferes with normal renal concentrat- New York, McGraw-Hill, 2001, pp 415446.
ciency, urine volume may vary. Typically, these patients are at risk to ing mechanisms. Trachtman H: Sodium and water homeostasis. Pediatr Clin N Am
develop hyperosmolar dehydration. 1995;42:1343.
12 Salt-losing nephropathies include any form of renal disease
4 Loss of water through the respiratory system may be in- that causes an impairment in sodium reabsorption and hence free
creased especially during mechanical ventilation. water excretion. For further details, see Hyponatremia.

5 GI tract losses may result in hypo-, iso- or hyperosmolar 13 The hyponatremic hypertensive syndrome is a rare disor-
dehydration. der seen mainly in infants and young children. It is caused by severe
primary or secondary hyperreninemia, severe hypertension and
6 In a patient with excessive sweating, one needs to rule out consequently pressure diuresis. Once the patient becomes severely
89
cystic fibrosis. dehydrated, urine volume declines. Losses of sodium and water stop
when the hypertension is corrected.
7 Insensible losses of water through the skin are more com-
mon in the newborn due to the higher skin surface area to body mass

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ratio. Especially prone to hypovolemia are preterm infants under
radiant warmers.

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Fluid/electrolyte/acid base balance U.S. Alon W. Proesmans Hypovolemia
Fluid/electrolyte/acid base balance W. Proesmans U.S. Alon Edema

/
Edema
90
Symmetrical Localized/unilateral

Hypoalbuminemia
Angioedema A Venous B Lymphatic C Infectious C

Yes No

Albuminuria TSHMT4m

No Yes No Yes

Malnutrition 0 Protein-losing Hepatic Hydrops Renal CHF ? Myxedema @


enteropathy 1 failure 2 fetalis 3

Serum creatinineM

No Yes

Idiopathic NS Systemic manifestations 8

Hematuria
No Yes

No Yes

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Minimal-change NS 4 FSGS 5 MGP 6 IgAN 7 MPGN 9 AGN : HUS ; ICGN < SLE = Vasculitis >

Univ. of California San Diego


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1 Presence of abnormally large amounts of fluid in the intercel- droplets. Roughly one third of these patients do not respond to any treat- 16 Vasculitis is a term used to describe a vascular lesion character-
lular spaces of the body. Clinically, edema is characterized by demon- ment and have a relentless progressive course towards end-stage renal ized by inflammation and necrosis of the blood vessels walls as can be
strable accumulation of excessive fluid in subcutaneous tissues. The fol- failure. In some patients, the underlying cause is genetic (see Nephrotic observed in a heterogeneous group of disorders (see Vasculitis).
lowing forms of edema can be distinguished (1) edema due to increased syndrome).
transudation of fluid as in NS resulting in pitting edema, (2) edema 17 CHF leads to cardiac edema. Rapidly occurring deficiency in
due to increased protein concentration in the interstitium as in lymph- 8 MGP is the most common cause of NS in adults but it is uncom- cardiac output is marked by venocapillary congestion, hypertension,
edema resulting in nonpitting, rubbery edema, and (3) edema due to mon in childhood. There is proteinuria and hematuria and sometimes edema and often lung edema. CHF is further clinically characterized by
increased interstitial gel formation as in myxedema resulting in non- hypertension. Histologically, the GBM is thickened by the presence of reduced excercise capacity and dyspnea.
compressible or brawny edema. Edema can be localized or generalized, immune deposits on the epithelial side and spikes which are extrusions
the latter is known as anasarca or, in the newborn, hydrops. of membrane-like material. Immunofluorescence demonstrates granular 18 Myxedema is a condition characterized by dry, waxy swelling
deposits of IgG and C3 to be located on the epithelial side of the GBM. of the skin with abnormal deposits of glycosaminoglycans in the skin and
2 Nutritional edema is the consequence of a longstanding diet Half of the children are carrying the hepatitis B virus. MGP resolves spon- other tissues. It is caused by hypothyroidism, a deficiency is thyroid ac-
deficiency of protein and is marked by ascites or anasarca. It is mainly taneously in the majority of children. tivity. Hypothyroidism can be congenital or acquired and sometimes he-
seen in the third world due to famine or war. Kwashiorkor is the more reditary.
common name for the syndrome produced by severe protein deficiency, 9 IgA nephropathy is the most frequent chronic glomerulopathy
characterized by growth retardation, changes in the skin and hair pig- in the world. It manifests itself by recurrent macroscopic hematuria, mi- 19 Angioedema, also called Quincke edema, is a vascular reaction
ments, edema, mental apathy, anemia and low serum albumin. Maras- croscopic hematuria plus proteinuria, the nephrotic syndrome and only involving the deep dermis, representing localized edema caused by dila-
mic kwashiorkor is a condition in which deficiency of both calories and exceptionally as chronic renal insufficiency. Histology shows a spectrum tation and increased permeability of the capillaries. Clinically, angioede-
protein is present. of lesions from minimal segmental mesangial proliferation to diffuse ma is characterized by the development of giant, urticarial wheals. There
crescentic glomerulonephritis. Immunofluorescence demonstrates the is eosinophilia and deficiencies in the complement system. Besides spo-
3 This is a nonspecific term referring to a series of conditions as- presence of IgA and C3, sometimes IgG and IgM as well, in the mesan- radic angioedema, which can be elicited by a large number of antigens,
sociated with excessive enteric loss of plasma protein. It occurs a.o in gium of all glomeruli. there is also hereditary angioedema which is due to a deficit in C1 inhibi-
inflammatory bowel disease, giant hypertrophic gastritis (Mntrier dis- tor. Angioedema is localized in the majority of cases; occasional patients
ease) and in congenital or acquired intestinal lymphangiectasies. It is 10 The term used here should be interpreted as widely as possible can display a more diffuse form of the disorder.
noteworthy that cardiac patients having undergone the Fontan proce- but does not include arterial hypertension. It comprises skin lesions (urti-
dure can develop intestinal protein losing. caria, redness, vasculitis), arthritis and arthropathies, abdominal and 20 Localized edema can be caused by venous obstruction as in
muscle pain, vomiting and diarrhea, headache and neurologic deficit. varices, venous thrombosis, thrombophlebitis and accidental venous
4 A large number of diseases can affect the liver to cause hepatic cutting. Klippel-Trenaunay-Weber syndrome is a congenital, nonheredi-
insufficiency which is characterized by defective synthesis of a number 11 MPGN is a prototypical form of chronic glomerulonephritis tary disorder comprising macular vascular nevus in combination with
of proteins including albumin. Low albumin causes reduced oncotic pres- characterized by proteinuria, hematuria, hypertension, some degree of bony and soft tissue hypertrophy and venous varicosities.
sure leading to ascites and edema of the legs or to anasarca. renal failure and hypocomplementemia. From the histological point of
view, 3 different types have been identified; type 2 is mainly referred to 21 Edema caused by obstruction of the lymph drainage from an ar-
5 This is a life-threatening syndrome characterized by severe hy- as dense deposit disease. The prognosis of this glomerulopathy is rather ea in the body is of rubbery consistence. Acquired lymphedema may result
poalbuminemia and ascites or anasarca before birth. In terms of patho- poor with a high incidence of recurrence after transplantation especially from inflammatory processes or from surgical or radiological obliteration
physiology, there are two categories of patients: (1) patients with circula- in type 2. There is no uniformly accepted and efficient therapy. of lymph nodes or lymph channels. Congenital lymphedema of both legs
tory failure, and (2) fetuses with primary hypoproteinemia. Etiologies of due to chronic lymphatic obstruction is referred to as Milroy disease.
the first category are a.o. erythroblastosis fetalis, congenital heart de- 12 The classical poststreptococcal acute GN presents with gross
fects, cardiac arrythmias, obstruction of the cava inferior, etc. Etiologies hematuria, mild edema, oliguria and hypertension, some days to weeks 22 Infections of the subcutaneous tissues can lead to edema
of the second category are intrauterine infections, inborn errors of me- after a streptococcal infection of the skin or amygdalae. It is a self-limit- which is accompanied by redness and pain. A classical example is erysip-
tabolism and congenital nephrotic syndrome. ing disorder with an almost 100% cure rate. elas, an acute form of superficial cellulitis usually caused by an infection
with group A streptococci. The lesion is hot, bright red, edematous and
6 In childhood, the most frequent form of the idiopathic nephrotic 13 HUS is the commonest cause of primary acute renal failure in sharply circumscribed with a raised border.
syndrome is an acquired illness of unknown etiology which presents be- childhood (see Hemolytic uremic syndrome).
tween the age of 18 months and 12 years and is histologically character-
ized by minimal glomerular lesions. It comprises massive proteinuria, 14 Diffuse crescentic GN is the morphologic substrate of rapidly Selected reading
hypoalbuminemia and hypercholesterolemia but, usually, not accompa- progressive GN. This clinicopathologic entity can be seen with a variety
nied by hematuria, hypertension or increased serum creatinine. Over of well-defined glomerular and systemic diseases or may be due to a Bukowski R, Saade GR: Hydrops fetalis. Clin Perinatol 2000;27:10071031.
91 90% of these patients go into complete remission when given 60 mg/m glomerular disease that does not fit into any of these conditions and is Franceschini P, Licata D, Rapello G, et al: Prenatal diagnosis of
of predniso(lo)ne but recurrence is common. therefore referred to as idiopathic crescentic GN (ICGN) (see Rapidly Nonne-Milroy lymphedema. Ultrasound Obstet Gynecol 2001;8:182183.
progressive glomerulonephritis). Haycock GB: Sodium and body fluids; in Barratt TM, Avner A,
7 FSGS. This term refers to a nonspecific glomerular lesion Harmon WE (eds): Pediatric Nephrology, ed 4. Baltimore, Lippincott
which can be observed in patients with idiopathic nephrotic syndrome 15 SLE is an immune complex-mediated disorder which has an Williams & Wilkins, 1999, chap 8, pp 133153.

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accompanied by hematuria and not responsive to steroids. The lesions autoimmune basis. Multiple organ involvement is caused by deposition Katz MA: Interstitial space: the forgotten organ. Med Hypotheses
are focal (touching only part of the glomeruli) and segmental (involving of circulating IC; if IC localize in the glomeruli, lupus nephritis develops 1980;6:885898.

Univ. of California San Diego


parts of the glomerular capillaries). The abnormal segment adheres to (see Vasculitis). Witt C, Ottesen EA: Lymphatic filariasis: an infection of childhood.
Bowmans capsule, has little cells, increased fibrous tissue and lipid Trop Med Int Health 2001;6:584606.

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Fluid/electrolyte/acid base balance W. Proesmans U.S. Alon Edema
Divalent ion metabolism G. Ariceta B. Hoppe C.B. Langman Hypocalcemia

/
Hypocalcemia Symptoms 0

92 mSerum PO4
MSerum alkaline phosphase

Yes No

PTHMand radiological signs Serum Mgm

Calcipenic rickets 1 No

Serum PTH
Serum 25(OH)D3

Elevated Low

Absent/low Normal
Serum creatinineM

Vitamin D-deficient Genetic disorders in Hypomagnesemia 4


rickets 2 vitamin D metabolism 3 No Yes

Serum 1,25(OH)2D3 PHP ; Hypoparathyoroidism 5

cAMP increase in PTH testing < Fam. Hypoparathyroidism 6


Absent/low Elevated DiGeorge syndrome 7
Other syndromes 8
Low Normal Secondary forms 9

PHP type 1 =

Gs A-protein reduced in
red blood cells

Yes No

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1-A hydroxylase Vitamin D-resistant PHP type 1a PHP type 1c PHP type 1b PHP type 2 > Renal osteodystrophy :

Univ. of California San Diego


deficiency rickets

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1 When serum albumin is normal, hypocalcemia is defined as 7 Hypocalcemia (usually associated with hyperphosphate- 14 To accurately define the types of PHP, urinary cAMP levels
a decrease in serum Ca concentration <2.1 mmol/l or 8.4 mg/dl, or as mia) may be due to transient or permanent hypoparathyroidism. following a PTH infusion test should be measured. In normal sub-
a decrease in ionized [Ca2+] <1.1 mmol/ or 4.4 mg/dl. If serum albumin Transient hypoparathyroidism is seen in neonates and is typically jects, cAMP levels obtained it this test will be elevated.
levels are low, serum total calcium might be low as well, but ionized categorized to early and late forms. The early form appears in the
Ca2+ values will still be in the normal range. Ionized Ca2+ levels are first few days of life, it usually presents with asymptomatic hypocal- 15 In PHP type 1, urinary cAMP elevation after PTH infusion is
dependent on the blood pH, with a decrease in [Ca2+] in alkalosis and cemia, and is seen most commonly in preterm and low-birth-weight reduced compared to normal. Three subtypes are further differenti-
an increase in acidosis (0.21 mmol/l change per 0.1 unit pH change). infants or in children of diabetic mothers. The late form is seen after ated. Types 1a and 1c appear phenotypically as McCune-Albright
the 1st week of life, it may present with seizures and tetany, and it is osteodystrophy with hypothyroidism and hypogonadotropism. The
2 Clinical symptoms of hypocalcemia are protean and in- caused most commonly by high phosphate content in milk. difference between the two forms is in Gs- protein levels in red
clude: neuromuscular changes (tetany), central nervous system blood which is reduced in type 1a and normal in type 1c. Type 1b is
manifestations (generalized or focal seizures, psychological distur- 8 Familial hypoparathyroidism may be autosomal recessive, characterized by a normal phenotype and abnormal biochemical
bances, intracranial Ca deposits), bradyarrthmias, ocular involve- autosomal dominant or x-linked. In the autosomal-dominant type, tests.
ment (cataracts), dental abnormalities as well as skin changes (xero- there is a gain of function mutation in the CaSR, leading to hypocal-
dermatosis, alopecia). cemic hypercalciuria. Although serum PTH levels can be within the 16 PHP type 2 is characterized by markedly increased PTH
normal range, they are inappropriate for the degree of hypocalcemia. levels with urinary cAMP levels elevated both before and after PTH
3 In patients with calcipenic rickets, additional biochemical infusion.
findings are hypophosphatemia, elevated levels of serum alkaline 9 Aplasia/hypoplasia of the parathyroid glands is often found
phosphatase and secondary hyperparathyroidism. Examining serum in DiGeorge anomaly, which includes, in addition to parathyroid hy-
levels of vitamin D metabolites [25(OH)D and 1,25(OH)2D3] are impor- poplasia, thymic hypoplasia, cardiac abnormalities (all of which are Selected reading
tant in the work-up of the child with hypocalcemic rickets. Hereditary related to the structures arising from the 3rd and 4th brachial arches),
forms of hypophosphatemic rickets are not associated with distur- facial dysmorphism, and often, a gene deletion in 22 q11. Velocardio- Al-Jenaidi F, Makitie O, Grunebaum E, Sochett E: Parathyroid gland
bances in serum calcium levels. facial syndrome, or other isolated 22q11 gene mutations may pro- dysfunction in 22q11.2 deletion syndrome. Horm Res 2007;67:
duce hypoparathyroidism as well. The hypocalcemia in these syn- 117122.
4 If serum 25(OH)D levels are low, vitamin D-deficient rickets dromes may disappear spontaneously in young children, although it Gelfand IM, Eugster EA, DiMeglio LA: Presentation and clinical
is suspected. The differential diagnosis includes vitamin D-poor diet, may return later in life. progression of pseudohypoparathyroidism with multi-hormone
insufficient exposure to sunlight (especially in dark-skinned infants), resistance and Albright hereditary osteodystrophy: a case series.
malabsorption secondary to gastrointestinal or hepatobiliary dis- 10 Hypoparathyroidism may occur in various syndromes in- J Pediatr 2006;149:877880.
eases and due to medications that alter normal 25(OH)D metabolism. cluding Kerns Sayre syndrome and other mitochondrial cytopathies, Hochberg Z: Vitamin-D-dependent rickets type 2. Horm Res 2002;
auto-immune endocrinopathy type 1 (associated with systemic can- 58:297302.
5 When serum 25(OH)D levels are normal, genetic disorders didiasis and Addison disease), Kenney-Caffey syndrome (small stat- Holick MF: Resurrection of vitamin D deficiency and rickets.
in vitamin D metabolism are suspected. This form of rickets [previ- ure, tubular long bones, osteosclerosis) and others. J Clin Invest 2006;116:20622072.
ously known as vitamin D-dependent rickets (VDDR)] can be further Langman CB: Disorders of phosphorus, calcium and vitamin D; in
differentiated by measuring serum levels of 1,25(OH)2D3. In 1- hy- 11 Secondary hypoparathyroidism is seen most commonly Avner ED, Harmon WE, Niaudet P (eds): Pediatric Nephrology, ed 5.
droxylase deficiency (called in the past VDDR type 1) serum levels of after (para)-thyroidectomy. Other reasons of secondary hypopara- Philadelphia, Lippincott Williams & Wilkins, 2004, pp 237254.
1,25(OH)2D3 are low or absent due to a mutation in the gene encoding thyroidism include infiltrative lesions such as tumors, hemosiderosis Thacher TD, Fischer PR, Pettifor JM: Rickets: vitamin D and calcium
the enzyme 1-hydroxylase which converts 25(OH)D to 1,25(OH)2D3 (thalassemia) and copper deposition (Wilson disease). deficiency. J Bone Miner Res 2007;22:638.
in the kidney. Administration of an active vitamin D analogue is the
therapy of choice. In vitamin D-resistant rickets (originally termed 12 The combination of hypocalcemia, hyperphosphatemia and
VDDR type 2) serum levels of 1,25(OH)2D3 are high. This rare entity is elevated serum creatinine concentration suggests the presence of
caused by end-organ resistance (often associated with alopecia) to secondary hyperparathyroidism secondary to chronic kidney dis-
vitamin D actions due to mutations in the vitamin D receptor gene. ease. For details see Renal osteodystrophy.
Therapy consists of high dose of 1,25(OH)2D3 as well as calcium sup-
plements. 13 PHP also known as Albright hereditary osteodystrophy is
characterized by hypocalcemia and hyperphosphatemia despite a
6 Severe hypomagnesemia, via its effect on the Ca2+/Mg2+ normal or even elevated serum levels of PTH. There are several
sensing receptor (CaSR), can lead to hypocalcemia through both a types of this genetic disorder which are caused by defects in the ad-
93
decrease in PTH production or secretion and end organ resistance to enylate cyclase system necessary for the PTH-receptor normal func-
this hormone. tion in end organs. PHP is usually a part of the McCune-Albright he-
reditary osteodystrophy the main clinical features of which are short
stature, psychomotoric and mental retardation, brachydactyly and

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subcutaneous Ca deposits adjacent to the joints.

Univ. of California San Diego


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Divalent ion metabolism G. Ariceta B. Hoppe C.B. Langman Hypocalcemia
Divalent ion metabolism B. Hoppe G. Ariceta C.B. Langman Hypercalcemia

/
Hypercalcemia Symptoms 0

94 Serum PTH 1

Low Normal/increased

Serum vitamin D metabolites


(25(OH)D and 1,25(OH)D)
Urine calciumM Urine calciumm

No Increased

Tumor

PTHrpM

No Yes

Syndromatic features

No Yes

Phosphate depletion 2 Jansen osseous dysplasia : Tumor hypercalcemia ; Vitamin D intoxication < Primary/tertiary Familial hypocalciuric
Vitamin A intoxication 3 Williams syndrome hyperparathyroidism = hypercalcemia >
High-dose hydrochlorothiazide therapy 4 Infantile idiopathic hypercalcemia
Adrenal insufficiency 5
Hypo-/hyperthyroidism 5
Immobilization 6
Hypophosphatasia 7

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Transient neonatal hypercalcemia 8
Sarcoidosis 9

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1 Hypercalcemia is defined as an increase in 10 Transient neonatal hypercalcemia is found in parathyroidism, medullary carcinoma of thyroid and
serum Ca concentration >2.65 mmol/l or 10.6 mg/dl or newborns of mothers with hypocalcemia (usually due bilateral pheochromocytoma. Tertiary hyperparathy-
as an increase in ionized Ca2+ >1.4 mmol/l or 5.6 mg/dl. to maternal hypoparathyroidism). The maternal hypo- roidism is the result of long-standing secondary hy-
Acid-base changes may affect the levels of ionized cal- calcemia leads to excessive fetal PTH production that, perparathyroidism which leads to hyperplasia of the
cium in the blood (see Hypocalcemia). in turn, causes hypercalcemia after birth. parathyroid gland with autonomous, uncontrolled se-
cretion of PTH.
11 Granulomatous diseases such as sarcoidosis
2 Clinical symptoms of hypercalcemia include
or tuberculosis might lead to hypercalcemia through 16 The combination of hypercalcemia, elevated
anorexia, weight loss, vomiting, psychological distur-
an increased ectopic production of 1,25(OH)2D. serum PTH levels and hypocalciuria is seen in FHH.
bances, hypertension, extraosseous Ca deposits,
This rare autosomal-dominantly inherited disease usu-
urine-concentrating defect, polydypsia and nephrocal-
12 In the infant with hypercalcemia and dysmor- ally presents clinically with asymptomatic hypercalce-
cinosis. In hyperparathyroidism, bone pain and radio-
phic features few disorders should be excluded: mia. The genetic defect in FHH is an inactivating muta-
logical signs such as subperiosteal defects at the ra-
Jansen osseous dysplasia is a rare hereditary disorder tion in the Ca-sensing receptor. Most children affected
dial side of the middle phalanges might be present.
belonging to the chondroplasia group of diseases. are asymptomatic and thus no specific therapy is
It is caused by a mutation in the gene encoding the needed.
3 In children with hypercalcemia, serum PTH
PTH/PTHR1 receptor. Williams-Beuren syndrome is a
level is an important diagnostic tool. Low or sup- genetic disorder caused by sporadic mutations in the
pressed PTH levels suggest a normal response of the gene encoding the elastin protein. Typical clinical fea- Selected reading
parathyroid glands to hypercalcemia. If, on the other tures include peculiar, elfin-like facies, failure to thrive,
hand, serum PTH level is elevated, primary or tertiary mild mental retardation with a cheerful, loveable Huang J, Coman D, McTaggart SJ, Burke JR: Long-
hyperparathyroidism or familial hypocalciuric hyper- personality and heart malformations (mostly supra- term follow-up of patients with idiopathic infantile
calcemia are suspected. valvular aortic stenosis). Infrequently, hypercalcemia hypercalcaemia. Pediatr Nephrol 2006;21:16761680.
accompanies this syndrome. Infantile idiopathic Raue F, Haag C, Schulze E, Frank-Raue K: The role of
4 Low phosphorus intake, especially in preterm hypercalcemia is a rare disorder characterized by the extracellular calcium-sensing receptor in health
infants will lead to hypercalcemia. Chronic hypophos- musculoskeletal abnormalities, hypertension, strabis- and disease. Exp Clin Endocrinol Diab 2006;114:
phatemia leads to hypercalcemia through increase in mus and hyperacusis. Although usually transient in 397405.
the levels of 1,25(OH)2D3 and by reducing bone mineral nature, serum calcium levels can be extremely high. Kollars J, Zarroug AE, van Heerden J, Lteif A,
content. Breast-milk feeding without phosphate sup- Stavlo P, Suarez L, Moir C, Ishitani M, Rodeberg D:
plementation can also lead to hypercalcemia by a simi- 13 In children with hematologic or solid organ Primary hyperparathyroidism in pediatric patients.
lar mechanism. malignancies (mostly carcinomas), hypercalcemia may Pediatrics 2005;115:974980.
be due to skeletal metastasis or to an increase in PTH- Langman CB: Disorders of phosphorus, calcium and
5 Vitamin A intoxication, administrated in the related protein levels, a gene product distinct from PTH. vitamin D; in Avner ED, Harmon WE, Niaudet P (eds):
same preparations as vitamin D, can lead to hypercal- Pediatric Nephrology, ed 5. Philadelphia, Lippincott
cemia. 14 Vitamin D intoxication can lead to hypercal- Williams & Wilkins, 2004, pp 237254.
cemia and hypercalciuria. Conditions leading to this Menegazzi JJ: Williams-Beuren syndrome. Science
6 Overdose of thiazide diuretics may lead to entity include overdosage of vitamin D given for pro- 2006;311:1552.
hypercalcemia by increasing urinary calcium reab- phylaxis or of vitamin D given as a supplementation to
sorption. formula preparations. Of note, vitamin D excess can
also result from an ectopic production of this hormone
7 Although rare, endocrine disorders such as in various disorders (granulomatous diseases, malig-
hypothyroidism, hyperthyroidism and adrenal insuf- nancies).
ficiency, may lead to hypercalcemia.
15 The laboratory findings of hyperparathyroid-
8 Prolonged Immobilization may lead to en- ism include, in addition to hypercalcemia, hypophos-
hanced bone Ca resorption, and, often, to hypercalce- phatemia and hypercalciuria. Conditions leading to
mia and hypercalciuria. primary hyperparathyroidism include adenoma of the
95
parathyroid glands. This condition can be isolated or a
9 Infantile hypophosphatasia (an inherited de- part of more generalized disorders of hyperplasia/neo-
fect in alkaline phosphatase activity) may lead to hy- plasia of endocrine glands called MEN. MEN type 1
percalcemia. Typical laboratory findings include nor- consists of primary hyperparathyroidism, endocrine

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mal serum phosphorus level and low alkaline phos- pancreatic hyperplasia and prolactinoma whereas
phatase level. Bone films demonstrate typical findings MEN type 2 includes, in addition to primary hyper-

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of rickets.

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Divalent ion metabolism B. Hoppe G. Ariceta C.B. Langman Hypercalcemia
Divalent ion metabolism C.B. Langman G. Ariceta B. Hoppe Hypophosphatemia

/
Hypophosphatemia Symptoms 0

96

P depletion

Urine P 2

Increased Reduced

PTH

Normal/low High

P redistribution 1 Nonselective renal P wasting 3 Selective renal P wasting 4 Hyperparathyroidism 5 P deprivation 6


Glucose infusion Fanconi syndrome Hypophosphatemic rickets (X-linked, Reduced absorption
TPN Relief to obstructive uropathy autosomal dominant, autosomal recessive, with hypercalciuria) Intestinal disorders
Refeeding Metabolic acidosis Vitamin D related rickets (deficiency, dependent rickets types I Phosphate binders
Respiratory alkalosis Drugs (glucocorticoids, diuretics) [absence of kidney 25(OH)D-1-A-OHase] and II Alcoholism
Drugs (insulin, glucagon, [mutations in VDR], and genetic absence of Hungry bone syndrome
androgens, B-agonists) liver vitamin D-25-OHase enzyme activity) Miscellaneous

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Oncogenic osteomalacia
Jansen chondrodysplasia

Univ. of California San Diego


Post-kidney transplant

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1 Serum P level is continuously declining with 5 In generalized proximal tubulopathy (termed 7 For details on hyperparathyroidism, see Hy-
age, and thus the definition of hypophosphatemia is Fanconi syndrome), excessive phosphaturia may be percalcemia and Renal osteodystrophy. Of note, after
age-dependent. Hypophosphatemia in adolescents associated with glycosuria, aminoaciduria, and bicar- long-standing hyperparathyroidism is resolved there
and adults is defined as a serum P level <2.5 mg/dl. bonaturia. For details, see Faconi syndrome and Meta- is an increased avidity of bone for Ca and P, termed
Normal values in other age groups include: infants: bolic Acidosis. After the relief of obstructed kidneys, hungry bone syndrome (see below).
mean 6.5 mg/dl, range 4.87.4; toddlers: mean excessive urinary losses of water and minerals includ-
5.0 mg/dl, range 4.55.8 mg/dl; children: mean 4.4 mg/ ing P, can be observed (postobstructive diuresis). A 8 Any condition leading to P deprivation may
dl, range 3.55.5 mg/dl. similar phenomenon might be seen during the diuretic lead to hypophosphatemia with low urinary P concen-
phase of acute tubular necrosis. High P excretion in tration. In addition, intestinal disorders leading to mal-
2 Hypophosphatemia may be asymptomatic or urine can also be observed after the administration of absorption will show the same abnormalities in P level.
associated with various symptoms. Symptoms result drugs such as glucocorticoids and diuretics (acetazol- Calcium carbonate and other drugs that can bind to
from decreased intracellular ATP level and impaired amide, thiazides). the P in the diet, may lead to hypophosphatemia.
oxygen delivery to tissues, and may include anorexia, After long-standing hyperparathyroidism (primary or
vomiting, muscle dysfunction (paraesthesias, hypore- 6 Selective urinary P wasting is seen in several secondary) has resolved, increased avidity of bone for
flexia, proximal myopathy), rickets or osteomalacia as genetic disorders collectively called hypophospha- Ca and P may lead to hypophosphatemia and hypocal-
well as hematologic disorders. Severe P deficit associ- temic rickets. XLH is characterized by reduced recla- cemia. This disorder is termed hungry-bone syn-
ated with acute shift of P into the cells can lead to life- mation of filtered phosphorus by the proximal tubule, drome and it is usually transient in nature.
threatening events: cardiac failure with ventricular ar- and normal levels of 1,25(OH)2D which are inappropri-
rhythmias, hypotension, rhabdomyolysis, respiratory ate for the degree of hypophosphatemia. XLH is
failure, or coma. caused by mutations in the PHEX gene. Autosomal Selected reading
dominant hypophosphatemic rickets result from muta-
3 More than 99% of P is found in the intracel- tions in the gene encoding FGF-23, a potent phospha- Cho HY, Lee BH, Kang JH, Ha IS, Cheong HI, Choi Y:
lular compartment and only less than 1% is extracel- turic agent. This mutation renders the FGF-23 resistant A clinical and molecular genetic study of hypophos-
lular. Most P content in the body is in bone. Acute to normal proteolytic cleavage and hence, exagger- phatemic rickets in children. Pediatr Res 2005;58:
shifts from extra- to intracellular space may reduce ates its phosphaturic action, and that of reducing the 329333.
serum P leading to hypophosphatemia. Increased 25(OH)D-1--OHase activity in the proximal nephron Hochberg Z: Vitamin-D-dependent rickets type 2.
carbohydrate intake stimulates insulin release which, mitochondria, too. Autosomal recessive XLH has re- Horm Res 2002;58:297302.
in turn, leads to P shift into cells. Thus, infusion of glu- cently been described to be due to mutations in DMP-1, Holick MF: Resurrection of vitamin D deficiency and
cose, fructose, lactate or amino acid salts (especially and seemingly, elevations in FGF23 level as well. In rickets. J Clin Invest 2006;116:20622072.
during refeeding malnourished patients or in diabetic HHH, the genetic abnormality is due to mutations in Kollars J, Zarroug AE, van Heerden J, Lteif A,
ketoacidosis) may lead to hypophosphatemia. Respira- the gene encoding NaPi IIc, a Na-P cotransporter of Stavlo P, Suarez L, Moir C, Ishitani M, Rodeberg D:
tory alkalosis, as a result of acute hyperventilation (e.g. the proximal tubule. In contrast to XLH and autosomal- Primary hyperparathyroidism in pediatric patients.
anxiety) or in a variety of respiratory disorders, may dominant or -recessive hypophosphatemic rickets, se- Pediatrics 2005;115:974980.
lead to hypophosphatemia. Various drugs such as in- rum levels of 1,25(OH)2D in HHH are elevated, leading Langman CB: Disorders of phosphorus, calcium and
sulin, glucagon, androgens and -adrenergic agonists to hypercalciuria. All of these disorders, if left untreat- vitamin D; in Avner ED, Harmon WE, Niaudet P (eds):
have a similar effect. ed in children, will lead to rickets and short stature. Pediatric Nephrology, ed 5. Philadelphia, Lippincott
Various forms of vitamin D related rickets lead to hypo- Williams & Wilkins, 2004, pp 237254.
4 With a normal dietary intake of P, 1520% of phosphatemia. In oncogenic osteomalacia, there is
the filtered P is excreted in the final urine. Total body P excessive production of FGF-23 by various tumors
deficit, in the presence of a normal functioning kidney, leading to hypophosphatemia. Phosphaturia and hy-
will maximally increase tubular reabsorption of this pophosphatemia may occur in 70% of patients follow-
mineral and will reduce P excretion to nil. ing renal transplantation within the first year, and be
either transient or permanent. Persistent secondary
hyperparathyroidism, corticosteroid therapy and in-
trinsic tubular dysfunction of the graft are possible
factors involved in this abnormality. Persistence of el-
97 evated levels of FGF23 after kidney transplantation
may be responsible for persistent hypophosphatemia.

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Divalent ion metabolism C.B. Langman G. Ariceta B. Hoppe Hypophosphatemia
Divalent ion metabolism C.B. Langman G. Ariceta B. Hoppe Hyperphosphatemia

/
Hyperphosphatemia Symptoms 0

98 Urine P 1

Reduced Increased

Serum creatinine

Increased Normal

Plasma Ca

Normal Low

PTH

Normal/high Low

Acute renal failure 2 Acromegaly 3 Pseudohypoparathyroidism 4 Hypoparathyroidism 5 Redistribution 6 MAbsorption 7


Chronic renal failure Hyperthyroidism Acute acidosis Enemas
Familial tumoral calcinosis Laxatives
Hyperostosis i.v. infusions
Biphosphonates

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Vitamin D intoxication

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1 Normal serum P level varies with age, so that 5 Mild hyperphosphatemia is typical of acro-
Selected reading
the definition of hyperphosphatemia is age dependent. megaly (growth hormone excess) and can be also de-
Normal P levels according to age are: neonates mean tected in thyrotoxicosis, as both growth hormone and Gelfand IM, Eugster EA, DiMeglio LA: Presentation
6.5 mg/dl, range 4.87.4; infants 4.55.8 mg/dl (mean thyroxine increase the tubular reabsorption of P. Famil- and clinical progression of pseudohypoparathyroid-
5.0), mid-childhood 3.55.5 mg/dl (mean 4.4 mg/dl) ial tumoral calcinosis is a rare hereditary disorder of ism with multi-hormone resistance and Albright
and by late adolescence, values are similar to those in mineral metabolism characterized by increased proxi- hereditary osteodystrophy: a case series. J Pediatr
adults: range 2.44.5 mg/dl. mal tubular reabsorption rate of P and increased levels 2006;149:877880.
of 1,25(OH)2D3. Clinically, the disease is characterized Gupta A, Winer K, Econs MJ, Marx SJ, Collins MT:
2 Hyperphosphatemia is often asymptomatic. by subcutaneous calcifications as well as periarticular FGF-23 is elevated by chronic hyperphosphatemia.
An acute elevation in serum P level may acutely re- calcifications located along the extensor surfaces of J Clin Endocrinol Metab 2004;89:44894492.
duce serum Ca levels with resultant symptoms of hy- major joints, and may be associated with nephrolithia- Langman CB: Disorders of phosphorus, calcium and
pocalcemia including: paresthesias, tetany, seizures, sis in some cases. Familial tumoral calcinosis has been vitamin D; in Avner ED, Harmon WE, Niaudet P (eds):
psychological disturbances, cardiac arrhythmias, hy- found to result from mutations in several genes in- Pediatric Nephrology, ed 5. Philadelphia, Lippincott
potension and death. During chronic hyperphosphate- volved in phosphorus metabolism, including GALNT3, Williams & Wilkins, 2004, pp 237254.
mia, serum Ca is usually normal or elevated and symp- SAMD9, KLOTHO, and FGF23. Endosteal hyperostosis Topaz O, Shurman DL, Bergman R, Indelman M,
toms are secondary to increased [P] [Ca] product and is another hereditary disease transmitted either in au- Ratajczak P, Mizrachi M, Khamaysi Z, Behar D,
include progressive metastatic tissue calcification or, tosomal recessive or autosomal-dominant fashion. Petronius D, Friedman V, Zelikovic I, Raimer S,
less often, acute calciphylaxis syndrome (rapid subcu- This disorder is characterized by asymmetric enlarge- Metzker A, Richard G, Sprecher E: Mutations in
taneous and small vessels calcification leading to pain- ment of mandibulas and nasal bridge as well as mild GALNT3, encoding a protein involved in O-linked
ful necrosis of skin and subcutaneous fat). frontal bone bossing. glycosylation, cause familial tumoral calcinosis.
Nat Genet 2004;36:579581.
3 With a normal dietary intake of P, 1520% of 6 7 For details on hypo- and pseudohypopara-
the filtered P is excreted in the urine. There is a maxi- thyrodism, see Hypocalcemia.
mum capacity of P reabsorption (TmpPO4) that varies
with the GFR. During the first 3 years of life, there is 8 During either acute respiratory or metabolic
relative renal P retention which constitutes an appro- acidosis, intracellular P is released into the extracel-
priate physiological adaptation to the demands for P lular fluid. Thus, hyperphosphatemia and subsequent
during somatic growth. Interestingly, the adolescent phosphaturia result.
growth spurt is not associated with P retention by the
kidney. 9 Acute P load with resulting hyperphosphate-
mia may be observed after hypertonic sodium phos-
4 By far the most common cause of hyperphos- phate enemas (especially in young children, or in
phatemia is acute or chronic renal failure. Hyperphos- those with an intestinal ileus) and also after inappro-
phatemia usually occurs when GFR is less than 30% of priately prescribed intravenous P infusions. Oral so-
normal, and although there is a low fractional reab- dium phosphate laxatives are less likely to cause sus-
sorption of P in the remaining functional nephrons, tained hyperphosphatemia. Long-term treatment of
absolute excretion falls. In acute renal failure, hyper- osteopenia with biphosphonates may rarely lead to
phosphatemia is usually observed during the oliguric mild hyperphosphatemia and phosphaturia. Hyper-
phase. phosphatemia and phosphaturia associated with hy-
Acute hyperphosphatemia occurs during the rapid percalcemia may appear in vitamin D intoxication.
breakdown of cells with release of intracellular P, such
as in tumor-lysis syndrome, rhabdomyolysis, or se-
vere hemolytic anemias. The levels of other intracel-
lular cations such as potassium (K) and magnesium
(Mg) are usually increased during these cytolytic pro-
cesses.
99

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Divalent ion metabolism C.B. Langman G. Ariceta B. Hoppe Hyperphosphatemia
Divalent ion metabolism I. Eisenstein P. Goodyer I. Zelikovic Hypomagnesemia

/
Hypomagnesemia Symptoms 0

100 FEMg2+ 1

FEMg2+ <2% FEMg2+ >2%

Renal losses
Decreased intake 2 Altered Mg2+ distribution 3 Gastrointestinal losses 4

Acquired 5 Genetic 6

Malnutrition Hungry bone syndrome Malabsorptive syndromes (celiac, IBD) Postobstructive diuresis Gitelman syndrome
Alcoholism Refeeding Diarrhea Recovery from ATN Familial hypomagnesemia,
Low-magnesium food Diabetic ketoacidosis Short bowel syndrome Renal transplantation hypercalciuria and nephrocalcinosis
Parenteral fluids Bowel resection Drugs Isolated hypomagnesemia
Laxative abuse Loop/thiazide diuretics (autosomal-dominant, autosomal-recessive)
Primary intestinal hypomagnesemia Aminoglycosides Autosomal-dominant hypoparathyrodism
Amphotericin B
Cisplatinum

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Calcineurin inhibitors

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1 Magnesium ion (Mg2+), which is the second tent (up to 200 mg/l) and thus may lead to hypomagne- variant are usually asymptomatic. An additional typi-
most common intracellular action, has an essential semia. In steatorrhea, hypomagnesemia can ensue cal laboratory finding is hypocalciuria. The genetic
role in many biological processes. The kidney is the due to the formation of magnesium lipid-salts. Primary defect is in the -subunit of the Na-K-ATPase trans-
main organ responsible for Mg2+ homeostasis. Of total intestinal hypomagnesemia with secondary hypocal- porter located in the basolateral membrane of the dis-
plasma Mg2+, 80% is filtered through the renal glom- cemia is a rare autosomal-recessive disorder. Patho- tal convoluting tubule. Autosomal-dominant hyper-
eruli and more than 95% of the filtered Mg2+ is reab- physiology is related to impaired intestinal absorption parathyroidism is caused by an activating mutation of
sorbed by the renal tubule, mainly in the thick ascend- of magnesium accompanied by renal magnesium the calcium-sensing receptor in the parathyroid gland.
ing limb of the loop of Henle. Normal serum Mg2+ lev- wasting as a result of a reabsorption defect in the dis- The mutation in this receptor, which also senses mag-
els range from 0.62 to 1 mmol/l (1.52.4 mg/dl). tal convoluted tubule. The disease is caused by muta- nesium levels, leads to renal magnesium and calcium
tions in the gene encoding TRPM6, a member of the wasting. PTH levels are inappropriately low for the de-
2 Hypomagnesemia is often asymptomatic. transient receptor potential family of cation channels gree of hypocalcemia. Very recently, a defect in the
The signs and symptoms may be nonspecific and in- which is expressed in the small intestine and the distal gene encoding epidermal growth factor has been im-
clude nausea, vomiting and muscle weakness. In more convoluting tubule. Primary intestinal hypomagnese- plicated in hereditary renal magnesium wasting.
severe cases, symptoms are mostly of neuromuscular mia with secondary hypocalcemia manifests clinically
origin and include tremor, tetany, seizures, irritability as refractory seizures in infancy with very low serum
and confusion. In addition, cardiac manifestation such calcium and magnesium levels. Selected reading
as tachycardia, premature contractions and prolonged
QT interval leading to fatal torsades de pointes may 7 Conditions leading to renal magnesium wast- Cole DE, Quamme GA: Inherited disorders of renal
exist. Of note, hypomagnesemia may lead to hypocal- ing include postobstructive diuresis and the recovery magnesium handling. J Am Soc Nephrol 2000;11:
cemia and hypokalemia. phase of ATN. In children who received renal trans- 19371947.
plantion, hypomagnesemia is usually the result of Greenbaum LA: Electrolyte and acid-base disorders;
3 Determination of urinary Mg2+ excretion is an therapy with calcineurin inhibitors [cyclosporine A, ta- in Behrman RE, Kliegman RM, Jenson HB (eds):
important part of the evaluation of the patient with hy- crolimus (FK-506)]. Other drugs causing hypomagne- Nelson Textbook of Pediatrics, ed 17. Philadelphia,
pomagnesemia. To differentiate GI losses or reduced semia are listed in the algorithm. Saunders, 2004.
intake from renal losses, fractional excretion of Mg2+ Groenestege WM, Thebault S, van der Wijst J,
(FEMg) should be determined. FEMg is calculated using 8 There are several hereditary disorders lead- van den Berg D, Janssen R, Tejpar S,
the following formula: (UMg Scr)/ ([0.8 SMg] Ucr) ing to renal magnesium losses. In Gitelman syndrome, van den Heuvel LP, van Cutsem E, Hoenderop JG,
100 when UMg/Ucr and SMg/Scr are urine and serum a variant of Bartter syndrome, patients present during Knoers NV, Bindels RJ: Impaired basolateral sorting
Mg2+ and urine and serum creatinine concentrations, late childhood or adolescence with muscle weakness of pro-EGF causes isolated recessive renal hypo-
respectively. The factor 0.8 is used because only ap- and tetany. Typical laboratory findings include, in addi- magnesemia. J Clin Invest 2007;117:22602267.
proximately 80% of plasma Mg2+ is filtered through the tion to hypomagnesemia, hypokalemia, metabolic al- Kang JH, Choi HJ, Cho HY, Lee JH, Ha IS, Cheong HI,
renal glomeruli. The additional 20% are protein (mainly kalosis and hypocalciuria. Although the most common Choi Y: Familial hypomagnesemia with hypercalci-
albumin)-bound and therefore are not filterable. Nor- genetic defect leading to GS is a mutation in the gene uria and nephrocalcinosis associated with CLDN16
mally, FEMg is under 2%. encoding the NaCl cotransporter in the distal convo- mutations. Pediatr Nephrol 2005;20:14901493.
luted tubule, a defect in the Cl- channel ClCKb may Riveira-Munoz E, Chang Q, Bindels RJ, Devuyst O:
4 Poor oral intake is a rare cause of hypomag- also lead to Gitelman syndrome. Familial hypomagne- Gitelmans syndrome: towards genotype-pheno-
nesemia in children. It may be seen along with other semia, hypercalciuria and nephrocalcinosis, previous- type correlations? Pediatr Nephrol 2007;22:326332.
electrolyte deficiencies. ly called Michellis-Castrillo syndrome, is an autosomal- Rodrguez Soriano J: Tubular disorders of electro-
recessive disorder causing severe renal magnesium lyte regulation; in Avner ED, Harmon WE, Niaudet P
5 In hungry bone syndrome, seen mostly after and calcium wasting leading to hypomagnesemia and (eds): Pediatric Nephrology, ed 5. Philadelphia,
parathyroidectomy, there is rapid bone formation nephrocalcinosis with normal serum calcium levels. Lippincott Williams & Wilkins, 2004, pp 729757.
leading to rapid intake of phosphorus, calcium and The typical patient presents in early childhood with Schlingmann KP, Konrad M, Seyberth HW: Genetics
magnesium and hence to low plasma levels of these seizures, tetany, recurrent urinary tract infections, kid- of hereditary disorders of magnesium homeostasis.
ions. The same clinical picture may be seen in the ney stones, polyuria and polydipsia. Renal failure de- Pediatr Nephrol 2004;19:1325.
refeeding phase of malnourished children. In diabetic velops later in most patients. Extrarenal manifesta- Zelikovic I: Molecular pathophysiology of tubular
ketoacidosis, insulin therapy leads to magnesium in- tions may include ocular involvement. The disease transport disorders. Pediatr Nephrol 2001;16:
101 take into the cells. is due to a mutation in the gene encoding paracellin-1, 919935.
a member of the claudin family of tight junction pro-
6 The small intestine is the major site of mag- teins located in the thick ascending limb of the loop of
nesium absorption. Any pathological process leading Henle. Isolated hypomagnesemia (autosomal-domi-

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to a disease in this part of the GI tract may cause mag- nant) is an extremely rare disorder of renal magne-
nesium deficiency. Diarrhea has high magnesium con- sium wasting. Patients with the autosomal-dominant

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Divalent ion metabolism I. Eisenstein P. Goodyer I. Zelikovic Hypomagnesemia
Divalent ion metabolism F.B. Stapleton J. Smith Hypercalciuria

Hypercalciuria
102 Urolithiasis, hematuria, dysuria

Urine calcium/creatinine ratio


24-hour collection or spot /

>0.2 mg/mg (0.56 mmol/mmol <0.2 mg/mg (0.56 mmol/mmol) Ultrasound


in children older than 2 years in children older than 2 years
Abnormal Normal

Normal Urolithiasis
History and physical examination 0 Nephrocalcinosis
Family history 1
Dietary history 2
Medication history 3
Defer evaluation if patient has urinary tract infection 4
Blood tests
Electrolytes, bicarbonate, pH, calcium, phosphorus,
magnesium, PTH and vitamin D metabolites
Repeat urinary testing including 24-hour collection for
calcium, sodium, citrate, creatinine:
onsider testing uric acid and oxalate levels 5

Idiopathic hypercalciuria Possible causes of secondary hypercalciuria (table)


Hypercalcemia
Hypophosphatemia
Urine calcium/creatinine Urine citrate Metabolic acidosis
Hypomagnesemia
Renal tubular acidosis
Dent disease
Bartter syndrome
>0.2 mg/mg <0.2 mg/mg <400 mg/mg creatinine
Hypercalciuria Normal (Consider distal RTA) High fluid intake 6
Reduced Na+ intake

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High K+ and low oxalate diet
Consider thiazides

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1 Whenever possible, the diagnosis of hyper- 5 Some of the medications that have been
Selected reading
calciuria should be made on the basis of a 24-hour uri- associated with hypercalciuria include furosemide,
nary excretion. In young children, timed urinary collec- corticosteroids, vitamin D and methylxanthines. Frick KK, Bushinsky DA: Molecular mechanisms of
tions may be impractical or impossible. Urinary cal- primary hypercalciuria. J Am Soc Nephrol 2003;14:
cium excretion in younger children is estimated by use 6 Diagnostic studies for hypercalciuria should 10821095.
of the ratio of urinary calcium to creatinine on a fasting be deferred if the patient has a urinary tract infection, Gillespie RS, Stapleton FB: Nephrolithiasis in
spot urine. Normal calcium excretion during childhood as pyelonephritis increases urinary calcium excretion. children. Pediatr Rev 2004;25:131138.
has been defined as <4 mg/kg per day while eating a Southwest Pediatric Nephrology Study Group:
routine diet. Normal values for fasting spot or 24-hour 7 Once an abnormal value is discovered, it Idiopathic hypercalciuria: association with isolated
urine calcium/creatinine ratio for children are: 06 should be re-confirmed and examined in relationship hematuria and risk urolithiasis in children.
months is <0.8 mg/mg, 712 months is <0.6 mg/mg, to urinary sodium excretion. If the urinary collections Kidney Int 1990;37:807811.
and >2 years is <0.2 mg/mg. Use of random urinary suggest a high dietary sodium intake, a collection fol- Stapleton FB, Kroovand RL: Stones in childhood;
collections may be misleading. The urine calcium to lowing 24 weeks of sodium restriction (23 g sodium in Coe FL, Favus MJ, Pan CYC, et al (eds): Kidney
creatinine ratio may increase by 40% or as high as 0.28 per day) is indicated. Additional urinary studies should Stones: Medical and Surgical Management.
following a meal. A first morning fasting collection be performed including creatinine level, to establish Philadelphia, Lippincott-Raven, 1996, pp 10651080.
along with a postprandial sample can provide consid- the adequacy of the collection and normalization of Stapleton FB, Noe HN, Jerkins GR, et al: Hyper-
erable information. If only a single random sample is values, and citrate level to evaluate for renal tubular calciuria in children with urolithiasis. Am J Dis Child
available, it would be desirable to collect a sample acidosis. Urinary uric acid and oxalate levels should be 1982;136:675678.
24 h following a meal in which milk is given. In such a tested if indicated. Both, hyperuricosuria and hyperox- Stapleton FB. McKay CP, Noe HN: Urolithiasis in
sample, if the ratio of urinary calcium to creatinine is aluria may coexist with hypercalciuria. Normal urinary children: the role of hypercalciuria. Pediatr Ann
<0.2, further evaluation for hypercalciuria is not neces- values for school-age children: calcium <4 mg/kg/day; 1987;16:980992.
sary. citrate >400 mg/g creatinine; uric acid <0.56 mg/dl Thomas SE, Stapleton FB: Leave no stone unturned:
GFR; oxalate <50 mg/1.73 m2/day; cystine <60 mg/ understanding the genetic basis of calcium-contain-
2 Hypercalciuria is most often considered in 1.73 m2/day. ing stones in children. Adv Pediatr 2000;47:199221.
the evaluation of urolithiasis, hematuria, or less com-
monly dysuria. The purpose is to identify idiopathic or 8 When idiopathic hypercalciuria is confirmed,
Table. Selected causes of hypercalciuria and urolithiasis
secondary causes of hypercalciuria. the next step is to assess whether dietary manipula-
tions can normalize calcium excretion. High fluid in- Increased intestinal calcium absorption
Vitamin D excess
3 As many as 80% of patients with idiopathic take is mandatory. A reduced sodium, high potassium,
hypercalciuria have a family member with urolithiasis. and low oxalate diet is recommended for children with Renal tubular dysfunction
Renal tubular phosphate leak
In familial idiopathic hypercalciuria, an autosomal- hypercalciuria. Sodium restriction is indicated be- Impaired renal tubular calcium absorption
dominant pattern of inheritance has been postulated. cause of the well-known calciuric effect of high dietary Hypercalciuric hypocalcemia
When males in multiple generations have hypercalci- sodium intake. Increased potassium intake may re- Hypomagnesemia-hypercalciuria syndrome
uria, urinary stones, and proteinuria (with or without duce urine calcium excretion. For children unrespon- Type 1 (distal) renal tubular acidosis
renal failure), one should suspect X-linked hypercalciu- sive to dietary sodium restriction and potassium sup- Dent disease
Bartter syndrome
ric nephrolithiasis (Dent disease) (table). plementation, hydrochlorothiazide (12 mg/kg/day)
and/or citrate therapy may be helpful. Dietary calcium Endocrine disturbances
restriction is not recommended for children with hy- Hypothyroidism
4 A careful dietary history should be obtained
Adrenocorticoid excess
in all children with hypercalciuria to ascertain if dietary percalciuria especially in the light of reports of osteo- Hyperparathyroidism
factors might account for the finding. High intake of penia in affected children, as well as increased urinary
Bone metabolism disorder
dietary sodium and/or protein may increase the uri- oxalate excretion with low-calcium diets. Immobilization
nary excretion of calcium. Rickets
Malignancies
Juvenile rheumatoid arthritis
Other
Familial idiopathic hypercalciuria
103 Drugs (certain diuretics, corticosteroids)
Urinary tract infection
Williams syndrome
Increased renal prostaglandin E2 production
Hypercalcemia

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Hypophosphatemia
Glycogen storage disease

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Divalent ion metabolism F.B. Stapleton J. Smith Hypercalciuria
Divalent ion metabolism F.B. Stapleton J. Smith Nephrolithiasis/urolithiasis

Nephrolithiasis/urolithiasis
104 Symptoms/signs of urinary stone /

History 0, physical examination, urinalysis 1, urine culture

Imaging 2

Stone passed and Stone identified in No stone identified but High fluid intake 5
recovered urinary tract history suggestive of stone Reduced sodium intake 5

+ + + + +
Urologic or Complete metabolic evaluation 3
surgical consultation Serum creatinine, calcium, bicarbonate, Hypercalciuria Hyperoxaluria Uric acid Cystinuria Struvite
uric acid, potassium, phosphorus, lithiasis
magnesium, PTH and vitamin D metabolites,
if indicated
24-hour urine volume, calcium, creatinine,
oxalate, uric acid, sodium, citrate, High K+ and Bicarbonate/citrate Prevent/treat
Options include
or random urine calcium/creatinine, low oxalate diet (urine pH 7.07.5) infection
observation, ESWL,
oxalate and uric acid Citrate when Allopurinol
surgical removal
indicated Avoid excessive
Consider thiazides purines

Stone analysis 4
Avoid oxalate-rich foods Bicarbonate/citrate
Supplemental citrate, (urine pH 7.07.5)
Mg2+ and orthophosphate MPG
Consider thiazides
Consider pyridoxine
Calcium oxalate Cystine Struvite Uric acid Avoid vitamin C supplements
Calcium phosphate

Complete metabolic Urine cystine Urine culture Urine and serum uric Evaluation positive for
evaluation 3 acid and creatinine stone disease

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1 Symptoms and signs of urolithiasis/nephrolithiasis may Cystine stones account for up to 5% of calculi in the pediatric popula-
tion. Cystinuria is a group of inherited tubular transport disorders Selected reading
include abdominal, flank, or pelvic pain, gross or microscopic hema-
turia and, occasionally, UTI. characterized by excessive urinary excretion of cystine and the diba- Danpure CJ: Genetic disorders and urolithiasis. Urol Clins N Am
sic amino acids arginine, lysine, and ornithine (see Cystinuria). Chil- 2000;27:287299.
2 The age of the patient can provide clues to a specific meta- dren may suffer from recurrent urinary calculi in childhood and into Gillespie RS, Stapleton FB: Nephrolithiasis in children. Pediatr Rev
bolic cause. A dietary history should include questions regarding adulthood. 2004;25:131138.
intake of fluid, vitamins, minerals and drugs (furosemide, and sulfa- Hulton SA: Evaluation of urinary tract calculi in children. Arch Dis
methoxazole). Particular attention should be paid to growth and de- 6 If a stone analysis reveals cystine, struvite, or uric acid cal- Childh 2001;84:320323.
velopment, blood pressure, and bone development. Any family his- culus, the metabolic work-up may be more focused. Calcium phos- Polinsky MS, Kaiser BA, Baluarte HJ, Grsukin AB: Renal stones and
tory of urolithiasis, hematuria, or renal failure is important to elicit. phate or calcium oxalate stones necessitate a broader metabolic hypercalciuria. Adv Pediatr 1993;40:353384.
Genetic conditions leading to nephrolithiasis include diseases such evaluation. Santos-Victoriano M, Brouhard BH, Cunningham RJ: Renal stone
as hereditary hyperoxaluria, cystinuria, Dent disease, hypoxanthine- disease in children. Clin Pediatr 1998;37:583600.
guanine phophoribosyl transferase deficiency, hereditary renal 7 Adequate fluid intake is a key to treatment regardless of the Stapleton FB, Kroovand RL: Stones in childhood; in Coe FL,
hypouricemia and xanthinuria. cause of stones. Patients should increase fluid intake even more dur- Favus MJ, Pan CYC, et al (eds): Kidney Stones: Medical and
ing hot weather or strenuous exercise. Water is preferable over other Surgical Management. Philadelphia, Lippincott-Raven, 1996,
3 The urinary sediment should be examined for crystalluria. beverages. Decreasing urinary sodium concentration by reducing pp 10651080.
Triphosphates suggest an infectious etiology. Uric acid and cystine sodium intake is another measure to prevent stone precipitation of Thomas SE, Stapleton FB: Leave no stone unturned: understanding
crystals may focus the work-up. Others require more extensive initial any cause. the genetic basis of calcium-containing stones in children.
evaluation. Hypercalciuria: A high potassium and low oxalate diet is recommend- Adv Pediatr 2000;47:199221.
ed for children with hypercalciuria. Citrate supplementation helps
4 Imaging studies for urolithiasis include sonogram of the prevent stones in patients who have renal tubular acidosis or hypo-
kidneys and the urinary tract, plain abdominal radiography, intrave- citraturia. For children unresponsive to dietary sodium restriction
nous pyelography and, occasionally, nonenhanced helical CT. and potassium supplementation, hydrochlorothiazide may be helpful
(see Hypercalciuria).
5 Metabolic evaluation is ideally performed while the patient Hyperoxaluria: Limiting or avoiding high-oxalate foods such as spin-
is at home, consuming his or her regular diet, and free of infection. ach, rhubarb, nuts, tea wheat bran, and strawberries is recommend-
Although 24-hour urinary collections form the criterion for most uri- ed. Supplemental citrate, magnesium, and phosphorus may help
nary measurements (table 1), obtaining such collections from small decrease urinary oxalate crystallization. Calcium intake should not
children can be difficult or impossible. Standards based on single be restricted because this can increase intestinal calcium absorption.
specimens have been developed (table 2). Oral citrate has been suggested as adjunctive therapy. Thiazides may
Hypercalciuria (see algorithm). be considered. Approximately 1040% of patients respond to pyri-
Primary hyperoxaluria types 1 and 2 are rare autosomal-recessive doxine supplementation, but vitamin C should be avoided.
disorders caused by defects in specific hepatic enzymes that result in Uric acid lithiasis: Treatment of uric acid stones includes urinary alka-
overproduction of oxalate. In type 1 hyperoxaluria, the defective en- linization. Supplementation with citrate or bicarbonate is indicated.
zyme is peroxysomal alanine- glyoxylate aminotransferase and in The resulting elevation in urinary pH increases the solubility of uric
type 2, glyoxylate reductase/hydroxyl pyruvate reductase. In most acid. Allopurinol decreases uric acid synthesis by inhibiting xanthine
patients, symptoms of urolithiasis occur in childhood. Definitive di- oxidase and is useful in disorders associated with excess uric acid Table 2. Normal urinary values in children based on random urine
agnosis requires a liver biopsy for appropriate enzyme studies. Sec- production. Dietary purine restriction is of limited value; however,
Age Norman values,
ondary hyperoxaluria occurs with excessive intake of oxalate precur- counseling patients to avoid unusual amounts of purine intake is ap-
mg/mg
sors (ethylene glycol, ascorbic acid), increased absorption of oxalate propriate.
Cystinuria: Treatment of cystinuria includes urinary alkalinization us- Calcium/creatinine 06 months <0.8
(extensive bowel resection, inflammatory bowel disease) or pyridox-
612 months <0.6
ine deficiency. ing citrate or bicarbonate. D-penicillamine, and -MPG may help in
28 years <0.2
Uric acid calculi account for 34% of urinary calculi in the pediatric refractory cases.
Oxalate/creatinine 06 months <0.3
population. Uric acid lithiasis may be associated with hereditary or
6 months to 4 years <0.15
acquired conditions leading to hyperuricosuria (see Hypouricemia >4 years to adult <0.1
and Hyperuricemia). These hereditary disorders include inborn er- Table 1. Normal urinary values for school aged children based on 24-hour urine
105 rors of metabolism associated with overproduction of uric acid such Cystine/creatinine all ages <0.02
collection Citrate/creatinine all ages <0.51
as Lesch-Nyhan syndrome and type 1 glycogen storage disease, and
Calcium <4 mg/kg/day
hereditary disorders of tubular transport of uric acid, such as familial Uric acid/GFR calculated as: 63 years <0.56 mg uric acid/dl
Uric acid <0.56 mg/dl GFR
renal hypouricemia. High purine intake, uricosuric drugs, hemolysis Urine uric acid* serum creatinine* glomerular filtrate
Oxalate <50 mg/1.73 m2/day

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Urine creatinine*
and myeloproliferative disorders may also result in hyperuricosuria Cystine <60 mg/1.73 m2/day
and uric acid stones. Volume 20 ml/kg/day
* All values in same units: mg/dl or mmol/l

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Divalent ion metabolism F.B. Stapleton J. Smith Nephrolithiasis/urolithiasis
Renal failure J.-P. Guignard R.N. Fine Oliguria/anuria

/
Oliguria/anuria
106

Oliguria Anuria

Assess volume status 0 Renal ultrasound

Hypovolemia Euvolemia Hypervolemia No renal pelvic dilatation Renal pelvic dilatation

Rehydration 1 Furosemide 4
15 mg/kg

Diuresis No diuresis No diuresis Diuresis

Fluid challenge 2
furosemide

Prerenal failure No diuresis Oliguric intrinsic Non-oliguric intrinsic Anuric intrinsic Postrenal failure
acute renal failure acute renal failure acute renal failure

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Maintenance Treat fluid and electrolyte abnormalities 5 Relief of obstruction 6
fluid therapy 3 Discontinue nephrotoxic drugs Treat fluid and

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Extracorporeal therapy electrolyte abnormalities

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1 Oliguria is defined as the excretion of less 6 In some cases of oliguric acute renal failure,
Selected reading
than 400 ml/m2 body surface area of urine. Anuria is high-dose furosemide (up to 5 mg/kg) may initiate di-
the complete cessation of urine output. Oligouria/an- uresis. Patients with nonoliguric renal failure have a Andreoli SP: Clinical evaluation and management
uria may be one of the first signs of impaired renal generally better prognosis and the management of of acute renal failure; in Avner ED, Harmon WE,
function. The purpose of this algorithm is to give the these patients in terms of drug and nutrition adminis- Niaudet P (eds): Pediatric Nephrology, ed 5.
clinical approach to the oligo-anuric child. The differ- tration is easier. If the child remains oligoanuric, fluid Philadelphia, Lippincott/Williams & Wilkins, 2004,
ential diagnosis of the conditions leading to oligo-an- intake should be restricted to 400 ml/m2 + ongoing pp 12331252.
uria are described in the algorithms on Neonatal losses (urine, vomiting, gastric drainage, etc.) of hypo- Bailey D, Phan V, Litalien C, Ducruet T, Merouani A,
acute renal failure and Acute renal failure (child/ado- tonic fluids. Lacroix J, Gauvin F: Risk factors of acute renal failure
lescent). in critically ill children: A prospective descriptive
7 In cases of intrinsic renal failure, apart from epidemiological study. Pediatr Crit Care Med 2007;8:
2 In the child with oliguria, assessment of treating the specific condition, fluids, electrolytes and 2935.
volume status is vital in order to proceed with the acid-base abnormalities should be addressed. If pos- Hui-Stickle S, Brewer ED, Goldstein SL: Pediatric
work-up. sible, nephrotoxic drugs should be discontinued. ARF epidemiology at a tertiary care center from
These include agents such as NSAIDs, ACE inhibitors, 1999 to 2001. Am J Kidney Dis 2005;45:96101.
3 4 When dehydration is present: the fluid angiotensin II AT1 receptors blockers, amphotericin B, Krause I, Cleper R, Eisenstein B, Davidovits M:
deficit should be corrected initially by administration aminoglycoside antibiotics and vancomycin. If the Acute renal failure, associated with non-steroidal
of 2040 ml/kg of isotonic fluid over 2 h. The use of conservative measures mentioned above fail to re- anti-inflammatory drugs in healthy children.
isotonic saline is a safe method of rehydration. If diure- store renal function or if complications of severely re- Pediatr Nephrol 2005;20:12951298.
sis does not ensue, consider the administration of a duced GFR occur (hyperkalemia, metabolic acidosis, Mannix R, Tan ML, Wright R, Baskin M: Acute
colloid such as plasma or albumin at a rate of 20 ml/kg pulmonary edema, pericarditis, hypertension) RRT pediatric rhabdomyolysis: causes and rates of renal
over 2 h. If the above measures do not initiate diuresis, must be started. The choice of RRT to be used (perito- failure. Pediatrics 2006;118:21192125.
furosemide at a dose of 25 mg/kg may be attempted. neal dialysis, hemodialysis or hemofiltration) depends
on a variety of factors.
5 Once normal urine output has been achieved,
maintenance fluid therapy should begin either intrave- 8 Whenever urinary tract obstruction is diag-
nously or orally: for the first 10 kg bodyweight, 100 ml/ nosed, the obstruction should be promptly relieved.
kg. For the next 10 kg body weight, 50 ml/kg. For each Of note, polyuria (postobstructive diuresis) and elec-
kg above 20 kg, 20 ml/kg. trolyte abnormalities are common after the relief of
obstruction.

107

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Renal failure J.-P. Guignard R.N. Fine Oliguria/anuria
Renal failure J.-P. Guignard R.N. Fine Neonatal acute renal failure

/
Neonatal acute renal failure
108 Assess volume status 1 Gestational/postnatal history 0
Clinical manifestations
Blood chemistry
Urinalysis and urine indices
Renal US
Hypovolemia Euvolemia Hypervolemia

Rehydration 2
Replacement of blood loss Consider furosemide 4
Restoration of cardiac output

Diuresis No diuresis

Prerenal failure Intrinsic renal failure Postrenal failure

CBC Fluid challenge CBC


Chest X-ray furosemide CPK
Echocardiogram Plasma and urine myoglobin
Blood and urine culture
Renal US + Doppler
No diuresis

Dehydration 3 Congenital nephropathies 5 Congenital obstructive uropathies 6


Inadequate fluid intake, vomiting, diarrhea, Bilateral renal agenesis or dysgenesis, Bilateral uretero-pelvic junction obstruction,
phototherapy, high environmental temperature infantile polycystic kidney disease bilateral vesico-ureteric junction obstruction,
Blood loss Acute tubular necrosis ureterocele, obstruction in a single kidney,
Perinatal hemorrhage, clamping of the aorta during cardiac surgery, Cortical necrosis posterior urethral valves
hypovolemia secondary to fluid shifts, feto-fetal transfusion Nephrotoxic agents Obstruction by fungal bezoar
Perinatal asphyxia Hemoglobinuria Closure of abdominal wall defects
Severe respiratory distress Vascular disorders Imperforated prepuce
Heart failure Renal vein thrombosis, renal artery thrombosis
Congestive/noncongestive Acute pyelonephritis

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Maintenance fluid therapy, Treat fluid and electrolyte abnormalities Relief of obstruction
Packed RBC infusion Discontinue nephrotoxic agents

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Repair of heart anomaly Intravenous antibiotics

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1 Acute renal failure is observed in 824% of attempted. In hypotensive neonates, dopamine may
Selected reading
neonates admitted to neonatal intensive care units. be used at a dose of 24 g/kg/min. Higher doses
Although acute renal failure in a neonate is a serious (<10 g /kg min) may produce renal vasoconstriction Andreoli SP: Acute renal failure in the newborn.
and life-threatening condition, prognosis in neonates by an -adrenergic agonist effect. Semin Perinatol 2004;28:112123.
with nonoliguric acute renal failure is excellent. In con- Cuzzolin L, Fanos V, Pinna B, di Marzio M, Perin M,
trast, mortality rates in neonates with oliguric acute 5 Any condition that causes hypovolemia, hy- Tramontozzi P, Tonetto P, Cataldi L: Postnatal renal
renal failure are high, ranging from 25 to 80%. potension or hypoxemia may decrease renal perfusion function in preterm newborns: a role of diseases,
and lead to prerenal failure. If severe and of long dura- drugs and therapeutic interventions. Pediatr
2 Detailed history (pre- and postnatal) and tion, prerenal failure may lead eventually to intrinsic Nephrol 2006;21:931938.
physical examination are mandatory in the work-up of renal damage. Gouyon JB, Guignard JP: Management of acute
the neonate with acute renal failure. Pre- and postnatal renal failure in newborns. Pediatr Nephrol 2000;14:
history should include information regarding: abnor- 6 In some cases of oliguric acute renal failure, 10371044.
mal perinatal sonogram findings (oligohydroamnios, high-dose furosemide (up to 5 mg/kg) may initiate di- Guignard JP, Drukker A: Why do newborn infants
hydronephrosis, kidneys size, kidneys location, ap- uresis. have a high plasma creatinine? Pediatrics 1999;
pearance of the parenchyma and appearance of the 103:e49.
urinary bladder), maternal or neonatal drug use (ACE 7 The main conditions leading to intrinsic renal Toth-Heyn P, Drukker A, Guignard JP: The stressed
inhibitors, angiotensin II AT1 receptor antagonists, failure in the neonatal period are congenital renal neonatal kidney: from pathophysiology to clinical
NSAIDs, aminoglycosides, amphotericin B, etc.), previ- anomalies and acute tubular necrosis. The most com- management of neonatal vasomotor nephropathy.
ous intrauterine fetal demise or stillbirth or congenital mon congenital kidney malformation leading to renal Pediatr Nephrol 2000;14:227239.
kidney malformations in family relatives. failure is bilateral renal agenesis/dysgenesis. This ab-
Physical examination should include: vital signs normality is commonly associated with Potter syn-
(tachypnea/dyspnea, hypotension/hypertension, drome (oligohydroamnios, pulmonary hypoplasia and
tachycardia/irregular pulse), cardiac murmur or gallop, distinctive facies). The manifestations of PKD (either
palpation of femoral pulses, signs of dehydration/hy- autosomal-dominant or autosomal-recessive) can
pervolemia, abnormal neurologic findings or abdomi- range from intrauterine fetal demise or neonatal ESRD,
nal masses. The initial evaluation of the neonate with to slowly deteriorating kidney function leading to
acute renal failure includes the following tests: serum ESRD later in life. For further details see Cystic kid-
levels of creatinine, BUN, electrolytes (potassium, so- neys. Renal ischemia (usually due to birth asphyxia,
dium, magnesium, calcium, phosphorus), albumin and septic shock, massive bleeding or heart failure) can
bicarbonate. Urine sample for sediment examination, lead to either medullary, papillary or most commonly
electrolytes and creatinine levels, osmolality and cul- cortical necrosis. Although prognosis is generally
ture. The urine sodium level and osmolality are very poor, the extent of necrosis, duration of oliguria, and
helpful in the differential diagnosis of acute renal fail- severity of associated conditions determine the ulti-
ure (table). In addition to the laboratory tests men- mate prognosis. The most common drugs causing re-
tioned above, a renal sonogram is mandatory in every nal impairment in the newborn period are aminoglyco-
neonate with acute renal failure. Additional tests sides and NSAIDs.
should be reserved for the subsequent evaluation de-
pending on the suspected condition (as outlined in the 8 The most common obstructive congenital
algorithm). malformations leading to neonatal acute renal failure
are bilateral UPJ obstruction, bilateral uretero-vesicle
3 Assessment of the volume status of the junction obstruction and posterior urethral valves.
neonate with acute renal failure according to the For details, see Fetal hydronephrosis.
physical examination and laboratory work-up
mentioned above is vital in order to proceed with
the work-up.
Table. Diagnostic urinary indices
109 4 When dehydration is present: the fluid deficit Prerenal Intrinsic
should be corrected initially by administration of
Urinalysis normal >5 RBC/HPF
2040 ml/kg of isotonic fluid over 2 h. The use of an Uosm, mosm/kg H2O >400 <400
isotonic saline is a safe method of rehydration. If UNa, mmol/l <30 >60

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diuresis does not ensue, administer plasma at a rate of FeNa, % <2 >3
20 ml/kg over 2 h. Furosemide, 25 mg/kg, may be U/Posm 61.3 ^1.0

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

/
Acute renal failure (child/adolescent)
110 Assess volume status 1 History 0
Clinical manifestations
Blood chemistry
Urinalysis and urine indices
Renal US
Hypovolemia Euvolemia Hypervolemia

Prerenal failure Intrinsic renal failure Postrenal failure

CBC, Serum: CBC, CPK, LDH, albumin, C3, C4, ANA, ANCA, Metabolic stones profile
Liver function tests anti-GBM ab, hepatitis serology, myoglobin Abdominal US/CT
Chest X-ray Urine: eosinophils, myoglobin
ECG Renal US + Doppler
Echocardiogram Kidney biopsy

Dehydration 2 Renovascular 3 Posterior urethral valves 4


Inadequate fluid intake Renal artery stenosis Nephro-/urolithiasis
GI losses (vomiting, diarrhea) RVT Blood clot
Third-spacing (sepsis, burns, pericarditis, NS) Vascular Fungal ball
Salt-wasting (renal/adrenal disease) Vasculitis Tumors
Blood loss HUS Retroperitoneal process
Reduced cardiac output Glomerular Fibrosis
Congestive heart failure Glomerulonephritides Hematoma
Cardiac tamponade RPGN
Cardiogenic shock Tubulointerstitial
Sepsis TIN
HRS Acute tubular necrosis (nephrotoxic drugs, rhabdomyolysis,

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radio-contrast nephropathy, uric acid nephropthy, etc.)

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1 Acute renal failure is defined as a rapid de- renal condition may eventually lead to intrinsic renal er iso-osmolar, nonionic agents. The prophylactic ad-
cline in GFR and the inability to maintain normal fluids, damage. Of note, some of the conditions that lead to ministration of N-acetylcysteine, may be helpful as
electrolytes and metabolic balance. It is observed in prerenal failure are characterized by total body fluid well. Uric acid nephropathy is most commonly due to
23% of children admitted to tertiary care centers. The overload (congestive heart failure, hepatorenal syn- tumor lysis syndrome seen after the treatment of tu-
outcome of the child with acute renal failure depends drome), but a decreased effective circulatory volume mors such as leukemia and lymphoma. In addition to
on the underlying etiology. The mortality rates in chil- which leads to the renal failure. HRS is defined as an the hyperuricemia, hyperkalemia and hyperphospha-
dren with acute renal failure secondary to multiorgan acute renal failure in a child with severe liver disease in temia are frequently observed. Treatment includes
failure are very high (up to 90%) in contrast to those the absence of any other identifiable causes of renal hyperhydration, diuretic therapy (mannitol or loop di-
with acute renal failure due to postinfectious glomeru- disease. Although not fully understood, HRS is be- uretics), alkalinization of the urine and the use of uric
lonephritis who have an excellent long-term prognosis. lieved to be the result of severe renal vasoconstriction. acid-lowering agents.
Depending on the etiology, acute renal failure may cul- HRS is characterized by a normal urinary sediment
minate in chronic renal failure. (like most other prerenal conditions), very low urinary 6 Obstructive stone may lead to acute renal
sodium concentration, resistance to fluids and diuret- failure if the obstruction is in both kidneys or ureters or
2 Detailed history (pre- and postnatal) and ics administration and a generally poor prognosis. if in a single kidney. For the workup and management
physical examination are mandatory in the workup of of the child with uro/nephrolithiasis, see appropriate
the child with acute renal failure. History should in- 5 Intrinsic renal failure can result from a dam- algorithms. Any tumor or other space-occupying pro-
clude information regarding: kidney, endocrine or age to any of the structures that compose the kidney cess in the retroperitoneal space may compress both
heart disease, decreased fluid intake, voiding abnor- (vascular bed, glomeruli, interstitium and tubule). Vas- ureters leading to acute renal failure.
malities (hematuria, dysuria, reduced urine output, cular conditions leading to acute renal failure include
etc.), edema, shortness of breath, fever, rash, arthritis/ renal artery stenosis, RVT, vasculitis and hemolytic-
arthralgia, recent intercurrent infection, hemoptysis, uremic syndrome. For details, see appropriate algo- Selected reading
drug use (ACE inhibitors, NSAID , aminoglycosides, rithms. Any type of glomerulonephritis, if severe
amphotericin B, etc.), previous history of stones or kid- enough, can lead to acute renal failure. These condi- Andreoli SP: Clinical evaluation and management
ney malformations in family relatives. tions lead to nephritic syndrome, which is character- of acute renal failure; in Avner ED, Harmon WE,
Physical examination should include: vital signs ized by gross hematuria with urinary casts, proteinuria, Niaudet P (eds): Pediatric Nephrology, ed 5.
(tachypnea/dyspnea, hypotension/hypertension, hypertension and variable degrees of decreased renal Philadelphia, Lippincott Williams & Wilkins, 2004,
tachycardia/irregular pulse), cardiac murmur or gallop, function. Severe injury may lead to RPGN. For details, pp 12331252.
signs of dehydration/hypervolemia, rash, purpura, ar- see algorithms on Hematuria, RPGN and Acute ne- Bailey D, Phan V, Litalien C, Ducruet T, Merouani A,
thritis, abdominal masses or loin pain. phritic syndrome. ATN results from severe damage to Lacroix J, Gauvin F: Risk factors of acute renal failure
The initial evaluation of the child with acute renal fail- the tubular cell either due to prolonged prerenal failure in critically ill children: a prospective descriptive
ure include the following tests: serum levels of creati- or as a result of direct injury to the tubular cell from epidemiological study. Pediatr Crit Care Med 2007;
nine, BUN, electrolytes (potassium, sodium, magne- various endogenous or exogenous toxins (drugs, ra- 8:2935.
sium), calcium, phosphorus, albumin and bicarbonate. diocontrasts, ethylene glycol, myoglobin, hemoglobin, Hui-Stickle S, Brewer ED, Goldstein SL: Pediatric
Urine sample for sediment examination, electrolytes uric acid). Major drugs that lead to ATN include amino- acute renal failure epidemiology at a tertiary care
and creatinine levels, osmolarity and culture. The glycoside antibiotics, amphotericin B, acyclovir, ifos- center from 1999 to 2001. Am J Kidney Dis 2005;45:
urine sodium level and osmolarity are very helpful in famide and cisplatin. Hemolysis and, more commonly, 96101.
the differential diagnosis of acute renal failure (table). rhabdomyolysis can lead to ATN. Since hemoglobin is Krause I, Cleper R, Eisenstein B, Davidovits M:
In addition to the laboratory tests mentioned above, a a relatively large molecule and because, it is mostly Acute renal failure, associated with non-steroidal
renal sonogram is mandatory in every child with acute bound to plasma proteins (haptoglobin, etc.), hemoly- anti-inflammatory drugs in healthy children.
renal failure. Additional tests should be reserved for sis rarely causes acute renal failure. Myoglobin, on the Pediatr Nephrol 2005;20:12951298.
the subsequent evaluation depending on the suspect- other hand, is filtered in the glomeruli and its presence Mannix R, Tan ML, Wright R, Baskin M: Acute
ed condition (as outlined in the algorithm). in the urine may lead to tubular injury. Treatment of pediatric rhabdomyolysis: causes and rates of renal
hemoglobinuria and myoglobinuria includes hyperhy- failure. Pediatrics 2006;118:21192125.
3 Assessment of the volume status of the child dration, diuretic therapy (mannitol or loop diuretics)
with acute renal failure according to the physical ex- and alkalinization of the urine. Radiocontrast agents
amination and laboratory workup mentioned above is may lead to acute renal failure due to intense renal va- Table. Diagnostic urinary indices
111 vital in order to proceed with the work-up. soconstriction, tubular obstruction or direct tubular Prerenal Intrinsic
damage. Pre-existing renal impairment, volume deple-
Urinalysis normal >5 RBC/HPF
4 Prerenal failure is defined as an acute deterio- tion, and drugs like NSAID and ACE inhibitors are the Uosm, mosm/kg H2O >400 <400
ration in kidney function due to renal hypoperfusion. main risk factors for radiocontrast-induced acute renal UNa, mmol/l <30 >60

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Any condition that causes hypovolemia may lead to failure. The incidence of radiocontrast nephropathy FeNa, % <2 >3
prerenal failure. If severe and of long duration, the pre- can be decreased by hydration and by the use of new- U/Posm 61.3 ^1.0

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

/
Chronic renal failure
112 Etiology 0

Congenital malformations Metabolic/genetic disorders Acquired disorders Miscellaneous


Hypoplasia/dysplasia Hyperoxaluria FSGS Tumors
Reflux nephropathy Cystinosis Chronic glomerulonephritidies Drugs
Obstructive uropathy PKD HUS Unknown
Posterior urethral valves Alport syndrome
Nephronophthisis
Congenital nephrotic syndrome

Prevent decline in GFR

Reduce proteinuria 1
Control blood pressure
Metabolic control
Optimize nutrition

Treat ESRD 2

Cardiovascular 3 Growth 4 Anemia 5 Renal bone disease 6 Infections 7 Development 8

Control hypertension Adequate nutrition Iron/folic acid supplements Identify bone disorder Treat blood-borne Physiotherapy
Prevent fluid overload Vitamin supplements Treat carnitine deficiency Control P, Ca2+, PTH levels infections Treat learning disabilities
Treat hyperlipidemia Correct acidosis and rHuEpo treatment Correct acidosis and Immunizations Treat speech/hearing
Treat carnitine deficiency sodium depletion sodium repletion impairments
Prevent renal bone disease Sociofamilial support
rhGH treatment

Renal replacement therapy 9

Dialysis

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Univ. of California San Diego
Renal transplantation :

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1 Chronic renal failure is defined as an irreversible reduction should include careful monitoring of weight and height, anthropo- 11 When ESRD (GFR <510 ml/min/1.73 m2) has been reached,
in GFR. When the chronic renal failure is severe enough to mandate metric measurements and monitoring of the daily intake of calories, RRT is indicated. The choice of the mode of RRT (hemodialysis or
the initiation of dialysis, it is termed ESRD. The prevalence of chronic protein, electrolytes, minerals, vitamins and trace elements recom- peritoneal dialysis) depends on a variety of disease-, patient- and
renal failure in children is approximately 18 per million children. The mended for the child with ESRD. Recombinant human growth hor- family-related factors. Hemodialysis is performed in the hospital 36
purpose of this algorithm is to discuss the major treatment strategies mone (rhGH) therapy should be considered when indicated. times per week depending on the childs age and condition. Perito-
and complications of chronic renal failure in children. For details on neal dialysis is usually performed at home using an automated ma-
the various disorders leading to chronic renal failure and ESRD, see 7 In children with chronic renal failure, hemoglobin levels de- chine (automated peritoneal dialysis).
appropriate algorithms. crease when the GFR is below 35 ml/min/1.73 m2 body surface area.
The most important cause for anemia in these children is inadequate 12 The ultimate goal of therapy in the child with ESRD is renal
2 The most common causes of chronic renal failure in chil- erythropoiesis secondary to low erythropoietin levels normally pro- transplantation. The options of donations for transplantation include
dren are congenital malformations (including aplastic/hypolastic/ duced by the kidneys. Other causes of anemia in ESRD include poor living-related, living-nonrelated and deceased donors. Renal trans-
dysplastic kidneys, reflux nephropathy and obstructive uropathies), iron intake, blood loss in children treated with hemodialysis, carni- plantation in children has become a well-established therapy. The
which account for 3540% of the cases. FSGS and other chronic glo- tine deficiency and hyperparathyroidism. The follow-up of anemia in graft survival rates have improved dramatically with current 5-year
merulopathies account for approximately 20% and metabolic/genetic children with ESRD includes blood testing for CBC, iron, ferritin and graft survival rates of 83% and 73% for living-related and deceased
diseases for an additional 10% of cases. transferrin levels checked at regular intervals. The recommended donors, respectively.
hemoglobin levels in children with ESRD are 1112 g/dl. Treatment
3 In the child with chronic renal failure who has not reached strategies of the anemia include iron, folic acid and, when indicated,
ESRD the goal is to halt the deterioration in renal function. Antipro- carnitine supplements. Recombinant erytheropoietin administration
Selected reading
teinuric agents such as ACE inhibitors and angiotensin II receptor has become the mainstay of the management of anemia in these
blockers have been shown to reduce the proteinuria in chronic renal children. Transfusion of RBCs is occasionally required. It should be Bakr A, Amr M, Sarhan A, Hammad A, Ragab M, El-Refaey A,
failure and thereby slow the progression of renal disease. In a child emphasized, however, that multiple transfusions of RBCs increase El-Mougy A: Psychiatric disorders in children with chronic renal
treated with these agents, it is important to monitor serum creatinine the risk of renal graft rejection following transplantation. failure. Pediatr Nephrol 2007;22:128131.
and potassium levels. Hypertension in children with chronic renal Filler G: Renal transplantation: literature review 2004-2005.
failure is caused by various factors including sodium and water re- 8 For details on Renal Bone Disease, see appropriate Pediatr Transplant 2006;10: 418428.
tention, activation of the renin-angiotensin-aldosterone system and algorithm. Fine RN, Whyte DA, Boydstun II: Conservative management of
sympathetic overactivity. Hypertension is a major pathogenic factor chronic renal insufficiency; in Avner ED, Harmon WE, Niaudet P
in the progression of chronic renal failure. For treatment of hyperten- 9 Children with ESRD are prone to develop infections. Rea- (eds): Pediatric Nephrology, ed 5. Philadelphia, Lippincott
sion, see Pediatric Hypertension. Metabolic control and adequate sons for this tendency include immune system dysregulation, in- Williams & Wilkins, 2004, pp 12911312.
nutrition are very important measures in the care of the child with dwelling catheters and treatment with immunomodulatory drugs. Mahan JD, Warady BA, the Consensus Committee: Assessment
chronic renal failure (see below). Meticulous handling of catheter and dialysis equipment as well as and treatment of short stature in pediatric patients with chronic
high index of suspicion for signs of infection should be exercised. kidney disease: a consensus statement. Pediatr Nephrol 2006;21:
4 ESRD has major adverse effects on the child afflicted with Follow-up of children with ESRD should include serological blood 917930.
this condition. A multidisciplinary approach is mandatory in the tests performed periodically to check the immunological status of Mitsnefes MM, Kimball TR, Kartal J, Witt SA, Glascock BJ, Khoury
management of these children in order to treat the variety of physical these children and to exclude viral infections such as HIV, hepatitis B PR, Daniels SR: Progression of left ventricular hypertrophy in
and developmental complications of ESRD and to maintain normal and C, varicella zoster, CMV and EBV. In addition, immunization ac- children with early chronic kidney disease: 2-year follow-up study.
lifestyle in these children. cording to the specific recommendations for children with chronic J Pediatr 2006;149:671675.
renal failure should be pursued. Schroder CH, European Pediatric Peritoneal Dialysis Working
5 The main cardiovascular complication in children with Group: The management of anemia in pediatric peritoneal
ESRD is left ventricular failure secondary to hypertension. Other car- 10 ESRD in children and its complications can lead to severe dialysis patients: guidelines by an ad hoc European committee.
diovascular complications include nonhypertrophic cardiomyopathy developmental handicaps, hearing and language disturbances as Pediatr Nephrol 2003;18:805809.
secondary to carnitine deficiency, hyperlipidemia, and, rarely, car- well as psychological and emotional disorders. Academic achieve-
diac arrhythmias. There is accumulating evidence that morbidity ments in children with ESRD are often less than optimal.
from cardiovascular complications in children with ESRD is higher They also have more neurologic deficits, microcephaly, seizures and
than previously recognized and may have serious, long-term effects hypotonicity than their normal peers. Untreated uremia, hearing im-
on the health of these children. pairments (secondary to adverse reactions of drugs), prolonged hos-
pitalization periods and, in the past, aluminum toxicity are important
113 6 Growth retardation is very common in children with chronic causative factors in these impairments. To prevent or minimize these
renal failure and ESRD. Growth failure in these children is caused by impairments, aggressive control of uremia, adequate nutrition and
metabolic acidosis, sodium depletion, inadequate nutrition, bone avoidance of ESRD-related complications as well as a team work of
disease and abnormalities in the growth hormone axis. Dietary con- the pediatric nephrologist, family physician, social worker, physio-

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sultation and follow-up is mandatory in every child with ESRD and therapist and a psychologist is needed.

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Renal failure R.N. Fine J.-P. Guignard Chronic renal failure
Renal failure R.N. Fine J.-P. Guignard Renal osteodystrophy

/
Renal osteodystrophy
114 Clinical manifestations 0
Blood chemistry
Bone films
Bone biopsy

Bone pain, calcifications Bone pain, pathologic fractures Bone deformities, bone pain
PhosphorusMCa2+mN, PTHM Ca2+Malkaline phosphatasemPTHm Phosphorusmalkaline phosphataseM
Subperiosteal erosions Metaphyseal widening

Osteitis fibrosa 1 Adynamic bone disease 3 Rickets/osteomalacia 5


(2nd hyper-PTH)

Dietary phosphate restriction 2 Reduce PTH suppression 4 Phosphate and calcium supplements 6
Phosphate binders Active vitamin D analogues
Active vitamin D analogues
Calcium-sensing-receptor agonist

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Univ. of California San Diego
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1 ROD is the term used for a variety of bone are initiated. Once serum phosphate level is controlled,
Selected reading
disorders secondary to renal failure. The metabolic treatment with an active vitamin D analog is initiated.
abnormalities leading to ROD have a tremendous ef- The recently introduced therapy with calcium-sensing- Kuizon BD, Salusky IB: Renal osteodystrophy; in
fect on a childs growth because if left untreated, ROD receptor agonists promises to be an effective treat- Avner ED, Harmon WE, Niaudet P (eds): Pediatric
can lead to severe growth retardation, pathologic frac- ment of 2nd hyperparathyroidism. Nephrology, ed 5. Philadelphia, Lippincott Williams
tures and developmental delay. As such, it is impor- & Wilkins, 2004, pp 13471374.
tant to identify the exact nature of the bone disease 5 Adynamic bone disease is characterized by Martin KJ, Olgaard K, Coburn JW, Coen GM,
and to treat it accordingly. Of note, although there are reduced activity of bone formation and, hence, is a Fukagawa M, Langman C, Malluche HH,
3 different types of ROD (see below), overlap between low-turnover bone disease. The pathophysiology of McCarthy JT, Massry SG, Mehls O, Salusky IB,
the different disorders is common. this disorder is not completely understood, but PTH Silver JM, Smogorzewski MT, Slatopolsky EM,
suppression, overtreatment with vitamin D analogs or McCann L, Bone Turnover Work Group: Diagnosis,
2 Evaluation of the child with ROD includes ob- aluminum toxicity (prevalent in the past) plays a major assessment, and treatment of bone turnover
taining history regarding bone pain, pathologic frac- role. Children with this type of bone disease suffer abnormalities in renal osteodystrophy. Am J Kidney
tures, restriction of motion and limping. In case of from higher rates of pathological fractures. Typical Dis 2004;43:558565.
limping, slipped capital femoral epiphyses should be laboratory findings include low PTH and alkaline phos- Salusky IB, Kuizon BG, Juppner H: Special aspects of
suspected. Physical examination includes height mea- phatase levels accompanied by hypercalcemia. Bone renal osteodystrophy in children. Semin Nephrol
surement, signs of rickets (bowing, frontal bossing, film cannot help in differentiating between this entity 2004;24:6977.
etc.), bone or muscle tenderness, or signs of periar- and other types of ROD. Histological findings are the Waller SC, Ridout D, Cantor T, Rees L: Parathyroid
ticular calcifications. Laboratory evaluation includes opposite of those seen in 2nd hyperparathyroidism hormone and growth in children with chronic renal
serum levels of creatinine, BUN, calcium, inorganic and include low osteoblast number and volume, low failure. Kidney Int 2005;67:23382345.
phosphorus, alkaline phosphatase, bicarbonate and bone formation rate and absence of fibrosis as well as Hruska KA, Teitelbaum SL: Renal osteodystrophy.
PTH. Bone film is an essential part of the work-up of reduced uptake of tetracycline. N Engl J Med 1995;333:166174.
the child with ROD. The radiologic findings depend on
the specific disorder (see below). If the above work-up 6 The treatment of adynamic bone disease
does not lead to the identification of the specific bone consists of reduction or cessation of the administra-
disorder, bone biopsy is needed (see below). Bone bi- tion of agents suppressing PTH activity (vitamin D an-
opsy is also needed in the case of unexplained hyper- alogs and phosphate binders).
calcemia or suspected aluminum bone disease.
7 The third type of ROD is ostemalacia/rickets.
3 The most common form of ROD in children is Similar to adynamic bone disease, ostemalacia/rickets
2nd hyperparathyroidism also known as osteitis fibro- is also a low-turnover bone disease. It is characterized
sa or high-turnover bone disease. The pathophysiol- by several features of adynamic bone disease but the
ogy of this disorder is the result of phosphorus reten- hallmark of this disorder is defective bone mineraliza-
tion and impaired synthesis of calcitriol, the active tion. If the defective bone mineralization occurs before
form of vitamin D. Clinical manifestations can range growth has ceased, it is called rickets. If, on the other
from asymptomatic disease to bone and muscle pain, hand, the defective mineralization occurs at mature,
height stunting, skeletal deformities and SCFE. The trabecular bone, the condition is termed osteomalacia.
biochemical abnormalities include hyperphosphate- In the past, the most common cause of ostemalacia/
mia, low-to-normal calcium levels and elevated PTH rickets in children with ESRD was aluminum toxicity.
levels in a child with GFR of <2530% of the normal Nowadays, however, phosphate and/or vitamin D defi-
values for age. The radiologic findings include subperi- ciency are the most common causes of this condition in
osteal erosions due to increased bone resorption. children with chronic renal failure. Laboratory findings
Bone biopsy demonstrates increased number and vol- are similar to those seen in adynamic bone disease. Hy-
ume of osteoclasts and osteoblasts, high bone forma- pophosphatemia is an additional finding in ostemala-
tion rate and, in severe cases, fibrosis. cia/rickets. Bone film may show widening of epiphyseal
growth plate and other signs typical of rickets. Bone
115 4 Treatment strategy in 2nd hyperparathyroid- histology has many similarities to adynamic bone dis-
ism is aimed towards the suppression of the excessive ease except for high osteid volume in ostemalacia/rick-
levels of PTH. Of note, recommended serum PTH lev- ets and low-to-normal in adynamic bone disease.
els in children with ESRD are between 150 and 300 pg/

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ml. If hyperphosphatemia is present, restriction of di- 8 In ostemalacia/rickets, phosphate and
etary phosphate and therapy with phosphate binders calcium supplements may be needed.

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Renal failure R.N. Fine J.-P. Guignard Renal osteodystrophy
Index of Signs and Symptoms
A Abdominal wall defects 108 Bone deformities 114 Cystic kidney diseases 44
116 Acromegaly 42, 98 Bone pain 114 Cystic nephroma 42, 48
Acute acidosis 98 Bowel resection 100 Cystinosis 36, 60, 62, 112
Acute glomerulonephritis 44, 90 Brain trauma 52 Cystinuria 62, 104
Acute hemolysis 82 Brain tumor 52 Cytomegalovirus 10
Acute lymphoblastic leukemia 42 Bromide poisoning 78
Acute pyelonephritis 108 Bronchopulmonary dysplasia 50 Defective renal secretion 82
Acute renal failure 68, 82, 98,106, 108 Burns 72, 74, 76, 80, 82, 88
D Dehydration 108, 110
Acute tubular necrosis 42, 44, 108, 110 Delayed bladder emptying 30
Acute tubulointerstitial nephritis 42 C Calcifications 114 Dent disease 60, 62,102
Acute urate nephropathy 42 Calcipenic rickets 92 Denys-Drash syndrome 10
Addison disease 84 Cardiac tamponade 110 Diabetes insipidus 74, 88
Adrenal insufficiency 94 Cardiogenic shock 110 Diabetes mellitus 42, 60, 66, 84, 88
Adrenocortical failure 82 Central diabetes insipidus 64 Diabetic ketoacidosis 100
Adrenogenital syndrome 64 Cerebral salt wasting 72 Diarrhea 72, 74, 100, 108, 110
Adynamic bone disease 114 Chronic active hepatitis 60 Dicarboxylic aminoacidosis 54
Alcoholism 96 Chronic glomerulonephritidies 112 Dietary calcium deficiency 70
Aldosterone 86 Chronic kidney disease 70 Dietary chloride deficiency 76
Aldosteronism 86 Chronic metabolic acidosis 70 Diffuse mesangial sclerosis 10
Alport syndrome 4, 16, 112 Chronic renal failure 44, 82, 88, 98 DiGeorge syndrome 92
Amiloride administration 60 Chronic tubulointerstitial damage 60 Distal renal tubular acidosis 84
Anal reflex 30 Churg-Strauss syndrome 4, 14, 18 Diuresis 106
Analgesic abuse 60 Cirrhosis 72 Diuretics 72, 76, 80, 88, 96
Anasarca 88 Classic cystinuria 54 Down syndrome 68
Anemia 112 Clear cell sarcoma 42, 48 Duplex kidney 42, 48
Aneurysms, coronary artery, hepatic artery, CNS bleeding 52 Dysplasia/hypoplasia 36, 44
renal artery 18 Coarctation of aorta 50, 52
Angioedema 90 Colonic adenoma 86 Ehlers-Danlos syndrome 60
Angiomyolipoma 42, 48 Column of Bertin 42, 48
E Elevated intracranial pressure 50
Antenatal ultrasonography 26 Complement dysregulation 20 Endocarditis 6
Anuria 106 Congenital adrenal hyperplasia 50, 52, 60, 82, 84 End-stage renal disease 112
Aortal stenoses 18 Congenital chloride diarrhea 80 Enemas 98
Apparent mineralocorticoid excess 76, 80 Congenital hemihypertrophy 42 Enterostomy losses 80
Ascites 88 Congenital nephropathies 108 Euvolemia 76, 106, 108, 110
Autosomal-dominant hypoparathyrodism 100 Congenital nephrotic syndrome 112 Excessive sweating 76, 80, 88
Congenital obstructive uropathies 108 Extracorporeal membrane oxygenation 50
Bacteriuria 22 Congenital rubella syndrome 50 Extracorporeal shock wave lithotripsy 104
B Barium poisoning 80 Congenital syphilis 10 Extrarenal losses 74
Bartter syndrome 64, 76, 80, 86, 102 Congestive heart failure 68, 90, 110 Extreme prematurity 58
Beckwith-Weidemann syndrome 42 Constipation 30
Benign familial hematuria 4 Continuous incontinence/drip 30 Fabrys disease 42
Bladder lesion 32 Contraction alkalosis 86
F Familial dysautonomia 52
Bladder rupture 34 Cortical necrosis 44, 108 Familial glucosuria 62
Blood anion gap 84 Corticosterone methyl oxidase deficiency 60, 82 Familial hyperkalemic periodic paralysis 82

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Blood clot 110 Cushing syndrome 44 Familial hypocalciuric hypercalcemia 94
Blood lactate 84 Cutaneous polyarteritis 18 Familial hypokalemic periodic paralysis 80

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Blood loss 108, 110 Cystic fibrosis 72, 76, 80, 86 Fanconi syndrome 54, 56, 58, 64, 70, 80, 96

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Fanconi-Bickel glycogenosis 60, 62 High-dose hydrochlorothiazide therapy 94 Intracranial hypertension 76
Fanconi-Bickel syndrome 58 Histidinuria 54 Intrinsic renal failure 108, 110
Fat deposition 44 HIV nephropathy 20 Ischemia 44
Fetal lobulation 42, 48 Hodgkin/non-Hodgkin lymphoma 42 Isolated cystinuria 54
Fever 74 Horseshoe kidney 48 Isolated glycinuria 54
Fibrosis 110 Human immunodeficiency syndrome 10 Isolated hereditary renal glycosuria 58
Focal segmental glomerulosclerosis 10, 12, 90, 112 Hungry bone syndrome 96, 100 Isolated hypomagnesemia 100
Fractures 114 Hydronephrosis 4 Isolated lysinuria 54
Fungal ball 110 Hydrops fetalis 90
Fungal bezoar 108 1--Hydroxylase deficiency 70 Jansen chondrodysplasia 96
Hypercalcemia 50, 52, 64, 102
J Jansen osseous dysplasia 94
G Galactosemia 60, 62 Hypercalciuria 44, 104 Jansen syndrome 70
Gastric drainage 76, 80 Hyperdibasic AA type I 54 Juvenile nephronophthisis 46
Gastrocystoplasty 86 Hyperkalemia 60
Gastrointestinal bleeding 82 Hyperkalemic distal renal tubular acidosis 84 K Kawasaki syndrome 18
Genetic cobalamin C defect 20 Hyperosmolality 82 Ketonuria 72
Giggle/stress incontinence 30 Hyperostosis 98
Gitelman syndrome 64, 76, 80, 86, 100
Glomerulocystic kidney disease 42
Hyperoxaluria 36, 44, 104, 112
Hyperparathyroidism 62, 96
L Laceration 34
Laxative abuse 100
Glomerulonephritides 52, 110 Hypertension 76 Laxatives 98
Glomerulonephritis 32, 42, 44 Hyperthyroidism 50, 52, 94, 98 Lazy bladder 30
Glucocorticoid deficiency 72 Hypertrophy 42 Lesch-Nyhan syndrome 68
Glucocorticoid-remediable aldosteronism 52, 76, 80 Hypervolemia 106, 108, 110 Leukemia 68, 84
Glucocorticoids 52, 96 Hypoadrenalism 88 Leukocyte esterase 22
Glucose infusion 96 Hypoaldosteronism 88 Licorice ingestion 76, 80, 86
Glucose-6-phosphatase deficiency 68 Hypocalcemia 64 Liddle syndrome 52, 76, 80, 86
Glucose-galactose malabsorption 58 Hypocomplementemic urticarial vasculitis 18 Liver disease 70, 88
Glucosuria 62 Hypokalemia 60 Liver failure 84
Glue sniffing 60, 62 Hypomagnesemia 92, 102 Loaded colon 30
Glycogen storage disease type 1 42, 60, 68 Hyponatremic hypertensive syndrome 88 Loin pain hematuria syndrome 4
Goodpasture syndrome 4, 14 Hypoparathyroidism 68, 86, 92, 98 Loop 86
Gordon syndrome 50, 52, 60, 82, 84 Hypophosphatasia 94 Lowe syndrome 60, 62
Guillain-Barr syndrome 52 Hypophosphatemia 102 Lower limb reflexes 30
Hypophosphatemic rickets 62, 70, 96 Low-magnesium food 100
H Hartnup disease 54
Heart failure 72, 108
Hypoplasia/dysplasia 40, 112
Hyporeninemic hypoaldosteronism 60, 82, 84
Lung hemorrhage 14
Lupus nephritis 4, 6
Heavy metal poisoning 52, 60, 62 Hypothyroidism 72, 94 Lymphangiectasis 48
Hematoma 48, 110 Hypovolemia 76, 106, 108, 110 Lymphoma 68
Hematuria 4 Lysinuric protein intolerance 54
Hemoglobinuria 42, 108 I Idiopathic crescentic glomerulonephritis 90
Hemolytic-uremic syndrome 4, 20, 52, 90,
110, 112
Idiopathic Fanconi syndrome 62
Idiopathic hypercalciuria 102
M Malabsorption 88
Malabsorptive syndromes 100
Hemophilia 42 Idiopathic nephrotic syndrome 90 Malnutrition 88, 90, 100
Henoch-Schnlein purpura 6, 18 Idiopathic renal hypouricemia 66, 72 Marfan syndrome 60
Hepatic failure 90 IgA nephropathy 4 Marked volume depletion 60
Hepatitis B glomerulonephritis 12 Imperforated prepuce 108 Maternal drug abuse 50
117 Hepatitis C glomerulonephritis 12 Inadequate fluid intake 108, 110 Medullary sponge kidney 44, 46
Hepatorenal syndrome 16, 110 Infantile idiopathic hypercalcemia 94 Melena 88
Hereditary fructose intolerance 60, 62 Insensible losses 74, 88 Membranoproliferative glomerulonephritis 6, 14,
Hereditary malformation syndrome 46 Insulin deficiency 82 16, 90

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Hereditary tyrosinemia 42 Insulin 80 Membranous glomerulonephritis 12
Hereditary/metabolic conditions 68 Interstitial nephritis 44, 60 Membranous glomerulopathy 90

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Index of Signs and Symptoms
Index of Signs and Symptoms

Meningitis 20 Osteitis fibrosa 114 Primary hyperparathyroidism 94


118 Mesoblastic nephroma 42, 48, 50 Osteomalacia 70, 114 Protein-losing enteropathy 90
Metabolic acidosis 78, 82, 88, 96, 102 Outdated tetracyclines 60, 62 Proteinuria, transient, persistent 8
Metabolic alkalosis 72, 80, 88 Overactive bladder 30 Proximal renal tubular acidosis 62
Metabolic disorders 66 Overload proteinuria 8 Proximal tublar defect 66
Metabolic storage diseases 44 Proximal tubulopathy 88
Metaphyseal widening 114 P Pancreatitis 72, 88 Prune belly syndrome 42, 48
Methioninuria 54 Pararenal mass 42 Pseudohypoaldosteronism 60, 64, 82
Microcystic kidneys 10 Parathyroid hormone 70 Pseudohypoparathyroidism 92
Microscopic polyangiitis 14, 18 Parenteral fluids 100 Pseudorickets 70
Mid-aortic coarctation 50 Passage of stone 56 Pseudotumor, cerebri 52
Mineralocorticoid excess 52, 74 Pelvic kidney 48 Pseudotumor, sarcoid 42
Minimal-change disease 12 Perinatal asphyxia 108 Psoriasis 68
Minimal-change nephrotic syndrome 90 Perinatal hemorrhage 108 Pyelonephritis 32, 42, 44, 52
Mitochondriopathies 60, 62 Perirenal hematoma 42 Pyloric stenosis, psychogenic 76
Moderate/severe urinary tract dilatation 24 Perirenal urinoma 42 Pyuria 22
Modified Chapel Hill Classification 18 Peritonitis 88
Moyamoya disease 52 Persistent asymptomatic hematuria 4 R Radiocontrast nephropathy 42
Multicystic dysplasia 40 Persistent glomerulonephritis 4 Rapidly progressive glomerulonephritis 4, 6, 110
Multicystic dysplastic kidney 42 Persistent stone 56 Reduced cardiac output 110
Multiple stones 56 Pheochromcytoma 52 Reflux nephropathy 36, 112
Muscle hyperactivity 84 Phosphate depletion 94 Reflux/obstructive nephropathy 52
Myelofibrosis 42 Phosphoribosyl pyrophosphate synthetase Renal agenesis 38
Myoglobinuria 42 overactivity 68 Renal amyloidosis 42
Myxedema 90 Plasma aldosterone 82 Renal angioplasty 42
Plasma renin activity 76, 80, 84 Renal artery stenosis 50, 52, 86, 110
N Nail-patella syndrome 16
Nasogastric suction 86
Pleural effusion 88
Pneumonia 20
Renal artery thrombosis 108
Renal bleeding 34
Necrotizing glomerulonephritis 14 Polyangiitis 12 Renal bone disease 112
Neonatal hyperechoic kidney with normal GFR 44 Polyarteritis nodosa 4, 6, 18 Renal candidiasis 44
Nephroblastomatosis 42 Polycystic kidney disease 4, 42, 46, 48, 50, 108, 112 Renal cell carcinoma 48
Nephrocalcinosis 102 Polycythemia 68 Renal contusion 34
Nephrogenic diabetes insipidus 64, 68 Posterior urethral valves 42 Renal disease 88
Nephronophthisis 44, 64, 112 Posthypercapnia 86 Renal dysplasia 74
Nephrotic syndrome 10, 44, 72 Postinfectious glomerulonephritis 4, 6 Renal failure 72
Nephrotoxic agents 108 Post-kidney transplant 96 Renal free water loss 64
Neuroblastoma 4, 42, 50, Postobstructive diuresis 80, 100 Renal hypertrophy 48
Nutcracker syndrome 4, 32 Postobstructive uropathy 88 Renal losses 74
Postrenal failure 106, 108, 110 Renal malakoplakia 42, 48
O Obesity 68
Obstructive nephropathy 36
Post-streptococcal glomerulonephritis 12, 14
Potassium wasting 62
Renal osteodystrophy 92
Renal pelvic diameter 26
Obstructive stones 56 Prebiliary obstruction 76 Renal salt wasting 64
Obstructive uropathy 26, 50, 60, 82, 112 Prerenal failure 106, 108, 110 Renal transplantation 100, 112
Oligomeganephronia 40 Primary biliary cirrhosis 60 Renal trauma 52

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Oliguria 106 Primary hyperaldosteronism 52, 76, 80, 86 Renal tubular acidosis 78, 80, 84, 102
Oncogenic osteomalacia 96 Primary intestinal hypomagnesemia 100 Renal tumors 52

Univ. of California San Diego


Osmotic diuresis 72, 74, 88 Primary polydipsia 72 Renal vein thrombosis 42, 44, 50, 82, 108, 110

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Renin-secreting tumor 80, 86 T Takayasu arteritis 18, 52 V Vascular congestion 44
Renovascular disease 80 Tamm-Horsfall protein 42, 44 Vascular disorders 108
Respiratory alkalosis 96 Tertiary hyperparathyroidism 94 Vascular pathology 88
Retroperitoneal hematoma 34 Thalassemia 42 Vasculitides 52
Retroperitoneal process 110 Thiazides 86 Vasculitis 18, 36, 90, 110
Rhabdomyolysis 82 Thick-walled bladder 24 Vesicoureteral reflux 24, 26, 28, 42
Rhabdomyosarcoma 4 Thin basement membrane disease 16, 32 Vitamin A intoxication 94
Rheumatoid arthritis 60 Thromboembolism 50 Vitamin D 52
Rickets 114 Thrombotic thrombocytopenic purpura 20 Vitamin D depletion 70
Rubella 10 Tissue hypoperfusion and hypoxia 84 Vitamin D intoxication 50, 70, 94, 98
Total parenteral nutrition 50, 78, 96 Vitamin D-deficient rickets 92
S Salicylates 84
Salt-losing CAH 82
Transient neonatal hypercalcemia 94
Transluminal angioplasty 18
Vitamin D-related rickets 96
Vitamin D-resistant rickets 70, 92
Salt-losing nephropathy 72, 88 Tuberous sclerosis 42 Vomiting 72, 76, 80, 86, 108, 110
Salt-wasting (renal/adrenal disease) 110 Tubular disorders 8
Sarcoidosis 68, 94 Tubulointerstitial nephritis 4, 36, 110 W Water deprivation test 74
Sepsis 110 Tumor hypercalcemia 94 Wegeners granulomatosis 4, 12, 14, 18
Serum aldosterone 88 Tumor lysis syndrome 68 Williams syndrome 94
Severe loin pain 28 Tyrosinemia 60, 62 Wilms tumor 4, 42, 48, 50
Severe respiratory distress 108 Wilson disease 36, 60, 62
Short bowel syndrome 100 Umbilical artery catheter 52
Sickle cell disease 36, 42, 60, 82
U Urate nephropathy 44 Xanthinuria 44, 66
Sjogren disease 42 Ureteropelvic avulsion 34
X Xanthogranulomatous malakoplakia 48
Sjogren syndrome 60 Ureteropelvic junction obstruction 42 X-linked hypophosphatemic rickets 70
Skin nodules 18 Ureterosigmoidostomy 78, 80
Solid tumors 84 Uric acid excretion 66
Splenic compression 42 Uric acid lithiasis 104
Starvation 68 Urinary stone 104
Strenuous exercise 4 Urinary tract abnormalities 38
Struvite 104 Urinary tract obstruction 64
Subperiosteal erosions 114 Urine anion gap 60, 78, 84
Sweat test 86 Urine chloride 86
Sweating 74 Urinoma 48
Syndrome of inappropriate antidiuretic hormone Urolithiasis 102
secretion 66 Uromodulim disorders 68
Systemic lupus erythematosus 10, 12, 14, 16, 36,
60, 83, 90
Systemic manifestations 90

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Univ. of California San Diego
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Index of Signs and Symptoms
Abbreviations
AA Aminoaciduria DMSA Dimercaptosuccinic acid LDH Lactate dehyrogenase
120 ABPM Ambulatory blood pressure monitoring DRTA Distal RTA LE Leukocyte esterase
ACE Angiotensin-converting enzyme DTPA Diethylene triamine pentaacetic acid LMW Low molecular weight
ACTH Adrenocorticotropin LPI Lysinuric protein intolerance
ADPKD Autosomal-dominant polycystic kidney ECF Extracellular fluid
disease ECMO Extracorporeal membrane oxygenation MA Metabolic acidosis
AGBMAb Anti-glomerular basement antoantibody EHEC Enterohemorrhagic Escherichia coli MAG3 Mercaptoacetyltriglycine
AGN Acute glomerulonephritis ESR Erythrocyte sedimentation rate MCD Minimal-change disease
AIDS Acquired immunodeficiency syndrome ESRD End-stage renal disease MCDK Multicystic dysplastic kidney
AIN Acute tubulointerstitial nephritis ESWL Extracorporeal shock wave lithotripsy MCKD Medullary cystic kidney disease
ALT Alanine transferase MCP Membrane co-factor protein
AME Apparent mineralocorticoid excess FENa Fractional excretion of urinary sodium MEN Multiple endocrine neoplasia
ANA Antinuclear antibody FH Complement factor H MGN Membranous glomerulonephritis
ANCA Antineutrophil cytoplasmic autoantibody FHH Familial hypocalciuric hypercalcemia MMF Mycophenolate mofetil
ANS Acute nephritic syndrome FI Complement factor I MPA Microscopic polyangiitis
ARPKD Autosomal-recessive polycystic kidney FJHN Familial juvenile hyperuricemic MPG Mercaptopropionylglycine
disease nephropathy MPGN Membranoproliferative glomerulonephritis
ASLO Antistreptolysin O FSGS Focal segmental glomerulosclerosis MRI Magnetic resonance imaging
AST Aspartate aminotransferase MSK Medullary sponge kidney
ATN Acute tubular necrosis G6P Glucose-6-phosphatase
AV Arteriovenous GBM Glomerular basement membrane NDI Nephrogenic diabetes insipidus
AZA Azathioprine GCKD Glomerulocystic kidney disease NPH-MCKD Nephronophtisis-medullary cystic kidney
GFR Glomerular filtration rate disease
BMT Bone marrow transplantation GLUT2 Glucose transporter 2 NS Nephrotic syndrome
BP Blood pressure GN Glomerulonephritis NSAID Nonsteroidal anti-inflammatory drugs
BPD Bronchopulmonary dysplasia
BUN Blood urea nitrogen HCMA Hyperchloremic metabolic acidosis PAN Polyarteritis nodosa
HGPRT Hypoxanthine guanine phosphoribosyl- P-ANCA Perinuclear ANCA
CAH Congenital adrenal hyperplasia transferase PE Plasma exchange
C-ANCA Cytoplasmic ANCA HHRH Hereditary hypophosphatemia with PHA Pseudohypoaldosteronism
CBC Complete blood cell count renal hypercalciuria PHE Physical examination
CCD Cortical collecting duct HIV Human immunodeficiency virus PHP Pseudohypoparathyroidism
CDI Central diabetes insipidus HIVN HIV nephropathy PKD Polycystic kidney disease
CHF Congestive heart failure HPF High power field PP Pregnancy puerperium
CKD Chronic kidney disease HRS Hepatorenal syndrome PRA Plasma renin activity
CMO Corticosterone methyl oxidase HSP Henoch-Schnlein purpura PRPS Phosphoribosyl pyrophosphate synthetase
CMV Cytomegalovirus HUS Hemolytic-uremic syndrome PRTA Proximal RTA
COPD Chronic obstructive pulmonary disease HUV Hypocomplementemic urticarial vasculitis PSGN Post-streptococcal glomerulonephritis
CPA Cutaneous polyarteritis Hx History PTH Parathyroid hormone
CPK Creatine phosphokinase PUV Posterior urethal valve
CT Computerized tomography IBD Irritable bowel disease
CUG Cystourethrogram IC Immune complexes RBCs Red blood cells
CYP Cyclophosphamide ICGN Idiopathic crescentic glomerulonephritis ROD Renal osteodystrophy
IF Immunofluorescence RPD Renal pelvic diameter

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DDAVP Desmopressin IgAN IgA nephropathy RPGN Rapidly progressive glomerulonephritis
DI Diabetes insipidus ISHG Isolated hereditary renal glycosuria RR Renal replacement

Univ. of California San Diego


DMS Diffuse mesangial sclerosis IVIG Intravenous immunoglobulins RRT Renal replacement therapy
IVP Intravenous pyelogram RTA Renal tubular acidosis
RVT Renal vein thrombosis

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SBE Subacute bacterial endocarditis
SCFE Slipped capital femoral epiphysis
S-Hcys Serum homocysteine
SIADH Syndrome of inappropriate antidiuretic
hormone secretion
SLE Systemic lupus erythematosus
SMX Sulfamethoxazole
Stx Shiga toxin

T4 Tyroxine
TAP Transluminal angioplasty
TBI Total body irradiation
TFA Thomsen-Friedenreich cryptantigen
TIN Tubulointerstitial nephritis
TINU Tubulointerstitial nephritis with uveitis
TMP Trimethoprim
TPN Total parenteral nutrition
TSH Thyroid-stimulating hormone
TTKG Transtubular potassium gradient
TTP Thrombotic thrombocytopenic purpura

U-mma Urinary methylmalonic acid


UPJ Ureteropelvic junction
US Ultrasound
UTI Urinary tract infection
UVJ Ureterovesical junction

VCUG Voiding cystourethrogram


VUR Vesicoureteral reflux
vWF von Willebrand factor

WBC White blood cell


WHO World Health Organization

XLH X-linked hypophosphatemic rickets

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Abbreviations