Heavy Chain Deposition Disease

Heavy chain deposition disease is a rare form of monoclonal immunoglobulin deposition disease in which a truncated monoclonal heavy chain (typically gamma, rarely alpha or mu), usually lacking the first constant domain (CH1), deposits along the glomerular and tubular basement membranes without associated light chain. About 5 to 10% of monoclonal immunoglobulin deposition disease is of this type.

Median age is about 55 years, and the disease is more often linked to B-cell lymphoproliferative disorders and smouldering myeloma than to overt myeloma (about 30 to 40% have myeloma). Gamma 1 and gamma 3 subclasses activate complement, so hypocomplementaemia may be present, a distinction from light chain deposition disease.

Pathophysiology. Absence of CH1 prevents binding of heavy chain to the endoplasmic reticulum chaperone and allows secretion of a free heavy chain that deposits in basement membranes, where it induces mesangial matrix expansion and nodular sclerosis, driven by transforming growth factor beta.

• Proteinuria (frequently nephrotic range), haematuria, hypertension (more common than in other deposition diseases), rapidly progressive loss of function with kidney failure in about 50% within 2 to 3 years.
• Low C3 with normal C4 (in gamma 1 and gamma 3 disease), or low C3 and C4.
• Extrarenal deposition (heart, liver) is less frequent than in light chain deposition disease.
• Features of a lymphoproliferative disorder: lymphadenopathy, splenomegaly, anaemia.

Red flags

• Rapid decline in kidney function with crescents or thrombotic microangiopathy on biopsy.
• Hypercalcaemia, lytic bone lesions or anaemia (myeloma).
• Low complement with a monoclonal protein: pathogenic complement activation.
• Serum free light chain ratio normal despite a monoclonal band.

• Serum and urine protein electrophoresis and immunofixation (gamma heavy chain band; antisera against heavy chain without light chain), quantitative immunoglobulins (low uninvolved immunoglobulins), serum free light chains (often normal), C3 and C4.
• Mass spectrometry or heavy chain immunofixation with anti-CH1 antibodies to confirm absent CH1.
• Bone marrow biopsy with plasma cell and B-cell clone characterisation, flow cytometry, cytogenetics; whole body imaging for lymphoma or lytic disease.
• Kidney biopsy: nodular mesangial sclerosis and thickened basement membranes; immunofluorescence with linear staining for heavy chain (IgG1, IgG2, IgG3 or IgG4 subclass staining) but negative for kappa and lambda; electron microscopy with granular, powdery electron dense deposits; Congo red negative.

Differential diagnosis

• Light chain deposition disease, light and heavy chain deposition disease, proliferative glomerulonephritis with monoclonal immunoglobulin deposits, cryoglobulinaemic glomerulonephritis, amyloid, diabetic nodular sclerosis, membranoproliferative glomerulonephritis.

First line: clone directed treatment

• Bortezomib based regimen: bortezomib 1.3 mg/m² subcutaneously on days 1, 8, 15 and 22 of 28-day cycles, cyclophosphamide 300 mg/m² (maximum 500 mg) weekly, dexamethasone 20 to 40 mg weekly, 4 to 6 cycles.
• Add daratumumab 1800 mg subcutaneously (weekly for 8 weeks, every 2 weeks for 16 weeks, then monthly) for myeloma or inadequate response.
• For a B-cell lymphoproliferative disorder, rituximab based therapy under haematology supervision: rituximab 375 mg/m² weekly for 4 doses, or rituximab with bendamustine 90 mg/m² on days 1 and 2 of 28-day cycles for 6 cycles.
• Assess response by serum immunofixation, heavy chain band, and kidney function. Because free light chains are often normal, use serum protein electrophoresis, immunofixation and quantitative immunoglobulins to track response.
• Autologous stem cell transplantation (melphalan 140 mg/m² when eGFR is under 30) for eligible patients with myeloma.

Complement mediated component. When C3 is low and biopsy shows complement activation, treatment of the clone usually normalises C3; no specific complement inhibitor is established.

Supportive care

• Blood pressure below 130/80 mmHg; ramipril 2.5 mg daily increased to 10 mg daily; furosemide 40 to 80 mg for oedema; sodium below 2 g daily; avoid nephrotoxins.
• Co-trimoxazole 480 mg daily and aciclovir 400 mg twice daily during therapy; bone protection for myeloma.

Kidney replacement therapy. Dialysis at eGFR 5 to 10 with symptoms; transplantation after sustained haematological remission; recurrence is high without remission.

Monitoring. Immunofixation and protein electrophoresis monthly during therapy; creatinine, protein:creatinine ratio, C3 every 1 to 3 months; imaging for lymphoma yearly.

Referral and escalation. Haematology and nephrology together from diagnosis; transplant centre when eGFR is under 20 mL/min/1.73 m².

Special groups

• Older adults: reduced intensity regimens; rituximab based therapy for lymphoproliferative clones.
• Pregnancy: rare; avoid cyclophosphamide and bortezomib; manage with haematology.