Monoclonal Gammopathy–Associated Proliferative Glomerulonephritis

doi:10.1016/j.mayocp.2013.08.002

Mayo Clinic Proceedings

Volume 88, Issue 11, November 2013, Pages 1284-1293

https://doi.org/10.1016/j.mayocp.2013.08.002 Get rights and content

Abstract

Monoclonal gammopathy is characterized by circulating monoclonal immunoglobulin owing to clonal proliferation of immunoglobulin-producing B lymphocytes or plasma cells. Clonal proliferation of B lymphocytes is seen in B-cell lymphoma/leukemia, and clonal plasma cell proliferation is seen in multiple myeloma and monoclonal gammopathy of undetermined significance. The monoclonal immunoglobulin in the setting of a B-cell or plasma cell disorder can cause a proliferative glomerulonephritis via 2 mechanisms: (1) glomerular deposition of the monoclonal immunoglobulin with activation of the classical pathway of complement (direct mechanism), resulting in an immunoglobulin-positive C3-positive glomerulonephritis, and (2) glomerular deposition of complement factors of the alternative and terminal pathway via inhibition of alternative pathway–regulating proteins by the monoclonal immunoglobulin (indirect mechanism), resulting in immunoglobulin-negative C3-positive glomerulonephritis (C3 glomerulopathy). Evaluation should include serum and urine electrophoresis and immunofixation as well as serum-free light-chain assay. If a monoclonal immunoglobulin is detected on these tests, bone marrow biopsy or imaging is needed to exclude more advanced plasma cell dyscrasia. Evaluation of alternative pathway of complement should be done in patients with Ig-negative C3-positive glomerulonephritis. If monoclonal gammopathy is due to an underlying malignant disease such as myeloma, lymphoma, or chronic lymphocytic leukemia, then specific treatment should be aimed at treating the malignant disease, with the goal of eradicating the clonal cells producing the immunoglobulin. In contrast, if monoclonal gammopathy is due to a monoclonal gammopathy of undetermined significance, treatment options include bortezomib, cyclophosphamide, and dexamethasone for a non-IgM monoclonal immunoglobulin and rituximab alone or in combination with cyclophosphamide and dexamethasone for an IgM monoclonal immunoglobulin.

Section snippets

Direct Mechanism

In the direct mechanism, proliferative glomerulonephritis results from the deposition of the monoclonal immunoglobulin and complement factors of the classical and terminal pathways in the glomeruli.

Indirect Mechanism

In the indirect mechanism, monoclonal immunoglobulin causes dysregulation of the alternative pathway, and thus, there is deposition of complement factors of the alternative and terminal pathways in the glomeruli, with the development of C3 glomerulopathy.

Recurrent Graft Injury

Membranoproliferative glomerulonephritis of any etiology tends to recur in the graft, and recent studies have reported a recurrence rate of 40% to 60%.³⁰ A recent study by Lorenz et al³⁰ found that the risk of recurrence is particularly high in the presence of circulating monoclonal immunoglobulin. The increased risk of recurrence is not surprising because monoclonal gammopathy has not been the target of treatment in these patients. Recurrence tends to be early and is often clinically much more

Evaluation

The diagnosis of monoclonal gammopathy–associated glomerulonephritis should be suspected in any patient with clinical or histopathologic evidence of proliferative glomerulonephritis in whom there are no other identifiable causes such as infections (especially hepatitis C) or autoimmune disease. Immunofluorescence examination of the kidney biopsy is essential for the evaluation of all cases of proliferative glomerulonephritis (Figure 4). In the direct mechanism, immunofluorescence microscopy

Management

Because monoclonal gammopathy–associated glomerulonephritis is a newly described entity, there are no studies to determine the optimal approach to therapy. Recommendations for therapy are therefore primarily based on clinical opinion and experience, as well as data on the feasibility, response rate, and toxicity of various regimens used in the treatment of multiple myeloma and related plasma cell malignant diseases, in which the goal of therapy is essentially the same, that is, eradication of

Conclusion

Monoclonal gammopathy–associated proliferative glomerulonephritis can occur either from the deposition of the monoclonal immunoglobulin and complement factors of the classical and terminal pathways (direct mechanism) or from the deposition of complement factors of the alternative and terminal pathways as a consequence of the activation of the alternative pathway of complement by the monoclonal immunoglobulin (indirect mechanism). We have proposed an algorithm for the evaluation and treatment of

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ReviewMonoclonal Gammopathy–Associated Proliferative Glomerulonephritis

Abstract

Section snippets

Direct Mechanism

Indirect Mechanism

Recurrent Graft Injury

Evaluation

Management

Conclusion

Blood

Lancet

Mayo Clin Proc

Mayo Clinic Proc

Mayo Clinic Proc

Am J Kidney Dis

Blood

Kidney Int

Kidney Int

Am J Kidney Dis

Kidney Int

Mod Pathol

Kidney Int

Kidney Int

Mayo Clin Proc

A long-term study of prognosis in monoclonal gammopathy of undetermined significance

N Engl J Med

Criteria for diagnosis, staging, risk stratification and response assessment of multiple myeloma

Leukemia

Review
Monoclonal Gammopathy–Associated Proliferative Glomerulonephritis