Case-Based Inference of Avacopan’s Impact on Renal Inflammation and Tissue damage in ANCA-associated Vasculitis Patients

ANCA-associated vasculitis (AAV) is a disease characterized by inflammation in small and medium-sized blood vessels throughout the body. The standard induction therapy for remission has been oral glucocorticoids (GC) combined with either cyclophosphamide (CY) or rituximab (RTX). Avacopan, a selective C5a receptor antagonist, has recently been introduced for the treatment of AAV. Avacopan’s clinical efficacy, especially in renal involvement, has been reported in ADVOCATE study and real-world settings from various countries. Because renal biopsies are usually performed at the time of disease onset or relapse, the underlying renal histopathological changes by the avacopan involved therapy remain unclear.

We present two cases where post-treatment biopsies were available following avacopan initiation, allowing assessment the degree of inflammation resolution and residual inflammation.

Case 1: A female in her 70s with PR3-ANCA-positive microscopic polyangiitis (MPA) achieved remission (BVAS=0) with moderate-dose GC, RTX, and avacopan, in consideration of the high risk of glucocorticoid-induced toxicity. She died suddenly 3.5 months later due to intravascular large B-cell lymphoma (IVLBL). Initial renal biopsy showed global sclerosis in 21/37 glomeruli and crescents in 14, corresponding to the Sclerotic class and AKRiS score of 7. Autopsy kidney revealed that 10–20% of glomeruli retained active lesions, while 80–90% had resolved. Assessment of peritubular capillaritis (PTCitis) was limited due to IVLBL infiltration.

Case 2: A male in his 60s with MPO-ANCA-positive MPA, previously stable on low-dose GC and maintenance RTX, experienced a relapse three months after recovering from COVID-19 pneumonia. As the relapse was limited to renal involvement, outpatient treatment was intensified with PSL 30mg plus avacopan. Despite this, the renal function continued to decline, and remission was not achieved. A repeat renal biopsy was therefore performed. The re-biopsy revealed global sclerosis in 16 out of 30 glomeruli. Among the remaining glomeruli, most showed no active lesions and only minimal PTCitis, while four glomeruli retained active lesions, one of which exhibited a necrotizing component. As no renal biopsy was performed prior to treatment intensification, accurately assessing the therapeutic response remains challenging. Notably, glomeruli with lesions showing weak or intermediate activity—between highly active and quiescent states—were extremely rare and distinctive. For reference, these findings corresponded to the Sclerotic class and AKRiS score of 7. Escalation of GC to 60 mg/day led to clinical remission.

In Case 1, three months after initiating induction therapy, the treatment for AAV appeared effective, and the presence of minimal residual inflammatory foci was interpreted as part of the expected clinical course. Avacopan may help improve eGFR by suppressing these inflammatory foci before they fully develop, thereby preserving normal glomerular architecture. In Case 2, however, a combination of PSL 30 mg and avacopan did not sufficiently suppress highly active lesions that had already progressed to necrosis. This suggests that avacopan alone may have relatively limited anti-inflammatory potency compared to GC.