Nephrotic Syndrome

Definition

1. Massive proteinuria - >3.5 g/day in adults (>40 mg/m²/hr in children)
2. Hypoalbuminemia - serum albumin <3 g/dL (typically <2.5 g/dL)
3. Generalized edema (anasarca)
4. Hyperlipidemia and lipiduria

• Robbins Pathologic Basis of Disease, p. 844
• Frameworks for Internal Medicine, p. 464

Pathophysiology

Proteinuria

Hypoalbuminemia

Edema - "Underfill" vs. "Overfill"

Hyperlipidemia and Lipiduria

• ↑ hepatic lipoprotein synthesis (compensatory response to low oncotic pressure)
• Abnormal transport of circulating lipid particles
• ↓ lipid catabolism
• Results in ↑ cholesterol, triglycerides, VLDL, LDL, Lp(a); ↓ HDL in some cases
• Lipoproteins also leak across the glomerular wall → lipiduria (free fat, oval fat bodies, fatty casts)

Complications

Causes

Primary (Idiopathic) Glomerular Diseases

Secondary Causes (~40% of adults)

• Diabetes mellitus (Kimmelstiel-Wilson nodular glomerulosclerosis)
• Amyloidosis (AL > AA)
• SLE (membranous pattern, Class V lupus nephritis)
• Drugs: NSAIDs, gold, penicillamine, heroin, captopril
• Infections: hepatitis B and C, HIV, malaria, syphilis, schistosomiasis
• Malignancy: carcinoma of lung/colon, melanoma, lymphoma (especially Hodgkin's with MCD)
• Preeclampsia (pregnancy-related)
• Endocarditis / shunt nephritis

Major Primary Glomerular Diseases in Detail

1. Minimal Change Disease (MCD)

• Demographics: #1 cause in children; also in adults (associated with NSAIDs, lymphoma/Hodgkin's)
• Pathogenesis: Systemic factor (likely T-cell derived) causing podocyte injury and effacement of foot processes; no immune complex deposition
• Light microscopy: Normal glomeruli
• Immunofluorescence: Negative
• Electron microscopy: Diffuse effacement (fusion) of podocyte foot processes - pathognomonic
• Clinical: Highly selective proteinuria; rapid onset; responds well to steroids
• Treatment: Corticosteroids - >80% remission rate; relapses are common; some become steroid-dependent or resistant

2. Focal Segmental Glomerulosclerosis (FSGS)

• Demographics: #1 in Black patients (APOL1 high-risk alleles); occurs at all ages
• Variants: Primary (idiopathic), secondary (reduced renal mass, obesity, HIV, COVID-19 - collapsing variant), genetic
• Pathogenesis: Podocyte injury and loss → denuded GBM → protein accumulation in mesangium → mesangial proliferation → progressive sclerosis. A vicious cycle of nephron loss drives further compensatory hyperfiltration and injury.
• Light microscopy: Segmental sclerosis (collapse, matrix deposition, hyalinosis, foamy macrophages) in a focal distribution - biopsy may miss involved glomeruli
• EM: Diffuse foot process effacement in primary FSGS; focal in secondary
• Clinical: Often poorly selective proteinuria; hypertension common; higher risk of progression to ESRD; highest thromboembolic risk among primary nephropathies
• Treatment: Steroids (less responsive than MCD); calcineurin inhibitors (tacrolimus/cyclosporine); RAS blockade for secondary FSGS; SGLT2 inhibitors for proteinuria reduction

3. Membranous Nephropathy (MN)

• Demographics: Most common primary nephrotic syndrome in older White adults; bimodal age distribution
• Pathogenesis: Immune complex-mediated - antibodies against podocyte surface antigens form subepithelial deposits:
  • Anti-PLA2R (M-type phospholipase A2 receptor) - ~60% of primary MN; clinically useful biomarker
  • Other antigens: THSD7A, NELL1, EXT1/2, NCAM1
  • IgG4 is the predominant subclass (poor classical complement activator)
  • Complement activation (C5b-9 membrane attack complex) causes podocyte injury
• Light microscopy: Diffuse thickening of capillary walls; "spike and dome" pattern on silver stain
• EM: Subepithelial electron-dense deposits
• IF: Granular IgG and C3 along capillary walls
• Clinical: Insidious onset; "rule of thirds" - one-third remit spontaneously, one-third stable/partial remission, one-third progress to ESRD
• Treatment: ACE inhibitor/ARB (first-line); immunosuppression for high-risk disease (cyclophosphamide + steroids [Ponticelli protocol]; rituximab increasingly preferred)

Diagnosis and Workup

1. Urine: Spot protein:creatinine ratio (correlates with 24-hr collection), urinalysis (oval fat bodies, fatty casts, lipid droplets), urine electrophoresis
2. Blood: Serum albumin, lipid panel, creatinine, CBC, complement (C3/C4 for secondary causes)
3. Serology for secondary causes: ANA, anti-dsDNA (SLE), HBsAg/HCV Ab, HIV, serum PLA2R antibodies (MN), SPEP (amyloid/myeloma), blood glucose/HbA1c
4. Renal biopsy: Indicated in adults (to determine cause and guide treatment); generally NOT required in children with classic presentation (presumed MCD, try steroids first)

Management

General Measures

• Edema: Loop diuretics (furosemide); note that hypoalbuminemia reduces furosemide binding to plasma proteins, enlarging its volume of distribution and sometimes causing resistance. In the underfill group, aggressive diuresis risks azotemia - use cautiously.
• Proteinuria reduction: ACE inhibitors or ARBs - reduce proteinuria, slow disease progression, and address coagulopathy and dyslipidemia. Adding a loop diuretic to ACE-I/ARB further reduces proteinuria.
• Hyperlipidemia: Statins
• Thromboembolism prophylaxis: Anticoagulation considered when serum albumin <2 g/dL, particularly in membranous nephropathy or when albumin is very low
• Infection prevention: Pneumococcal vaccination; prophylactic penicillin in children

Disease-Specific Therapy

Recent Evidence (2025-2026)