renal amyloidosis

**Definition:** Systemic or localized deposition of amyloid, an abnormal proteinaceous material made of misfolded proteins arranged as β-pleated sheets. The deposits are extracellular, eosinophilic and amorphous on H&E. In the kidney, amyloid deposits in the glomeruli (mesangium and capillary walls), and also in vessels and the interstitium.

**Major types affecting the kidney:** - **AL (primary):** Immunoglobulin light chains (usually λ) from a plasma cell dyscrasia, such as multiple myeloma or MGUS. It is the most common type of renal amyloid in developed countries. - **AA (secondary):** Serum amyloid A, an acute-phase reactant made in the liver. It is associated with chronic inflammation: rheumatoid arthritis, IBD, ankylosing spondylitis, chronic infections (TB, osteomyelitis), and familial Mediterranean fever (FMF). AA is the classic cause of renal involvement in "secondary" amyloidosis. - **Hereditary (ATTR, AApoAI, fibrinogen Aα, etc.):** Mutant transthyretin and others. ATTR mostly affects the heart and nerves, with less renal involvement. - **Aβ2-microglobulin:** Seen in long-term dialysis. It deposits mainly in joints and causes carpal tunnel syndrome, with little renal involvement. - **Senile (wild-type ATTR):** Mainly cardiac.

**Pathophysiology:** Overproduction or impaired clearance of a precursor protein leads to misfolding and aggregation into fibrils. Fibrils are stabilized by serum amyloid P component and glycosaminoglycans. Mesangial expansion and capillary wall deposition disrupt the glomerular filtration barrier. This causes heavy proteinuria and progressive loss of GFR.

**Clinical features:** - Nephrotic syndrome: proteinuria >3.5 g/day, hypoalbuminemia, edema, hyperlipidemia, lipiduria. It is a common presentation. - Kidneys are normal or enlarged, even with advanced CKD. This is a high-yield contrast with most chronic kidney diseases, in which the kidneys shrink. - Progression to CKD/ESRD. Hematuria is usually minimal. - Extrarenal findings suggest the type. AL: macroglossia, periorbital purpura ("raccoon eyes"), restrictive cardiomyopathy, hepatosplenomegaly, peripheral/autonomic neuropathy, carpal tunnel syndrome. AA: hepatosplenomegaly, with the heart usually spared. - Complications of nephrotic syndrome: hypercoagulability (renal vein thrombosis), infections. - Orthostatic hypotension can occur from autonomic neuropathy or loss of volume.

**Diagnosis:** - Urinalysis and quantification of proteinuria. Check serum and urine protein electrophoresis with immunofixation and serum free light chains for AL. - **Biopsy** (renal, or abdominal fat pad/rectal biopsy) is the gold standard: - Congo red stain shows **apple-green birefringence under polarized light**. - Electron microscopy shows non-branching fibrils about 7–10 nm in diameter. - Typing by mass spectrometry or immunohistochemistry is essential because treatment depends on type. - On light microscopy, glomeruli show **amorphous, pale eosinophilic hyalinized material** in the mesangium and capillary walls. It is PAS negative (or weakly positive) and **does not stain with silver (silver-negative)**, unlike the silver-positive mesangium in diabetic nodules. - Differential: diabetic nephropathy (Kimmelstiel-Wilson nodules) and light chain deposition disease (Congo red negative).

**Treatment:** - **AL:** Treat the underlying clonal plasma cell disorder: daratumumab-based regimens (daratumumab, cyclophosphamide, bortezomib, dexamethasone), with autologous stem cell transplant in selected patients. - **AA:** Control the underlying inflammatory disease, for example with anti-TNF or anti-IL-1/IL-6 agents. Use **colchicine for FMF** to prevent amyloidosis. - Supportive: diuretics, salt restriction, ACE inhibitor/ARB with caution because of hypotension, dialysis, and kidney transplant in selected patients.

**Prognosis:** It depends on type and cardiac involvement. AL has a worse prognosis, with cardiac involvement the main determinant of mortality.

**High-yield pearls:** - Congo red + apple-green birefringence = amyloid. - Nephrotic syndrome in an older adult with a normal-sized or large kidney: think amyloid, and screen for myeloma. - AA amyloid comes from the acute-phase reactant SAA, in chronic inflammatory disease. - AL amyloid is from light chains, and AL has cardiac, tongue and neurologic involvement. - Other nephrotic causes to compare: minimal change disease (children; fusion of foot processes), FSGS, membranous nephropathy (spike and dome), diabetic nephropathy.