NEPHROTIC SYNDROME/DEVELOPMENTAL ISSUES
| NEPHROTIC SYNDROME IN CHILDREN —Robert C. Holleman Jr, MD, Associate Professor of Clinical Pediatrics, Division
of Pediatric Nephrology, University of South Carolina School of Medicine, and Director, Pediatric Residency Program,
Palmetto Health Children’s Hospital, Columbia, SC
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| Definition of nephrotic syndrome (NS): systemic or primary renal disease that leads to proteinuria, hypoalbuminemia,
and edema; hyperlipidemia not required to make diagnosis; disruption in normal glomerular filtration barrier allows proteins
to leak into urine
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| Clinical classification: primary; secondary; subcategories—minimal-change nephrotic syndrome (MCNS); focal segmental
glomerular sclerosis (FSGS)
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| Epidemiology: incidence of primary nephrotic syndrome in United States, 2 to 3 cases per 100,000 children; slight predominance
in boys; peak incidence in toddlers and preschoolers; MCNS most common and has best prognosis; FSGS
second most common (prognosis much worse)
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| Etiologies of secondary NS: systemic; postinfectious (group A streptococcal infection classic); viral (HIV nephropathy
causes FSGS; syphilis); vasculitides that affect kidneys; hereditary metabolic diseases (diabetes, Alport’s syndrome,
sickle cell disease); malignancies (particularly leukemia and lymphoma); medications; exogenous toxins (eg, insect
stings, snake venom)
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Diagnostic Evaluation
| Proteinuria: frothy urine indicates proteinuria; urine dipstick test useful screen for proteinuria and hematuria; next most accurate
test random urine protein/creatinine ratio (PCR); gold standard 24-hr urine collection for quantification; serum albumin
helpful in nonedematous patient to determine significance of proteinuria; proteinuria defined on dipstick as ≥1+ in
dilute urine (specific gravity ≥1.015); if urine concentrated, dipstick result ≥2+ abnormal; PCR normally <0.2 (younger
children allowed ratio up to 0.5); for 24-hr measurement of total protein excretion, nephrotic-range proteinuria 1 g/m2 per
day
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| Pathophysiology of edema: hydrostatic pressure exceeds oncotic pressure in vascular space (albumin key to maintaining
oncotic pressure in blood); when albumin low, oncotic pressure drops and plasma water extrudes into lax or dependent
tissues; sites—lower extremities; scrotum, labia; pleural space; periorbital region (alternatively, allergy commonly presents
with periorbital edema); ascites
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| Comorbid conditions (overview): complications of NS include infection, thrombosis, and symptomatic edema; hyperlipidemia
greater problem in chronic refractory NS; endocrinopathies and their treatment may be more toxic than disease;
hypovolemia may set stage for acute renal failure; when marked edema present, do not restrict fluids (patients already
somewhat depleted intravascularly); prerenal injury and acute tubular necrosis with florid renal failure more likely if
other reason for volume loss present (intercurrent illness with vomiting or diarrhea, overzealous use of outpatient oral diuretics,
sepsis, or rapid removal of fluid)
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| Infection: mortality with MCNS ≈2% (primarily due to infection and sepsis); classic pneumococcal peritonitis (child with fever
and abdominal pain requires emergent intervention); sepsis, cellulitis, and pneumonitis can occur; classic organism Streptococcus
pneumoniae (Staphylococcus also seen); skin barrier breaks down due to edema, fluid, and loss of
immunoglobulins; medical suppression of immune system—exposure to varicella virus more worrisome in children on
high-dose prednisone
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| Symptomatic edema: some children develop profound edema and need help with diuresis (respiratory compromise major
indication for hospitalization and diuretic therapy); pulmonary edema rare and typically occurs when albumin level <1 g/
dL; at times, scrotal and labial edema painful (consider diuresis); skin breakdown can occur due to fluid in subcutaneous
tissues; younger children may have so much ascites that they do not eat; bowel wall edema (removing fluid helpful); minority
of patients need diuretic therapy
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| Hyperlipidemia: not typical problem in patient with MCNS; if NS responsive to therapy, hyperlipidemia transient and inconsequential;
low-density lipoprotein (LDL) and very-low-density lipoprotein (VLDL) levels elevated due to hepatic
synthesis; high-density lipoprotein (HDL) decreased; early-onset cardiovascular disease—hyperlipidemia associated
with NS (other than MCNS) increases risk for coronary death in adults 5-fold; elevated cholesterol leads to more rapid
progression of renal disease (consider statins to treat hyperlipidemia in refractory cases)
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| Endocrinopathies: not common (more problematic in chronic refractory NS); patients with NS become vitamin D-deficient
due to loss of vitamin D-binding protein; calcium absorption impaired (reasons unclear); if patient admitted for albumin
therapy, check ionized calcium (albumin binds calcium and lowers ionized fraction further (can precipitate tetany)
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| Prednisone therapy: wide range of toxicity; side effects—Cushingoid features, acne, gastrointestinal (GI) distress, mood
and sleep disturbances; longer-term issues—bone health and growth, cataracts, hypertension, and glucose intolerance
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| Minimal-change nephrotic syndrome: most common cause of idiopathic (ie, primary) NS; 90% to 95% of patients respond
to steroids; etiology not well understood but believed to involve T-cell immunity; viral infections can trigger relapses;
many affected children have atopic conditions; most patients present before 6 yr of age, and majority relapse (rate
70%; prepare families); prognosis excellent if disease responsive to steroids; prepare families for duration of disease; disease
persists 5-11 yr
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| Focal segmental glomerular sclerosis: prevalence increases with age and significantly higher among blacks; types—
primary; secondary (eg, obesity-related NS); treatment—high-dose prednisone for 6 mo (problem of toxicity); response
to steroids not as good as in MCNS (rate 20%-25% with standard therapy [up to 25% with prolonged therapy]);
prognosis—depends on response to steroids (if complete remission achieved, likelihood of end-stage renal disease <15%
[almost 0% for MCNS]); if disease unresponsive, risk for end-stage renal disease at 5 yr 50%; pathophysiology—focus of
research has shifted to epithelial cell structure and function; circulating permeability factor believed involved; familial—
mutations identified in genes that affect proteins in podocyte (eg, α-actinin 4 and podicin 2); viral—HIV, parvovirus, and
cytomegalovirus
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| Congenital NS: rare; presents within first 3 mo of life; includes primary and secondary forms; prognosis poor; patients refractory
to therapy (outcome nephrectomy)
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| Approach to first episode of NS: thorough history and physical examination; laboratory evaluation—can be limited if
clinical findings suggest MCNS; urinalysis looking for cell casts; obtain good microscopic review of urine (comprehensive
metabolic panel or basic metabolic panel with albumin); complete blood cell count to identify hemoconcentration
that would benefit from albumin therapy; consider checking varicella immune status in immunized patients in endemic
areas; purified protein derivative (PPD) test appropriate; in older children, chest x-ray may be indicated due to risk for
lymphoma; if red flags present based on patient age, urinary findings, BP, or renal function, renal serologies appropriate,
eg, complement levels C3 and C4; antinuclear antibody testing; screens for hepatitis B and C, and HIV (diseases associated
with FSGS membranous nephropathy and membranoproliferative genome)
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Treatment
| Steroid therapy: in general, all patients given prednisone; acceptable to start prednisone therapy in any child <6 yr of age
with clinical picture of MCNS; classic dose 2 mg/kg per day divided bid, with maximum of 40 mg bid; recent study in
Germany showed that 12-wk course at initial onset leads to fewer relapses; tapering medication—many physicians
keep patients on daily therapy for 6 wk and switch to every other day; speaker’s approach (once patient in full remission,
switch to alternate-day therapy and taper slowly so that patient off prednisone at ≈12 wk); most MCNS responds within 2
wk; more tips—low-sodium diet indicated while patients actively nephrotic; temporary fluid restriction appropriate if
profound hyponatremia or severe edema present and physician worried about pulmonary edema; calcium supplementation
helpful because of effects of prednisone on bones; if BP elevated and needs treatment, angiotensin-converting enzyme
(ACE) inhibitors best choice; make sure that hydration adequate and serum creatinine normal
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| Problems associated with steroid therapy
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 | Steroid resistance: consider high-dose pulse methylprednisolone (eg, Solu-Medrol) with gradual tapering; usually these
patients need oral cyclophosphamide (eg, Cytoxan) to help induce and sustain remission; consider calcineurin inhibitors
(cyclosporine, tacrolimus) as alternatives (less risk for sterility and long-term malignancy, compared to cyclophosphamide;
however, cyclophosphamide induces true remission and allows patients to discontinue therapy (cyclosporine
and tacrolimus work only as long as patient continues to take them); ACE inhibitors used in refractory NS; lipid-lowering
agents
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| Managing steroid dependence: levamisole—antihelminthic; more immune-stimulant properties; tends to work in MCNS;
safe and effective steroid-sparing drug; mycophenolate (CellCept)—another potential agent
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| Treatment of edema: reassurance; sodium restriction; inpatient diuresis—25% albumin infusions followed by furosemide
(Lasix) effective and reasonably safe; classic dose 1 g/kg given over 2 hr; if concerned about respiratory status,
hypertension, or renal function, start at half dose; cautious outpatient use of oral diuretics reasonable, but maintain intravascular
volume
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| Prognosis: excellent for steroid-sensitive patients (mortality low and primarily related to sepsis); MCNS can persist for
several years with multiple relapses (educate parents); effects of steroid therapy can be worse than NS; FSGS leads to
end-stage renal disease (incidence increasing and can occur after organ transplantation)
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| MEDICAL TESTING FOR DEVELOPMENTAL PROBLEMS: WHEN TO SCAN OR FISH —Carolyn Bridgemohan,
MD, Assistant Professor of Pediatrics, Harvard Medical School, and Assistant in Medicine, Developmental Medicine Center,
Children’s Hospital, Boston, MA
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| Etiology of developmental problems
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| Mental retardation (MR) or global developmental delay (GDD): higher rate of detection for more significant delays; up to
one-third of individuals with severe MR have chromosome abnormality; cause of severe MR identifiable in ≤80% of
cases (only 40%-50% with mild MR)
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| Autism spectrum disorders (ASD): >90% of etiologies accounted for by genetics; most likely multigenic; known genetic
conditions account for 1% to 5% of etiologies (including tuberous sclerosis, fragile X syndrome, Rett mutation, and abnormalities
on chromosome 15)
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| Clinical evaluation: history and physical examination reveal etiology in up to one-third of patients
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| History: review current medical history for clues to associated organ involvement and conditions associated with specific
syndromes; other concerns—seizures (incidence increased in children with MR or ASD); red flags suggestive of metabolic
disorder (unexplained illnesses, periods of regression, and unusual food intolerances); family history through 3
generations
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| Physical examination: patients with micro- or macrocephaly at increased risk for developmental problems; dysmorphic
features may guide genetic testing; Woods lamp examination in children with ASD (incidence of tuberous sclerosis
1%); neurologic examination; many children with developmental disabilities have associated hearing and vision problems
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Genetic Testing
| Genetic syndromes: often associated with GDD and MR; abnormal chromosome number—abnormal number of autosomes
associated with moderate to severe MR (eg, Down syndrome [trisomy 21]); sex chromosomes (learning disabilities
or borderline-to-mild MR, eg, Klinefelter’s or Turner’s syndromes); other abnormalities—chromosome deletions,
point mutations; changes that affect gene function—gene methylation or activation defect
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| Karyotype: photographic representation of chromosomes of single cell, cut and arranged in pairs based on banding pattern;
identifies breaks and missing or extra chromosomes or fragments; order resolution ≥500-band level to avoid false-
negative results
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| Direct DNA test: recommended for Rett syndrome; mutation scanning identifies variant gene regions; mutation analysis
more focused look at specific region
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| Gene function: fluorescent in situ hybridization (FISH) test for chromosome 15 detects only 70% of patients with Prader-
Willi syndrome (use methylation test)
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| FISH technique: fluorescently labeled probes specific for small regions of DNA detect microdeletions or additions; expensive
(order FISH only if specific diagnosis suspected); subtelomeric FISH testing—part of assessment for children
with GDD and MR; technique targets gene-rich areas at ends of chromosomes (difficult to see on karyotype because areas
do not stain well); included in comparative genomic hybridization (CGH)
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| Microarray CGH: DNA bound to multiple probes on glass plate; scans multiple loci for deletions or duplications; panels
available through major laboratories that include clinically important loci; indications include suspected Williams or
Prader-Willi syndrome; helpful alternative to multiple FISH tests
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| GDD evaluation: for GDD or MR, high-resolution karyotype; fragile X DNA test; subtelomeric FISH test (may be replaced
in future by CGH test [more information for same cost]); additional tests—guided by clinical presentation;
consider genetics referral if patient has ≥3 minor or ≥1 major dysmorphic features or organ anomaly
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| ASD evaluation: lead test (severe lead poisoning associated with development of ASD; autistic children with mouthing
behaviors at higher risk); high-resolution karyotype; fragile X DNA test; subtelomeric FISH; controversy—American
Academy of Pediatrics recommends karyotype only for children with ASD who also have MR; speaker also obtains
CGH; additional tests guided by clinical profile—chromosome 15; if Angelman’s or Prader-Willi syndromes suspected,
FISH or methylation testing; for girls with significant delay and regression, testing for Rett syndrome; consider
genetics referral if dysmorphic features present
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Other Tests
| Neuroimaging: indications—micro- or macrocephaly; focal neurologic findings; significant developmental regression;
MRI better than CT—particularly for imaging myelination; GDD—abnormalities seen on MRI in up to 30% of affected
patients; issue of sedation (may need to delay MRI if child very young); ASD—≈25% of affected patients have
macrocephaly; neuroimaging not recommended for macrocephaly alone because head growth accelerated in first 2 yr of
life (exception extreme or increasing macrocephaly and physician worried about hydrocephalus)
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| Electroencephalography: indicated in work-up for paroxysmal events, unexplained staring spells, seizures, and regression;
up to one-third of patients with ASD develop seizures
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| Metabolic testing: routine screening has low yield in patients with MR or ASD; indications—newborn screening not
done or not available; in patient with ASD, when phenylketonuria screening not verified; ataxia, seizures, or loss of
skills; hepatosplenomegaly or coarse facial features may suggest storage disorder; unexplained deafness or family history
of deafness; ophthalmologic abnormalities
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Resources
www.genetests.org
Suggested Reading
Berns JS, Siegel NJ: Steroid resistance in childhood nephrotic syndrome. Kidney Int 69:1915, 2006; Dijkhuizen T et al:
FISH and array-CGH analysis of a complex chromosome 3 aberration suggests that loss of CNTN4 and CRBN contributes to
mental retardation in 3pter deletions. Am J Med Genet A 140:2482, 2006; Furth SL et al: Varicella vaccination in children
with nephrotic syndrome: a report of the Southwest Pediatric Nephrology Study Group. J Pediatr 142:145, 2003; Kitamura
A et al: A familial childhood-onset relapsing nephrotic syndrome. Kidney Int 71:946, 2007; Loeffler K et al: Tacrolimus
therapy in pediatric patients with treatment-resistant nephrotic syndrome. Pediatr Nephrol 19:281, 2004; Makker SP et al:
A prospective comparison of prednisone plus cyclosporin and prednisone alone in pediatric nephrotic syndrome. Nat Clin
Pract Nephrol 2:550, 2006; Moeshler JB, Shevell M, American Academy of Pediatrics Committee on Genetics:
Pediatrics 117:2304, 2006; Picker JD et al: Multicolor karyotypic interpretation of a heterochromatin-associated marker
chromosome in a dysmorphic girl with developmental delay. Am J Med Genet 110:393, 2002; Pilowsky T et al: Neuropsychological
functioning of siblings of children with autism, siblings of children with developmental language delay, and siblings
of children with mental retardation of unknown genetic etiology. J Autism Dev Discord 37:537, 2007; Rauch A et al:
Diagnostic yield of various genetic approaches in patients with unexplained developmental delay or mental retardation. Am J
Med Genet A 140:2063, 2006; Salsano ME et al: Atopy in childhood idiopathic nephrotic syndrome. Acta Paediatr
96:561, 2007; Schaefer GB, Lutz RE: Diagnostic yield in the clinical genetic evaluation of autism spectrum disorders.
Genet Med 8:549, 2006.
Educational Objectives
| The goal of this program is to improve the care of children with nephrotic syndrome (NS) and to guide appropriate
medical testing for developmental problems. After hearing and assimilating this program, the clinician
will be better able to:
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| 1. Describe the epidemiology of NS.
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| 2. Identify known causes of NS.
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| 3. Provide appropriate therapy for managing NS.
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| 4. Choose appropriate genetic tests for children with developmental delay due to, eg, autism spectrum
disorders or mental retardation.
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| 5. Describe other medical tests for developmental delay, including neuroimaging, electroencephalography,
and metabolic screening.
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Faculty Disclosure
In adherence to ACCME Standards for Commercial Support, Audio-Digest requires all faculty and planning committee members
to disclose relevant financial relationships within the past 12 months that might create any personal conflicts of interest.
Any identified conflicts were resolved to ensure that this educational activity promotes quality in health care and not a proprietary
business or commercial interest. For this program, the faculty and planning committee reported nothing to disclose.
Acknowledgments
Dr. Holleman was recorded at the 10th Annual Frontiers in Pediatrics, presented November 30 to December 2, 2007, in
Charleston, SC, by the Department of Pediatrics, Office of Continuing Medical Education, and co-sponsored by the Office of
Continuing Education, College of Nursing, Medical University of South Carolina, Charleston; Dr. Bridgemohan was recorded
at the 29th Annual Las Vegas Seminars, presented November 15-18, 2007, in Las Vegas, NV, by the American
Academy of Pediatrics, California District IX, Chapters 1,2,3,4.
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