Kidney transplant outcomes in patients with complement dysregulation.

Abstract

Background: Complement dysregulation is a key mechanism underlying atypical hemolytic uremic syndrome and complement-mediated thrombotic microangiopathy in kidney transplantation, and is associated with post-transplant recurrence, graft dysfunction, and graft loss. Although Western cohort data are well established, integrated transplant outcome data combining genetic analysis, anti-factor H (AFH) antibody profiling, and individualized therapy from Indian and other South Asian populations remain limited, despite a distinct biologic profile in this region.

Aim: To evaluate clinical characteristics, complement biologic profile, post-transplant recurrence, and graft outcomes in kidney transplant recipients with complement dysregulation managed at a tertiary transplant center in Central India, with particular emphasis on genotype-phenotype correlation and outcomes in a resource-constrained setting.

Methods: This single-center retrospective cohort study included kidney transplant recipients with evidence of complement dysregulation identified from January 2018 to March 2025 at a tertiary transplant center in Central India. Complement dysregulation was defined as the presence of a pathogenic or likely pathogenic complement gene variant, AFH antibody positivity, or both. Genetic testing was performed using multiplex ligation-dependent probe amplification and/or clinical exome sequencing covering the alternative complement pathway gene panel, and AFH antibodies were measured using enzyme-linked immunosorbent assay. All patients underwent comprehensive evaluation including hematological, biochemical, and complement (C3, C4) profiling, with kidney biopsy when clinically feasible. The primary outcome was post-transplant recurrence of thrombotic microangiopathy; secondary outcomes included graft loss, patient survival, renal function, and treatment response. Median post-transplant follow-up was approximately 12 months.

Results: Of the 335 patients evaluated for complement abnormalities, 136 had complement dysregulation, of whom 38 underwent kidney transplantation and constituted the study cohort. Mean age was 36.3 ± 9.3 years, 84.2% were male, and 97.4% had hypertension; 73.7% were on maintenance hemodialysis at diagnosis. Complement genetic abnormalities were identified in 34/38 recipients (89.5%), with CFHR1-CFHR3 structural variants predominating (78.9%) and complement factor H abnormalities in 18.4%; no pathogenic variants were detected in CFI, C3, CD46, THBD, or DGKE. AFH antibodies were detected in 15 patients (39.5%), with 11 having concomitant genetic abnormalities. Pre-transplant immunomodulation with plasma exchange and rituximab reduced mean AFH antibody levels from 179.9 AU/mL to 59.7 AU/mL (approximately 67% reduction). Post-transplant recurrence occurred in 7/38 recipients (18.4%), all biopsy-confirmed, donor-specific antibody and C4d-negative, and clustered within 1-3 weeks of transplantation; recurrence occurred exclusively in patients with complement genetic abnormalities, and not in those with isolated AFH antibody positivity. All 7 recipients with recurrence maintained functioning grafts after disease-directed therapy. Overall patient survival was 94.7%; two deaths (5.3%) were attributable to severe infections, and one graft loss followed invasive mucormycosis unrelated to recurrent disease.

Conclusion: In this Indian transplant cohort with complement dysregulation, CFHR1-CFHR3 structural variants and AFH antibody positivity defined the predominant biologic substrate, post-transplant recurrence clustered within the early weeks after transplantation, and disease-directed therapy with plasma exchange, rituximab, and selective eculizumab achieved durable graft preservation despite limited access to long-term complement inhibition. Comprehensive pre-transplant complement evaluation and biologic risk stratification are essential for safe transplantation in complement-mediated kidney disease, particularly in resource-limited settings.