amyloid nephropathy

Amyloid nephropathy results from extracellular deposition of misfolded, insoluble protein fibrils in the kidney, most commonly in the glomerular mesangium and capillary walls, though tubulointerstitial and vascular deposition can also occur. There are two main types relevant to renal disease: AL (primary) amyloidosis, derived from immunoglobulin light chains produced by a clonal plasma cell dyscrasia (associated with multiple myeloma or MGUS), and AA (secondary) amyloidosis, derived from serum amyloid A protein, an acute phase reactant elevated in chronic inflammatory or infectious conditions (e.g., rheumatoid arthritis, inflammatory bowel disease, chronic osteomyelitis, familial Mediterranean fever). Both fibril types share a beta-pleated sheet structure that binds Congo red stain and exhibits apple-green birefringence under polarized light—the classic diagnostic finding on renal biopsy. Electron microscopy shows randomly arranged, non-branching fibrils approximately 8-12 nm in diameter. Clinically, amyloid nephropathy typically presents with nephrotic syndrome: heavy proteinuria (often >3.5g/day), hypoalbuminemia, edema, and hyperlipidemia. Renal function may be normal early but progressively declines as amyloid deposits accumulate, potentially leading to end-stage renal disease. Kidneys may appear large and waxy on imaging, differentiating it from other causes of chronic kidney disease where kidneys are typically shrunken. Systemic amyloidosis often involves other organs including the heart (restrictive cardiomyopathy, arrhythmias), liver (hepatomegaly), peripheral and autonomic nervous system, and GI tract (macroglossia is characteristic of AL type). Diagnosis requires tissue biopsy (renal or other affected organ, or fat pad aspirate) with Congo red staining; immunohistochemistry or mass spectrometry helps distinguish AL from AA type, which is critical since treatment differs significantly. Treatment for AL amyloidosis targets the underlying plasma cell clone (e.g., bortezomib-based chemotherapy, autologous stem cell transplant), while AA amyloidosis treatment focuses on controlling the underlying inflammatory disease and reducing serum amyloid A levels. Prognosis is generally poor, particularly with cardiac involvement, though early diagnosis and treatment can improve outcomes.