Immunotactoid Glomerulopathy

Immunotactoid glomerulopathy is a rare glomerular disease characterised by organised microtubular deposits of immunoglobulin 30 to 50 nm in diameter (above 30 nm), arranged in parallel arrays within the mesangium and capillary walls, which are Congo red negative and DNAJB9 negative. It accounts for under 0.1% of native kidney biopsies, about one tenth as common as fibrillary glomerulonephritis.

Unlike fibrillary disease, deposits are usually monoclonal (IgG kappa or lambda, with IgG1 and IgG3 predominance), and most patients have a B-cell lymphoproliferative disorder (chronic lymphocytic leukaemia, lymphoma, or a monoclonal gammopathy) or an autoimmune disease. Typical age is 50 to 60 years, with males slightly more affected.

Pathophysiology. Monoclonal immunoglobulin with high self-aggregation propensity forms organised microtubules that deposit in glomeruli, activating complement and inducing mesangial and endocapillary proliferation, with membranoproliferative or membranous patterns.

• Nephrotic syndrome (about 60%), proteinuria, microscopic haematuria, hypertension, and chronic kidney disease or kidney failure.
• Rapid deterioration with crescents in a minority.
• Features of the underlying clone: lymphadenopathy, splenomegaly, lymphocytosis, anaemia, hypogammaglobulinaemia.
• Cryoglobulinaemia in some patients (purpura, neuropathy, low C4).

Red flags

• Rapid decline in kidney function or nephrotic syndrome with thrombosis.
• Lymphocytosis (absolute lymphocyte count above 5 x 10⁹/L), lymphadenopathy or constitutional symptoms.
• Hypocomplementaemia or cryoglobulins: overlapping cryoglobulinaemic glomerulonephritis.

• Full blood count and film, flow cytometry of peripheral blood, serum protein electrophoresis and immunofixation, free light chains, quantitative immunoglobulins, C3, C4, cryoglobulins, rheumatoid factor, hepatitis B and C, HIV, antinuclear antibodies.
• Imaging (CT chest, abdomen and pelvis) and bone marrow biopsy with flow cytometry and cytogenetics to identify the clone.
• Kidney biopsy: membranoproliferative, membranous or mesangial proliferative pattern on light microscopy. Immunofluorescence with IgG (often monotypic IgG with light chain restriction) and C3. Electron microscopy shows hollow microtubules 30 to 50 nm in diameter in parallel arrays. Congo red negative; DNAJB9 negative; mass spectrometry shows immunoglobulin without DNAJB9.

Differential diagnosis

• Fibrillary glomerulonephritis (fibrils 12 to 24 nm, DNAJB9 positive), cryoglobulinaemic glomerulonephritis (type I or II cryoglobulin, microtubules in cryoglobulin deposits), amyloid, lupus nephritis, light chain proximal tubulopathy, proliferative glomerulonephritis with monoclonal immunoglobulin deposits.

First line: treat the underlying clone

• Chronic lymphocytic leukaemia or small lymphocytic lymphoma needing therapy:
  • Ibrutinib 420 mg orally daily, or acalabrutinib 100 mg twice daily.
  • Or rituximab with bendamustine (bendamustine 90 mg/m² on days 1 and 2, rituximab 375 mg/m² in cycle 1 then 500 mg/m², every 28 days for 6 cycles).
  • Indications to treat the haematological disease include progressive kidney disease.
• Monoclonal gammopathy of renal significance or plasma cell clone:
  • Bortezomib 1.3 mg/m² subcutaneously on days 1, 8, 15 and 22 with cyclophosphamide 300 mg/m² (maximum 500 mg) weekly and dexamethasone 20 to 40 mg weekly, for 4 to 6 cycles.
  • Add daratumumab 1800 mg subcutaneously for myeloma or inadequate response.
• B-cell lymphoma: rituximab based chemoimmunotherapy under haematology.
• Without a clone, or when response is incomplete: rituximab 1 g intravenously on days 1 and 15 (or 375 mg/m² weekly for 4 doses), repeated every 6 months if effective.
• Crescentic or rapidly progressive disease:
  • Methylprednisolone 500 mg to 1 g intravenously for 3 days, then prednisolone 1 mg/kg daily (maximum 60 mg) tapered over 6 months.
  • Plus cyclophosphamide 15 mg/kg intravenously every 2 weeks for 3 doses, then every 3 weeks; reduced to 12.5 mg/kg at age 60 to 70 and 10 mg/kg over age 70.
• Prophylaxis: co-trimoxazole 480 mg daily, aciclovir 400 mg twice daily, hepatitis B screening before rituximab, and immunoglobulin replacement if IgG is under 4 g/L with recurrent infection.

Supportive care

• Blood pressure under 130/80 mmHg; ramipril 2.5 mg daily increased to 10 mg daily (stop if potassium exceeds 6.0 mmol/L); sodium restriction under 2 g daily; furosemide 40 to 80 mg for oedema; statin; anticoagulation for albumin under 20 g/L with additional risk.
• Dapagliflozin 10 mg daily if eGFR is at least 25.

Kidney failure. Dialysis at eGFR 5 to 10 with symptoms; kidney transplantation after remission of the clone; recurrence in the graft can occur, particularly if the clone persists.

Monitoring. Creatinine, protein:creatinine ratio and albumin every 1 to 3 months; immunofixation and free light chains every 3 months; lymphocyte count and imaging as set by haematology.

Referral and escalation. Nephrology and haematology together from diagnosis; transplant planning when eGFR is under 20.

Special groups

• Older adults: lower intensity regimens and attention to infection risk.
• Pregnancy: avoid cyclophosphamide, bendamustine and bortezomib; manage with haematology.