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Practical Algorithms Nephrology
Practical Algorithms Nephrology
Algorithms in
n g
Pediatric
Nephrology
b e
e r
Editors
k t
Israel Zelikovic, Haifa
Israel Eisenstein, Haifa
d o
56 graphs, 1 figure and 10 tables, 2008
Kainan University
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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
48 Renal mass
Kainan University
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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. Rodríguez Soriano G. Ariceta; B. Hoppe; C.B. Langman J.-P. Guignard; R.N. Fine
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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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, CH–4009 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 978–3–8055–8539–2
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
Kainan University
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Contributors
Raymond Adelman, MD Bernd Hoppe, MD Juan Rodríguez Soriano, MD
Department of Pediatrics University Children’s Hospital Division of Pediatric Nephrology
Phoenix Children’s 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 Children’s Mercy Hospital and Clinics The Birmingham Children’s 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, Children’s Memorial Hospital Division of Pediatric Nephrology
Chicago, IL, USA Children’s 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
Children’s 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 Children’s Hospital and Regional Medical Center
Minneapolis, MN, USA University of Washington Sandra Watkins, MD
Seattle, WA, USA Division of Pediatric Nephrology
Paul Goodyer, MD Children’s Hospital and Regional Medical Center
Willem Proesmans, MD University of Washington
Division of Pediatric Nephrology
Seattle, WA, USA
The Montreal Children’s 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 Children’s Hospital and
Kainan University
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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 patient’s 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- Ze’ev 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 specialist’s
management.
/
Hematuria
4
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
Neuroblastoma Trauma
Rhabdomyosarcoma
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 >2–3 nephropathy and postinfectious glomerulonephritis granular), proteinuria, hypertension and variable
RBCs/high power field or >5 RBCs/µl. 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;159:353–355.
(sections 7–11) 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;14:65–72.
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: Alport’s syndrome, Goodpasture’s
7 – Glomerular diseases can cause a spectrum of ria’). syndrome, and type IV collagen. N Engl J Med
clinical manifestations ranging from asymptomatic 2003;348:2543–2556.
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;53:401–412.
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;20:609–613.
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 474–478, 481–485.
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;45:135–141.
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.
/
Acute nephritic syndrome – Macroscopic hematuria, oliguria, acute renal failure,
salt retention (hypertension and edema), proteinuria
Transient Persistent 3
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
Tubular disorders 2 Overload proteinuria 3 Nephritic syndrome 5 Nephrotic syndrome 5 Chronic renal disease 6
/
Nephrotic syndrome in the first year of life
10
Congenital NS 0 Infantile NS 0
MCD
MGN
SLE
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, GFR–mor N BPM or N BPMor N BPM or N BPM or N
BP-N MASLO GFR–m or N GFR–mor N GFR–mor N GFR–mor N
GFR-N mC3, C4-N ANA (+) C3, C4-N ASLO-N C3, Cr-N, occasionallym
C3, C4-N ANA (–) C3, C4–m mC3 ANA (–)
ANA (–) Group A B-streptococcus in C4–mor N ASLO-N
throat or skin (±) (–) ANA
Permanent Frequent relapses Steroid dependent HepB Abs (+) HepC Ab(+) ANCA (+) HIV (+) ;
remission 4
Glomerular and vascular disease S.P. Makker · F. Santos Nephrotic syndrome in the child and adolescent
Glomerular and vascular disease S.P. Makker · F. Santos Rapidly progressive glomerulonephritis
/0
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
Pauci-immune GN
Group A B-streptococci, ANA, C3, C4, ANCA
Anti-GBM disease
ANCA
Throat/skin culture (+) ANA (+), C3, C4– ANA (–), C3–m ANA (–)
Lung hemorrhage (+) Lung hemorrhage (–) for group A B-streptococci mor N C4–mor N C3, C4–N
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
Glomerular and vascular disease S.P. Makker · F. Santos Rapidly progressive glomerulonephritis
Glomerular and vascular disease S.P. Makker · F. Santos Chronic nephritic syndrome
/
Chronic nephritic syndrome
16 History and examination 0
Laboratory tests 1
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
Steroids Interferon 2 Antiviral agents 2
Immunosuppressive agents 2
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;14:25–30.
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;69:1934–1938.
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;17:703–712.
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 don’t. Pediatr Nephrol 2005;20:1027–1035.
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 1–2 weeks.
17
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
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
Takayasu arteritis 2 Kawasaki syndrome 3 PAN 4 CPA 5 Wegener’s Churg-Strauss HSP 8 MPA 9 HUV :
granulomatosis 6 syndrome 7
/
Hemolytic uremic syndrome
20
Diarrhea 0 No diarrhea 3
S. dysenteriae Yersinia
EHEC Campylobacter
Pneumococci 5 HIV/AIDS 6 Cancer 7 Glomerulonephritis 8 Inf. (–)
C. Freundii Salmonella
Cancer (–)
GN (–)
Glomerular and vascular disease W. Proesmans · U.S. Alon Hemolytic uremic syndrome
Urinary tract disease/tubulointerstitial nephropathy R. Adelman · S. Hulton Urinary tract infection
Urinalysis 0
LE, nitrate negative LE, nitrate positive Pyuria Bacteriuria Bacteriuria and pyuria
Treatment Evaluation 6
Nonspecific pyuria
False negative
Trauma
Tuberculosis
Asymptomatic Uncomplicated UTI 3 Complicated UTI 4 Adjunctive U/S 7 VCUG 8 Radionuclide IVP :
bacteriuria 3 therapy 5 scan 9
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 5–7 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;155:60–65.
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;53:379–400.
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 1007–1026.
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;86:419–420.
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;357:1329–1333.
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;90:663–664.
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;69:970–974.
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-
ureteral reflux tends to resolve over time. Severe reflux
has about a 50% chance of resolving over 5–10 years.
/
Dilated/obstructed urinary tract
24 Abnormal US
VCUG
No Yes
No Yes
If severe, drainage
Prophylactic Repeat US Consider surgical relief 5 Suprapubic/urethral Prophylactic antibiotics Repeat US If severe, drainage
antibiotics 3–6 months 4 catheter drainage 3–6 months 4
DMSA renal scan 1 Cystourethroscopy and valve DMSA renal scan 1 Consider surgical
fulguration/ablation relief 5
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;82:9–14.
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;53:429–447.
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;53:413–427.
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;34:89–101.
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;168:1118–1120.
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;36:16–35.
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. 30–40% 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.
Fetal hydronephrosis
26 Antenatal US /
US at 3–7 days
No reflux
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
Negative Positive
/
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
VCUG IVP Pelvic floor exercises U/S (renal/bladder) and Laxatives A -Blocker
urodynamic flow rates 6 No (Prazocin) <
Response
Non-neuropathic Intermittent bladder
‘neuropathic’ bladder catheterization
(Hinman) =
Stop antibiotics Yes
Mitroffanoff – last resort
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 4–5 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 child’s voiding pattern. infrequent voiding every 8–12 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 20–40 µg 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 30–40% 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 6–8 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;173:969–973.
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;21:336–340.
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;18:139–147.
8 – US is very useful to image the upper urinary tract to demon- Nørgaard 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 0.45–1 mg Br J Urol 1998;81(suppl 3):1–16.
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;31:481–490.
cant when they represent, on repeated occasions, volumes of >20 ml
/
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
Hyperuricosuria
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;10:216–220.
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;160:1232–1235.
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;49:168–173.
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;13:229–237.
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, 1537–1539.
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 patient’s 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
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)
35
/
Tubulointerstitial nephritis
36 Renal insufficiency/ failure
Tubular dysfunction
Therapy 5
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 817–831.
2 – The presence of more than 1% eosinophils of Clarkson MR, Giblin L, O’Connell FP, O’Kelly P,
the total WBC in the urine is considered significant and 6 – Idiopathic AIN is a diagnosis of exclusion and Walshe JJ, Conlon P, D’Amico 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;26:124–132.
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 1–3 weeks after anti-inflammatory drugs in healthy children.
injury. stopping presumed inciting agent may be of benefit. Pediatr Nephrol 2005;20:1295–1298.
O’Meara 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;19:2778–2783.
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;13:426–432.
• 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.
/
Single kidney (renal agenesis)
38
Association of nonurological malformations 0
Clinical evaluation 1
US 2
VCUG 3
DMSA renal scan 4
39
/
Renal hypoplasia-dysplasia
40 Assessment of renal function 0
US
VCUG
DMSA renal scan
Nephrological follow-up
41
/
Nephromegaly
42
Normal/minor anomaly Pathological Pseudoenlargement, transient nephromegaly 1
Physiological response 0
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
Downloaded by:
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 Bowman’s 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 6–12 months. Other causes of hydronephro- renomegaly. Glycogen storage disease type 1 can present at 3–4 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- Fabry’s 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 12–14 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-
Downloaded by:
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
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
Downloaded by:
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
/
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;
/0
Neonatal hypertension
50 Clinical Features
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
Cortical necrosis
HUS
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 3–8 days. It rises
Hydralazine vasodilator bolus: 0.15–0.6 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: 0.75–5.0 µg/kg
neonate (glucocorticoids, theophylline), or due to per min
maternal drug abuse that leads to hypertension in their
Labetalol ␣- and -blocker 1.20–3.0 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 1–3 µg/kg per min constant infusion may cause reflex tachycardia
ture infants is intracranial hemorrhage.
Sodium vasodilator 0.5–10 µg/kg per min constant infusion thiocyanate toxicity can occur with
nitroprusside (arteriolar and prolonged (>72 h) use or in renal failure
venous)
/0
Pediatric hypertension
Evaluation 1
52
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-Barré 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
Treatment 9
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-
1.2–13% 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;114:555–576]. 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 1125–1152.
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. 1011–1028.
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;23:545–556.
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;15:370–378.
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;130:178–184.
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; 12:561–568.
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 20–40% 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;114:555–576.
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; 14:141–147.
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 café-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-
lined in the algorithm).
/
Aminoaciduria
54
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
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- 2211–2233.
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;451:511–517.
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):S27–37.
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;36:1003–1007.
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 701–729.
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
/
Cystinuria
(hexagonal crystals in urine; urine cystine >100 µmol/g creatinine)
56
Nephrolithiasis 2
57
/
Glycosuria
58
59
/
Renal tubular acidosis
60 History and physical examination 0
Serum creatinine, Na+, K+, Ca2+, P, HCO–3, plasma aldosterone, renin
Urine-urinalysis, osmolarity, Cl–, Na+, K+, Ca2+, pH
Renal US
Hypokalemia Hyperkalemia
/
Proximal tubulopathy (Fanconi syndrome)
62
Therapeutic strategies 4
Fluids, NaCl, KCl, NaHCO3 , PO4 , calcitrol, carnitine, specific therapy,
organic solute replacement unnecessary
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 (2–8 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 (25–100 mg elemen-
2 – In the early 1930s, Fanconi (Switzerland), analyzer or by slip lamp identification of corneal crys- tal phosphate/kg divided in 3–4 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 45–60 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 10–40 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 10–20 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- Hyperglykämien des älteren Kindes. Jahrb Kinder-
coni syndrome there may be several grams of LMW ness and usually require tissue diagnosis. In Fanconi- heilk 1931;133:257–300.
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 789–806.
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;347:111–121.
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;20:460–464.
(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;14:495–498.
range = 4–6. 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;2:213–227.
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
/
Polyuria
64
Hypouricemia
66 Serum uric acid <2 mg/dl
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
Diabetes mellitus 7
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;37:391–418.
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;7:105–118.
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;20:125–133.
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;15:164–173.
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.
/
Hyperuricemia
68
Elevated serum uric acid level (table 1)
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
/
Rickets
70 Serum total [Ca] 0
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
Fanconi syndrome/chronic deficiency A
metabolic acidosis ?
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, 15–80). 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 20–80 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;58:329–333.
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
58:297–302.
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;116:2062–2072.
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;6:136–140.
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 237–254.
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,
(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-
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-
/
Hyponatremia
(Serum Na+ <130 mEq/l)
72
Exclude pseudohyponatremia or hypertonic hyponatremia /
Variable 8
[Na+] >20 [Na+] <20 [Na+] <20 29 [Na+] >20
Sodium and water replacement ; Water restriction ; Sodium and water restriction ;
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;24:23–30.
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;20:1687–1700.
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 703–712.
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;12:769–771.
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 125–145.
a combination of water excess and excessive urinary Na+ excretion
3 – Once fluid status is assessed, patient’s 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: Bartter’s syndrome and Gitelman’s 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-Barré 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)
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 Vasopressin, desmopressin, oxytocin
water. In the setting of gastrointestinally driven hyponatremia, se-
rum aldosterone levels and sodium avidity of the kidneys are high.
/
Hypernatremia
(Serum Na+ >150 mEq/l)
74
>800 <300
Yes No
CDI 5 NDI 6
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
sparing diuretics
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;24:23–30.
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;20:1687–1700.
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 750–758.
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 125–145.
9 – Sodium excess can be due to exogenous administration of
2 – Once fluid status is assessed, patient’s 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-Barré 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-
nancies or infiltrative diseases (e.g. histiocytosis X).
/
Hypochloremia
(Serum Cl– <100 mEq/l)
76
Yes 2 No
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
Chloride diarrhea
Congenital, sporadic
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- Rodríguez 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;103:209–214.
accompanied by either hypovolemia or euvolemia/ remic metabolic alkalosis, urinary chloride wasting, Rodríguez 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 12:315–327.
in order to proceed with the work-up: (1) History: Infor- levels) or pseudohyperaldosteronism (with low/nor- Rodríguez 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 729–756.
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 555–557.
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;340:1177–1187.
tions in the gene encoding renal 11-hydroxysteroid Sojo A, Rodríguez Soriano J, Vitoria JC, Vázquez 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;153:825–828.
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. 919–935.
/
Hyperchloremia
(Serum Cl– >110 mEq/l)
78
No Yes
Negative 2 Positive 3
79
/
Hypokalemia
(Plasma K+ <3.5 mEq/l)
80
Urine K+
PRA
Parenteral fluids
Protein-calorie malnutrition
Low 5 High 8
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
Laxative or enema abuse administration
Villous adenoma
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;24:597–613.
becomes more and more significant (up to 30%) when Rodríguez 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- 315–327.
2 – Decreased intake of K+ is a rare cause of emia is characteristic of hyperaldosteronism (with high Rodríguez 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). 364–374.
enteritis, is the most common cause of hypokalemia in Rodríguez 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 729–756
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;340:1177–1187.
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 919–935.
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
/
Hyperkalemia
(Plasma K+ >5.2 mEq/l)
82
Exclude spurious hyperkalemia or pseudohyperkalemia 0
Urine K+
PRA
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
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 P–R 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;24:597–613.
rare entity called familial pseudohyerkalemia.
secretion of K+ is more frequently seen as a conse- Rodríguez 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 315–327.
lemia unless there is reduced renal function, as occurs
presence of preexisting renal disease. Rodríguez 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. 364–374.
rone deficiency with elevated PRA is generally Rodríguez 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 729–756.
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;340:1177–1187.
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- 919–935.
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.
develops in oliguric acute renal failure even in the ab-
sence of excessive K+ intake because of tissue catabo-
/
Metabolic acidosis
84 Renal failure 0
No Yes
Normal (10–12 mEq/l) Blood anion gap 1 Increased < Blood lactate
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
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)
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 – Gordon‘s 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). 471–478.
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 757–776.
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 2073–2130.
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;16:194–198.
chondrial cytopathies and Wilson disease), drugs (aminoglycosides, the epithelial Na+ channel. There is also a secondary form of aldoste- Rodríguez 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;13:2160–2170.
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; 24:48–54.
mary isolated RTA. Acetazolamide is an inhibitor of carbonic anhy-
/
Metabolic alkalosis
86 Urine chloride
No Low Cl intake
Normal High
No Loop, thiazides
Diarrhea Yes
High 3 Low 4
No Congenital CI diarrhea
Colonic adenoma
/
Hypovolemia
88 Trauma, bleeding Normal/high 9
Environmentally induced hypovolemia
Serum Na
No
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
Ascites
Anasarca Acute Vascular Normal Low
abdomen 8 pathology
High Negative
Serum
aldosterone
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
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;13:520–528.
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;32:995–1003.
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;23:277–282.
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;21:887–890.
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 415–446.
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
ratio. Especially prone to hypovolemia are preterm infants under
radiant warmers.
/
Edema
90
Symmetrical Localized/unilateral
Hypoalbuminemia
Angioedema A Venous B Lymphatic C Infectious C
Yes No
Albuminuria TSHMT4m
No Yes No Yes
Serum creatinineM
No Yes
Hematuria
No Yes
No Yes
Minimal-change NS 4 FSGS 5 MGP 6 IgAN 7 MPGN 9 AGN : HUS ; ICGN < SLE = Vasculitis >
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 (Ménétrier 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;27:1007–1031.
91 90% of these patients go into complete remission when given 60 mg/m² 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;8:182–183.
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 133–153.
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;6:885–898.
parts of the glomerular capillaries). The abnormal segment adheres to (see ‘Vasculitis’). Witt C, Ottesen EA: Lymphatic filariasis: an infection of childhood.
Bowman’s capsule, has little cells, increased fibrous tissue and lipid Trop Med Int Health 2001;6:584–606.
/
Hypocalcemia Symptoms 0
92 mSerum PO4
MSerum alkaline phosphase
Yes No
Calcipenic rickets 1 No
Serum PTH
Serum 25(OH)D3
Elevated Low
Absent/low Normal
Serum creatinineM
PHP type 1 =
Gs A-protein reduced in
red blood cells
Yes No
1-A hydroxylase Vitamin D-resistant PHP type 1a PHP type 1c PHP type 1b PHP type 2 > Renal osteodystrophy :
deficiency rickets
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- 117–122.
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;149:877–880.
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- 58:297–302.
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;116:2062–2072.
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 237–254.
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
subcutaneous Ca deposits adjacent to the joints.
/
Hypercalcemia Symptoms 0
94 Serum PTH 1
Low Normal/increased
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
Transient neonatal hypercalcemia 8
Sarcoidosis 9
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;21:1676–1680.
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 397–405.
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;115:974–980.
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 237–254.
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
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-
of rickets.
/
Hypophosphatemia Symptoms 0
96
P depletion
Urine P 2
Increased Reduced
PTH
Normal/low High
/
Hyperphosphatemia Symptoms 0
98 Urine P 1
Reduced Increased
Serum creatinine
Increased Normal
Plasma Ca
Normal Low
PTH
Normal/high Low
/
Hypomagnesemia Symptoms 0
100 FEMg2+ 1
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
Calcineurin inhibitors
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 (1.5–2.4 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- 1937–1947.
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;117:2260–2267.
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;20:1490–1493.
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- Gitelman‘s syndrome: towards genotype-pheno-
nesemia in children. It may be seen along with other semia, hypercalciuria and nephrocalcinosis, previous- type correlations? Pediatr Nephrol 2007;22:326–332.
electrolyte deficiencies. ly called Michellis-Castrillo syndrome, is an autosomal- Rodríguez 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 729–757.
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;19:13–25.
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, 919–935.
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-
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
Hypercalciuria
102 Urolithiasis, hematuria, dysuria
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
Nephrolithiasis/urolithiasis
104 Symptoms/signs of urinary stone /
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 7.0–7.5) 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 7.0–7.5)
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
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;27:287–299.
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;25:131–138.
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;84:320–323.
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;40:353–384.
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;37:583–600.
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 1065–1080.
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;47:199–221.
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 10–40% 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 0–6 months <0.8
(extensive bowel resection, inflammatory bowel disease) or pyridox-
6–12 months <0.6
ine deficiency. ing citrate or bicarbonate. D-penicillamine, and ␣-MPG may help in
2–8 years <0.2
Uric acid calculi account for 3–4% of urinary calculi in the pediatric refractory cases.
Oxalate/creatinine 0–6 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
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
/
Oliguria/anuria
106
Oliguria Anuria
Rehydration 1 Furosemide 4
1–5 mg/kg
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
107
/
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
Maintenance fluid therapy, Treat fluid and electrolyte abnormalities Relief of obstruction
Packed RBC infusion Discontinue nephrotoxic agents
Repair of heart anomaly Intravenous antibiotics
1 – Acute renal failure is observed in 8–24% of attempted. In hypotensive neonates, dopamine may
Selected reading
neonates admitted to neonatal intensive care units. be used at a dose of 2–4 µg/kg/min. Higher doses
Although acute renal failure in a neonate is a serious (<10 µg /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;28:112–123.
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;21:931–938.
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, 1037–1044.
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;14:227–239.
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
20–40 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
diuresis does not ensue, administer plasma at a rate of FeNa, % <2 >3
20 ml/kg over 2 h. Furosemide, 2–5 mg/kg, may be U/Posm 61.3 ^1.0
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
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
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
Reduce proteinuria 1
Control blood pressure
Metabolic control
Optimize nutrition
Treat ESRD 2
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
Dialysis
Renal transplantation :
1 – Chronic renal failure is defined as an irreversible reduction should include careful monitoring of weight and height, anthropo- 11 – When ESRD (GFR <5–10 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 3–6
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 child‘s 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 35–40% 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 11–12 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;22:128–131.
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: 418–428.
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 1291–1312.
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 917–930.
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;149:671–675.
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;18:805–809.
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-
sultation and follow-up is mandatory in every child with ESRD and therapist and a psychologist is needed.
/
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
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
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 child‘s 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 1347–1374.
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;43:558–565.
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;24:69–77.
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;67:2338–2345.
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;333:166–174.
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 <25–30% 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/
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.
Selçuk Universitesi
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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-Barré 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-Schönlein 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,
Selçuk Universitesi
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Index of Signs and Symptoms
Index of Signs and Symptoms
Selçuk Universitesi
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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 Wegener’s 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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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
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