Monoclonal Immunoglobulin Deposition Disease

Monoclonal immunoglobulin deposition disease is a group of non-amyloid disorders in which a monoclonal immunoglobulin or part of one deposits along basement membranes of glomeruli, tubules and blood vessels, producing nodular glomerulosclerosis and progressive loss of kidney function. It has three forms: light chain deposition disease (about 80% of cases), light and heavy chain deposition disease, and heavy chain deposition disease.

Patients are typically aged 55 to 60 years. A plasma cell neoplasm (multiple myeloma in 40 to 60%, smouldering myeloma or monoclonal gammopathy of renal significance in the rest) underlies the disease. The deposits are granular, electron dense and powdery, and are not Congo red positive.

Pathophysiology. Abnormal monoclonal immunoglobulin variable region structure (kappa light chains, especially VK4, or heavy chains lacking the first constant domain) makes the protein prone to deposit. Deposited protein stimulates mesangial cells to secrete transforming growth factor beta, driving matrix expansion and nodular sclerosis.

• Proteinuria, usually albumin predominant and under 3 g daily in light chain disease, with nephrotic syndrome in 40%.
• Microscopic haematuria, hypertension (more frequent than in amyloid), rapidly or slowly progressive loss of kidney function, often to kidney failure within 2 to 3 years.
• Extrarenal deposits in the heart, liver, nerves and skeletal muscle; cardiac failure and hepatic dysfunction in a minority.
• Features of myeloma: bone pain, anaemia, hypercalcaemia.

Red flags

• Rapid decline in eGFR with a monoclonal band.
• Heart failure with preserved ejection fraction and low voltage ECG.
• Hypercalcaemia, lytic bone lesions, bone marrow plasma cells above 10%: myeloma.
• Cast nephropathy superimposed (acute kidney injury, markedly raised free light chains).

• Serum protein electrophoresis with immunofixation, urine immunofixation, serum free light chains with ratio and quantitative immunoglobulins. The ratio is abnormal in 90 to 95% of light chain deposition disease and may be near normal in heavy chain forms.
• Bone marrow aspirate and biopsy with cytogenetics, skeletal imaging, calcium, haemoglobin, beta-2 microglobulin and lactate dehydrogenase to stage the plasma cell disorder.
• Kidney biopsy, light microscopy: nodular glomerulosclerosis (Kimmelstiel-Wilson-like nodules) and thickened tubular basement membranes.
• Kidney biopsy, immunofluorescence: linear glomerular and tubular basement membrane staining for a single light chain (kappa in 80%) or heavy chain.
• Kidney biopsy, electron microscopy: punctate, powdery electron dense deposits on the inner aspect of basement membranes. Congo red is negative.
• Typing by mass spectrometry when immunofluorescence is equivocal.

Differential diagnosis

• Diabetic nodular glomerulosclerosis (diabetes, retinopathy, no paraprotein).
• Amyloid (Congo red positive, fibrils).
• Membranoproliferative glomerulonephritis, fibrillary glomerulonephritis, proliferative glomerulonephritis with monoclonal immunoglobulin deposits and light chain cast nephropathy.

First line: clone directed therapy

• Bortezomib based induction: bortezomib 1.3 mg/m² subcutaneously on days 1, 8, 15 and 22 of 28-day cycles, cyclophosphamide 300 mg/m² (maximum 500 mg) orally or intravenously weekly, and dexamethasone 20 to 40 mg weekly, for 4 to 6 cycles, then reassess.
• Add daratumumab 1800 mg subcutaneously (weekly for weeks 1 to 8, every 2 weeks for weeks 9 to 24, then monthly) in patients with myeloma or high risk features.
• Aim for a very good partial haematological response or better (involved free light chain under 40 mg/L or a fall of at least 90%); the speed and depth of response predict kidney recovery.
• Autologous stem cell transplantation with melphalan 140 to 200 mg/m² (140 mg/m² if eGFR is under 30) for eligible patients with persistent disease or high risk myeloma.
• Prophylaxis: aciclovir 400 mg twice daily, co-trimoxazole 480 mg daily, bisphosphonate (zoledronic acid dose adjusted for eGFR) for myeloma bone disease, venous thromboembolism prophylaxis if immunomodulatory drugs are used.

Supportive care

• Blood pressure below 130/80 mmHg; ramipril 2.5 mg daily increased to 10 mg daily (creatinine and potassium in 1 to 2 weeks; stop if potassium exceeds 6.0 mmol/L); sodium restriction under 2 g daily; furosemide 40 to 80 mg for oedema; statin.
• Treat anaemia, mineral and bone disorder and acidosis at usual thresholds; plan renal replacement therapy when eGFR is under 15 mL/min/1.73 m².

Kidney transplantation. After sustained haematological complete response (at least 6 to 12 months); recurrence risk is high (about 70%) in untreated clones, so continue surveillance of free light chains.

Monitoring. Free light chains, immunofixation, creatinine and urine protein monthly during therapy, then every 3 months; bone marrow after treatment if complete response is claimed.

Referral and escalation. Haematology and nephrology together from diagnosis; transplant centre when kidney failure is approaching.

Special groups

• Older adults: reduced doses of dexamethasone and bortezomib, avoid melphalan.
• Dialysis dependent: bortezomib needs no dose reduction; avoid renally cleared drugs; kidney recovery is possible in some after complete response.