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PA27.7 | Glomerular Manifestations of Systemic Disease — SDL Guide (Part 2)

Renal Amyloidosis

Multi-panel medical diagram showing gross, light microscopic, Congo red, polarized light, electron microscopic, and classification features of renal amyloidosis. — **Panel A:** Enlarged pale waxy firm kidney, lardaceous kidney, renal cortex, renal medulla, amyloid deposition in systemic amyloidosis. **Panel B:** Glomerulus, mesangium, amorphous acellular eosinophilic deposits, expanded mesangium, glomerular basement membrane, subendothelial/GBM amyloid deposits, capillary loops. **Panel C:** Congo red stain, salmon-pink/orange amyloid deposits, polarized light inset, apple-green birefringence, diagnostic feature of amyloid. **Panel D:** Electron microscopy fibrils, 8-10 nm non-branching randomly arranged fibrils, AL amyloidosis, immunoglobulin light chains, lambda restriction, multiple myeloma, AA amyloidosis, serum amyloid A, chronic inflammation, tuberculosis in India.

Amyloidosis is the deposition of insoluble fibrillar proteins (β-pleated sheet conformation) in tissues. The kidney is the most commonly and most seriously affected organ in systemic amyloidosis, and renal disease is the leading cause of death in patients with amyloidosis.

Types relevant to renal pathology:
• AL amyloidosis (primary/myeloma-associated) — amyloid derived from immunoglobulin light chains (most often lambda). Occurs in multiple myeloma and plasma cell dyscrasias.
• AA amyloidosis (secondary/reactive) — derived from serum amyloid A protein (SAA), an acute-phase reactant. Occurs in chronic inflammatory conditions: rheumatoid arthritis, tuberculosis, bronchiectasis, chronic osteomyelitis, familial Mediterranean fever.
• In India, AA amyloidosis secondary to tuberculosis is a significant contributor.

Morphology:
• Grossly: enlarged, pale, waxy, firm kidneys ("lardaceous kidney").
• LM: H&E shows amorphous, acellular, eosinophilic deposits in mesangium, expanding it, and along GBM. Initially mesangial, then subendothelial/GBM. Later — tubular basement membranes and vessel walls.
• Congo red stain — deposits stain salmon-pink/orange. Under polarised light: apple-green birefringence — the single most important diagnostic feature of amyloid.
• EM: 8–10 nm non-branching randomly arranged fibrils — distinct from collagen or immune complex deposits.
• IF: AL amyloid may show light-chain restriction (kappa or lambda); AA amyloid is IF-negative for immunoglobulins.

Clinical: Insidious onset nephrotic syndrome is the dominant presentation (massive proteinuria, hypoalbuminaemia, oedema). Renal vein thrombosis is a complication. Renal failure develops over years. Hepatosplenomegaly may be present; cardiac amyloid (stiff heart, low voltage ECG) adds to mortality.

SELF-CHECK

A 45-year-old man with a 20-year history of pulmonary tuberculosis presents with 6+ g/day proteinuria and bilateral leg oedema. Renal biopsy shows acellular eosinophilic deposits in the mesangium and along GBM. Congo red stain is performed. What is the expected finding under polarised light?

A. Yellow-green fluorescence (thioflavin T pattern)

B. Apple-green birefringence

C. Salmon-pink without polarisation change

D. Negative — Congo red is not used for amyloid

Reveal Answer

Answer: B. Apple-green birefringence

Apple-green birefringence under polarised light after Congo red staining is the pathognomonic finding for amyloid. The salmon-pink/orange colour on conventional light microscopy is also characteristic, but polarisation is the diagnostic confirmatory step. This is AA amyloidosis secondary to chronic tuberculosis. Thioflavin T (option A) also stains amyloid (yellow-green fluorescence) but is less specific and not the primary diagnostic stain. Congo red is absolutely the stain of choice for amyloid — option D is incorrect.

Hypertensive Nephrosclerosis — Benign and Malignant

Comparison diagram showing how chronic benign hypertension causes hyaline arteriolosclerosis and granular contracted kidneys, while acute malignant hypertension causes fibrinoid necrosis and onion-skin arteriolitis. — **Panel A:** Vicious cycle of hypertension causing renal arteriolar and glomerular injury, leading to CKD, sodium retention, RAAS activation, and worsening hypertension.. **Panel B:** Benign hypertensive nephrosclerosis with finely granular contracted kidney, hyaline arteriolosclerosis of afferent arteriole, narrowed lumen, ischemic global glomerulosclerosis, wrinkled collapsed GBM, periglomerular fibrosis, tubular atrophy, and interstitial fibrosis.. **Panel C:** Malignant hypertensive nephrosclerosis with acute severe hypertension, cortical petechial hemorrhages, fibrinoid necrosis of arterioles, PAS-negative eosinophilic necrotic wall material, hyperplastic arteriolitis, onion-skin smooth muscle proliferation, and markedly narrowed vascular lumen..

Hypertension is both a cause and a consequence of chronic kidney disease, creating a vicious cycle. Two distinct morphological patterns reflect the speed and severity of BP elevation.

Benign hypertensive nephrosclerosis (chronic, controlled hypertension):

Hyaline arteriolosclerosis — deposition of homogeneous, eosinophilic, glassy hyaline material in the intima and media of afferent arterioles (plasma protein insudation + smooth muscle degeneration). This is the hallmark vascular change.
Fibrous intimal thickening of interlobular arteries — concentric intimal fibromuscular proliferation narrows the lumen.
Glomeruli: ischaemic obsolescence — global glomerulosclerosis (wrinkling and collapse of GBM, periglomerular fibrosis). Tubular atrophy. Interstitial fibrosis.
Gross appearance: finely granular contracted kidney — diffuse cortical granularity from alternating ischaemic contracted nephrons and compensatorily hypertrophied ones.
Clinical: slowly progressive CKD; mild proteinuria (usually <1.5 g/day, rarely nephrotic); CKD in hypertensive Afro-Caribbean patients is disproportionately from nephrosclerosis.

Malignant hypertensive nephrosclerosis (BP typically >200/120 mmHg, acute elevation):

Fibrinoid necrosis of arterioles — vessel wall destroyed by plasma protein insudation → bright eosinophilic granular necrosis; PAS-negative.
Hyperplastic arteriolitis ("onion-skin" lesion) — concentric layers of smooth muscle proliferation and laminated collagen in interlobular arteries create a distinctive onion-skin appearance, severely narrowing the lumen.
Glomeruli: necrotising glomerulitis — segmental fibrinoid necrosis of glomerular tufts; capillary thrombosis; crescents.
Gross: petechial haemorrhages on cortex ("flea-bitten kidney" — red dots on pale cortex from glomerular haemorrhages).
Clinical: acute kidney injury, haematuria, rapidly rising creatinine, hypertensive encephalopathy, retinal haemorrhages. Medical emergency.

Side-by-side histology comparison of benign hypertensive hyaline arteriolosclerosis and malignant hypertensive onion-skin hyperplastic arteriolitis with fibrinoid necrosis. — **Panel A:** PAS-stained arteriole showing narrowed lumen, homogeneous PAS-positive hyaline deposit, thickened arteriolar wall, and endothelial lining in benign hypertensive nephrosclerosis.. **Panel B:** Interlobular artery showing concentric laminated smooth muscle layers, severely narrowed lumen, adjacent arteriole, and fibrinoid necrosis in malignant hypertensive nephrosclerosis..

SELF-CHECK

Autopsy of a 40-year-old man who died of hypertensive encephalopathy shows kidneys with a cortical surface resembling a flea-bitten appearance. Histology reveals concentric laminated layers of smooth muscle in interlobular arteries with near-total luminal occlusion, and fibrinoid necrosis in arterioles. Which pattern is being described?

A. Benign hypertensive nephrosclerosis with hyaline arteriolosclerosis

B. Malignant hypertensive nephrosclerosis with hyperplastic arteriolitis

C. Diabetic nephropathy with efferent arteriolar hyalinosis

D. Thrombotic microangiopathy from TTP

Reveal Answer

Answer: B. Malignant hypertensive nephrosclerosis with hyperplastic arteriolitis

The flea-bitten kidney (cortical petechial haemorrhages) + fibrinoid necrosis of arterioles + hyperplastic onion-skin arteriolitis in interlobular arteries = malignant hypertensive nephrosclerosis. Benign hypertensive nephrosclerosis produces a finely granular contracted kidney (NOT flea-bitten) with hyaline arteriolosclerosis (NOT fibrinoid necrosis). TTP also causes fibrinoid-like deposits but is microangiopathic haemolytic anaemia with systemic microthrombi (platelet-fibrin thrombi in glomerular capillaries), not the concentric onion-skin lesion in arteries.

Other Systemic Causes of Glomerular Injury

Three-panel medical diagram comparing IgA vasculitis, Goodpasture syndrome, and multiple myeloma cast nephropathy as systemic causes of renal glomerular or renal injury. — **Panel A:** Henoch-Schonlein Purpura / IgA vasculitis; palpable purpura on lower limbs and buttocks; abdominal pain; arthralgia; hematuria/proteinuria; mesangial IgA deposits; mesangial proliferation; crescent formation in severe disease.. **Panel B:** Goodpasture syndrome / anti-GBM disease; alveolar hemorrhage; hemoptysis; rapidly progressive crescentic GN; hematuria; rising creatinine; linear IgG along GBM; anti-alpha3 type IV collagen antibody.. **Panel C:** Multiple myeloma cast nephropathy; plasma cell clone; free immunoglobulin light chains / Bence Jones proteins; filtered light chains; renal tubule; large laminated fractured PAS-positive casts; macrophages; multinucleated giant cell reaction..

Several additional systemic diseases produce characteristic glomerular findings that frequently appear in examinations and clinical practice.

Henoch-Schönlein Purpura (IgA vasculitis)
• Systemic IgA-dominant small-vessel vasculitis (skin, gut, joints, kidney).
• Renal biopsy: mesangial IgA deposits (identical to IgA nephropathy — HSP is its systemic form). Focal to diffuse mesangial proliferation; crescents in severe cases.
• Clinical: palpable purpura on lower limbs and buttocks + abdominal pain + arthralgia + haematuria/proteinuria. Commonest vasculitis in children.

Goodpasture Syndrome (Anti-GBM Disease)
• Autoantibodies against α3 chain of type IV collagen in GBM and alveolar BM → simultaneous pulmonary haemorrhage + rapidly progressive (crescentic) GN.
• IF: linear IgG along GBM — the classic "linear" pattern (vs granular in immune complex, vs negative/pauci in ANCA vasculitis).
• Clinical: haemoptysis + haematuria + rapidly rising creatinine. Medical emergency.
• (Cross-reference: type I RPGN mechanism.)

Multiple Myeloma and Cast Nephropathy
• Free immunoglobulin light chains (Bence Jones proteins) are filtered and overwhelm tubular reabsorption → "myeloma kidney" or cast nephropathy.
• Casts: large, laminated, fractured, PAS-positive tubular casts with surrounding giant cell reaction (macrophage/multinucleated giant cells) — these casts are NOT ordinary hyaline casts.
• AL amyloidosis and light-chain deposition disease are separate myeloma-associated renal conditions.
• Clinical: renal failure + lytic bone lesions + hypercalcaemia + anaemia.

Cryoglobulinaemic GN
• Cryoglobulins are immunoglobulins that precipitate in cold. Type I (monoclonal, myeloma/Waldenström's); Type II and III (mixed, often hepatitis C-associated — MC cause in India).
• Renal: MPGN-like pattern with intraluminal hyaline thrombi (precipitated cryoglobulins), endocapillary proliferation, monocyte infiltration.
• IF: IgM, IgG, C3. EM: organised microtubular or crystalline substructure.

Thrombotic Microangiopathy (TMA)
• Umbrella term: HUS (Shiga toxin — E. coli O157:H7 → primarily in children), TTP (ADAMTS13 deficiency → platelet-fibrin thrombi, thrombocytopaenia, MAHA).
• Renal: glomerular capillary and arteriolar microthrombi, GBM duplication ("double-contour"), endothelial swelling.
• (Brief cross-reference — detailed in vascular pathology module.)

Radial overview diagram showing systemic metabolic, immune, haemodynamic, and haematological causes of glomerular injury pointing inward toward a central glomerulus. — **Panel A:** Central glomerulus silhouette with inward arrows from Diabetic nephropathy, Lupus nephritis, Amyloidosis, Hypertensive nephrosclerosis, HSP / IgA vasculitis, Goodpasture syndrome, Myeloma kidney, Cryoglobulinaemia, and TMA; mechanism colour legend for metabolic, immune, haemodynamic, and haematological causes..