Urinary C5a as a Noninvasive Marker of Renal Activity, Histopathological Severity, and Outcomes in ANCA-Associated Vasculitis

Abstract

Background: Complement activation plays a central role in the pathogenesis of ANCA-associated vasculitis (AAV). However, the clinical implications of urinary complement fragments remain unclear. We investigated whether urinary complement fragments reflect the severity of renal injury and whether they are associated with renal outcomes in patients with AAV . Methods: We retrospectively analyzed 57 patients with AAV and renal involvement. Urinary complement C3a, C5a, and C5b-9 levels were measured at diagnosis or relapse and normalized to urinary creatinine (U-C3a/Cr, U-C5a/Cr, and U-C5b-9/Cr). The primary outcome was a composite of ESKD requiring chronic dialysis or all-cause mortality. Secondary analyses evaluated longitudinal changes in eGFR and myeloperoxidase-ANCA titers, and associations with renal histopathological findings at diagnosis. Results: Over a median follow-up of 21.5 months, 14 patients reached the primary outcome. Event-free survival was significantly lower in the high U-C3a/Cr and U-C5a/Cr groups than in the corresponding low groups. High baseline U-C3a/Cr and U-C5a/Cr were associated with 3.86-fold and 3.73-fold higher unadjusted risks of the primary composite outcome, respectively. However, the U-C5a/Cr ratio showed a broader association with renal disease severity. Higher U-C5a/Cr ratios were associated with less improvement in eGFR during follow-up and with several histopathological abnormalities, including a higher proportion of cellular crescents, lower proportion of normal glomeruli, and more severe tubulointerstitial lesions. Exploratory analyses combining urinary complement markers with baseline eGFR demonstrated progressive separation of renal risk categories, particularly for the U-C5a/Cr–eGFR classification. Conclusions: U-C5a/Cr was associated with renal outcomes, impaired renal functional recovery, and histopathological severity of AAV. Although U-C3a/Cr and U-C5a/Cr showed prognostic associations, U-C5a/Cr reflected intrarenal disease severity more consistently. Exploratory urinary complement–eGFR classifications may provide complementary noninvasive information for renal risk stratification in AAV. Further prospective multicenter studies are required to validate these findings.