Are There Sex-based Differences in Excess Risk of Death With Graft Function After Kidney Transplant?

Even though kidney transplantation offers improved mortality compared with dialysis,1 there is still an excess risk of death after transplantation compared with the general population. These deaths may be attributed to graft loss or may occur in recipients with a functioning transplant (commonly caused by infection, malignancy, and cardiovascular disease). Death with graft function (DWGF) represents the largest cause of death for adults in the first year after kidney transplantation.2 The need to explore sex disparities in posttransplant outcomes is critical because it is known that female patients have reduced access to kidney transplantation and a higher rate of graft loss compared with male patients.3 Previously published retrospective cohort analyses have demonstrated higher rates of DWGF for adult male kidney transplant recipients compared with adult female recipients,4 but these analyses do not account for sex-based differences in mortality in the general population.5 To address this, Vinson et al6 have previously used the metric of excess mortality (which benchmarks posttransplant mortality against general population mortality) and have shown that female recipients younger than 45 y and older than 60 y who received a kidney from a male deceased donor had higher excess mortality after kidney transplantation compared with male recipients of the same age. However, whether the excess mortality in women is driven by DWGF, is related to whether the donor is male or female, or is attributed to death or after graft loss remains unknown. In this issue, Vinson et al report their findings of a follow-up retrospective cohort analysis of 3 large datasets (The American Scientific Registry of Transplant Recipients, International Collaborative Transplant Study, and Australia and New Zealand Dialysis and Transplant Registry) to investigate sex differences in the excess risk of DWGF among kidney transplant recipients.7 All recipients of a first deceased donor kidney transplant were categorized into age groups to account for how biologic differences between sexes change with development and aging. The death rate was then compared with publicly available data for the general population for each region in the study to calculate each patient’s expected probability of death. Overall, there was no significant difference in the excess risk of DWGF in women and men at all age groups, except for female recipients 0–12 y of age with male donors (relative excess risk, 1.68; 95% confidence interval, 1.24-2.29). Notably, having a male donor for a female recipient did not associate with an increased excess risk of death in all other age groups, suggesting that the findings in recipients 0–12 y of age in this study should likely not dissuade female patients from receiving a transplant from a male donor. The findings of this study contradict prior analyses4 that have demonstrated a higher risk of DWGF in male recipients and imply that the increased risk of DWGF among men reported in these studies may be attributed to population wide sex-based differences in mortality. Furthermore, these findings suggest that the increased excess risk of posttransplant mortality in women that was previously reported by Vinson et al cannot be attributed to DWGF, suggesting that there may be a higher risk of death among women during or after graft loss. Importantly, death after graft loss was not assessed in this analysis; therefore, it remains unknown if women indeed have a higher risk compared with men. Therefore, findings by Vinson et al point to the need for further evaluation of sex-specific mortality risks after transplant loss, including an evaluation of causes of graft loss and cause-specific death after graft loss. Importantly, the authors appropriately acknowledge that such an analysis may be challenging to do within the constraints of a retrospective analysis because it would risk introducing significant confounding bias.8 Therefore, prospective cohort studies may be indicated in this patient population to further understand sex-based disparities. The use of registry data remains critical in expanding our understanding of transplant care, and Vinson et al should be congratulated on attempting to provide a more comprehensive understanding of this issue across various regions. However, transplant registry analyses are limited by a lack of granular information about rejection, cause of graft failure, and cause of death. Additionally, there may be incomplete capture of death data. These limitations may explain the findings in this study of an increased excess risk of mortality among female recipients 0–12 y of age with male donors, which is a challenging observation to explain. Ultimately, these limitations speak to the need to enhance existing registries and the need for dedicated prospective studies. Although the results of the study are somewhat reassuring, because there is no demonstrated evidence of sex-based disparity in excess DWGF, the implication that sex-based differences in excess mortality after transplantation may be attributed to events related to graft loss is sobering and highlights the urgent need to further our understanding of this issue.

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