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Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?

ABSTRACT: BACKGROUND AND OBJECTIVES: Glomerular deposition of monoclonal Ig has been exceptionally described as the cause of membranoproliferative glomerulonephritis, through activation of the complement alternative pathway (CAP). DESIGN, SETTING, PARTICIPANTS, & MEASUREMENTS: We retrospectively studied six adults with monoclonal gammopathy and glomerulonephritis (GN) characterized by isolated C3 deposits. RESULTS: All patients presented with hematuria, associated with chronic renal failure and proteinuria in five patients, three of whom had nephrotic syndrome. Five patients had monoclonal gammopathy of undetermined significance and one had smoldering myeloma. The serum monoclonal IgG (κ four of six, λ two of six) was associated with light chain (LC) proteinuria in five patients. Four patients had low serum C3 and/or factor B levels. C4, factor H (CFH), and I protein levels were normal in five of five patients; none had detectable C3NeF. IgG anti-CFH activity was positive in one case. No mutations in CFH, CFI, and MCP genes were identified in four of four patients. Deposits were intramembranous, subepithelial, and mesangial by electron microscopy, and stained positive for C3 (six of six), properdin, and CFH (two of two) but negative for Ig LC and heavy chains, C4, and C1q (6/6) by immunofluorescence. Five patients progressed to end-stage renal disease over a median period of 47 months, despite chemotherapy in four patients. In one patient, monoclonal λLC deposits were observed on a follow-up kidney biopsy after 4 years. CONCLUSIONS: GN with isolated glomerular C3 deposits might represent an unusual complication of plasma cell dyscrasia, related to complement activation through an autoantibody activity of the monoclonal Ig against a CAP regulator protein.

SUBMITTER: Bridoux F

PROVIDER: S-EPMC3358988 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?

Bridoux Frank F Desport Estelle E Frémeaux-Bacchi Véronique V Chong Christine Fen CF Gombert Jean-Marc JM Lacombe Corinne C Quellard Nathalie N Touchard Guy G

Clinical journal of the American Society of Nephrology : CJASN 20110722 9

<h4>Background and objectives</h4>Glomerular deposition of monoclonal Ig has been exceptionally described as the cause of membranoproliferative glomerulonephritis, through activation of the complement alternative pathway (CAP).<h4>Design, setting, participants, & measurements</h4>We retrospectively studied six adults with monoclonal gammopathy and glomerulonephritis (GN) characterized by isolated C3 deposits.<h4>Results</h4>All patients presented with hematuria, associated with chronic renal fai ...[more]

PMID: 21784830

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Project description:C3 glomerulonephritis (GN) is a proliferative GN resulting from glomerular deposition of complement factors due to dysregulation of the alternative pathway of complement. Dysregulation of the alternative pathway of complement may occur as a result of mutations or functional inhibition of complement-regulating proteins. Functional inhibition of the complement-regulating proteins may result from a monoclonal gammopathy.Case series.32 Mayo Clinic patients with C3 GN, 10 (31%) of whom had evidence of a monoclonal immunoglobulin in serum.Clinical features, hematologic and bone marrow biopsy findings, kidney biopsy findings, kidney measures, complement pathway abnormalities, treatment, and follow-up of patients with C3 GN that was associated with a monoclonal gammopathy.Mean age of patients with C3 GN associated with monoclonal gammopathy was 54.5 years. Bone marrow biopsy done in 9 patients revealed monoclonal gammopathy of undetermined significance in 5 patients, small lymphocytic lymphoma/chronic lymphocytic leukemia in one patient, and no abnormal clones in the other 3 patients. Kidney biopsy showed membranoproliferative GN with bright capillary wall C3 staining in all 10 patients. Evaluation of the alternative pathway of complement showed abnormalities in 7 of 9 patients tested. No mutation in complement-regulating proteins was detected in any patient. As an index case, one patient with C3 GN and chronic lymphocytic leukemia was treated with rituximab, cyclophosphamide, vincristine, and prednisone, and one patient with C3 GN and monoclonal gammopathy of undetermined significance was treated with dexamethasone and bortezomib. Both patients showed significant decreases in hematuria and proteinuria and stabilization of kidney function.Studies to show evidence of direct activation of the alternative pathway by monoclonal immunoglobulin were not done.The study highlights the association of C3 GN and monoclonal gammopathy, in particular in the older population, and the importance of targeting the underlying hematologic malignancy as an approach to treating C3 GN.

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Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?

Publications

Glomerulonephritis with isolated C3 deposits and monoclonal gammopathy: a fortuitous association?

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