BACKGROUND: Complement may contribute to donor-specific antibody (DSA)-triggered transplant injury. Here, we investigated whether the intrinsic strength of classical pathway and alternative pathway (AP) relates to the pathogenicity of DSA. METHODS: Classical pathway and AP high-activity genotypes were defined according to C4 gene copy number and the presence of functional polymorphisms in C3 (C3102G), factor B (fB32R), and factor H (fH62V) genes. Associations of these genotypes with blood complement profiles and morphologic/molecular rejection features were evaluated in a cohort of 83 DSA-positive patients (antibody-mediated rejection [AMR], n = 47) identified upon cross-sectional screening of 741 kidney allograft recipients ≥180 days posttransplantation. Associations with long-term graft survival were evaluated in a larger kidney transplant cohort (n = 660) not enriched for a specific type of rejection. RESULTS: In the cohort of DSA-positive subjects, the number of C4 gene copies was related to C4 protein levels in serum and capillary C4d staining, but not AMR activity. Patients with a high-activity AP complotype, which was associated with complement consumption in serum, showed enhanced microcirculation inflammation (median glomerulitis plus peritubular capillaritis score, 2 [interquartile range, 0-4 versus 1 0-2]; P = 0.037). In the larger transplant cohort, this complotype was associated with a slightly increased risk of graft loss (hazard ratio, 1.52; 95% confidence interval, 1.02-2.25; P = 0.038 and multivariable Cox model, 1.55; 1.04-2.32; P = 0.031). CONCLUSIONS: Our study suggests a contribution of complement genetics to the phenotypic presentation of AMR. Future studies will have to clarify whether a possible association of AP strength with graft survival relates to enhanced antibody-triggered injury.

Alberta Transplant Applied Genomics Centre ATAGC University of Alberta Edmonton AB Canada

Department of Laboratory Medicine Medical University of Vienna Vienna Austria

Department of Nephrology Transplant Center Institute for Clinical and Experimental Medicine Prague Czech Republic

Department of Pathology Medical University of Vienna Vienna Austria

Department of Pediatrics and Adolescent Medicine Medical University of Vienna Vienna Austria

Division of Nephrology and Dialysis Department of Medicine 3 Medical University of Vienna Vienna Austria

Research Laboratory 3rd Department of Internal Medicine and MTA SE Research Group of Immunology and Hematology Hungarian Academy of Sciences and Semmelweis University Budapest Hungary

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