Journal
TRANSPLANTATION DIRECT
Volume 6, Issue 3, Pages -Publisher
LIPPINCOTT WILLIAMS & WILKINS
DOI: 10.1097/TXD.0000000000000978
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Funding
- National Research Fund of Hungary (NKFIH) [ANN110909]
- Higher Education Institutional Excellence Programme of the Ministry of Human Capacities in Hungary within Semmelweis University
- Austrian Science Fund [KLI190]
- Vienna Science and Technology Fund [LS16-019]
- Austrian Science Fund (FWF) [KLI190] Funding Source: Austrian Science Fund (FWF)
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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 (C3(102G)), factor B (fB(32R)), and factor H (fH(62V)) 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.
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