C3 Glomerulonephritis Associated With Monoclonal Gammopathy: A Case Series

Abstract

Background C3 Glomerulonephritis (C3GN) is a proliferative glomerulonephritis resulting from glomerular deposition of complement factors due to dysregulation of the alternative pathway of complement. The 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 and Participants 32 Mayo Clinic patients of C3GN, of which 10 patients (31.25%) had evidence of a monoclonal immunoglobulin in the serum. Outcomes Clinical features, hematological and bone marrow biopsy findings, kidney biopsy findings, renal outcomes, complement pathway abnormalities, treatment and follow-up of patients with C3GN that was associated with a monoclonal gammopathy. Results The mean age of patients with C3GN associated with monoclonal gammopathy was 54.5 years. Bone marrow biopsy done in 9 patients revealed monoclonal gammopathy of undetermined significance (MGUS) in 5 patients, small lymphocytic lymphoma/chronic lymphocytic leukemia (CLL) in one patient ,and no abnormal clones in the remaining 3 patients. Kidney biopsy showed a membranoproliferative glomerulonephritis with bright capillary wall C3 staining in all 10 patients. Evaluation of the alternative pathway of complement showed abnormalities in 7 of the 9 patients tested. None of the patients had a mutation in the complement regulating proteins. As an index case, one patient with C3GN and CLL was treated with Rituximab, cyclophosphamide, vincristine and prednisone and one patient with C3GN and MGUS was treated with dexamethasone and bortezomib. Both patients showed significant decrease in hematuria and proteinuria, and stabilization of renal function. Limitations Studies to show evidence of direct activation of the alternative pathway by the monoclonal immunoglobulin were not done. Conclusions The study highlights the association of C3GN and monoclonal gammopathy, in particular in the older population, and the importance of targeting the underlying hematologic malignancy as an approach to treating C3GN.

The role of the alternative pathway of complement activation in glomerular diseases

“…Also, the exact trigger of AP dysregulation is unidentified. Some authors are seeking the answer in the frequent prevalence of monoclonal Ig deposition along with C3 and high frequency of plasma monoclonal Ig in C3G patients (approximately 31% of cases diagnosed with C3GN and 71% of DDD cases) [93,94]. An assumption that monoclonal Ig acts as autoantibody activating the AP has been made [82,83].…”

Dysproteinemias and Glomerular Disease

“…This topic is discussed in greater detail elsewhere in this issue. Direct evidence implicating the monoclonal gammopathy as a cause is lacking in most patients (27,28,30). Rather, the association is on the basis of epidemiologic data.…”

A Patient with Abnormal Kidney Function and a Monoclonal Light Chain in the Urine

“…Light-chain casts occasionally have a crystalline structure that fractures during processing of the tissue. The entities that have nonorganized deposits are MIDD (Randall type), PGNMID, and C3 glomerulopathy (including C3GN and dense deposit disease, which have dominant C3 deposits) with MG (29)(30)(31). Of note, recent studies found that about one third of patients with C3GN have C3GN associated with an MG (31).…”

“…The entities that have nonorganized deposits are MIDD (Randall type), PGNMID, and C3 glomerulopathy (including C3GN and dense deposit disease, which have dominant C3 deposits) with MG (29)(30)(31). Of note, recent studies found that about one third of patients with C3GN have C3GN associated with an MG (31). Although the Ig is not well seen on standard immunofluorescence performed on frozen tissue, the Ig can be unmasked by pronase digestion of the paraffin-embedded tissue (32).…”

“…If negative, serum should be tested for C3 nephritic factor (C3nef) and C4 nephritic factor, which are autoantibodies that protect the alternative pathway C3 convertase C3bBb (C3nef) or the classic C3 convertase C4b2a (C4 nephritic factor), causing persistent activation of the complement system (50). The alternative pathway could also be activated by monoclonal proteins acting as autoantibodies against complement inhibitors, such as factor H (29,31). Evaluation for genetic defects in the complement system should also be considered.…”