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MUHS 2nd MBBS Pathology - Renal Pathology Complete Notes

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TOPIC 1: RENAL CELL CARCINOMA

Definition

Epidemiology

• Peak incidence: 6th-7th decade
• Men:Women = 2:1
• Risk factors: Smoking, hypertension, obesity, cadmium exposure, acquired polycystic disease (30x risk)

Classification of RCC

Pathogenesis - Clear Cell Carcinoma (MOST IMPORTANT)

• Loss/inactivation of VHL gene on chromosome 3p25 is the molecular hallmark
• VHL protein normally degrades HIF (Hypoxia Inducible Factor)
• Without VHL → HIF stabilizes → ↑VEGF (promotes angiogenesis) → highly vascular tumor
• Sporadic tumors: monoallelic deletion of 3p + mutation of second allele
• Familial: VHL disease (autosomal dominant) - bilateral/multiple CCCs in 40-60%

Pathogenesis - Papillary RCC

• MET gene (tyrosine kinase receptor) on chr 7q - activating mutations or increased copy number
• Frequently multifocal and bilateral

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GROSS MORPHOLOGY

┌─────────────────────────────────────────────────────┐
│           CLEAR CELL CARCINOMA - GROSS               │
│                                                      │
│  • Large, solitary, spherical mass (3-15 cm)         │
│  • Located in CORTEX                                 │
│  • Cut surface: YELLOW TO ORANGE (lipid-rich)        │
│  • Areas of necrosis, hemorrhage, cystic softening  │
│  • Often pseudocapsulated (well-circumscribed)       │
│  • May grow into renal vein / inferior vena cava    │
│    (tumor thrombus - CLASSICAL FEATURE)              │
└─────────────────────────────────────────────────────┘

• Papillary RCC: Frequently multifocal, bilateral; often early-stage tumors
• Chromophobe RCC: Pale lightly eosinophilic cut surface

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MICROSCOPIC MORPHOLOGY

Clear Cell Carcinoma:

• Cells arranged in solid, tubular, or cystic patterns separated by a delicate vascular network
• Tumor cells have clear cytoplasm (dissolved lipid and glycogen in routine sections)
• Nuclei variable from small/bland to large/irregular

Papillary RCC:

• Papillary architecture with fibrovascular cores
• May be multifocal; psammoma bodies may be seen

Chromophobe RCC:

• Cells are pale (chromophobe) but NOT clear like clear cell type
• Large cells with prominent cell membranes ("plant cell" appearance)

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CLINICAL FEATURES

• Hematuria (most common symptom)
• Classic triad: hematuria + flank pain + palpable mass (10%)
• Paraneoplastic syndromes (IMPORTANT for exam):
  • Polycythemia (ectopic EPO)
  • Hypercalcemia (PTHrP)
  • Hypertension (renin)
  • Cushing syndrome (ACTH)
  • Feminization/masculinization (gonadotropins)
• Spread: hematogenous (lung "cannonball" mets), lymphatic; tumor thrombus in renal vein/IVC

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TOPIC 2: CLASSIFICATION OF GLOMERULAR DISEASES

A. Clinical Syndromes of Glomerular Disease

┌───────────────────────────────────────────────────────────────────────┐
│          GLOMERULAR SYNDROMES (MUHS Exam Important)                   │
├────────────────────┬──────────────────────────────────────────────────┤
│  NEPHRITIC         │ Hematuria (RBC casts), Proteinuria (subnephrotic)│
│  SYNDROME          │ Azotemia, Oliguria, Hypertension, Edema          │
├────────────────────┼──────────────────────────────────────────────────┤
│  NEPHROTIC         │ Massive proteinuria (>3.5g/day), Hypoalbuminemia │
│  SYNDROME          │ Generalized edema, Hyperlipidemia, Lipiduria     │
├────────────────────┼──────────────────────────────────────────────────┤
│  RAPIDLY           │ Acute renal failure + features of nephritic      │
│  PROGRESSIVE GN    │ syndrome; crescents on biopsy                    │
├────────────────────┼──────────────────────────────────────────────────┤
│  CHRONIC GN        │ Slowly progressive renal failure, proteinuria,   │
│                    │ hematuria, hypertension                          │
├────────────────────┼──────────────────────────────────────────────────┤
│  ASYMPTOMATIC      │ Incidental hematuria/proteinuria without         │
│  HEMATURIA/        │ systemic symptoms                               │
│  PROTEINURIA       │                                                  │
└────────────────────┴──────────────────────────────────────────────────┘

B. Classification by Primary Glomerular Diseases

Diseases Presenting as NEPHRITIC Syndrome:

1. Acute proliferative (post-streptococcal) GN
2. Rapidly progressive (crescentic) GN
3. IgA nephropathy (Berger disease)

Diseases Presenting as NEPHROTIC Syndrome:

1. Minimal Change Disease (MCD) - #1 in children
2. Focal Segmental Glomerulosclerosis (FSGS)
3. Membranous Glomerulopathy - #1 in adults
4. Membranoproliferative GN (MPGN)

Diseases Presenting as BOTH:

• Lupus nephritis
• MPGN

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TOPIC 2B: MEMBRANOUS GLOMERULOPATHY

Definition

Causes

Pathogenesis

• Main antigen: M-type phospholipase A2 receptor (PLA2R) on podocytes
• Anti-PLA2R antibodies (mainly IgG4 subclass) bind to PLA2R on basal surface of glomerular epithelial cells
• → Complement activation → Immune aggregates shed → Subepithelial immune complex deposits
• C5b-9 membrane attack complex injures podocytes → loss of foot processes → proteinuria
• No significant neutrophil/monocyte infiltration (paucicellular injury)

PATHOGENESIS DIAGRAM:
Anti-PLA2R Ab → binds podocyte PLA2R → immune complex formed
      ↓
Subepithelial deposits form (IgG4 + complement)
      ↓
C5b-9 MAC activates → podocyte injury
      ↓
Foot process effacement → Massive proteinuria (NEPHROTIC SYNDROME)
      ↓
GBM material deposited between deposits → "SPIKE" formation

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MORPHOLOGY OF MEMBRANOUS GLOMERULOPATHY

Light Microscopy:

• Early: Glomeruli appear normal or uniform, diffuse thickening of capillary wall
• Silver stain: Characteristic "spike and dome" pattern - spikes of GBM material project between subepithelial deposits
• Advanced: Spikes close over deposits → markedly thickened, irregular GBM
• May progress to segmental sclerosis → global sclerosis
• No cellular proliferation, no inflammatory infiltrate (paucicellular)

Electron Microscopy (MOST DIAGNOSTIC):

• Subepithelial electron-dense deposits between GBM and podocytes
• Effacement of podocyte foot processes
• GBM material laid down between deposits → spikes
• Progressive: spikes form dome-like protrusions → deposits buried inside thickened GBM

Immunofluorescence:

• Granular deposits of IgG and C3 along capillary walls (diffuse, global)
• IgG4 predominant in PLA2R-associated disease

STAGES OF MEMBRANOUS GN (Ehrenreich-Churg):
Stage I:  Subepithelial deposits only - LM near normal
Stage II: GBM spikes between deposits (Silver stain)
Stage III: Deposits enclosed within thickened GBM
Stage IV: Advanced scarring, glomerulosclerosis

Clinical Features:

• Most common cause of nephrotic syndrome in adults (ages 30-50, male predominance)
• Insidious onset of nephrotic syndrome
• "Rule of thirds": 1/3 spontaneous remission, 1/3 proteinuria without progression, 1/3 progressive renal failure
• Increased risk of renal vein thrombosis (due to loss of antithrombin III)

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TOPIC 3: CHRONIC PYELONEPHRITIS

Definition

Types / Pathogenesis

1. Obstructive Chronic Pyelonephritis: Recurrent infections due to obstruction (calculi, strictures, prostatic hypertrophy)
2. Reflux Nephropathy (most common): Vesicoureteral reflux (VUR) allows infected urine to reflux into renal pelvis → intrarenal reflux → polar scars

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GROSS MORPHOLOGY

┌────────────────────────────────────────────────────────────┐
│          CHRONIC PYELONEPHRITIS - GROSS FEATURES           │
│                                                            │
│  • Kidneys: IRREGULARLY SCARRED                            │
│  • Involvement: ASYMMETRIC (unlike chronic GN = symmetric) │
│  • Hallmark: COARSE, DISCRETE, CORTICOMEDULLARY SCARS      │
│    overlying DILATED, BLUNTED, DEFORMED CALYCES            │
│  • Flattening of papillae                                  │
│  • Scars predominantly in UPPER AND LOWER POLES            │
│    (sites of greatest VUR)                                 │
│  • Remaining parenchyma may show compensatory hypertrophy  │
└────────────────────────────────────────────────────────────┘

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MICROSCOPIC MORPHOLOGY

• Predominantly tubular and interstitial changes:
  1. Tubular atrophy in some areas
  2. Hypertrophy or dilation in others
  3. "Thyroidization" - Dilated tubules with flattened epithelium filled with proteinaceous casts resembling thyroid colloid (PATHOGNOMONIC feature)
  4. Interstitial fibrosis and chronic inflammatory infiltrate (lymphocytes, plasma cells)
  5. Fibrosis around calyceal epithelium
• Glomerular changes (secondary):
  • Periglomerular fibrosis
  • Fibrous obliteration
  • Ischemic changes (wrinkled GBM)
  • Secondary FSGS in late stages (causes proteinuria)

Special variant: Xanthogranulomatous Pyelonephritis

• Rare form of chronic pyelonephritis
• Characterized by foamy macrophages (xanthoma cells) + plasma cells + lymphocytes + PMNs + giant cells
• Associated with Proteus infections and obstruction
• Large yellowish-orange nodules - can mimic RCC grossly (important!)

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CLINICAL FEATURES

• Silent onset OR recurrent acute pyelonephritis (fever, back pain, pyuria, bacteriuria)
• Loss of tubular concentrating ability → polyuria, nocturia
• Hypertension common
• Radiologic: asymmetrically contracted kidneys, coarse scars, blunted/deformed calyces
• Late: secondary FSGS → significant proteinuria → poor prognosis sign
• Bacteriuria often absent in late stages

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TOPIC 4: RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)

Definition

• Rapidly progressive renal failure (days to weeks)
• Features of nephritic syndrome
• Severe oliguria
• Glomerular crescents in majority of glomeruli on biopsy → also called Crescentic GN

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CLASSIFICATION (3 Types - MOST IMPORTANT FOR EXAM)

╔══════════════╦════════════════════════╦═══════════════════════╗
║ TYPE         ║ MECHANISM              ║ IF PATTERN            ║
╠══════════════╬════════════════════════╬═══════════════════════╣
║ Type I       ║ Anti-GBM antibody      ║ LINEAR IgG + C3       ║
║ (Anti-GBM)   ║ Autoantibodies vs α3   ║ along GBM             ║
║ ~20%         ║ chain of collagen IV   ║                       ║
║              ║ ± Goodpasture syndrome ║                       ║
╠══════════════╬════════════════════════╬═══════════════════════╣
║ Type II      ║ Immune complex         ║ GRANULAR IgG + C3     ║
║ (Immune      ║ deposition (post-GN,   ║ (mesangium + GBM)     ║
║ complex)     ║ SLE, IgA nephropathy,  ║                       ║
║ ~25%         ║ HSP, MPGN)             ║                       ║
╠══════════════╬════════════════════════╬═══════════════════════╣
║ Type III     ║ ANCA-mediated          ║ PAUCI-IMMUNE          ║
║ (Pauci-      ║ (PR3-ANCA or MPO-ANCA) ║ (little/no Ig or C3)  ║
║ immune)      ║ Systemic vasculitis    ║                       ║
║ ~55%         ║ (GPA, MPA) or renal-   ║                       ║
║              ║ limited                ║                       ║
╚══════════════╩════════════════════════╩═══════════════════════╝

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PATHOGENESIS

Type I - Anti-GBM GN (Goodpasture Syndrome):

• Autoantibodies target α3 chain of type IV collagen in GBM
• Same antigen present in pulmonary alveolar basement membrane → lung hemorrhage
• Goodpasture syndrome = renal failure + pulmonary hemorrhage
• HLA-DRB1 predisposition; triggered by viruses, hydrocarbon solvents
• Treatment: Plasmapheresis (to remove circulating antibodies)

Type II - Immune Complex GN:

• Deposition of circulating antigen-antibody complexes in glomeruli
• May complicate: postinfectious GN, SLE, IgA nephropathy, Henoch-Schönlein purpura
• Cannot be treated with plasmapheresis

Type III - Pauci-Immune GN (ANCA-associated):

• >90% have circulating ANCAs - either:
  • PR3-ANCA (c-ANCA): Granulomatosis with Polyangiitis (Wegener's)
  • MPO-ANCA (p-ANCA): Microscopic Polyangiitis
• ANCAs activate neutrophils → degranulation → vascular/glomerular injury
• Majority of all RPGN cases

Crescent Formation (Common to All Types):

GBM rupture (by inflammatory injury)
      ↓
Plasma proteins (fibrin, coagulation factors) leak into Bowman's space
      ↓
Fibrin clot formation → thrombin activates → triggers crescent formation
      ↓
Proliferation of PARIETAL EPITHELIAL cells lining Bowman's capsule
      +
Migration of MONOCYTES/MACROPHAGES into urinary space
      ↓
CRESCENT formation - fills and compresses glomerular tuft
      ↓
Obliteration of capillary loops → ↓↓ GFR → Renal failure

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MORPHOLOGY OF RPGN

GROSS:

• Kidneys enlarged and pale
• Petechial hemorrhages on cortical surfaces

LIGHT MICROSCOPY:

• Cellular crescents in Bowman's space - hallmark
• Crescents consist of:
  • Proliferating parietal epithelial cells
  • Migrated monocytes and macrophages
  • ± Neutrophils, lymphocytes
• Fibrin strands prominent between cellular layers of crescents
• Focal and segmental glomerular fibrinoid necrosis
• Crescents may obliterate urinary space, compress glomerular tuft
• Breaks in GBM visible on electron microscopy
• Evolution: Cellular crescents → Fibrous crescents (organized/healed) → Segmental scars

IMMUNOFLUORESCENCE (varies by type):

• Type I: Linear IgG along GBM
• Type II: Granular Ig deposits in mesangium/GBM
• Type III: Negative/trace (pauci-immune)

Clinical Course:

• Severe oliguria, azotemia, hematuria with RBC casts
• Rapidly progresses to end-stage renal disease in weeks-months if untreated
• Poor prognosis; treatment: high-dose steroids + cyclophosphamide ± plasmapheresis (Type I)

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TOPIC 5: NEPHROTIC SYNDROME

Definition

TETRAD of Features

╔════════════════════════════════════════════════════════════╗
║              NEPHROTIC SYNDROME - 4 CARDINAL FEATURES     ║
╠═══════════════════════════════════╦════════════════════════╣
║ 1. MASSIVE PROTEINURIA            ║ >3.5 g/day in adults   ║
║    (Hallmark/defining feature)    ║ >40 mg/m²/hr in child  ║
╠═══════════════════════════════════╬════════════════════════╣
║ 2. HYPOALBUMINEMIA                ║ <3.5 g/dL              ║
╠═══════════════════════════════════╬════════════════════════╣
║ 3. GENERALIZED EDEMA (Anasarca)   ║ Periorbital (morning)  ║
║                                   ║ Pitting edema, ascites ║
╠═══════════════════════════════════╬════════════════════════╣
║ 4. HYPERLIPIDEMIA + LIPIDURIA     ║ Cholesterol >300 mg/dL ║
╚═══════════════════════════════════╩════════════════════════╝

Pathophysiology of Each Feature

PROTEIN LOSS IN URINE (>3.5 g/day)
  ↓
↓ Serum albumin (Hypoalbuminemia)
  ↓
↓ Plasma oncotic pressure
  ↓
Fluid shifts to interstitium → EDEMA + ↓ circulating volume
  ↓
Stimulates renin-angiotensin-aldosterone → Na+ and water retention
  → worsens edema

HYPERLIPIDEMIA:
↓ Plasma oncotic pressure → Liver compensates by ↑ lipoprotein synthesis
↓ Clearance of lipoproteins (loss of lipase activating factors in urine)
→ Hypercholesterolemia + Hypertriglyceridemia

LIPIDURIA:
Lipoproteins leak through damaged GBM → appear as:
• Free fat droplets
• "Maltese cross" oval fat bodies (lipid-laden epithelial cells/macrophages)
• Fatty casts in urine

Complications of Nephrotic Syndrome

Causes of Nephrotic Syndrome

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TOPIC 6: POST-STREPTOCOCCAL GLOMERULONEPHRITIS (PSGN) / ACUTE PROLIFERATIVE GN

Definition

Etiology

• Causative organism: Group A β-hemolytic Streptococcus (Streptococcus pyogenes)
• Nephritogenic strains: Types 1, 4, 12 (identified by M protein typing) - >90% of cases
• Preceding infection:
  • Pharyngitis (strep throat) - more common in temperate regions
  • Skin infection/Impetigo - associated with overcrowding, poor hygiene
• Latent period:
  • Pharyngitis → GN: 1-3 weeks (avg 10 days)
  • Impetigo → GN: 3-6 weeks
• Most common age: Children 6-10 years (but any age)
• Inciting antigen: Streptococcal Pyrogenic Exotoxin B (SpeB) - found in characteristic "hump" deposits

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PATHOGENESIS (Etiopathogenesis)

NEPHRITOGENIC STREPTOCOCCAL INFECTION (pharynx/skin)
         ↓ (latent period 1-4 weeks)
Production of ANTIBODIES vs streptococcal antigens
         ↓
IMMUNE COMPLEX FORMATION (Ag-Ab complexes)
         ↓
TWO MECHANISMS:
  ①  Antigens PLANTED in subendothelial location
     → In situ immune complex formation
     → Inflammatory response
  ②  Complexes MIGRATE across GBM
     → Reform as SUBEPITHELIAL deposits
     → Characteristic "HUMPS" (electron-dense subepithelial deposits)
         ↓
COMPLEMENT ACTIVATION (C3 consumed → LOW serum C3)
         ↓
CHEMOTACTIC FACTORS (C5a) → NEUTROPHIL + MONOCYTE INFILTRATION
         ↓
Proteases, free radicals → GBM damage → Hematuria
         ↓
Inflammatory mediators → ↓ GFR → Oliguria, Azotemia, Hypertension

1. Latent period matches antibody formation time
2. ↑ Anti-streptolysin O (ASO) titers in pharyngitis cases
3. ↑ Anti-DNAse B (anti-hyaluronidase) titers in impetigo cases
4. Low serum complement (C3) during active disease
5. Granular immune deposits in glomeruli (IF)

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MORPHOLOGY

GROSS MORPHOLOGY:

┌───────────────────────────────────────────────────────┐
│      POST-STREPTOCOCCAL GN - GROSS FEATURES           │
│                                                       │
│  • Kidneys: BILATERALLY ENLARGED AND SWOLLEN          │
│  • Color: PALE/GRAY appearance                        │
│  • Petechial hemorrhages on surface                   │
│    → "FLEA-BITTEN" kidney appearance                  │
│  • Smooth surface (diffuse process)                   │
└───────────────────────────────────────────────────────┘

LIGHT MICROSCOPY:

• Diffuse proliferative GN - all glomeruli affected
• Glomerular hypercellularity due to:
  1. Proliferation of mesangial and endothelial cells (intrinsic cells)
  2. Infiltration of neutrophils (most characteristic early on) and monocytes
• Glomeruli appear enlarged and hypercellular
• Capillary lumina occluded by swollen cells and infiltrating leukocytes
• May show subepithelial deposits as small bumps
• Tubules: contain RBC casts, protein casts
• In severe cases: crescent formation (indicates bad prognosis)

IMMUNOFLUORESCENCE:

• Granular ("starry sky") deposits of IgG and C3 in mesangium and along GBM
• Complement components predominate (C3 > IgG)

ELECTRON MICROSCOPY (MOST SPECIFIC):

• Subepithelial "humps" - discrete, electron-dense, dome-shaped deposits on epithelial side of GBM (PATHOGNOMONIC)
• Represent antigen-antibody-complement complexes
• Subendothelial and mesangial deposits also present
• Neutrophil in capillary lumen

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CLINICAL COURSE

Presentation:

• Develops 1-4 weeks after streptococcal pharyngitis (or 3-6 weeks post-impetigo)
• Acute Nephritic Syndrome: sudden onset of:
  • Hematuria (smoky/cola-colored urine - RBC casts)
  • Oliguria
  • Edema (periorbital and peripheral)
  • Hypertension
  • Azotemia (raised BUN, creatinine)
  • Mild-moderate proteinuria (occasionally nephrotic range)

Laboratory:

• ↑ ASO titer (pharyngitis)
• ↑ Anti-DNAse B, Anti-hyaluronidase (impetigo/skin infection)
• ↓ Serum C3 (low complement - complement consumption)
• Urinalysis: hematuria, proteinuria, RBC casts, granular casts

Prognosis:

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QUICK COMPARISON TABLE (EXAM-READY)

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IMPORTANT MNEMONICS

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RENAL PATHOLOGY - GROSS & HISTOPATHOLOGY DIAGRAMS

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1. RENAL CELL CARCINOMA

GROSS APPEARANCE

• Cortical location (derived from tubular epithelium)
• Yellow to orange cut surface (due to lipid in clear cells)
• Areas of hemorrhage, necrosis, cystic change
• Well-defined pseudocapsule
• Tumor thrombus in renal vein/IVC (classic)

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HISTOPATHOLOGY - All 3 Types

• (A) Clear Cell - Cells with vacuolated clear cytoplasm (lipid/glycogen dissolved in processing), arranged in nests/sheets separated by thin fibrovascular stroma. Small, round nuclei.
• (B) Papillary - Papillary architecture with central fibrovascular cores; cuboidal to columnar cells
• (C) Chromophobe - Pale (chromophobe) cells with prominent cell membranes and perinuclear halos; eosinophilic cytoplasm

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2. MEMBRANOUS GLOMERULOPATHY

HISTOPATHOLOGY (LM + IF + EM)

• Diffuse thickening of glomerular basement membrane (highlighted in black by silver stain)
• No cellular proliferation, no inflammatory infiltrate - paucicellular
• Arrow points to characteristic spike-and-dome pattern on the GBM outer surface
• Spikes = GBM matrix projections between subepithelial deposits

• Granular pattern of IgG (and C3) along the entire GBM - "string of beads" / continuous granular fluorescence
• Contrast with linear pattern of anti-GBM disease

• Subepithelial electron-dense deposits (between GBM and overlying podocyte epithelium)
• Arrow = subepithelial deposit
• End = endothelium, CL = capillary lumen, US = urinary space, Ep = epithelium
• Effacement of podocyte foot processes (key feature)

SPIKE AND DOME FORMATION - Schematic:
                                        
Urinary space (above)
     Podocyte foot process
     |   ↕ effacement        
     ▼   
 ██ deposit ██ deposit ██ deposit
 ┃   ↑        ↑        ↑         ┃
 ┃  SPIKE  SPIKE   SPIKE (GBM)  ┃
 ┃__________________________________┃ ← GBM
     (Capillary lumen below)
     
Silver stain: spikes = black, deposits = clear gaps

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3. CHRONIC PYELONEPHRITIS

GROSS + HISTOPATHOLOGY

• Left panel: Kidney surface shows coarse, irregular scars (depressed areas)
• Right panel (cut section): Note blunted, deformed calyces and loss of papillae
• Scarring is at poles (upper and lower) - sites of greatest VUR
• Asymmetric involvement distinguishes it from chronic GN

• Corticomedullary scar (fibrotic area) overlying a deformed calyx
• THYROIDIZATION (top of image): Dilated tubules with flat epithelium filled with homogeneous pink proteinaceous casts resembling thyroid colloid - PATHOGNOMONIC
• Cortical tubules show atrophy with surrounding interstitial fibrosis
• Periglomerular fibrosis (ischemic changes)

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┌────────────────────────────────────────────────────────────┐
│        CHRONIC PYELONEPHRITIS - MICROSCOPIC FEATURES       │
│                                                            │
│  TUBULES:                                                  │
│  ┌──────────┐  ┌──────────┐  ┌──────────┐                  │
│  │ Atrophic │  │ Dilated  │  │THYROID-  │                  │
│  │ tubules  │  │ tubules  │  │IZATION   │                  │
│  └──────────┘  └──────────┘  │(colloid  │                  │
│                               │ casts)  │                  │
│                               └──────────┘                  │
│                                                            │
│  INTERSTITIUM: Fibrosis + lymphocytes, plasma cells        │
│                                                            │
│  GLOMERULI: Periglomerular fibrosis, ischemic wrinkling    │
│             (Secondary FSGS in late stages)                │
│                                                            │
│  CALYX: Fibrous thickening + chronic inflammation          │
└────────────────────────────────────────────────────────────┘

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4. RAPIDLY PROGRESSIVE (CRESCENTIC) GLOMERULONEPHRITIS

ANTIBODY-MEDIATED MECHANISMS DIAGRAM

• Type I (Anti-GBM) = Panel B + Panel E (linear IF)
• Type II (Immune complex) = Panel C + Panel D (granular IF)
• Type III (Pauci-immune) = No deposits on IF

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RPGN HISTOPATHOLOGY (LM + EM)

• Crescent = Large cellular mass of proliferating parietal epithelial cells + monocytes filling and compressing Bowman's space
• Two glomeruli shown - both with crescents compressing the capillary tufts
• Fibrin strands visible between cellular layers of crescent
• Compressed, collapsed capillary tuft (the tufts are squeezed to one side)

• Wrinkled, collapsed GBM
• Focal disruptions (arrows) = Breaks/ruptures in GBM - pathognomonic
• These ruptures allow fibrin and leukocytes into Bowman's space → crescent formation

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NORMAL GLOMERULUS          RPGN - CRESCENTIC GN
                                    
  Bowman's capsule                  Bowman's capsule
  ___________                ___________________________
 (           )              (CRESCENT: parietal cells  )
 (   capillary)    →→→      ( monocytes + fibrin fill  )
 ( tufts intact)            (  ██████████████████      )
 (           )              (   compressed tuft  ▼     )
  ‾‾‾‾‾‾‾‾‾‾‾               ‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾‾

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5. POST-STREPTOCOCCAL GLOMERULONEPHRITIS (PSGN)

GROSS APPEARANCE

┌──────────────────────────────────────────────────────────────┐
│          POST-STREPTOCOCCAL GN - GROSS ("FLEA-BITTEN KIDNEY")│
│                                                              │
│         ┌─────────────────────────────┐                      │
│         │   ·  ·  ·  ·  ·  ·  ·      │ ← Petechial          │
│         │  ·  ·  ·  ·  ·  ·  ·  ·    │   hemorrhages        │
│         │   ·  ·  ·  ·  ·  ·  ·      │   (red dots)         │
│         │   ENLARGED + SWOLLEN KIDNEY │                      │
│         │     Smooth surface          │                      │
│         │     Pale/grey color         │                      │
│         └─────────────────────────────┘                      │
│                                                              │
│  • Both kidneys enlarged and pale                            │
│  • Petechial hemorrhages = "FLEA-BITTEN" kidney              │
│  • SMOOTH surface (diffuse/global involvement)               │
│  • Contrast with chronic pyelo (coarse irregular scars)      │
└──────────────────────────────────────────────────────────────┘

HISTOPATHOLOGY (LM + IF + EM)

• Hypercellular, enlarged glomerulus - capillary lumina nearly obliterated
• Increased cellularity due to:
  1. Proliferation of mesangial and endothelial cells
  2. Infiltration of neutrophils (PMNs) - the classic early finding
• Glomerulus fills entire Bowman's space

• Coarsely granular IgG and C3 deposits - "starry sky" pattern
• Deposits in mesangium and along GBM walls
• Granular pattern = immune complex disease

• Subepithelial electron-dense "HUMP" - large dome-shaped immune complex deposit on the epithelial (urinary) side of GBM
• Neutrophil in capillary lumen (arrowhead area)
• This "hump" is the most characteristic EM finding of PSGN

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┌────────────────────────────────────────────────────────────────┐
│              PSGN MICROSCOPY AT A GLANCE                      │
├──────────────────────┬─────────────────────────────────────────┤
│ LIGHT MICROSCOPY     │ Diffuse hypercellularity                │
│                      │ PMN (neutrophil) infiltration           │
│                      │ Enlarged glomeruli                      │
│                      │ Occluded capillary lumina               │
├──────────────────────┼─────────────────────────────────────────┤
│ IMMUNOFLUORESCENCE   │ Granular IgG + C3 ("starry sky")        │
│                      │ Mesangial + GBM pattern                 │
├──────────────────────┼─────────────────────────────────────────┤
│ ELECTRON MICROSCOPY  │ Subepithelial "HUMPS" (PATHOGNOMONIC)   │
│ (Most Specific)      │ Dome-shaped electron-dense deposits      │
│                      │ Subendothelial + mesangial deposits too │
└──────────────────────┴─────────────────────────────────────────┘

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QUICK REFERENCE - IMMUNOFLUORESCENCE PATTERNS

╔═══════════════════════════════════════════════════════════════╗
║            IF PATTERN = KEY EXAM DISCRIMINATOR               ║
╠══════════════════╦════════════════════════════════════════════╣
║ LINEAR (IgG)     ║ Anti-GBM disease (RPGN Type I)            ║
║                  ║ Goodpasture syndrome                       ║
╠══════════════════╬════════════════════════════════════════════╣
║ GRANULAR         ║ Immune complex GN (all types)              ║
║                  ║ PSGN: "starry sky" (coarse granular)       ║
║                  ║ Membranous GN: continuous granular         ║
║                  ║ IgA nephropathy: mesangial IgA             ║
╠══════════════════╬════════════════════════════════════════════╣
║ NEGATIVE/TRACE   ║ Pauci-immune RPGN (ANCA-associated)        ║
║                  ║ Minimal Change Disease                     ║
╚══════════════════╩════════════════════════════════════════════╝

EM FINDINGS COMPARISON TABLE

╔═══════════════════╦══════════════════════════════════════════╗
║ DISEASE           ║ ELECTRON MICROSCOPY FINDING              ║
╠═══════════════════╬══════════════════════════════════════════╣
║ PSGN              ║ Subepithelial HUMPS (dome-shaped)        ║
╠═══════════════════╬══════════════════════════════════════════╣
║ Membranous GN     ║ Subepithelial deposits + GBM SPIKES      ║
╠═══════════════════╬══════════════════════════════════════════╣
║ RPGN              ║ GBM RUPTURES/BREAKS + crescents          ║
╠═══════════════════╬══════════════════════════════════════════╣
║ Minimal Change    ║ Diffuse foot process EFFACEMENT only     ║
║ Disease           ║ No deposits                              ║
╠═══════════════════╬══════════════════════════════════════════╣
║ IgA Nephropathy   ║ Mesangial electron-dense deposits        ║
╠═══════════════════╬══════════════════════════════════════════╣
║ MPGN              ║ Subendothelial deposits + GBM splitting  ║
║                   ║ "tram-track" / double contour            ║
╚═══════════════════╩══════════════════════════════════════════╝

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