C3 Glomerulopathy: Ten Years' Experience at Mayo Clinic

Abstract

Objective: To describe the clinicopathological features, complement abnormalities, triggers, treatment, and outcomes of C3 glomerulopathy.

Patients and methods: A total of 114 patients with C3 glomerulopathy seen at Mayo Clinic from January 1, 2007, through December 31, 2016, were evaluated in this study.

Results: The mean age at diagnosis for the entire cohort was 40.4±22.3 years, with a median serum creatinine level and proteinuria value of 1.6 mg/dL (range: 0.3-14.7) (to convert to mmol/L, multiply by 0.0259) and 2605 mg/24 h (range: 233-24,165), respectively. Hematuria was present in 100 patients (87.7%). The C3 and C4 levels were low in 50 of 112 (44.6%) and 13 of 110 (11.8%) patients, respectively. A history of infection, positive autoimmune findings, and monoclonal gammopathy (MIg) were present in 33 of 114 (28.9%), 28 of 114 (24.6%), and 36 of 95 (37.9%) patients, respectively. However, 28 of 43 patients 50 years or older (65.1%) had MIg. A genetic variant in complement genes, C3 nephritic factor (C3Nef), and other autoantibodies was present in 26 of 70 (37.1%), 30 of 69 (43.5%), and 9 of 67 (13.4%) patients, respectively. Membranoproliferative and mesangial proliferative glomerulonephritis were the common patterns of injury. Patients without MIg were younger (mean age, 32.3±20.6 years), with a median serum creatinine level and proteinuria value of 1.4 mg/dL (range: 0.3-7.9) and 2450 mg/24 h (range: 250-24, 165) and with low C3 and C4 levels in 38 of 77 (49.4%) and 9 of 75 (12.0%) patients, respectively. Most patients received corticosteroids and other immunosuppressive drugs. In patients without MIg, at a median follow-up of 22.3 months (range: 0.1-201.1), the median serum creatinine level and proteinuria value were 1.4 mg/dL (range: 0.3-3.7) and 825.5 mg/24 h (range: 76-22, 603), and 7 patients (9.2%) had progression to end-stage renal disease.

Conclusion: C3 glomerulopathy is a heterogeneous disease entity with complex triggering events and abnormalities of the alternative pathway of complement. The disease tends to be progressive and exhibits a variable response to immunosuppressive therapy.

Figure 1:

Breakdown of C3G by presence of monoclonal gammopathy and complement abnormalities.

Figure 2:

C3G triggers/associated disorders. The percentage of patients with a monoclonal gammopathy, infection or an autoimmune laboratory finding at the time of development of renal disease is given for the total group of C3G, as well as for the C3GN and DDD subgroups.

Figure 3:

Kidney biopsy findings in C3GN and DDD. Top panel shows a biopsy of C3GN and bottom panel shows a biopsy of DDD. A. Light microscopy demonstrating an MPGN pattern of injury (silver methenamine 40x); B. Immunofluorescence microscopy confirming bright C3 staining in the mesangium and along capillary walls (40x); C. Electron microscopy revealing mesangial and capillary wall deposits (2500x); D. Light microscopy showing an MPGN pattern of injury (periodic acid Schiff 40x); E. Immunofluorescence microscopy highlighting bright C3 staining in the mesangium and along capillary walls (40x); F. Electron microscopy displaying intramembranous dense deposits (4800x).

Figure 4:

Flow Chart depicting the summary of clinical parameters among patients managed conservatively versus immunosuppressive treatment.

Figure 5:

Kaplan Meier analysis of renal survival of C3G (without MIg) patients 5(A): Overall renal survival of C3G patients. 5(B) Renal survival of C3G patients treated conservatively (dotted line) and C3G patients treated with immunosuppressants (solid line), p-value (Wilcoxon): .05, p-value (Log-Rank): .10.

Figure 5:

Kaplan Meier analysis of renal survival of C3G (without MIg) patients 5(A): Overall renal survival of C3G patients. 5(B) Renal survival of C3G patients treated conservatively (dotted line) and C3G patients treated with immunosuppressants (solid line), p-value (Wilcoxon): .05, p-value (Log-Rank): .10.

Figure 6:

Schematic depicting that C3G often results due to interactions between the triggering events and abnormalities of the AP of complement.