Time to Procurement and Post-Kidney Transplant Outcomes

There has been miraculous advancement of organ transplantation in the years following the first human-to-human kidney transplant performed less than a century ago (1). That initial attempt at transplant was using a kidney from a deceased donor who had died 6 hours before the procurement, an extreme attempt by today’s standards, and the graft had immediate failure. Over time, we learned to control the donor variables and surgical precision to refine the quality of the graft, enabling the eventual success of the transplant experiment by optimizing what could be controlled. In present day, our donor selection practice has come full circle with expansion of the donor pool using extended criteria donors of all varieties, including a large proportion from those procured after cardiac death. Our transplant history has been rich with research throughout this timeline, with the aim always to optimize graft outcomes in balance with expanded access to this lifesaving and life-altering therapy. Maximizing the potential of each donor lays at the crux of this dilemma. One of the historical questions that continues to be debated is centered around donor management and mitigating the potential effects of the primary insult these organs sustain in the context of the donor’s death, which leads again to the more fundamental question of how we optimize this precious resource.

As far as transplant science has come over the past century, the rest of modern health care has equally advanced. This has drastically altered our life expectancy as well as the constitutional makeup of our aging societal donor pool and their burden of comorbid disease, leading to increased organ discards. The obesity and opioid epidemics and, most recently, the coronavirus disease 2019 pandemic further complicate our donor pool. Even as we have advanced our techniques and ability to utilize a wider breadth of organs, the need for transplantation grows at an accelerated clip in comparison. This results in ever-increasing waiting lists and disparities in access to this therapy. One way we can directly affect the donor shortage is through living donation; every gift a living donor makes is a gift to the recipient as well as a gift to society at large, allowing everyone else in line waiting to take a step forward. However, not all recipients will have those coveted living donor opportunities, and therefore, we are left embracing both spectrums of donors, optimizing both living- and deceased-donor organ utilization to meet this unmet need of access to transplant.

One of the most challenging aspects of transplantation from deceased donors is that one never knows where or in what context the next donor may come from, necessitating that a system is in place to support the act of donation as well as prioritize and distribute the donor organs to the appropriate recipient. These tasks occur in a very limited time window at unpredictable and sometimes overwhelming intervals. This relies on complex systems between referring hospitals and transplant centers to facilitate appropriate donor and recipient matching, balancing the needs and wishes of the organ donors themselves and their loved ones regarding timing and manner of donation. Therefore, widely varying practices exist across the world with regard to these systems, highly dependent on local health care, resources, and culture.

Eerola et al. (2), in this issue of CJASN, have addressed this age-old question of donor optimization with regard to the association between time to organ procurement and short- and long-term outcomes, looking at both European and US kidney transplant cohorts from brain-dead donors. Reflecting on the history of this fundamental question, there are known deleterious effects of brain death itself—most notably, a proinflammatory cascade that contributes to the potential for graft dysfunction and poorer post-transplant outcomes—and efforts were therefore made to minimize the procurement delay (2,3). However, there have been other studies suggesting that more time between declaration of brain death and procurement may have its advantages, although these retrospective studies are limited by smaller numbers and potential confounding variables (4,5). Additional conflicting reports have both warned of potential donor losses with prolonged brain death management protocols and supported the safety of very long procurement delays following brain death (6,7). We continue to seek clarity on the ideal balance to strike with regard to timing of procurement following declaration of brain death.

By looking at modern era cohorts with data extracted from the Finnish Kidney Transplant Registry and the Scientific Registry of Transplant Recipients for the US data, Eerola et al. explore the association of procurement delay with delayed graft function and kidney graft survival with robust multivariable analysis (2). The strength of this paper is the very large cohorts across two continents, with great attention to their statistical approach adjusting for confounders in their analyses. This presents the largest analysis to date, as well as being representative of our contemporary cohort.

Overall, this study confirms some of the earlier work that the “sweet spot” for procurement delay from the time of declaration of brain death is likely 24–48 hours and that very short delays were associated with worse graft survival, whereas very long delays were associated with delayed graft function. It is also striking the difference in the delays between the two health systems, with the median of the longest quartile of the Finnish delays still being shorter than the median of the short-delay quartile in the US cohort.

There are limitations to this analysis being rooted in retrospective observational registry data, as well as the likelihood that some covariates act as both confounders and mediators of the effects seen. Additionally, the sample size of the Finnish dataset limits the ability to adjust for all confounding variables. The authors also point out that these data are kidney specific and that, potentially, the ideal procurement delay is organ specific and not generalizable to other solid organs. Likely the biggest limitation of the application of the results of this analysis, however, is inherent to our processes and the logistical complexities of the act of donation.

Even if we could conclusively know the ideal procurement delay to optimize all donor organs from a brain-dead donor, the logistics of achieving that timing within the previously discussed systems constraints may be impractical.

How then do we optimize these organs and apply these data to benefit the greatest number of patients, while working within the reality of the complex and heterogenous systems in play? Perhaps the most encouraging result of this paper is that there is likely a point at which organs are ideally preconditioned within the donor to achieve more favorable long-term outcomes, and so, if we are able to induce those conditions reliably, we may be able to optimize more organs for transplant with better outcomes. Because of all the logistical challenges of donor management that may not be able to be modified, as well as the potential need to achieve different ideal conditions for each of the solid organs, the solution may come in the form of ex vivo normothermic machine perfusion as a platform for deceased-donor organ assessment and repair.

Normothermic machine perfusion is a technology that has been evolving rapidly over the past decade as a promising new platform to assist transplant professionals in optimizing both quality and utilization of deceased donor organs. Our challenges in donor management to achieve these ideal conditions (allow time for assessment, be sensitive to logistical complexities, and remain fiscally responsible as well as sensitive to the donor family wishes) may all be more easily attained by shifting some of these tasks to follow organ procurement. Observing the organ’s performance and delivering therapeutics to achieve an ideal preconditioned state may be the future role of normothermic machine perfusion as a way station to transplantation. DiRito et al. (8) have presented the vision of the potential of this technology and the ways it may revolutionize the challenges we currently face in achieving this “ideal” donor state. Although initially, normothermic machine perfusion was utilized for the rescue of marginal grafts that would have otherwise been discarded by allowing more time for the assessment to take place and observe perfusion quality, more recent exciting work expands our potential for therapeutic drug delivery. Tietjen et al. (9) presented their foundational work in nanoparticle delivery to the kidney on ex vivo normothermic machine perfusion, however, microvascular obstructions were prohibitive to reliable and effective targeting to the endothelium. The group's most recent work demonstrated the ability to eliminate cold storage–induced microvascular obstructions with ex vivo treatment of marginal kidneys on normothermic machine perfusion, opening the door for more effective subsequent nanoparticle drug delivery (10). A better understanding of the specific preconditioning required for each deceased donor organ to optimize performance will allow for individualized therapy, as the cargo for these nanoparticles can be readily tailored to the organ's specific needs.

The platform of normothermic machine perfusion and development of reliable vehicles for drug delivery on that platform may become the cornerstone of how we ultimately achieve a personalized medicine approach to ready each of these invaluable gifts to achieve their greatest potential. By utilizing as many of these gifts as possible in both transplant and high-impact translational research, we will be not only honoring those transplant recipients we care for but, importantly, also honoring the altruistic donors and donor families that make this gift of life a possibility.

Disclosures

D.J. Haakinson reports employment with Yale University.

Funding

None.