H-Y Incompatibility Predicts Short-Term Outcomes for Kidney Transplant Recipients

A recent report suggested that female recipients of male deceased-donor kidneys are at increased risk for graft failure because of H-Y antigen mismatch. In an attempt to confirm and extend these results, we studied all adult recipients of deceased-donor kidney transplants from 1990 through 2004 in the US Renal Data System. Compared with all other gender combinations, female recipients of male donor kidneys had a 12% increased risk for graft failure at 1 yr (hazard ratio 1.12; 95% confidence interval 1.05 to 1.19) but no excess risk at 10 yr (hazard ratio 1.03; 95% confidence interval 0.98 to 1.07). We observed a similar pattern of short- and long-term risk for both death-censored graft failure and mortality. The main results were consistent across several prespecified patient subgroups and were robust to sensitivity analyses. In conclusion, compared with other recipient-donor gender combinations, female recipients of male donor kidney transplants in the United States have an increased short-term risk but not long-term risk for adverse outcomes.Allorecognition of human major histocompatibility antigens (i.e., HLA) and the associated immune response has important short- and long-term implications for successful kidney transplantation. Although much effort has been placed on trying to understand and control the immune response to these major histocompatibility antigens, relatively little is known about the role of minor histocompatibility antigens as determinants of outcome. H-Y antigens, derived from the Y chromosome, are a group of minor histocompatibility antigens that are widely expressed in human tissues¹ and have been found to be prognostically important for the survival of recipient–donor gender-mismatched hematopoietic stem cell transplants.^2–9Several studies of heart, lung, liver, and corneal transplantation have suggested that female recipients of male donor organs/tissues are at increased risk for adverse graft outcomes^10–13; however, other studies have failed to show this effect.^14–18 Recently, a report by Gratwohl et al.,¹⁹ using data from the Collaborative Transplant Study (CTS), suggested that, after adjustment for the independent effects of recipient and donor gender, female recipients of male deceased-donor kidney transplants (versus all other recipient–donor gender combinations) were significantly associated with a 6 to 8% increase in the risk for graft failure and a 10 to 11% increase in the risk for death-censored graft failure during 10-yr of follow-up. They termed this phenomenon the “H-Y effect”; however, only 18.6% of the patients in the study by Gratwohl et al. were from North America, and a previous report failed to show an H-Y effect in zero-mismatched, US living-donor kidney transplants.²⁰ In addition, the impact of adjusting for a more extensive set of covariates (including recipient and donor weight) was not assessed.Given their greater susceptibility to unmeasured or residual confounding (as compared with randomized, controlled trials), it is important to reproduce the results of observational studies in different patient populations from different data sources.²¹ In an attempt to confirm the results of Gratwohl et al. and to determine the relevance of the H-Y effect in deceased-donor kidney transplants performed in the United States, we undertook a retrospective cohort study using data from the US Renal Data System (USRDS). We used a modeling strategy similar to that of Gratwohl et al. and then extended it to include additional covariate data, an evaluation of prespecified subgroups, and various sensitivity analyses.