Amyloid Nephrotic Syndrome

Amyloid nephrotic syndrome is nephrotic range proteinuria caused by glomerular amyloid deposition. It is the presenting kidney manifestation of systemic amyloidosis in over 70% of patients with renal involvement. Heavy albuminuria with preserved or enlarged kidneys, normal or low blood pressure and early heart involvement characterise the syndrome.

Types of amyloid:

• AL amyloid is the commonest type. It derives from a monoclonal light chain from a plasma cell or B-cell clone, usually lambda. It accounts for about 70% of renal amyloid in high income settings.
• AA amyloid derives from serum amyloid A in chronic inflammation, such as rheumatoid arthritis, inflammatory bowel disease, familial Mediterranean fever, bronchiectasis, chronic osteomyelitis and tuberculosis. It is the commonest type in many low resource settings.
• Rarely, ALECT2, hereditary fibrinogen, apolipoprotein A-I and lysozyme amyloid.

Median survival of untreated AL amyloid with cardiac involvement is under 1 year, whereas kidney limited disease progresses over years.

Pathophysiology. Misfolded precursor proteins aggregate into non-branching fibrils 7 to 12 nm in diameter. These infiltrate the mesangium, capillary walls and vessels, distorting the filtration barrier and effacing podocytes. Amyloid fibrils and precursor light chains are directly toxic to cells.

• Nephrotic syndrome: heavy albuminuria (3 to 15 g daily), hypoalbuminaemia, oedema, hyperlipidaemia, often with normal or low blood pressure and postural hypotension.
• Kidney size normal or enlarged on ultrasound even with advanced loss of function.
• AL amyloid: macroglossia, periorbital purpura, bruising, carpal tunnel syndrome, neuropathy (sensory and autonomic), hepatomegaly, restrictive heart failure, acquired factor X deficiency with bleeding.
• AA amyloid: background chronic inflammation; splenomegaly, diarrhoea, hepatomegaly; heart involvement is rare.
• Thrombosis risk is lower than in other nephrotic syndromes, and bleeding is a feature of AL disease.

Red flags

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

• Baseline tests: urine protein:creatinine ratio, albumin, lipids, creatinine, eGFR, liver tests, coagulation including factor X, thyroid function, cortisol.
• Paraprotein tests: urine and serum protein electrophoresis with immunofixation, serum free light chains (difference between involved and uninvolved above 50 mg/L supports AL), serum amyloid A, C-reactive protein.
• Tissue diagnosis: biopsy of the kidney (diagnostic yield about 100%) or fat pad aspirate, rectal or salivary gland biopsy (70 to 90% sensitive in AL).
• Congo red shows apple green birefringence under polarised light. Electron microscopy shows fibrils of 7 to 12 nm.
• Typing is essential: immunohistochemistry or immunofluorescence, and laser microdissection with mass spectrometry as the reference method.
• Do not assume AL because a paraprotein is present (up to 10% of AA and transthyretin patients have a coincidental paraprotein).
• Cardiac assessment: ECG, echocardiography with strain (apical sparing), NT-proBNP and troponin T, cardiac MRI (group II agents only when eGFR is at least 30), technetium pyrophosphate scintigraphy for transthyretin.
• Bone marrow biopsy with clonality studies, skeletal survey or low dose whole body CT, genetic testing for hereditary types.

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: daratumumab 1800 mg subcutaneously weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, then every 4 weeks.
• Give it 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). Use 28-day cycles for 6 cycles, then daratumumab maintenance for up to 2 years.
• Premedicate with paracetamol 1 g, chlorphenamine 4 mg and methylprednisolone 100 mg. Give co-trimoxazole 480 mg daily and aciclovir 400 mg twice daily.
• Autologous stem cell transplantation (melphalan 140 mg/m² when eGFR is under 30, 200 mg/m² otherwise) only in selected patients with minimal cardiac involvement, troponin T under 0.06 microg/L, eGFR at least 30 and good performance status.
• Response is judged by involved free light chain fall and proteinuria. Renal response is at least 30% fall in proteinuria without a drop in eGFR above 25%. Depth and speed of response predict kidney survival.
• Refractory or relapsed: venetoclax if t(11;14) is present, or pomalidomide, with haematology.

AA amyloid: suppress inflammation

• Treat the cause (antimicrobials, 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 (halve when eGFR is under 30; monitor creatine kinase and blood count). Refractory: anakinra 100 mg subcutaneously daily or canakinumab 150 mg every 4 weeks.
• Rheumatoid arthritis: 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 daily, vutrisiran 25 mg subcutaneously every 3 months, or patisiran 0.3 mg/kg every 3 weeks, with cardiology and neurology. Hereditary fibrinogen amyloid: liver kidney transplantation. ALECT2: supportive care.

Supportive care for the nephrotic syndrome

• Furosemide 40 to 80 mg once or twice daily (torasemide 20 to 40 mg for gut oedema); sodium 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 with caution for oedema.
• ACE inhibitors and angiotensin receptor blockers are poorly tolerated. Use only if systolic pressure is above 110 mmHg (ramipril 2.5 mg daily). Avoid digoxin, verapamil, diltiazem and beta blockers in cardiac amyloid.
• Albumin infusion (20% albumin 100 mL with furosemide 40 mg) for refractory oedema with symptomatic hypotension.
• Anticoagulation for atrial fibrillation (apixaban 5 mg twice daily; 2.5 mg twice daily with 2 of age 80 or over, weight 60 kg or under, creatinine 133 micromol/L or over), or for albumin under 20 g/L with other risks.
• Bleeding from factor X deficiency: fresh frozen plasma or cryoprecipitate.
• Nutrition, treat anaemia, and plan early for dialysis (peritoneal dialysis may be better tolerated than haemodialysis because of hypotension). Kidney transplantation after a sustained haematological complete response.

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. Haematology and nephrology the same week for AL; cardiology for cardiac involvement; specialised amyloidosis centre where available.

Special groups

• Older adults: reduce dexamethasone and bortezomib doses; prioritise cardiac status.
• Dialysis patients: beta-2 microglobulin amyloid affects bones and joints, not the kidneys.
• Children: AA amyloid from juvenile arthritis or familial Mediterranean fever; colchicine from diagnosis prevents it.
• Low resource settings: AA amyloid from tuberculosis, bronchiectasis and chronic infection is more frequent; treat the infection and use colchicine for familial Mediterranean fever where available.