Amyloid Nephropathy

Amyloid nephropathy is glomerular and vascular deposition of amyloid fibrils. These are insoluble beta pleated sheet proteins that stain with Congo red and show apple green birefringence under polarised light.

In the kidney the common types are:

• AL amyloid (monoclonal immunoglobulin light chain, usually lambda): about 70 to 80% of renal amyloid in high income countries.
• AA amyloid (serum amyloid A): from chronic inflammation or infection.
• Less often, ALECT2, hereditary fibrinogen A alpha chain, apolipoprotein A-I, lysozyme and transthyretin amyloid.

AL amyloid has an incidence of about 10 cases in each million people each year, with a median age of 65 years, and arises from a plasma cell or B-cell clone. Kidney involvement occurs in about 70% of AL amyloid and 90% of AA amyloid.

Pathophysiology. Misfolded precursor proteins aggregate into fibrils that deposit in the mesangium and along glomerular capillary walls, effacing podocytes and causing nephrotic range proteinuria. Vascular and interstitial deposition causes progressive loss of function. Amyloid is directly toxic to cells, notably cardiomyocytes in AL disease.

• Nephrotic syndrome is the commonest presentation, with heavy albuminuria, hypoalbuminaemia, oedema and hyperlipidaemia. Isolated proteinuria also occurs. Blood pressure is usually normal or low (orthostatic hypotension).
• Kidney size is normal or enlarged, even with advanced loss of function.
• AL amyloid extrarenal features: macroglossia, periorbital purpura ("raccoon eyes"), easy bruising, hepatomegaly, carpal tunnel syndrome, sensory and autonomic neuropathy, diarrhoea or constipation, weight loss.
• AL amyloid cardiac and haematological features: heart failure with restrictive cardiomyopathy, and acquired factor X deficiency causing bleeding.
• AA amyloid: background of rheumatoid arthritis, inflammatory bowel disease, bronchiectasis, osteomyelitis, tuberculosis, familial Mediterranean fever or chronic skin sepsis; splenomegaly and diarrhoea.

Red flags

• Proteinuria with heart failure with preserved ejection fraction and low voltage ECG: cardiac amyloid.
• Syncope or postural hypotension, rapidly falling eGFR, or NT-proBNP above 1800 ng/L with troponin T above 0.025 microg/L (poor prognosis).
• Unexplained bleeding or periorbital bruising.
• Nephrotic syndrome in a patient over 50 with a monoclonal band.

• Urine protein:creatinine ratio (albumin dominant, 3 to 15 g daily), albumin, creatinine, cholesterol.
• Urine and serum protein electrophoresis with immunofixation, and serum free light chains (difference between involved and uninvolved above 50 mg/L supports AL).
• Tissue diagnosis: biopsy of the kidney (diagnostic yield about 100%) or an easier site (abdominal fat pad aspirate, rectal or salivary gland biopsy, about 70 to 90% sensitive in AL).
• Congo red shows apple green birefringence. Electron microscopy shows randomly arranged non-branching fibrils 7 to 12 nm in diameter.
• Typing is essential: immunohistochemistry or immunofluorescence, and laser microdissection with mass spectrometry as the reference method. Do not assume AL because of a paraprotein.
• Cardiac assessment: ECG, echocardiography with strain (apical sparing), NT-proBNP and troponin T.
• Also cardiac MRI with late gadolinium enhancement (use group II agents only if eGFR is at least 30), and technetium pyrophosphate scintigraphy for transthyretin amyloid.
• Bone marrow biopsy with plasma cell clonality, skeletal survey or whole body low dose CT.
• Serum amyloid A and C-reactive protein for AA, and genetic testing for hereditary types (transthyretin, fibrinogen, apolipoprotein A-I).
• Liver, thyroid and adrenal function, coagulation including factor X, and bleeding risk.

Differential diagnosis

• Light chain deposition disease, fibrillary glomerulonephritis (Congo red negative, DNAJB9 positive), diabetic nephropathy, minimal change disease, membranous nephropathy, focal segmental glomerulosclerosis, cryoglobulinaemic glomerulonephritis.

AL amyloid: treat the clone (urgent; start within weeks)

• First line (not transplant dependent): daratumumab 1800 mg subcutaneously weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, then every 4 weeks.
• Combine with cyclophosphamide 300 mg/m² weekly (maximum 500 mg), bortezomib 1.3 mg/m² subcutaneously weekly and dexamethasone 40 mg weekly (20 mg in frail patients or with fluid retention). Give in 28-day cycles for 6 cycles, then daratumumab maintenance for up to 2 years.
• Premedicate daratumumab with paracetamol 1 g, chlorphenamine 4 mg and methylprednisolone 100 mg. Give co-trimoxazole prophylaxis and aciclovir 400 mg twice daily (zoster prophylaxis during bortezomib).
• Autologous stem cell transplantation (melphalan 140 to 200 mg/m²) only in selected patients with no or limited cardiac involvement, troponin T below 0.06 microg/L, eGFR at least 30, and good performance status.
• Response is judged by the fall in involved free light chain (haematological response) and by proteinuria (renal response: at least 30% reduction in proteinuria and no worsening of eGFR by more than 25%). A rapid, deep haematological response prolongs kidney survival.
• Refractory or relapsed: venetoclax if t(11;14) is present, or pomalidomide, with haematology.

AA amyloid: suppress the inflammation

• Treat the cause (antimicrobials for infection, surgery for osteomyelitis, biological therapy for arthritis or inflammatory bowel disease). Target serum amyloid A under 10 mg/L.
• Familial Mediterranean fever: colchicine 1 to 2 mg daily (reduce by half when eGFR is under 30 and monitor creatine kinase and blood count). Refractory: anakinra 100 mg subcutaneously daily or canakinumab 150 mg subcutaneously every 4 weeks.
• Rheumatoid arthritis or other autoimmune disease: tocilizumab 8 mg/kg intravenously every 4 weeks (or 162 mg subcutaneously weekly) or a TNF inhibitor.

Transthyretin amyloid with kidney involvement. Tafamidis 61 mg orally daily, or vutrisiran 25 mg subcutaneously every 3 months, or patisiran 0.3 mg/kg intravenously every 3 weeks, with cardiology and neurology input. ALECT2 and fibrinogen amyloid: supportive care; liver kidney transplantation for fibrinogen type.

Supportive care

• Diuretics: furosemide 40 to 80 mg once or twice daily (torasemide 20 to 40 mg for gut oedema); salt restriction under 2 g daily; spironolactone only with close potassium monitoring.
• Postural hypotension: midodrine 5 to 10 mg three times daily (last dose 4 hours before bed), compression stockings, fludrocortisone 0.1 mg daily (caution with oedema).
• ACE inhibitors and angiotensin receptor blockers are poorly tolerated with low blood pressure. Use only if systolic pressure is above 110 mmHg. Avoid digoxin, verapamil, diltiazem and beta blockers in cardiac amyloid.
• Anticoagulation for atrial fibrillation or albumin under 20 g/L with thrombotic risk. Bleeding from factor X deficiency: cryoprecipitate or fresh frozen plasma, and avoid antiplatelets.
• Nutritional support, treat anaemia, and plan early for dialysis (poor tolerance from hypotension; peritoneal dialysis may be better).
• Kidney transplantation after a sustained haematological complete response; combined heart kidney transplantation for selected patients.

Monitoring. Free light chains and immunofixation monthly during treatment, proteinuria and eGFR every 3 months, NT-proBNP and troponin every 3 months. Serum amyloid A and C-reactive protein every 1 to 3 months in AA.

Referral and escalation. Same week haematology and nephrology for AL amyloid; cardiology for any cardiac involvement; specialised amyloidosis centre if available.

Special groups

• Older adults: reduced dexamethasone and bortezomib dose; focus on cardiac status.
• Dialysis patients: dialysis related beta-2 microglobulin amyloid affects joints and bones rather than kidneys.
• Children: AA amyloid from juvenile arthritis or familial Mediterranean fever; early colchicine prevents it.