How Do We Provide A Personalized Medicine Approach To Optimizing Organ Donation

Organ transplantation has made miraculous progress after the first human-to-human kidney transplant was performed less than a century ago. The initial transplant attempt was using a kidney from a deceased donor who died 6 hours before transplantation, an extreme attempt by today's standards, and the transplant failed immediately. Over time, we have learned to control donor variables and surgical precision to improve the quality of the graft by optimizing controllable factors for the ultimate success of the transplant experiment. Our donor selection practice has now completed a full cycle, expanding the donor pool using extended criteria to include all species of donors, including a large proportion of donors obtained from post-death cardiac sources. Our transplant history has been richly researched during this time, and the goal has always been to optimize transplant outcomes while expanding the use of this life-saving and life-changing therapy. Maximizing the potential of each donor is the key to this dilemma. A historical issue that continues to be debated is the potential impact of donor stewardship and mitigating the major stigma these organs endure in the context of donor death, which again leads to the more fundamental question of how we optimize this valuable resource.

In terms of how to transplant science has evolved over the past century, and other aspects of modern healthcare have advanced as well. This has dramatically altered our life expectancy and the composition of our increasingly aging society's donor pool and their burden of comorbidities, leading to increased organ discards. The obesity and opioid epidemics and the recent 2019 coronavirus pandemic have further complicated our donor pool. While advances have been made in our technology and ability to utilize a broader range of organs, the demand for transplants has accelerated in comparison. This has resulted in growing waiting lists and gaps in access to this treatment. One way we can directly impact the donor shortage is through a living donation; every gift from a living donor is a gift to the recipient and a gift to society as a whole, allowing everyone else waiting in line to take a step forward. However, not all recipients have those coveted living donor opportunities, so we can only accept two types of donors, optimizing the use of living and deceased donor organs to meet this unmet need for transplantation.

Click here to know the effects of Cistanche on Kidney

One of the most challenging aspects of the transplantation of deceased donors is that one never knows where the next donor may come from or under what circumstances, which requires a system to support the act of donation and to prioritize and allocate donor organs to appropriate recipients. These tasks occur at unpredictable and sometimes overwhelming intervals over a very limited period of time. This relies on complex systems between referral hospitals and transplant centers to facilitate appropriate donor-recipient matching, balancing the needs and desires of organ donors themselves and their loved ones in terms of timing and modalities of donation. As a result, widely varying practices exist around the world with respect to these systems, highly dependent on local health care, resources, and culture.

In this issue of CJASN, Eerola et al. address the age-old question of donor optimization regarding the relationship between time to organ acquisition and short- and long-term outcomes by looking at kidney transplant cohorts of brain-dead donors in Europe and the United States. Looking back at the history of this fundamental question, brain death itself is known to have deleterious effects-most notably, a pro-inflammatory cascade response that can lead to graft dysfunction and poorer post-transplant prognosis-and thus, efforts have been made to minimize procurement delays. However, there are other studies suggesting that a long time between the declaration of brain death and procurement may have its advantages, although these retrospective studies are limited by the small number and potential confounding variables. Other conflicting reports have warned of the potential for donor loss with extended brain death management protocols and support the safety of delaying procurement long after brain death. We continue to seek a clear declaration of the ideal balance in the timing of procurement after brain death.

Eerola et al. extracted modern cohort data from the Finnish Renal Transplant Registry and the US Scientific Registry of Transplant Recipients to explore the relationship between graft delay and delayed graft function and renal graft survival through robust multivariate analyses. The strength of this paper is the very large cohort spanning two continents and the great attention paid to their statistical approach to adjusting for confounders in the analysis. This is the largest analysis to date and is representative of our contemporary cohort.

Herba Cistanche

Overall, this study confirms some earlier work that the "sweet spot" for procurement delay may be 24-48 hours from the time of declaration of brain death, with very short delays associated with worse graft survival and very long delays associated with delayed graft function. The difference in delay between the two health systems is also striking, with the median of the quartiles with the longest delay in Finland remaining shorter than the median of the quartiles with the shortest delay in the US cohort.

This analysis based on retrospective observational registration data has limitations, and some covariates may act as both confounders and mediators of the effects seen. In addition, the sample size of the Finnish data set limits the ability to adjust for all confounding variables. The authors also note that these data are kidney-specific and, potentially, the ideal procurement delay is organ-specific and not generalized to other solid organs. However, the greatest limitation to applying the results of this analysis may be the logistical complexity of our process and donation behavior.

Even if we could know exactly the ideal procurement delay to optimize all donor organs from brain-dead donors, the logistics of achieving this timing under the systemic constraints discussed earlier may be impractical.

Cistanche extract

So how do we optimize these organs and apply this data to benefit the maximum number of patients while working within the reality of complex and heterogeneous systems? Perhaps the most encouraging result of this paper is that there is likely a tipping point at which organs are ideally pre-conditioned in the donor for more favorable long-term outcomes, and therefore if we can reliably induce these conditions, we may be able to optimize more organs for transplantation with better outcomes. With all the logistical challenges of donor management that may not be modifiable and the potential need to achieve different ideal conditions for each solid organ, the solution may come in the form of ex vivo thermostatic machine perfusion as a platform for dead donor organ evaluation and repair.

Thermostatic machine perfusion is a technology that has rapidly evolved over the past decade as a promising new platform to help transplant professionals optimize the quality and utilization of deceased donor organs. Our challenges in achieving these ideal conditions for donor management (allowing time for evaluation, being sensitive to logistical complexity, maintaining fiscal responsibility, and being sensitive to the wishes of the donor family) may be more easily achieved by shifting some of these tasks to after-organ procurement. DiRito et al. have demonstrated the potential of this technology and the way it may revolutionize the challenges we currently face in achieving this "ideal" donor state. While initially, thermostatic machine perfusion was used to salvage marginal grafts that would otherwise have been discarded by giving more time to evaluate and observe perfusion quality, recent exciting work has expanded our potential for therapeutic drug delivery. reliable and effective targeting of the endothelium. The group's recent work demonstrates that ex vivo treatment of marginal kidneys under thermostatic machine perfusion can eliminate the refrigerated-induced microvascular obstruction, opening the door to more effective subsequent nanoparticle drug delivery. A better understanding of the specific pretreatment required for each deceased donor organ to optimize its performance will allow for individualized therapy, as these nanoparticle shipments can be easily tailored to the specific needs of the organ.

The thermostatic machine perfusion platform and the development of reliable drug delivery tools on that platform may become the cornerstone of our ultimate personalized medicine approach to prepare these valuable gifts to achieve their maximum potential. By leveraging as many of these donations as possible in transplantation and high-impact translational research, we will honor not only the transplant recipients we care about but more importantly, the selfless donors and donor families who make this gift of life possible.

Standardized Cistanche

Kidney transplantation is a common treatment option for end-stage renal disease (ESRD) that can significantly improve quality of life and survival rates. The procedure involves replacing a damaged kidney with a healthy one from a donor. However, the process of transplanting a kidney can be associated with several complications, such as ischemia-reperfusion injury, delayed graft function, and rejection.

Cistanche is a herb commonly used in traditional Chinese medicine to treat kidney-related conditions. Recent studies have reported that Cistanche extract can reduce inflammation and oxidative stress, which can help protect against renal damage. Additionally, it can promote cellular regeneration, which can aid in the healing process after transplantation.

It is important to note that while Cistanche may have potential benefits for individuals who have undergone kidney transplantation, research in this area is still limited. Further clinical studies are needed to evaluate the safety and effectiveness of Cistanche as an adjunct therapy for kidney transplant recipients.

References

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2. Eerola V, Helantera¨ I, But A, Lempinen M, Ma¨kisalo H, Nordin A, Isoniemi H, Sallinen V: The association of time to organ procurement on short- and long-term outcomes in kidney transplantation. Clin J Am Soc Nephrol 16: 427–436, 2021

3. Nijboer WN, Schuurs TA, van der Hoeven JAB, Fekken S, Wiersema-Buist J, Leuvenink HGD, Hofker S, Homan van der Heide JJ, van Son WJ, Ploeg RJ: Effect of brain death on gene expression and tissue activation in human donor kidneys. Transplantation 78: 978–986, 2004

4. Ergu¨n M, O¨ Zdemir-van Brunschot DMD, Donders RART, Hilbrands LB, Hoitsma AJ, Warle´ MC: Prolonged duration of brain death was associated with better kidney allograft function and survival: A prospective cohort analysis. Ann Transplant 24: 147–154, 2019

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6. Westphal GA, Slaviero TA, Montemezzo A, Lingiardi GT, de Souza FCC, Carnin TC, Soares DR, Hachiya AH, Ferraz LL, de Andrade J: The effect of brain death protocol duration on potential donor losses due to cardiac arrest. Clin Transplant 30: 1411–1416, 2016

7. Inaba K, Branco BC, Lam L, Salim A, Talving P, Plurad D, Green DJ, Demetriades D: Organ donation and time to procurement: Late is not too late. J Trauma 68: 1362–1366, 2010

8. DiRito JR, Hosgood SA, Tietjen GT, Nicholson ML: The future of marginal kidney repair in the context of normothermic machine perfusion. Am J Transplant 18: 2400–2408, 2018

9. Tietjen GT, Hosgood SA, DiRito JR, Cui J, Deep D, Song E, Kraehling JR, Piotrowski-Daspit AS, Kirkiles-Smith NC, Al-Lamki R, Thiru S, Bradley JA, Saeb-Parsy K, Bradley JR, Nicholson ML, Saltzman WM, Pober JS: Nanoparticle targeting to the endothelium during normothermic machine perfusion of human kidneys. Sci Transl Med 9: eaam6764, 2017

10. DiRito JR, Hosgood SA, Reschke M, Albert C, Bracaglia LG, Ferdinand JR, Stewart BJ, Edwards CM, Vaish AG, Thiru S, Mulligan DC, Haakinson DJ, Clatworthy MR, Saltzman WM, Pober JS, Nicholson ML, Tietjen GT: Lysis of cold-storage induced microvascular obstructions for ex vivo revitalization of marginal human kidneys. Am J Transplant 21: 161–173, 2021

Danielle J. Haakinson