Note: The book "Ramdasnaik" (Ramdas Naik's Pathology) is not available in this textbook library. The content below is drawn from Comprehensive Clinical Nephrology, 7th Edition and Brenner and Rector's The Kidney — the standard nephrology references — and reflects the same pathogenesis content taught in Indian medical curricula textbooks on this topic.

Pathogenesis of Nephrotic Syndrome

Core Defect: Glomerular Barrier Dysfunction

1. Fenestrated glomerular endothelium — negatively charged, repels anionic proteins
2. Glomerular basement membrane (GBM) — type IV collagen, laminin, heparan sulfate (negative charge)
3. Podocytes (visceral epithelial cells) — foot processes linked by the slit diaphragm (nephrin, podocin)

Consequences of Proteinuria

1. Hypoalbuminaemia

2. Oedema Formation — Two Theories

• Proteinuria → ↓ serum albumin → ↓ plasma oncotic pressure
• Fluid shifts from intravascular → interstitial compartment (Starling forces)
• ↓ Effective arterial blood volume (EABV) → activates:
  • Renin-Angiotensin-Aldosterone System (RAAS) → Na⁺ and water retention
  • Sympathetic Nervous System (SNS) → renal vasoconstriction
  • ADH → water retention
• This leads to renal Na⁺/water retention → worsens oedema
• More common in Minimal Change Disease (MCD) with severe hypoalbuminaemia (<2 g/dL), normal/low BP, preserved GFR

• Primary intrinsic renal Na⁺ retention occurs independently of oncotic pressure
• Mechanisms: ↓ GFR + interstitial inflammation + increased abundance/apical targeting of ENaC (epithelial sodium channels) in collecting tubules
• Filtered proteases (serine proteases) in tubular fluid proteolytically cleave ENaC, activating it → excess Na⁺ reabsorption
• Results in: ↑ plasma volume, hypertension, suppressed RAAS
• More common in inflammatory glomerulonephritides (membranous, FSGS, diabetic nephropathy)

In clinical practice, components of both mechanisms coexist, with the dominant mechanism varying by disease type and stage.

3. Hyperlipidaemia & Lipiduria

• ↓ Oncotic pressure → liver increases lipoprotein synthesis (VLDL, LDL)
• ↓ Lipoprotein lipase activity → impaired triglyceride clearance
• Lipiduria: oval fat bodies, fatty casts in urine

4. Hypercoagulable State

• Loss of anticoagulant proteins in urine: antithrombin III, protein C, protein S
• ↑ Hepatic synthesis of clotting factors (fibrinogen, factor V, VIII)
• ↑ Platelet aggregation
• → Risk of renal vein thrombosis, DVT, pulmonary embolism

5. Susceptibility to Infections

• Urinary loss of immunoglobulins (IgG) and complement factors (factor B, properdin)
• Impaired opsonisation → susceptibility to encapsulated organisms (e.g., Streptococcus pneumoniae)

Summary Flow

Glomerular injury (immune, toxic, genetic)
        ↓
Podocyte/slit diaphragm damage
        ↓
Massive proteinuria (>3.5 g/day)
        ↓
Hypoalbuminaemia
        ↓
↓ Plasma oncotic pressure
        ↓
    ┌────────────────┬────────────────┐
Underfill theory              Overfill theory
↓ EABV                     Primary ENaC activation
↑ RAAS, SNS, ADH           ↑ Na⁺ tubular reabsorption
Renal Na⁺/H₂O retention    ↑ Plasma volume
        └────────────────┴────────────────┘
                        ↓
                     Oedema
        +
Hyperlipidaemia, lipiduria, hypercoagulability, infections