C3 glomerulopathy associated with monoclonal Ig is a distinct subtype

Abstract

Monoclonal immunoglobulins (MIg) may play a causal role in C3 glomerulopathy (C3G) by impairing regulation of the alternative pathway of complement. Ninety-five patients with C3G were tested for MIg of which 36 were positive. Their mean age at diagnosis was 60 years and among patient 50 years and older, 65.1% had a MIg. At presentation, median serum creatinine and proteinuria were 1.9 mg/dL and 3.0 g/24 hours. Hematuria was present in 32 (88.9%) patients. Twelve (34.3%) patients had low C3 levels. C3 nephritic factor was detected in 45.8% patients; pathogenic variants in complement protein genes were rare. Hematologic evaluation revealed monoclonal gammopathy of renal significance in 26 patients, multiple myeloma in five, smoldering multiple myeloma in two, and chronic lymphocytic leukemia, lymphoma, or type I cryoglobulin each in one patient. After a median follow-up of 43.6 months, the median serum creatinine and proteinuria were 1.4 mg/dL and 0.8g/24 hours. Nine patients developed ESRD. Sixteen patients received MIg-targeted treatment, 17 patients received non-targeted treatment while three patients were managed conservatively. Of the 16 patients receiving MIg-targeted treatment, ten achieved complete/very good/partial hematologic response. Of these, seven achieved a complete/partial/stable renal response. Five patients receiving targeted treatment did not achieve hematologic response, none had a renal response. Patients receiving targeted treatment were more likely to have multiple myeloma/smoldering multiple myeloma. Patients receiving non-targeted treatment were more likely to have monoclonal gammopathy of renal significance. Thus, C3G with MIg is seen in older patients, C3 nephritic factor is the most common autoantibody detected, and MIg-targeted treatment may result in remission and stabilization of kidney function in a subset of these patients.

Keywords: C3 glomerulonephritis; C3 glomerulopathy; alternative pathway of complement; dense deposit disease; monoclonal Ig.

Figure 1:

Hematologic evaluation of the C3G associated with monoclonal Ig. MGRS is the most common condition associated with C3G. *One monoclonal gammopathy of renal significance and one smoldering multiple myeloma progressed to multiple myeloma and two monoclonal gammopathy of renal significance progressed to smoldering multiple myeloma during the course of C3 glomerulopathy.

Figure 2:

Representative kidney biopsy of C3G with monoclonal Ig. A. Light microscopy showing a membranoproliferative glomerulonephritis (periodic acid Schiff stain, 40x), B. Immunofluorescence microscopy showing bright mesangial and capillary wall staining for C3 (40x), C-D. Electron microscopy showing subendothelial deposits (thin arrows) and a subepithelial deposit (thick arrow) (C-2900x, D-9300x).

Figure 3:

Kaplan-Meier analysis of renal survival in C3G patients with and without a monoclonal Ig. Black line represents C3G with monoclonal Ig and dotted line represents C3G without monoclonal Ig; mo: months. The analysis demonstrates no significant difference in ESRD free renal survival in C3G patients with and without monoclonal Ig (p= 0.0791).

Figure 4:

C3G with a monoclonal Ig: A) Renal outcomes of patients with and without targeted therapy; *3 received conservative therapy only; B) Renal and Hematological outcomes of patients with targeted therapyAbbreviations; CR, complete response; PR, partial response; VGPR, very good partial response; NR, no response; CLL, chronic lymphocytic leukemia; MGRS, monoclonal gammopathy of renal significance; SMM: smoldering multiple myeloma; MM, multiple myeloma.

Figure 4:

C3G with a monoclonal Ig: A) Renal outcomes of patients with and without targeted therapy; *3 received conservative therapy only; B) Renal and Hematological outcomes of patients with targeted therapyAbbreviations; CR, complete response; PR, partial response; VGPR, very good partial response; NR, no response; CLL, chronic lymphocytic leukemia; MGRS, monoclonal gammopathy of renal significance; SMM: smoldering multiple myeloma; MM, multiple myeloma.