Renal Amyloidosis — Comprehensive Review

Types of Renal Amyloidosis

AL (Light-Chain) Amyloidosis (60–70% of renal amyloidosis) - Amyloid fibrils composed of misfolded immunoglobulin light chains (kappa or lambda) [3] - Derived from bone marrow plasma cells (usually non-clonal; rarely frank myeloma) - Median age at diagnosis 65 years; rare <50 years - Affects kidney, heart, nervous system, soft tissues

AA (Serum Amyloid A) Amyloidosis (20–30% of renal amyloidosis) - Amyloid fibrils derived from acute-phase reactant serum amyloid A - Associated with chronic inflammation (rheumatoid arthritis, chronic infections, malignancy) - Now less common in developed countries; endemic in Mediterranean (familial Mediterranean fever) - Usually kidney-limited involvement

Hereditary Amyloidosis (5–10%) - ATTRwt (wild-type transthyretin): Older men; cardiac and neurologic predominance; renal involvement less common - ATTRv (hereditary transthyretin): Rare; various mutations - ApoA-I, ApoA-IV, Lysozyme: Very rare familial forms - Genetic testing/family screening important

Light-Chain Misfolding & Aggregation

AL amyloidosis mechanism: - Plasma cell produces misfolded light chain (kappa or lambda) - Intrinsically unstable light chain polymerizes - Aggregated beta-pleated sheet structure resistant to degradation - Deposits in kidney glomeruli → injury

Factors promoting misfolding: - Point mutations in light-chain variable domain (V-domain instability) - Specific kappa or lambda germline subsets (κIV, λVI associated with amyloidosis) - Rare: overproduction of normal light chains (still forms amyloid)

AA Amyloidosis Mechanism

• Chronic inflammation → sustained elevation of serum amyloid A (SAA)
• SAA persistently overproduced
• Proteolytic cleavage of SAA → N-terminal A-alpha fragments
• Fragments aggregate → amyloid fibrils
• Deposits in glomerular basement membrane and mesangium

Glomerular Injury

Amyloid-specific injury mechanisms: - Direct cytotoxicity from fibrils - Disruption of slit diaphragm architecture - Mesangial expansion → decreased filtration surface - Foot process effacement (variable) - Rarely: crescent formation (suggests secondary vasculitis or ANCA overlap)

Renal Features (Cardinal)

• Nephrotic syndrome (proteinuria often >3 g/day; sometimes >10 g/day)
• Dysmorphic hematuria: Minimal to absent (mild microscopic hematuria common)
• Hypertension: Variable; less frequent than some GN types
• Preserved or slightly reduced GFR at presentation (may decline rapidly once manifest)

Extrarenal Manifestations (Crucial Diagnostic Clues)

AL Amyloidosis: - Cardiac: Restrictive cardiomyopathy (stiff ventricles → dyspnea, edema, arrhythmia) - Neuropathy: Peripheral (distal, symmetric) + autonomic (orthostatic hypotension, impotence) - Hepatomegaly: Usually non-tender; preserved synthetic function - Macroglossia: Enlarged, stiff tongue (pathognomonic but rare) - Skin: Easy bruising, papules around eyelids - GI: Diarrhea/constipation, malabsorption (weight loss)

AA Amyloidosis: - Systemic inflammation manifestations (pain, fever, joint involvement) - Underlying chronic disease: Rheumatoid arthritis, IBD, chronic osteomyelitis, tuberculosis, malignancy

Laboratory Features

Serum studies: - Serum creatinine: Variable; may be normal early - Serum albumin: Markedly low (aggressive proteinuria losses) - Immunoglobulin levels: Often ↓ (from urinary loss) - Serum amyloid A (SAA): Elevated in AA amyloidosis; normal in AL

Urine: - Nephrotic-range proteinuria (typically 3–15 g/day) - Minimal hematuria (distinguishes from most GN types) - No casts or specific findings - Selective proteinuria pattern (some cases)

Serum/Urine Protein Electrophoresis & Immunofixation: - AL amyloidosis: Monoclonal light-chain spike (kappa or lambda); lambda more common (60%) - AA amyloidosis: Polyclonal pattern; negative for monoclonal component

Free Light Chains (Serum): - Elevated in AL (often κ/λ ratio >1 or <1 markedly) - Normal in AA

Cardiac Function: - Echocardiography: Restrictive pattern, wall thickening, preserved ejection fraction - NT-pro-BNP/BNP: Markedly elevated (cardiac involvement) - Troponin: May be elevated (myocardial injury)

Clinical Suspicion Triggers

• Nephrotic syndrome + organomegaly (hepatomegaly especially)
• Nephrotic syndrome + cardiomyopathy (restrictive pattern)
• Nephrotic syndrome + peripheral neuropathy
• Age >60 with nephrotic syndrome + monoclonal spike
• Nephrotic syndrome + persistent fatigue/weight loss
• AA amyloidosis risk: Chronic rheumatoid arthritis, IBD, chronic infection with nephrotic syndrome

Kidney Biopsy

Light Microscopy: - Homogeneous glomerular deposits (nodular or diffuse) - Mesangial and capillary wall involvement - May mimic diabetic nephropathy (though nodules typically more extensive) - Basement membrane normal (unlike FSGS) - Minimal or no inflammation

Congo Red Staining (Definitive): - Apple-green birefringence under polarized light = amyloid (pathognomonic) [2] - Essential for diagnosis confirmation - All biopsies with suspicion should have Congo red performed

Immunofluorescence: - AL: Kappa or lambda light chain restriction (monoclonal) - AA: Serum amyloid A staining - May be negative (depends on staining technique) - Negative IF does NOT exclude amyloidosis if Congo red positive

Electron Microscopy: - Random-appearing fibrils 8–10 nm in diameter - Fibrils may fill deposits or form nodular structures - Foot process effacement variable

Mass Spectrometry (Proteomic Analysis): - Gold standard for determining amyloid subtype - Required for definitive classification - Can detect rare amyloid subtypes (transthyretin, apolipoprotein) - Increasingly available; should be performed on biopsy material

AL Amyloidosis (Light-Chain Directed)

Goal: Suppress pathogenic plasma cell clone → halt light-chain production → allow amyloid fibril resorption

Standard induction regimen: - Bortezomib (proteasome inhibitor): 1.3 mg/m² SC weekly (days 1, 8, 15 of 21-day cycle) × 4–6 cycles - Dexamethasone: 20 mg PO weekly (days 1, 8, 15) - Melphalan: 0.1 mg/kg/day (if additional cytotoxic therapy needed)

Alternative/modified regimens: - Lenalidomide + dexamethasone (if bortezomib intolerant) - Bortezomib + cyclophosphamide + dexamethasone (higher intensity for fit patients) - Daratumumab (anti-CD38 monoclonal antibody; emerging use in AL amyloidosis)

Response assessment: - Hematologic response: Reduction in serum/urine free light chains - Cardiac response: Improvement in BNP, echocardiography (may lag behind hematologic) - Renal response: Decline in proteinuria; stabilization of creatinine

Autologous stem cell transplant (ASCT): - Reserved for fit patients (age <70, good cardiac/renal function) with excellent hematologic response - Can induce durable remissions - High early mortality (5–10%); requires experienced centers - Long-term outcomes superior in selected patients

Supportive care: - ACE inhibitor/ARB to reduce proteinuria - Diuretics for volume overload - Cardiac management if restrictive cardiomyopathy (avoid >200 mg IV albumin or aggressive hydration) - Monthly monitoring of light chains and organ function during therapy

AA Amyloidosis

Primary strategy: Treat underlying chronic inflammation

• Rheumatoid arthritis: DMARDs, biologics (TNF inhibitors, IL-6 antagonists) to suppress SAA
• Inflammatory bowel disease: Optimize IBD therapy
• Chronic infection: Treat infection (TB, osteomyelitis) → SAA ↓
• Malignancy: Treat cancer; sometimes amyloid regresses if malignancy controlled

Direct anti-amyloid therapy (if inflammation-control inadequate): - Diflunisal: NSAIDs that stabilize transthyretin; not effective in AA - SAA modulation: Miridesap (anti-SAA monoclonal antibody) emerging in trials - Most effective: Control underlying inflammation remains standard

Supportive care: Similar to AL (ACE-I/ARB, diuretics)

Hereditary Amyloidosis

ATTRwt (wild-type transthyretin): - Limited specific therapy; supportive care - Tafamidis (stabilizes transthyretin) may slow progression - Renal involvement usually mild

ATTRv (hereditary transthyretin mutations): - Tafamidis (stabilizer) or inotersen (TTR silencer) for neurologic manifestations - Genetic counseling for family members - Renal involvement variable

Renal Outcomes by Type

AL Amyloidosis: - Untreated: Median renal survival 2–3 years (progression to ESRD) - With bortezomib/lenalidomide-based induction: 50% achieve hematologic response; renal outcomes improve significantly [5] - Renal response: Proteinuria may decrease slowly (6–12 months); creatinine typically stabilizes if hematologic response achieved - ASCT in fit patients: Potentially curative in subset; long-term dialysis-free survival improved [1,2]

AA Amyloidosis: - Outcome dependent on underlying disease control: - If inflammation suppressed → amyloid may stabilize or regress - If inflammation persists → progressive renal failure (median 2–5 years) - Rheumatoid arthritis-related: Better prognosis with modern DMARDs/biologics (can slow/halt progression)

Prognostic Factors (AL Amyloidosis)

5-Year Renal Survival

• AL (treated): 60–70% with bortezomib ± ASCT
• AA (inflammation controlled): 60–80%
• Hereditary: Variable (slowly progressive)