Residency · Residency · Medicine Pediatrics
Nephrotic Syndrome: Minimal Change to Membranous
Overview
Nephrotic syndrome is characterized by heavy proteinuria (>=3.5 g/day in adults, >=40 mg/m2/hr in children), hypoalbuminemia, edema, and hyperlipidemia. The predominant histologic causes differ by age: minimal change disease (MCD) dominates in children, while membranous nephropathy and FSGS are more common in adults. This divergence drives fundamentally different diagnostic and management approaches between pediatric and adult nephrology.
Definition and Clinical Features
Nephrotic Syndrome Criteria
Pediatric: urine protein/creatinine ratio >2.0 (mg/mg), or >=40 mg/m2/hr, or 3+ protein on dipstick. Adult: proteinuria >3.5 g/day (or equivalent ratio) Hypoalbuminemia: <2.5 g/dL. Edema: periorbital (characteristic in children, especially morning), peripheral, ascites, scrotal/labial, pleural effusions. Hyperlipidemia: elevated total cholesterol, LDL, triglycerides (hepatic compensation for albumin loss)
Complications of Nephrotic Syndrome (All Ages)
Thromboembolism: loss of antithrombin III, protein C/S; hypercoagulable state; renal vein thrombosis, DVT, PE; risk highest with membranous nephropathy (adult) and albumin <2.0 g/dL. Infection: loss of immunoglobulins; encapsulated organism risk (especially S. pneumoniae); spontaneous bacterial peritonitis in children with ascites. AKI: hypovolemia, sepsis, NSAID use, bilateral renal vein thrombosis. Dyslipidemia: accelerated atherosclerosis with prolonged nephrotic state.
Etiology by Age
| Histology | Children (1-10 yrs) | Adolescents | Adults |
|---|---|---|---|
| Minimal change disease | 80-90% | ~50% | 10-15% |
| FSGS | 10-20% | ~30% | 20-25% (most common in Black adults) |
| Membranous nephropathy | <5% | <10% | Most common primary cause in White adults |
| Diabetic nephropathy | Rare | Rare | Most common secondary cause |
| Amyloidosis | Very rare | Very rare | Consider in older adults |
Pediatric Nephrotic Syndrome
Minimal change disease (MCD): 80-90% of cases in children ages 1-10; 50% of adolescent nephrotic syndrome. Focal segmental glomerulosclerosis (FSGS): 10-20%; more common in Black children; worse prognosis. Membranous nephropathy: rare in children (<5%); consider secondary causes (lupus, hepatitis B) Membranoproliferative GN (MPGN): rare; consider complement-mediated or immune complex-mediated forms. Congenital nephrotic syndrome: presents <3 months of age; Finnish type (NPHS1 mutation), WT1 mutations (Denys-Drash, Frasier syndromes); usually requires nephrectomy and transplant.
Adult Nephrotic Syndrome
Membranous nephropathy: most common primary cause in White adults; anti-PLA2R antibodies in 70% of primary cases. FSGS: most common primary cause in Black adults; podocin (NPHS2) and APOL1 gene variants. MCD: 10-15% of adult nephrotic syndrome. Diabetic nephropathy: most common SECONDARY cause overall. Amyloidosis: AA (chronic inflammation) or AL (plasma cell dyscrasia) Lupus nephritis: especially class V (membranous) IgA nephropathy: can present with nephrotic-range proteinuria. Secondary causes: medications (NSAIDs, lithium, gold, penicillamine), infections (hepatitis B/C, HIV, syphilis), malignancy (solid tumors with membranous, lymphoma with MCD)
Diagnostic Approach
Pediatric (Ages 1-10)
Empiric steroid trial WITHOUT biopsy: standard of care for first episode of nephrotic syndrome in children aged 1-10 with typical features (age-appropriate, normal complement, normal renal function, no hematuria or hypertension) Rationale: 80-90% have MCD, which responds to steroids; biopsy would not change initial management. Biopsy indications in children: Age <1 year or >12 years (higher likelihood of non-MCD) Steroid resistance (no remission after 4-8 weeks of adequate steroid therapy) Frequently relapsing or steroid-dependent nephrotic syndrome (consider before escalating immunosuppression) Atypical features: gross hematuria, low complement, elevated creatinine, hypertension. Family history of steroid-resistant nephrotic syndrome (consider genetic testing first)
Adult
Renal biopsy for ALL adults with nephrotic syndrome (standard of care) Rationale: diverse histologic differential; treatment varies significantly by histology. Pre-biopsy workup: serology panel (anti-PLA2R, ANA, anti-dsDNA, complement levels, hepatitis B/C, HIV, serum/urine protein electrophoresis, free light chains, HbA1c) Controversy: whether adults with clinical features strongly suggesting MCD (young adult, abrupt onset, no hematuria, normal complement, normal renal function) can be treated empirically -- some centers now consider this approach.
Laboratory Evaluation (All Ages)
Urinalysis: proteinuria (3-4+), lipiduria (oval fat bodies, Maltese crosses), may have microscopic hematuria (FSGS, MPGN) Urine protein quantification: spot protein/creatinine ratio or 24-hour urine collection. Serum albumin, total protein, lipid panel. BMP: creatinine, electrolytes. Complement levels: C3, C4 (low in MPGN, lupus nephritis, post-infectious GN) Renal ultrasound: kidney size, echogenicity. Anti-PLA2R antibodies: 70% sensitivity and near 100% specificity for primary membranous nephropathy; can potentially avoid biopsy in adults with classic presentation and high-titer anti-PLA2R.
Management
Initial Treatment of Pediatric MCD
Steroid Protocol (ISKDC Standard)
Prednisone/prednisolone 2 mg/kg/day (max 60 mg) for 4-6 weeks (daily dosing) Then 1.5 mg/kg alternate days (max 40 mg) for 4-6 weeks, then taper over 2-4 months. Total initial course: 12-16 weeks (extended initial course reduces relapse rate) Response: >90% of MCD achieves complete remission within 4 weeks (steroid-sensitive nephrotic syndrome, SSNS)
Definitions of Steroid Response
Complete remission: protein/creatinine ratio <0.2 or dipstick negative/trace for 3 consecutive days. Steroid-sensitive (SSNS): remission within 4 weeks of adequate steroid therapy. Steroid-resistant (SRNS): no remission after 8 weeks of daily prednisone at 2 mg/kg -- requires biopsy and likely represents FSGS. Frequently relapsing (FRNS): >=2 relapses within 6 months or >=4 within any 12-month period. Steroid-dependent (SDNS): relapse during taper or within 14 days of stopping steroids.
Steroid-Sparing Agents for FRNS/SDNS (Pediatric)
Levamisole: antihelminthic with immunomodulatory properties; well-tolerated; first-line steroid-sparing agent in some centers. Mycophenolate mofetil (MMF): increasingly used as first-line steroid-sparing; monitor CBC. Calcineurin inhibitors (CNIs): cyclosporine or tacrolimus; effective but relapse rate high on discontinuation; nephrotoxicity risk. Cyclophosphamide: 2-3 mg/kg/day for 8-12 weeks; can induce sustained remission; cumulative dose toxicity (gonadal toxicity, malignancy risk); limit to 1-2 courses. Rituximab: anti-CD20; emerging evidence as highly effective steroid-sparing agent; RITURNS study and others.
Treatment of Adult Nephrotic Syndrome
MCD in Adults
Prednisone 1 mg/kg/day (max 80 mg) for 4-16 weeks until remission, then taper. Response is slower than in children (median 4-8 weeks vs. 2 weeks in children) Steroid-sparing: CNIs, MMF, rituximab, cyclophosphamide.
Membranous Nephropathy
Observation period: up to 6-12 months for patients with preserved renal function and sub-nephrotic proteinuria; supportive care with ACEi/ARB, statin, anticoagulation if albumin <2.5. Anti-PLA2R titer monitoring: declining titers predict immunologic remission; persistently high titers predict progression. Immunosuppression (KDIGO 2021): Rituximab: increasingly first-line (MENTOR trial: rituximab non-inferior to cyclosporine with more durable remission) Cyclophosphamide + corticosteroids (Ponticelli regimen): alternating monthly cycles; effective but more toxic. CNIs (cyclosporine, tacrolimus): alternative; high relapse rate on discontinuation. Thromboprophylaxis: prophylactic anticoagulation recommended if albumin <2.5 g/dL (highest VTE risk of all nephrotic etiologies)
FSGS
Primary FSGS: corticosteroids first-line (prolonged course, up to 16 weeks); CNIs if steroid-resistant or relapsing. Secondary FSGS (obesity, reflux, single kidney, HIV, drugs): treat underlying cause; ACEi/ARB for proteinuria reduction; immunosuppression generally NOT effective. Genetic FSGS: typically steroid-resistant; genetic testing guides management; immunosuppression usually ineffective.
Supportive Care (All Ages)
ACEi/ARBs: reduce proteinuria by 30-50%; renoprotective; standard in all proteinuric patients (caution in acute nephrotic syndrome with hypovolemia) Edema management: sodium restriction (<2 g/day), loop diuretics (furosemide, often with albumin co-infusion in severe hypoalbuminemia); avoid excessive diuresis in children (intravascular depletion risk) Statin therapy: for persistent hyperlipidemia. Anticoagulation: prophylactic for membranous nephropathy with albumin <2.5; consider for other etiologies with severe hypoalbuminemia or additional risk factors. Pneumococcal vaccination: loss of immunoglobulins increases encapsulated organism risk. Penicillin prophylaxis: some pediatric centers use during active nephrotic syndrome in children.
<image>A side-by-side comparison of the diagnostic approach to nephrotic syndrome in children versus adults. The pediatric panel shows the empiric steroid trial pathway: age 1-10 with typical features (no hematuria, normal complement, normal creatinine) proceeds directly to prednisone without biopsy, with biopsy reserved for steroid resistance, atypical features, or age outside the typical range. The adult panel shows the biopsy-first pathway for all patients, with a pre-biopsy serologic workup checklist (anti-PLA2R, ANA, complement, hepatitis serologies, SPEP/UPEP, free light chains). The two approaches converge at treatment selection based on histologic diagnosis.</image>
<image>A pie chart comparison of nephrotic syndrome etiologies by age group. The pediatric pie (ages 1-10) shows MCD as 80-90% with small segments for FSGS, membranous, and other. The adolescent pie shows MCD 50%, FSGS 30%, and other 20%. The adult pie shows membranous nephropathy, FSGS, MCD, diabetic nephropathy, amyloidosis, and other in roughly equal segments. Below, a bar graph shows steroid response rates by histology: MCD greater than 90%, FSGS 20-30%, membranous nephropathy less than 30% with steroids alone.</image>
<image>A treatment algorithm for frequently relapsing and steroid-dependent nephrotic syndrome in children. Starting from the third relapse or steroid dependence, the flowchart shows escalating steroid-sparing options: levamisole or mycophenolate mofetil as first-line, calcineurin inhibitors as second-line, cyclophosphamide for selected cases, and rituximab for refractory disease. Each option shows expected relapse-free duration, key monitoring parameters, and major side effects. A parallel track shows genetic testing consideration for steroid-resistant cases (NPHS2, WT1, NPHS1 mutations).</image>
Clinical Pearls
In children aged 1-10 with typical nephrotic syndrome, empiric steroid treatment WITHOUT biopsy is the standard of care -- biopsy is reserved for steroid resistance or atypical features. Over 90% of childhood nephrotic syndrome is steroid-sensitive MCD -- response to steroids is itself a diagnostic and prognostic tool. ALL adults with nephrotic syndrome should undergo renal biopsy (with the possible exception of classic MCD presentation in young adults) Anti-PLA2R antibodies are nearly pathognomonic for primary membranous nephropathy and can be used to monitor treatment response. Membranous nephropathy carries the highest thromboembolism risk of all nephrotic etiologies -- prophylactic anticoagulation is recommended when albumin <2.5 g/dL. Rituximab is revolutionizing the management of both frequently relapsing pediatric MCD and adult membranous nephropathy. In children with nephrotic syndrome, periorbital edema is the classic early finding (often mistaken for allergic reaction) SBP (spontaneous bacterial peritonitis) in a child with ascites and nephrotic syndrome should be treated empirically with ceftriaxone pending cultures. FSGS in Black patients is often associated with APOL1 gene risk variants -- genetic testing may guide prognosis and management.
References
- Trautmann A, Vivarelli M, Samuel S, et al. IPNA clinical practice recommendations for the diagnosis and management of children with steroid-resistant nephrotic syndrome. Pediatr Nephrol. 2020;35(8):1529-1561.
- KDIGO 2021 Clinical Practice Guideline for the Management of Glomerular Diseases. Kidney Int. 2021;100(4S):S1-S276.
- Fervenza FC, Appel GB, Barbour SJ, et al. Rituximab or cyclosporine in the treatment of membranous nephropathy (MENTOR trial). N Engl J Med. 2019;381(1):36-46.
- Lombel RM, Gipson DS, Hodson EM, et al. Treatment of steroid-sensitive nephrotic syndrome: new guidelines from KDIGO. Pediatr Nephrol. 2013;28(3):415-426.
- Noone DG, Iijima K, Parekh R. Idiopathic nephrotic syndrome in children. Lancet. 2018;392(10141):61-74.
