Transplantation Higher mortality risk found for female recipients of male-donor transplant kidneys

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

Amanda Vinson

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

Immunosuppression optimisation “does not delay” transplant failure

The use of immunosuppressant drugs to facilitate allograft success in kidney transplant recipients “does not delay failure of renal transplants after development of donor-specific antibodies (DSAs)”. That is the conclusion of the OuTSMART trial, which has been published in eClinicalMedicine and coordinated by Dominic Stringer, corresponding author Anthony Dorling (King’s College London, London, UK) and colleagues.

KIDNEY TRANSPLANT RECIPIENTS CAN experience graft dysfunction, followed by graft failure, as a result of “chronic immune-mediated injury”, according to the OuTSMART authors, who outline the context and purpose of the investigation. These failures lead to tens of thousands of patients a year returning to dialysis after a transplant has failed, and have been linked to the development of antibodies (Abs) to human leukocyte antigens (HLAs) in the transplant recipient.

DSAs have been associated by other studies with “a higher risk of graft loss compared to [antibodies] that are not donor-specific”. This has led to the use of immunosuppression as a strategy against “immune-mediated damage”.

The study authors set out to illuminate immunosuppression with a trial that took place across 13 UK transplant centres, where 2037 transplant patients were randomised, 1028 to unblinded care and 1009 to double-blinded care. Patients were grouped according to HLA Ab status, which was known at time of transplant for 91% of patients. Most recruited patients were taking tacrolimus (73%), MMF (67%) or prednisolone (55%) at randomisation, while 27% were taking all three and “baseline immunosuppression was balanced across groups”. The primary outcome of the study was time to graft failure in an intention to treat analysis, and was measured at 43 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”.

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.”

Amanda Vinson

Graft failures for DSA-positive patients

15–20%

Graft failures for negative patients

7% months remotely due to the COVID-19 pandemic. From the cohort, 198 patients were found with DSA and 818 with non-DSA. DSA development, though not non-DSA development was found by the authors to be “predictive of graft failure”. The authors state that their results confirmed the prognostic value of monitoring DSA” but failed to show statistically significant change to graft failure rates with optimised oral immunosuppression, with “confirmatory 95% confidence intervals for hazard ratios that included the null value”. They found that 15–20% of grafts failed for DSA-positive patients, compared with 7% for negative patients, but for those undergoing immunosuppression optimisation “we failed to see an impact on time to graft failure”. While rejection was reduced by immunosuppression, this did not translate into decreased rates of transplant failure.

Speaking on the implications of their findings, Stringer et al state that the data “will impact significantly on how transplant centres around the world organise their post-transplant monitoring”. They make the case that it should also spark an international effort to find new approaches to the question of ensuring graft success.