C3 glomerulonephritis associated with monoclonal gammopathy: a case series

Abstract

Background: 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.

Study design: Case series.

Setting & participants: 32 Mayo Clinic patients with C3 GN, 10 (31%) of whom had evidence of a monoclonal immunoglobulin in serum.

Outcomes: 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.

Results: 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.

Limitations: Studies to show evidence of direct activation of the alternative pathway by monoclonal immunoglobulin were not done.

Conclusions: 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.

Keywords: C3 Glomerulonephritis (C3 GN); membranoproliferative glomerulonephritis (MPGN); monoclonal gammopathy; monoclonal gammopathy of undetermined significance (MGUS).

Figure 1

Representative light, immunofluorescence, and electron microscopy in a C3GN patient with monoclonal gammopathy (patient # 4). A–B. Light microscopy showing a membranoproliferative pattern of injury (PAS stain, A 10x, B 40x). C. Immunofluorescence studies show bright C3 in the mesangium and along capillary walls (40x). D–E. Electron microscopy showing mesangial deposits (thick white arrows), subendothelial deposits (thick black arrows), and subepithelial deposits (thin black arrows) and intramembranous deposits (thin white arrows). (D- 7830x, E- 17900x).

Figure 2

Laser microdissection and mass spectrometry analysis of glomerular proteins in C3GN associated with CLL (patient # 9) in 2 samples (S1 and S2). The proteomic data show large spectra for C3, C4, and CFHR-1. Small spectra numbers for C9 and CFHR-5 are also present. Kappa or lambda light chains were not detected and spectra for IgG-1 C region in sample 1 was below the level that is deemed clinically valid.

Figure 3

C3GN associated with CLL (patient #9). Change in renal parameters in months after diagnosis, number of cycles of R-CVP completed is marked with thick black arrows.