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KIDNEY PATHOLOGY - COMPLETE EXAM NOTES (2nd MBBS / MUHS)

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1. RENAL CELL CARCINOMA (RCC)

Introduction

• Most common malignant tumor of the kidney (80-85% of all primary renal malignancies)
• Derived from renal tubular epithelium - located predominantly in cortex
• 2-3% of all adult cancers; ~65,000 cases/year in the USA
• Peak incidence: 6th-7th decade; Males:Females = 2:1
• Risk factors: smoking, hypertension, obesity, cadmium exposure, acquired polycystic disease (30x risk)

Classification (Three Main Types)

GROSS FEATURES

• Clear cell carcinoma: Large, solitary, well-circumscribed tumor in the cortex; bright yellow-orange due to lipid-laden clear cells; variegated cut surface with areas of hemorrhage, necrosis, and cystic degeneration; frequently invades the renal vein (may extend as a tumor thrombus into the IVC)
• Papillary RCC: Bilateral and multiple; less vibrantly yellow; often shows necrosis, hemorrhage, and cystic degeneration
• Chromophobe RCC: Tan-brown, well-circumscribed

MICROSCOPIC FEATURES

• Clear cell carcinoma: Sheets or nests of large cells with clear cytoplasm (due to dissolved lipid and glycogen in standard processing); abundant delicate vasculature between cell nests; nucleus varies from small/regular to markedly enlarged, hyperchromatic, pleomorphic; variable mitotic figures; cells form abortive tubules or cords
• Papillary RCC: Cuboidal to low columnar cells with eosinophilic to clear cytoplasm lining papillae with fibrovascular cores; foam cells often present within papillary stalks
• Chromophobe RCC: Cells with eosinophilic cytoplasm mixed with pale granular cells; very prominent, distinct cell membranes and perinuclear haloes - classic feature

Clinical Features ("Classic Triad" - seen in only 10%)

1. Painless hematuria (most frequent; >50% of cases - intermittent, macroscopic)
2. Palpable abdominal/flank mass
3. Dull flank pain

• Polycythemia (5-10%) - erythropoietin secretion
• Hypercalcemia (PTHrP)
• Hypertension (renin secretion)
• Cushing syndrome (ACTH)
• Feminization/masculinization

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2. CLASSIFICATION OF GLOMERULAR DISEASES

Normal Glomerulus (Quick Recap)

Mechanisms of Glomerular Injury

Classification of Glomerular Diseases

I. Nephrotic Syndrome (Proteinuria >3.5 g/day)

II. Nephritic Syndrome (Hematuria, Hypertension, Oliguria, Azotemia)

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Morphology of Membranous Glomerulopathy (Membranous Nephropathy)

• Primary (80%): Autoantibodies against podocyte antigen Phospholipase A2 Receptor (PLA2R) - present in 70-80% of primary cases
• Secondary (20%):
  • Infections: chronic Hepatitis B, syphilis, schistosomiasis, malaria
  • Malignancies: carcinomas, B-cell tumors (CLL)
  • Autoimmune: SLE
  • Drugs: penicillamine, captopril, NSAIDs
  • Heavy metals: gold, mercury

• Light Microscopy: Diffuse thickening of glomerular capillary walls without endothelial/mesangial proliferation or leukocytic infiltration; silver stain shows characteristic "spike and dome" pattern - spikes of GBM material projecting between subepithelial deposits (best seen on Jones methenamine silver stain)
• Immunofluorescence: Granular deposits of IgG and C3 along the entire GBM ("continuous granular")
• Electron Microscopy: Subepithelial electron-dense deposits ("humps"); effacement of podocyte foot processes; GBM projects around the deposits as "spikes"

• Nephrotic syndrome (massive proteinuria, hypoalbuminemia, edema, hyperlipidemia)
• Slow, indolent course
• "Rule of thirds": 1/3 spontaneous remission, 1/3 persistent proteinuria but stable renal function, 1/3 progressive renal failure over 10-20 years
• Increased risk of renal vein thrombosis (loss of antithrombin III in urine)
• Treatment: Immunosuppression (steroids + cyclophosphamide or calcineurin inhibitors); monitor PLA2R antibody levels

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3. CHRONIC PYELONEPHRITIS

• Reflux nephropathy (most common) - due to vesicoureteric reflux (VUR); recurrent infections lead to repeated renal inflammation and scarring
• Obstructive pyelonephritis - due to calculi, posterior urethral valves, unilateral obstructive ureteral lesions; obstruction can be unilateral or bilateral

GROSS APPEARANCES

• Hallmark: Coarse, discrete, irregular corticomedullary scars (not fine or symmetric)
• Overlying dilated, blunted, or deformed calyces and flattening of the papillae
• One or both kidneys may be involved
• When bilateral, scarring is asymmetric (distinguishes from chronic GN which gives fine, symmetrical scarring)
• Kidneys are asymmetrically contracted on imaging

DIAGRAM: Cross-section of kidney in Chronic Pyelonephritis
_____________________________________________
|  SCAR (coarse, irregular)                  |
|       ↕  ↕  ↕   ↕                         |
|  Cortex  [thinned over scarred calyx]      |
|  _________   ___________   _________       |
| | Normal  | | Dilated   | | Scarred |      |
| | Calyx   | | Blunted   | | Area    |      |
|_|_________|_|_Calyx_____|_|_________|_____|
  ← Asymmetric involvement characteristic →

MICROSCOPIC APPEARANCES

• Patchy interstitial fibrosis with infiltrate of lymphocytes, plasma cells, and occasionally neutrophils
• Tubular atrophy alternating with tubular dilation
• Dilated tubules contain PAS-positive, pink-to-blue glassy casts - "colloid casts" or "thyroidization" (tubules resemble thyroid follicles - pathognomonic)
• Glomeruli: normal or show variable periglomerular fibrosis and sclerosis
• Blood vessels: arteriolar sclerosis (due to hypertension)

• Gradual onset of renal insufficiency; sometimes detected incidentally
• Hypertension (common)
• Bilateral progressive disease: tubular dysfunction → inability to concentrate urine → hyposthenuria, polyuria, nocturia
• Radiologic: asymmetrically contracted kidneys with calyceal blunting/deformity
• Some progress to secondary glomerulosclerosis with proteinuria

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4. RAPIDLY PROGRESSIVE GLOMERULONEPHRITIS (RPGN)

Definition

• Acute renal failure (renal function deteriorates over days to weeks)
• Features of nephritic syndrome (hematuria, hypertension, oliguria)
• Often severe oliguria progressing to anuria
• Histologic counterpart = Crescentic GN

Classification (Three Types) - Most Important for Exam

Pathogenesis of Crescent Formation

CRESCENT FORMATION DIAGRAM:
Severe glomerular injury
         ↓
Breaks in GBM → fibrin leaks into Bowman's space
         ↓
Fibrin acts as scaffold
         ↓
Proliferation of PARIETAL epithelial cells
    +
Migration of MONOCYTES/MACROPHAGES into Bowman's space
         ↓
CRESCENT formation (fills Bowman's space)
         ↓
Compresses glomerular tuft → obliterates blood flow
         ↓
Progressive glomerulosclerosis → ESRD

MORPHOLOGY (RPGN / Crescentic GN)

• Hallmark: Crescents - crescent-shaped accumulations of cells filling Bowman's space
• Crescents composed of: parietal epithelial cells + monocytes/macrophages + fibrin
• The glomerular tuft is compressed
• Segmental necrosis of capillary loops (fibrinoid necrosis)
• Breaks/disruptions in GBM
• In immune complex types: additional endocapillary proliferation and leukocyte infiltration within the tuft

• Type I: Linear IgG + C3
• Type II: Granular IgG + C3
• Type III: Negative (pauci-immune)

• Onset resembles nephritic syndrome but oliguria and azotemia are more pronounced
• Proteinuria may approach nephrotic range
• If untreated: renal failure within weeks to months; some become anuric
• Prognosis: Correlated to % glomeruli with crescents - <80% crescents = better prognosis
• Treatment: Immunosuppressive agents (high-dose steroids + cyclophosphamide); plasmapheresis for Type I (anti-GBM) and Type III (ANCA-associated)

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5. NEPHROTIC SYNDROME

Definition

Classic Tetrad of Features

┌─────────────────────────────────────────────────────────┐
│              NEPHROTIC SYNDROME                          │
│                                                          │
│  1. MASSIVE PROTEINURIA (>3.5 g/24h)                    │
│       ↓ (loss of serum proteins)                        │
│  2. HYPOALBUMINEMIA                                      │
│       ↓ (reduced oncotic pressure)                      │
│  3. GENERALIZED EDEMA (Anasarca)                         │
│       ↓ (secondary hyperaldosteronism)                  │
│  4. HYPERLIPIDEMIA + LIPIDURIA                           │
│       (compensatory liver synthesis; lipoprotein lipase  │
│        lost in urine)                                   │
└─────────────────────────────────────────────────────────┘

Additional Features

• Lipiduria: Oval fat bodies (tubular cells + free lipid) seen on urinalysis; Maltese cross pattern under polarized light
• Increased thrombotic tendency: Loss of antithrombin III, Protein C and S in urine → deep vein thrombosis, renal vein thrombosis (especially in membranous nephropathy)
• Increased susceptibility to infections: Loss of immunoglobulins (IgG) in urine → encapsulated organisms (Pneumococcal peritonitis in children)
• Lipoid nephrosis = old term for minimal change disease

Causes by Age

Pathophysiology of Edema

• Proteinuria → hypoalbuminemia → ↓oncotic pressure → fluid shifts to interstitium
• ↓ circulating volume → RAAS activation → sodium and water retention → generalized edema
• Edema is typically pitting and most pronounced in areas of low tissue tension (periorbital in children, ankle in adults)

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6. POST-STREPTOCOCCAL GLOMERULONEPHRITIS (PSGN)

Definition

Etiology

• Causative organism: Group A β-hemolytic Streptococcus (Streptococcus pyogenes) - specific nephritogenic strains
• Nephritogenic antigens:
  • Streptococcal Exotoxin B (SpeB) - highly immunogenic, detected in GBM deposits
  • Streptokinase (plasminogen-related)
  • Neuraminidase
• Common following:
  • Pharyngeal infection (throat): latent period 1-3 weeks
  • Skin infection (impetigo): latent period 3-6 weeks
• Other postinfectious GN: Pneumococcus, Staphylococcus, mumps, measles, hepatitis B/C

Etiopathogenesis

Group A β-hemolytic Streptococcus (nephritogenic strains)
        ↓
Infection: Pharyngitis or Pyoderma/Impetigo
        ↓ (1-4 weeks latent period)
Formation of STREPTOCOCCAL ANTIGENS (e.g., Exotoxin B)
        ↓
Two mechanisms operate:
  (A) Preformed circulating immune complexes deposit in GBM
               +
  (B) In situ complex formation - Ag deposits in GBM, then Ab binds
        ↓
GRANULAR immune complex deposits (IgG + C3) in GBM
        ↓
CLASSICAL COMPLEMENT PATHWAY ACTIVATION
        ↓
Chemotaxis of neutrophils + monocytes
        ↓
Release of proteases, reactive oxygen species
        ↓
GBM damage → HEMATURIA
Endothelial/mesangial proliferation → ↓GFR → OLIGURIA, AZOTEMIA
Sodium + water retention → HYPERTENSION, EDEMA
        ↓
ACUTE NEPHRITIC SYNDROME

GROSS FEATURES

• Kidneys are bilaterally enlarged and swollen
• Pale cortical surface with petechial hemorrhages (flea-bitten appearance)
• Pale gray cut surface - due to diffuse glomerular involvement
• Congestion and hemorrhage visible

GROSS DIAGRAM:
  _____________________
 /    KIDNEY            \
|  ● ● ●  ●  ● ●  ●    |  ← Petechial hemorrhages
|    ●   ●    ●  ●      |     ("flea-bitten" appearance)
|     enlarged, pale     |
|   (bilateral)          |
 \______________________ /

MICROSCOPIC FEATURES

• Diffuse (all glomeruli involved) glomerulonephritis
• Increased cellularity of glomerular tufts - the hallmark
  • Proliferation of endothelial cells and mesangial cells
  • Infiltration by neutrophils and monocytes (intracapillary)
• Glomeruli appear hypercellular, enlarged, bloodless
• Occasional capillary wall necrosis
• In severe cases: crescents (RPGN superimposed)

• Granular (lumpy-bumpy) deposits of IgG and C3 in the capillary walls and mesangium
• Complement is activated by the classical pathway → C3 levels reduced in serum

• Subepithelial electron-dense deposits ("humps") - pathognomonic
• These are located on the epithelial side of GBM (between podocytes and GBM)
• Also: subendothelial and mesangial deposits may be seen
• Deposits cleared within 2 months after resolution of infection

Clinical Course

• Acute nephritic syndrome: sudden onset hematuria (cola/smoky/tea-colored urine), oliguria, hypertension, periorbital edema, mild to moderate azotemia
• Proteinuria (usually <3.5 g/day; occasionally nephrotic range)

• ↑ ASO (Antistreptolysin O) titer - rises after pharyngitis
• ↑ Anti-DNase B - rises after skin infection (ASO may be normal in pyoderma)
• ↓ Serum C3 (complement consumed via classical pathway) during active disease
• Urinalysis: RBC casts (pathognomonic of GN), proteinuria, granular casts
• ↑ Blood urea, creatinine

• Children: Excellent - >95% recover completely; C3 normalizes in 6-8 weeks
• Adults: More guarded - 15-50% develop chronic renal disease over years to decades
• Poor prognostic indicators: crescents in >80% of glomeruli, persistent proteinuria, hypertension, elderly age
• Small percentage develop RPGN (crescentic GN) - requires aggressive treatment

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QUICK COMPARISON: NEPHROTIC vs. NEPHRITIC SYNDROME

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GLOMERULAR SYNDROMES - ENUMERATION

1. Nephrotic Syndrome - Minimal Change Disease, FSGS, Membranous Nephropathy, MPGN
2. Nephritic Syndrome - Post-infective GN, RPGN, IgA Nephropathy, Lupus Nephritis
3. Rapidly Progressive (Crescentic) GN - Type I (anti-GBM), Type II (IC), Type III (Pauci-immune)
4. Asymptomatic hematuria/proteinuria - IgA nephropathy, thin basement membrane disease
5. Chronic renal failure - End-stage of any progressive GN

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ACUTE PROLIFERATIVE GN (SAME AS PSGN - see Section 6 above)

• The term "proliferative" refers to endocapillary (inside the capillary loop) proliferation
• "Diffuse" = >50% of glomeruli involved
• Immunological basis: Type III hypersensitivity (immune complex mediated)
• Complement pathway: Classical (IC activates C1q → C3 consumption → low serum C3)
• Exotoxin B acts as a "planted antigen" in the GBM → in situ IC formation adds to circulating IC deposition

• Children: >95% complete recovery
• The fact that most are caused by specific nephritogenic M-types of Strep means not all Strep infections cause GN
• The incidence has declined in high-income countries due to antibiotic use

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