Nephrotic Syndrome

Definition

• Comprehensive Clinical Nephrology, 7th Ed., p. 240

Classification

Primary Causes (by histology)

Secondary Causes

• Frameworks for Internal Medicine, p. 465

Pathophysiology

1. Edema - Two mechanisms

• Urinary albumin loss → hypoalbuminemia → decreased plasma oncotic pressure → fluid shifts into interstitium → reduced effective circulating volume → RAAS activation → aldosterone-driven sodium retention

• Primary defect in distal nephron sodium excretion, possibly from proteolytic activation of the epithelial sodium channel (ENaC) by proteinuric enzymes entering the tubular lumen → sodium retention → expanded blood volume → transudation despite low oncotic pressure
• Kidney is also relatively resistant to atrial natriuretic peptide (ANP) in this state

2. Hypoalbuminemia

• Massive urinary albumin loss exceeds hepatic compensatory synthesis
• Up to 10-20% of lean body mass can be lost (masked by edema)
• Hepatic protein synthesis increases non-discriminately - large molecules (fibrinogen, lipoproteins) rise, while small molecules are lost in urine

3. Hypercoagulability

• Raised: Fibrinogen, factors V, VII, von Willebrand factor, protein C, alpha-1-macroglobulin
• Reduced (urinary loss): Antithrombin III, proteins C and S (paradox: despite protein C being raised in synthesis, functional anticoagulants net decrease)
• Platelet aggregability increases
• Compounded by immobility, hemoconcentration, dehydration
• Most common sites: renal veins (10-50% on systematic imaging), lower extremity veins, pulmonary emboli
• Arterial thrombosis (coronary, cerebrovascular) can occur in adults

4. Hyperlipidemia

• Hypoalbuminemia stimulates hepatic synthesis of LDL, VLDL, and lipoprotein(a)
• Defective peripheral lipoprotein lipase reduces VLDL clearance
• Urinary loss of HDL
• PCSK9 overexpression in kidney and liver (emerging therapeutic target)
• Nephrotic patients have ~5-fold increased risk for coronary death, except MCD (transient nephrotic state)
• Cholesterol may exceed 500 mg/dL; xanthelasmas can develop rapidly

5. Susceptibility to Infection

• Loss of IgG in urine → hypogammaglobulinemia
• Reduced complement activity
• Diminished T-cell function
• Common: cellulitis, spontaneous bacterial peritonitis (encapsulated organisms: Streptococcus pneumoniae, E. coli)

6. Other Metabolic Effects

• Hypothyroidism: loss of thyroid-binding globulin and T3/T4 in urine
• Hypocalcemia: loss of vitamin D-binding protein → 25-OH vitamin D deficiency → secondary hyperparathyroidism
• Drug binding alterations: Hypoalbuminemia reduces furosemide protein binding, enlarging volume of distribution; albumin-premixed furosemide administration is not confirmed to enhance diuresis
• Negative nitrogen balance: wasting illness

Diagnosis

Workup

1. Urine: Dipstick (proteinuria 3+ to 4+), urine protein:creatinine ratio, urine microscopy (oval fat bodies, fatty casts, Maltese cross under polarized light)
2. Blood: Serum albumin, LFTs, lipid panel, renal function (BMP), complement levels (C3, C4), ANA, anti-dsDNA, ANCA, anti-PLA2R, hepatitis B/C serology, HIV, serum protein electrophoresis
3. 24-hour urine or spot urine protein:creatinine for quantification
4. Renal biopsy: Indicated in adults (necessary to determine etiology); in children with typical presentation, empiric steroid therapy is started first - biopsy reserved for atypical features (age <1 year, macroscopic hematuria, hypertension, hypocomplementemia, steroid resistance)

Management

General / Supportive Measures

Disease-Specific Treatment

Steroid Response Categories (Pediatric)

• Steroid-sensitive NS (SSNS): Remission within 8 weeks
• Frequently-relapsing NS (FRNS): ≥2 relapses within 6 months, or ≥4 relapses in any 12 months
• Steroid-dependent NS (SDNS): Relapses during or immediately after steroid taper
• Steroid-resistant NS (SRNS): No remission after 8 weeks of adequate steroids - requires biopsy, genetic testing (NPHS1, NPHS2, WT1, TRPC6, etc.)

Complications Summary

Recent Evidence (2024-2026)