Waitlist Mortality for Second Kidney Transplants : Clinical Journal of the American Society of Nephrology

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Editorial

Waitlist Mortality for Second Kidney Transplants

Fallahzadeh, Mohammad Kazem; Birdwell, Kelly A.

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CJASN 17(1):p 6-7, January 2022. | DOI: 10.2215/CJN.15021121

Kidney transplantation is the treatment of choice for kidney failure, associated with higher survival and quality of life outcomes compared with long-term dialysis (1). Kidney transplantation has been associated with higher risk of survival in different patient populations including those with diabetes mellitus, obesity, or older age (2). A recent observational study that used data from the French registry to emulate a randomized controlled trial (RCT) where patients were assigned to kidney transplantation versus awaiting transplantation showed that, at 10 years’ follow-up, first kidney transplantation was associated with life expectancy gain of 6.8 months compared with remaining on the waiting list (3). However, whether second kidney transplantation clearly offers a higher risk of survival over being waitlisted on dialysis remains to be determined.

Second kidney transplant candidates comprise a sizable portion of waiting list populations (e.g., 11.8% in the United States; 27.5% in Austria) (4,5). In addition, concerns exist that second kidney transplant recipients may have worse outcomes compared with first kidney transplant recipients due to longer exposure to dialysis, the cumulative effects of immunosuppression, and more difficulty finding a suitable donor due to higher immunologic sensitization (6,7). In the studies by Khalil et al. and Magee et al., second kidney transplants were associated with higher risk of allograft failure than first kidney transplants (6,7). Given the scarcity of available kidney allografts, it is prudent to know if this limited resource is being used with optimal equity and utility. Previous observational studies have suggested higher survival risk and quality of life benefits with second kidney transplantation compared with remaining on the waiting list (8,9). However, these studies were limited due to immortal time or selection biases. Although a RCT would be the best research design to compare survival benefit with kidney transplantation versus awaiting transplantation on dialysis, it is not ethically and logistically feasible to conduct a RCT for this purpose.

To overcome the impracticality of conducting a RCT and the limitations of previous studies, in this issue of CJASN, Kainz et al. (5) employed a pragmatic clinical target trial emulation to compare the survival difference between second kidney transplant and remaining on the waiting list after a first failed transplant. Using the data from the Austrian Dialysis and Transplant Registry supplemented by Eurotransplant data, the authors included 2346 kidney transplant recipients who were older than 18 years and were waitlisted for second kidney transplant between January 1980 to August 2019. The primary endpoint of interest in this study was overall mortality. The authors presented the average survival difference between second transplantation and remaining on the waiting list as the difference in restricted mean survival time (RMST). RMST is a well-established but underutilized measure of efficacy in RCTs that can be intuitively interpreted as the average survival time from baseline to a prespecified time point. Difference in RMST indicates gain or loss in the event-free survival time due to treatment or control during the studied time (10). To provide a suitable control group for comparison with patients who received a second transplant, the authors employed a series of auxiliary trials in a sequential Cox approach. Any time a patient received a second transplant at time T, the authors emulated an auxiliary trial starting at time T, where the treatment group included all patients who had a second kidney transplant at time T compared with the control group that consisted of all patients who were on the waiting list at time T since the time of first graft loss for both groups. The authors stacked the data from all auxiliary trials and analyzed them in a single Cox proportional-hazards model using the treatment group as exposure, with this method allowing them to address competing hazards. The authors used the stabilized inverse probability of treatment weights to address confounding and lack of randomization in the observational data. The other strengths of the methodology included bootstrapping to calculate the 95% confidence interval (95% CI) for the quantities of interest and extensive sensitivity analyses to assess the robustness of the results.

This study showed that a second kidney transplantation, compared with remaining on the waiting list, was associated with a longer RMST of 1.6 (95% CI, 0.3 to 2.9) and 5.8 (95% CI, 0.9 to 11.1) months over a follow-up time of 5 and 10 years, respectively. However, this association with higher survival was less in patients with longer waiting time since first graft loss, with those waiting more than 3 years having no statistically significant survival difference. This finding was mainly attributed to improved relative survival in patients who remained on dialysis awaiting transplantation. The authors speculated this might be due to biologic selection of long-term survivors. The other interesting finding of this study was that it took a few years for the association with higher risk of survival of second kidney transplantation to manifest on the survival curves. This could potentially be due to higher risk of complications associated with transplant surgery and high-dose immunosuppression therapy in the immediate post-transplant period (1). It should be also noted that the overall mortality in the studied cohort was high at 41% with a median observed follow-up time of 10.7 years, with a higher proportion of these in the waitlist group. The sensitivity analyses showed that the general results remained compatible. When data before 1994 (when cyclosporine was adopted as the standard immunosuppression regimen in the Eurotransplant region) were excluded, an even higher risk of survival with second kidney transplant was observed, showing the positive impact of current transplant practices, possibly due to standard immunosuppression regimens using calcineurin inhibitors. In contrast, a lower risk of survival was observed in second kidney transplant recipients of deceased donors, indicating a possible advantage of living donors for this population.

Given that this study was carried out in Austria, which has a predominantly White population and uses the Eurotransplant kidney allocation algorithm, its results may not be generalizable to other countries with different racial backgrounds and kidney allocation systems. Even though robust methodologies were used, the presence of unmeasured confounding is always possible in an observational study. Although commonly considered clinical covariates were collected, these were limited to what was available in the registry and did not include important characteristics such as the cause of primary kidney failure or the presence of diabetes, which may affect survival. Also, individuals were removed from the analysis once they were delisted, which could have affected the results.

In summary, the authors took advantage of an innovative methodology, target trial emulation, to address an important question of survival risk of second kidney transplantation that could not be easily addressed by traditional RCT and was less hindered by common biases found in observational studies. Overall, they showed second kidney transplantation was associated with a higher risk of survival versus remaining waitlisted on dialysis for the Austrian population, with a statistically significant difference for those with waiting times below 3 years. If these results are reproduced in imitated trials from other countries, it would signify the importance of decreasing time on the waiting list for second kidney transplant candidates by measures such as expedited workup and the enlistment of patients with failing first kidney transplants before they require dialysis. Given the importance of patient-reported outcomes such as quality of life, future studies should also try to incorporate these outcomes in their analyses.

Disclosures

All authors have nothing to disclose.

Funding

None.

Published online ahead of print. Publication date available at www.cjasn.org.

See related article, “Waiting Time for Second Kidney Transplantation and Mortality,” on pages .

Acknowledgments

The content of this article reflects the personal experience and views of the author(s) and should not be considered medical advice or recommendation. The content does not reflect the views or opinions of the American Society of Nephrology (ASN) or CJASN. Responsibility for the information and views expressed herein lies entirely with the author(s).

References

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Keywords:

kidney transplantation; mortality; transplant outcomes

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