The nephrotic syndrome

1. Definition

• Set of clinical signs from ↑ glomerular capillary permeability.
• Children: usually primary kidney lesion.
• Adults: often renal manifestation of systemic disease.

2. Characteristic Features (the pentad)

• Massive proteinuria (> 3.5 g/day)
• Hypoalbuminemia (< 3.0 g/dL)
• Generalized edema (anasarca)
• Hyperlipoproteinemia / hypercholesterolemia
• Lipuria (oval fat bodies, “Maltese cross” under polarized light)

3. Chain of Events

• Capillary wall derangement → ↑ permeability → proteinuria.
• Severe protein loss → hypoalbuminemia → ↓ colloid osmotic pressure → edema.
• Fluid leak → ↓ plasma volume → ↑ aldosterone + ↓ GFR → salt/water retention → anasarca (vicious cycle).
• Hypoalbuminemia → compensatory hepatic ↑ lipoprotein synthesis → hyperlipidemia + lipuria.
• Also: ↓ antithrombin III, ↓ IgG → hypercoagulable + infection risk.

4. Minimal Change Disease (Lipoid Nephrosis)

Key facts

• #1 cause of nephrotic syndrome in CHILDREN (2–6 yr).
• Name “lipoid nephrosis” — PCT cells loaded with lipoproteins reabsorbed from filtrate.

Morphology

• Normal by light microscopy and IF.
• EM: diffuse effacement of podocyte foot processes + podocyte detachment.

Pathogenesis

• Often follows respiratory infection / immunization.
• T-lymphocyte cytokines damage foot processes → detachment + loss of anionic charge barrier → selective albuminuria.

Clinical course

• Highly selective proteinuria — albumin only.
• 90 % respond to corticosteroids.
• ~5 % progress to chronic renal failure within 25 yr.

5. Focal Segmental Glomerulosclerosis (FSGS)

Definition

• Sclerosis in some glomeruli (focal) and part of each affected glomerulus (segmental); juxtamedullary glomeruli first.

Settings

• Primary (idiopathic)
• Secondary to other GN
• Inherited/congenital podocyte defects (e.g., nephrin, podocin mutations)
• HIV nephropathy, heroin abuse
• Adaptive (obesity, reflux, reduced nephron mass)

Distinguish from minimal change

• Higher rate of hematuria + HTN in FSGS.
• Non-selective proteinuria in FSGS.
• Poor response to steroids.

Pathogenesis

• Initial event: podocyte injury → ↑ permeability → plasma protein leak → hyaline deposits → sclerosis.

Morphology

• Focal + segmental distribution.
• Affected glomeruli: ↑ mesangial matrix, obliterated capillary lumens, hyaline masses.
• Late: diffuse sclerosis + tubular atrophy + interstitial fibrosis.
• EM: podocyte foot process effacement / detachment.
• IF: IgM + C3 in hyaline masses (mesangial).

Clinical course

• Hematuria + HTN.
• 50 % → chronic renal failure within 10 yr.
• Poor response to steroids.

6. Membranous Nephropathy (Membranous GN)

Definition

• Diffuse thickening of GBM from immune complex precipitation.
• Slowly progressive; most common in 30–50 yr.
• #1 cause of primary nephrotic syndrome in non-diabetic adults.
• Experimental model = Heymann nephritis (anti-podocyte Abs; human equivalent anti-PLA2R).

Causes

• 85 % idiopathic (anti-PLA2R Abs).
• Secondary:
  • Infections — HBV, malaria, syphilis
  • Malignancy — lung, colon, melanoma (paraneoplastic)
  • Autoimmune — SLE
  • Drugs — NSAIDs, penicillamine, gold

Pathogenesis

• Chronic immune complex nephritis.
• IC deposition → complement → MAC (C5b-9) → activation of mesangial cells + podocytes → proteases/oxidants → leaky capillary walls.

Morphology — stages of GBM thickening

1. Spike-and-dome: subepithelial IC deposits flanked by spike-like GBM protrusions.
2. Incorporated deposits: podocytes lay down new BM → ICs incorporated.
3. Dissolved deposits: macrophages clear ICs → thick GBM with holes; sclerosis + hyalinization.

• IF: granular IgG + C3 along GBM.

Clinical course

• Non-selective proteinuria → nephrotic.
• 10–30 % complete remission; 40 % → chronic GN over 2–20 yr.
• Does not respond to corticosteroids.

7. Membranoproliferative GN (MPGN)

Definition

• GBM thickening with double contour / “tram-track” appearance from GBM splitting + mesangial cell interposition.
• Hypercellular glomeruli with mesangial + endothelial proliferation + leukocyte infiltration.

Type I MPGN

• Subendothelial electron-dense deposits.
• Due to circulating immune complexes → granular deposits.
• Causes: HBV, HCV, SLE, other chronic infections, cryoglobulinemia.

Type II MPGN (Dense Deposit Disease)

• Lamina densa of GBM becomes ribbon-like → “tram-track” double contour.
• Pathogenesis: C3 nephritic factor (autoantibody, often IgG) stabilizes C3 convertase → persistent alternative complement activation → ↓ serum C3.
• IF: prominent C3 deposits (little Ig).

Clinical course

• 50 % present with nephrotic syndrome.
• 40 % progress to chronic GN / end-stage kidney.
• 30 % variable renal failure.
• Poor prognosis overall.

8. Quick Comparison — Nephrotic Causes

Disease	Population	EM / Morphology	IF	Steroids
Minimal change	Children 2–6 yr	Foot process effacement only	Negative	Excellent
FSGS	HIV, heroin, obesity, AA adults	Focal segmental sclerosis	IgM + C3 (hyaline)	Poor
Membranous	Adults; HBV, SLE, malignancy	Spike-and-dome subepithelial	Granular IgG + C3	Poor
MPGN type I	HBV, HCV, SLE	Tram-track; subendothelial	Granular IgG + C3	Variable
MPGN type II (DDD)	Children/young	Lamina densa dense deposits	C3 only (C3 nephritic factor)	Poor

💡 High-yield: Nephrotic = >3.5 g proteinuria + hypoalbuminemia + edema + hyperlipidemia + lipuria; plus hypercoag + infection risk. Minimal change = kids, foot process effacement, selective albuminuria, steroid-responsive. FSGS = HIV/heroin, juxtamedullary segmental sclerosis, steroid-resistant. Membranous = adults, spike-and-dome, anti-PLA2R (or HBV/SLE/malignancy/NSAIDs). MPGN type I = HCV/HBV, tram-track, subendothelial. MPGN type II (DDD) = C3 nephritic factor, dense intramembranous deposits.