A new Kidney International-published multinational cohort study has found that the excess risk of mortality for women who receive a kidney transplant is greater than for men when the donor is male—though not to a statistically significant degree if the donor is female. The differences were found for recipients aged 0–44 years and those over 60 years. The authors of the study, led by Amanda Vinson (Dalhousie University, Halifax, Canada), say their results “suggest that management may need to be modified to optimise transplant outcomes among females”.
The introduction to the study draws attention to the increased risk of mortality for transplant recipients compared to the general population even given improvements in transplant care and graft survival. The authors make the claim that understanding sex-based differences in transplant recipient mortality can illuminate new ways to improve outcomes more generally, but that untangling such differences from the higher mortality rates of men in the general population means comparing excess mortality risk for those undergoing such procedures. Noting previous studies, such as the 2017 investigation by Fanny Lepeytre (University of Montreal, Montreal, Canada) et al that found immunologic factors to be driving sex-based differences in graft failure, they contend that differences in graft failure risk are the main cause of differences in mortality risk.
The study drew on three of the world’s largest transplant databases: the American Scientific Registry of Transplant Recipients (SRTR), the Australia and New Zealand Dialysis and Transplant Registry (ANZDATA), and the international Collaborative Transplant Study (CTS) database. The SRTR and CTS data accounted for patients between 1 January 1988 and 31 December 2018, with the former followed to 1 June 2019 and the latter until 28 October 2020. The ANZDATA cohort included transplantations between 1 January 1988 and 31 December 2019, and was followed until 31 December 2019.
Setting out the study’s primary exposure as recipient sex, its authors also describe how they delineated between different combinations of donor and recipient sex. They also included “a donor-recipient sex combination by recipient current age interaction term in all models”, which they state allowed them to “account for the possibility that the association between excess mortality and recipient sex may differ by age”. It was an important element of the study, they argue, to recognise the variation in sex-related biological differences between men and women across age, owing to “sexual development and senescence”.
The primary outcome, meanwhile, was “overall mortality with observation censored at re-transplant, end of observation, or end of the study period”, with observation limited to a first transplant due to changes in donor characteristics with subsequent transplants. The SRTR included 243,371 patients (58.6% male), while the CTS included 209,340 (62.6% male) and ANZDATA 14,181 (62.3% male) who had a first kidney-only deceased donor transplant. The variables across these cohorts were harmonised, before the data of all 466,892 were combined.
The analysis found that, with a male kidney donor, female recipients 0–12 years (relative excess risk [RER] 1.54, 95% confidence interval [CI] 1.20–1.99), 13–24 years (RER 1.17, CI 1.01–1.34), 25–44 years (RER 1.11, CI 1.05–1.18) and 60 years and older (RER 1.05, CI 1.02–1.08) demonstrated greater excess mortality risks than same-age male recipients. With a female donor, meanwhile, the excess mortality risk for those >12 years was similar to when the donor was male, “but there were no significant differences in excess mortality rates in any age interval”.
Discussing their findings, Vinson et al note that they conflict with the earlier findings of a 2009 study led by S Joseph Kim (University of Toronto, Toronto, Canada) which suggested a survival advantage for female versus male kidney transplant recipients. Except for those aged 45–59 years, in Vinson’s study all ages demonstrated a greater risk of excess female mortality, though they note that any sex-based differences were only statistically significant with a male donor.
Making reference to another study, this time a 2021 report by Nicole De La Mata (University of Sydney, Camperdown, Australia) utilising ANZDATA finding that “the number of life years lost by females is significantly greater than by males” undergoing kidney transplantation, Vinson et al argue that their work contributes to a growing evidence base backing the increased risk for female recipients of male-donor kidneys. Though women demonstrated higher graft loss rates, they note that they found differences in mortality even without loss of graft function, something they posit may be due to the greater risk of drug toxicity in women.
The authors outlined several limitations to the study, including missing data on cause of death in all three cohorts. They also state that “the unavailability of donor to recipient weight ratio in the CTS cohort may have resulted in biased pooled RER estimates”. Despite such limitations, however, they stress the uniformity of their findings across international cohorts, and make the case that their findings should prompt further investigation into the excess risk of graft loss for women and the mechanism behind it.
Vinson spoke exclusively to Renal Interventions to review the findings: “This study is important because it highlights the importance of considering sex-based differences in mortality risk in the context of the higher baseline mortality risk in males in the general population. Earlier studies that looked at mortality (but not excess mortality) have shown better survival in women post-transplant, but important information is lost; the bias towards higher mortality rates in males should be preserved among transplant recipients—unless there are sex differences in the effects of transplant, its treatment, or both.
“The fact excess mortality risk is higher post-transplant in female recipients of a male donor kidney—that is, there is less survival benefit with a transplant if you are a woman—is an important finding that requires further investigation.”
