Light Chain Deposition Disease

Light chain deposition disease is the commonest form of monoclonal immunoglobulin deposition disease, in which a monoclonal light chain (kappa in about 80%, usually of VK4 subgroup) deposits as granular, non-amyloid material along glomerular and tubular basement membranes. It presents at a median age of 58 years, with 40 to 60% having multiple myeloma and most of the rest having monoclonal gammopathy of renal significance.

Nodular mesangial sclerosis and thickened basement membranes cause proteinuria and progressive loss of kidney function. Without treatment, about 60 to 70% reach kidney failure within 3 years.

Differences from amyloid. Deposits are Congo red negative, granular on electron microscopy, and consist of whole light chain variable regions that are less prone to fibril formation.

• Proteinuria (mean 2 to 4 g daily; nephrotic syndrome in about 40%), microscopic haematuria, hypertension in two thirds, oedema.
• Rapidly or slowly progressive loss of kidney function; acute kidney injury in coexisting cast nephropathy.
• Extrarenal: cardiac (heart failure, arrhythmia), hepatic (abnormal liver tests), neurological (neuropathy), and rarely joint or lung involvement.
• Myeloma features: anaemia, bone pain, hypercalcaemia, recurrent infection.

Red flags

• Creatinine rising over days to weeks, or oliguria.
• Hypercalcaemia, anaemia, lytic lesions with kidney injury (myeloma with cast nephropathy).
• Heart failure or conduction disease.
• Free light chain ratio markedly abnormal (above 100) or involved free light chain above 500 mg/L.

• Serum free light chains with ratio (kappa:lambda abnormal in over 90%), serum protein electrophoresis and immunofixation (a band is present in only 60%), urine immunofixation; urine protein:creatinine ratio, creatinine, calcium, albumin, haemoglobin.
• Bone marrow biopsy with plasma cell percentage and cytogenetics (including t(11;14), del(17p)), skeletal imaging.
• Kidney biopsy: nodular glomerulosclerosis, thickened tubular basement membranes.
• Immunofluorescence: linear staining for a single light chain (kappa in 80%) along glomerular and tubular basement membranes.
• Electron microscopy: powdery, punctate, electron dense deposits on the inner aspect of the tubular basement membrane.
• Congo red negative.

Differential diagnosis

• Diabetic nodular glomerulosclerosis, light chain amyloidosis, light chain cast nephropathy, membranoproliferative glomerulonephritis, hypertensive nephrosclerosis, fibrillary glomerulonephritis, idiopathic nodular glomerulosclerosis in smokers with hypertension.

First line: suppress the light chain

• Bortezomib 1.3 mg/m² subcutaneously on days 1, 8, 15 and 22 (28-day cycle) with cyclophosphamide 300 mg/m² (maximum 500 mg) weekly and dexamethasone 20 to 40 mg weekly, for 4 to 6 cycles, followed by response assessment. Add daratumumab 1800 mg subcutaneously weekly for 8 weeks, every 2 weeks for 16 weeks, then monthly in myeloma or inadequate response.
• Target: involved free light chain reduction of at least 90% (or involved free light chain under 40 mg/L) within 3 to 6 months; complete or very good partial responses are associated with stabilisation or improvement of kidney function in two thirds of patients.
• Autologous stem cell transplantation (melphalan 140 mg/m² if eGFR is under 30; 200 mg/m² otherwise) for suitable patients, with consolidation using bortezomib.
• Cast nephropathy with acute kidney injury (urgent treatment of myeloma): dexamethasone 40 mg daily for 4 days, bortezomib based chemotherapy, hydration to maintain urine output above 3 litres daily, correction of hypercalcaemia, and high-cut-off haemodialysis for dialysis dependent patients in selected settings.
• Supportive: aciclovir 400 mg twice daily, co-trimoxazole 480 mg daily, antacid or proton pump inhibitor.

Renoprotection

• Blood pressure below 130/80 mmHg with ramipril 2.5 mg to 10 mg daily; furosemide 40 to 80 mg for oedema; sodium under 2 g daily; avoid NSAIDs, iodinated contrast and other nephrotoxins; adequate hydration.

Kidney replacement therapy. Dialysis at eGFR 5 to 10 with symptoms or complications; transplant after complete haematological remission (preferably 12 months), with free light chain surveillance every 3 months (recurrence risk is high without remission).

Monitoring. Free light chains monthly during induction, then every 3 months; proteinuria and eGFR every 1 to 3 months.

Referral and escalation. Haematology and nephrology same week; urgent admission for acute kidney injury with hypercalcaemia or very high free light chains.

Special groups

• Older adults: lower intensity regimens (bortezomib weekly with cyclophosphamide and reduced dose dexamethasone).
• Transplant recipients: recurrence after kidney transplantation may reach 70% if the clone is not suppressed.