13.1 Glomerular Disease Mechanisms

13.1 Glomerular Disease Mechanisms

Quick Answer: Nephritic urine shows RBC casts and mild proteinuria with hypertension/azotemia; nephrotic shows heavy protein loss (≥3.5 g/day), hypoalbuminemia, edema, and hyperlipidemia. Use light microscopy (hypercellularity, crescents, sclerosis), immunofluorescence (linear vs granular vs pauci), and electron microscopy (deposit location) to classify minimal change, FSGS, membranous, MPGN, diabetic nephropathy, amyloid, post-strep GN, IgA nephropathy, RPGN subtypes, Alport, and Goodpasture.

Glomerular disease on the CBSE is almost always a pattern-recognition triad: clinical syndrome → morphology (LM/IF/EM) → mechanism or systemic association. Build one decision tree for nephritic vs nephrotic, then hang each classic entity on deposit location and immunofluorescence.

Nephritic vs Nephrotic Laboratory Patterns

Exam framing: Hematuria + RBC casts → think glomerular inflammation (nephritic/RPGN). Massive proteinuria without active sediment → podocyte or GBM charge/structure disease (nephrotic). Mixed pictures (e.g., MPGN, some diabetic or lupus nephritis) are allowed—classify by the dominant lab pattern and biopsy findings.

Structural Concepts: Hypercellularity, Crescents, Sclerosis

Hypercellularity on light microscopy means too many cells in the glomerular tuft—proliferation of mesangial cells, endothelial cells, and/or influx of leukocytes (exudative GN). Acute post-streptococcal GN classically shows diffuse hypercellular, inflamed glomeruli.

Crescents are proliferations of parietal epithelial cells and macrophages in Bowman space, often with fibrin. They signal severe glomerular injury with rupture of the capillary wall and leakage of plasma proteins/fibrin into Bowman space. Extensive crescents define rapidly progressive GN (RPGN) clinically (days–weeks of rising creatinine) and pathologically (crescentic GN). Crescents are a final common pathway, not a single etiology—always ask which of the three IF patterns produced them.

Sclerosis is irreversible scarring of the glomerular tuft (global or segmental). Focal means only some glomeruli; segmental means only part of a glomerular tuft. FSGS = focal segmental glomerulosclerosis. Global sclerosis of many glomeruli indicates chronic scarring and reduced renal reserve.

Nephrotic-Range Glomerular Diseases

Minimal Change Disease (MCD)

• Who: Most common nephrotic syndrome in children; also adults after NSAIDs or Hodgkin lymphoma association in some cases.
• LM: Essentially normal glomeruli.
• IF: Negative (no immune deposits).
• EM: Diffuse foot-process effacement only.
• Clinical: Often sudden edema; selective albuminuria; highly steroid-responsive in kids; excellent prognosis if treated.
• Mechanism pearl: Cytokine-mediated podocyte injury (T-cell related hypothesis); loss of charge selectivity of GBM → albumin leaks.

Focal Segmental Glomerulosclerosis (FSGS)

• LM: Segmental sclerosis and hyalinosis in some glomeruli; may see podocyte hyperplasia in collapsing variant.
• IF: Usually negative or nonspecific IgM/C3 trapping in sclerotic areas (not true immune-complex disease).
• EM: Foot-process effacement (diffuse in primary FSGS).
• Associations (secondary): HIV (collapsing FSGS), heroin, obesity, reduced renal mass/hyperfiltration, APOL1 risk alleles in African ancestry, interferon therapy.
• Clinical: Nephrotic or sub-nephrotic proteinuria; worse prognosis than MCD; less steroid-responsive; may recur in transplant (primary FSGS).

Membranous Nephropathy

• LM: Diffuse capillary wall thickening without much hypercellularity; silver stain → spike-and-dome appearance as GBM spikes between subepithelial deposits.
• IF: Granular IgG and C3 along capillary walls.
• EM: Subepithelial electron-dense deposits with intervening GBM spikes.
• Primary: Autoantibodies to PLA2R (phospholipase A2 receptor) on podocytes (most common adult primary membranous).
• Secondary associations: Solid tumors (carcinoma), HBV/HCV, SLE (class V), drugs (penicillamine, gold, NSAIDs), syphilis.
• Clinical: Adult nephrotic syndrome; hypercoagulability especially renal vein thrombosis classic vignette.

Membranoproliferative GN (MPGN)

• LM: Mesangial hypercellularity and matrix expansion with tram-track double contours of GBM (new basement membrane around deposits/mesangial interposition).
• IF/EM: Pattern depends on type—classic immune-complex MPGN shows subendothelial ± mesangial deposits and granular IF; dense-deposit disease (C3 glomerulopathy related) shows intramembranous dense ribbons and C3-dominant staining.
• Associations: Chronic infections (HCV with cryoglobulins classic), SLE, complement dysregulation (C3 glomerulopathy).
• Clinical: Can present nephritic, nephrotic, or mixed; often hypocomplementemia.

Diabetic Nephropathy

• Most common cause of nephrotic-range proteinuria and ESRD in many adult populations.
• LM progression: Diffuse mesangial sclerosis → nodular glomerulosclerosis (Kimmelstiel–Wilson nodules); arteriolar hyalinosis (afferent and efferent); thickened GBM.
• IF: Linear trapping of IgG along GBM can occur (nonspecific, not anti-GBM disease)—do not confuse with Goodpasture linear IgG of immune attack.
• Clinical path: Microalbuminuria → overt proteinuria → declining GFR; accelerated by hypertension; ACEI/ARB renoprotective framing on exams.

Amyloidosis of the Kidney

• LM: Amorphous eosinophilic material in mesangium and vessel walls; Congo red → apple-green birefringence under polarized light.
• EM: Randomly oriented 9–11 nm fibrils.
• Types: AL (light chain, plasma cell dyscrasia); AA (chronic inflammation).
• Clinical: Nephrotic syndrome; enlarged kidneys sometimes; systemic clues (macroglossia, heart, neuropathy for AL).

Nephritic and Rapidly Progressive Patterns

Acute Post-Streptococcal GN (PSGN)

• Follows group A strep pharyngitis (~1–3 weeks) or skin infection (~3–6 weeks)—latent period distinguishes from IgA’s synpharyngitic timing.
• Clinical: Child with cola-colored urine, periorbital edema, hypertension, oliguria after strep; low C3; ↑ ASO and/or anti-DNase B.
• LM: Diffuse proliferative/exudative GN (neutrophils).
• IF: Granular IgG and C3 (starry sky).
• EM: Classic subepithelial humps.
• Usually self-limited in children; adult outcomes more variable.

IgA Nephropathy (Berger Disease)

• Most common primary GN worldwide in many series.
• Clinical: Episodic gross hematuria concurrent with or within days of URI (synpharyngitic)—contrast with delayed PSGN.
• LM: Mesangial proliferation and matrix expansion (variable severity).
• IF: Dominant mesangial IgA (± C3).
• EM: Mesangial deposits.
• Systemic cousin: Henoch–Schönlein purpura (IgA vasculitis) has same renal IF with purpura, arthritis, abdominal pain—often kids.

Rapidly Progressive (Crescentic) GN — Three Types by IF

RPGN clinical: Rapid rise in creatinine, oliguria, active sediment, often systemic symptoms in vasculitis; emergency biopsy and immunosuppression framing.

Goodpasture Syndrome (Anti-GBM Disease with Pulmonary Involvement)

• Autoantibodies against noncollagenous domain of type IV collagen (α3 chain) in GBM and alveolar basement membrane.
• Kidney: RPGN type I, linear IF.
• Lung: Pulmonary hemorrhage (hemoptysis, infiltrates)—younger male smoker classic vignette; isolated anti-GBM nephritis can occur without lung disease.
• Distinguish from granulomatosis with polyangiitis (GPA), which is pauci-immune ANCA+ with upper/lower respiratory and kidney disease but not linear IF.

Alport Syndrome

• Genetic defect in type IV collagen (most often X-linked COL4A5; also autosomal COL4A3/A4).
• Clinical: Persistent microscopic hematuria from childhood → progressive renal failure; sensorineural hearing loss; ocular lesions (anterior lenticonus, dot-and-fleck retinopathy).
• EM: Irregular GBM thickening and thinning with lamellation/splitting (“basket-weave”).
• Contrast: Thin basement membrane nephropathy (benign familial hematuria) has uniformly thin GBM without systemic features—better prognosis.
• Heterozygous carriers may have isolated hematuria; transplant anti-GBM can rarely develop if immune system sees normal collagen as foreign.

Immunofluorescence Patterns — Exam Anchor

1. Linear GBM staining → anti-GBM / Goodpasture (type I RPGN).
2. Granular (“lumpy-bumpy”) capillary or mesangial staining → immune-complex disease (PSGN, membranous, lupus, IgA mesangial, many MPGN).
3. Pauci-immune → ANCA vasculitis RPGN (type III); diagnosis relies on serology and clinical vasculitis, not deposits.

Deposit location memory aids (EM):

• Subepithelial humps → PSGN.
• Subepithelial with spikes → membranous.
• Subendothelial → lupus class IV, MPGN immune-complex patterns.
• Mesangial → IgA, some lupus.
• No deposits + foot-process only → MCD (and primary FSGS pattern of injury).

Integrated Clinical Reasoning for CBSE Vignettes

When the stem gives a child after strep with low C3 and humps → PSGN. Teen with hematuria during a cold → IgA. Adult with cancer or HBV and spikes → membranous. Child with sudden nephrotic syndrome and normal LM → MCD. African-American patient with HIV and collapsing sclerosis → FSGS. Smoker with hemoptysis and linear IF → Goodpasture. Sinusitis, lung nodules, RPGN, c-ANCA → GPA (pauci-immune). Long diabetes with KW nodules → diabetic nephropathy. Congo red apple-green → amyloid. Boy with hematuria, deafness, split GBM → Alport.

Always close the loop: syndrome → IF pattern → deposit site → named disease → association. That four-step map is how CBSE/Step-style renal pathology items are written and how you should answer them under time pressure.

Complement Clues

Low C3 (sometimes low C4) points toward complement-consuming immune-complex or alternative-pathway disease: PSGN, MPGN/C3 glomerulopathy, SLE nephritis, dense-deposit disease. Normal complement is typical of IgA, anti-GBM, ANCA, MCD, FSGS, and most membranous (primary). Use complement as a laboratory tie-breaker when morphology is not yet given.

Overlap and Secondary Forms

Lupus can produce almost any pattern (ISN/RPS classes I–VI); class IV diffuse proliferative is a nephritic/RPGN picture with full-house IF (IgG, IgA, IgM, C3, C1q). HCV-related cryoglobulinemic GN often looks MPGN-like with hypocomplementemia and purpura. Remember that malignant hypertension and TMA injure glomeruli secondarily (thrombi, onion-skin arteries)—covered with vascular disease in 13.2—but can produce active sediment and rising creatinine that mimic primary GN until biopsy or systemic clues clarify.