Monoclonal Gammopathy in ANCA-Negative Pauci-Immune Crescentic Glomerulonephritis: Is There Causality? Case Series

Background: In a subset of patients with diagnosis of ANCA-associated vasculitis, no antibodies(MPO or PR3)can be identified,and these cases are referred to as“ANCA-negative”. The antibody or trigger for the disease in this subset of patients has remained elusive. Monoclonal gammopathy(MG) has been shown to directly activate neutrophils. We hypothesized that MG may be the cause for the renal presentation in such patients. We therefore explored the role of MG and its association with disease presentation in cases of ANCA-negative vasculitis. Methods: We retrospectively analyzed database between Jan2000 through Dec2023 and identified patients with a diagnosis of pauci-immune crescentic glomerulonephritis who had undergone testing for MPO, PR3, and monoclonal gammopathy (MG).Patients positive forMPO,PR3,or anti-GBM and those with a kidney transplant,were excluded.Time-to-event analysis was conducted using the Kaplan-Meier method,death as the event of interest Results: 14 patients diagnosed with ANCA-negative vasculitis who had undergone monoclonal testing. 8(57%) had evidence of MG, prevalence significantly higher than the anticipated (3%) in the general population over 50 years of age. Mean age of this group was 60.3 (12.2) years,75% were female,with mean serum creatinine of 4.3(1.92) mg/dL. Most common histological characteristics were Focal Berden Classification(n=5, 62.5%) and Mayo Clinic/Renal Pathology Society Chronicity Score(MCS) of moderate(n=5, 62.5%). Most common heavy chain was IgG(n=4, 50%), and Kappa light chain(n=4, 50%) with serum free light chain ratio of 2.3[1.01-3.41] for involved to uninvolved light chain. Median follow-up time was 3.2 years. At the last follow-up, 3 patients progressed to end-stage kidney disease, and 4 patients died (2 without ESKD).Mean time to death of 3.0(4.1)years.Estimated one-year survival was 85.7%(95% CI 13.2 to 63.3) and two-year survival was 68% (95% CI:18.6 to 40.3). Conclusion: Our study shows that majority of patients with ANCA-negative vasculitis have evidence of MG and it is possible that the MG is involved in the pathogenesis of the disease and may need to be considered as MGRS lesion in the future. Additional research is needed to better understand the role of MG in causing pauci-immune crescentic GN.