The Future of Kidney Transplantation

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The facts are straightforward. A kidney transplant is the optimal therapy for renal replacement therapy in ESRD. It is optimal from the point of view of its ability to restore both the health and quality of life of the individual affected and its long-term cost-effectiveness. Dialysis, whether hemo- or peritoneal and whether in-center or at home, is life preserving and necessary, but in the final analysis, it cannot compete with transplantation.

Today, 104,706 people are on the waiting list for a kidney transplant. In 2016, only 19,061 kidney transplants were accomplished. Roughly one-third of these involved living organ donors, and two-third involved deceased donors. An eligible person waits a median of 3.6 years for a kidney transplant, with some waiting 8 years or more. Sadly, one-fifth of those on the waiting list die every year (13 die each day) or become too sick or frail to undergo the surgical transplant procedure. Clearly, this is not acceptable.

This article is part of a series arising from a roundtable recently held at The Rogosin Institute. Other articles have explored many of the issues related to increasing living and deceased organ donation and transplantation. Among the concerns addressed were how more kidneys can be made available for transplantation, the use of extended criteria donor kidneys, the incentives and disincentives transplant centers face in using not just the healthiest of kidneys with the best immunological matches, reduction of the kidney discard rate, and the optimization of the allocation system.

Here, we will look at not only additional ways to increase both living and deceased donation in the future but also, prospects for the repair and rebuilding of whole kidneys, such that the shortage of kidneys for transplantation can be eliminated. We can now envision the possibilities of using an individual’s own stem cells to create a new immunologically matched replacement kidney or editing the genome of banked human stem cells to create a kidney that is a “perfect” immunological match with no requirement for immunosuppression.

Rebuilt or newly built kidneys are an exciting prospect for the treatment of ESRD. Research still has a way to go before such kidneys are available, but the progress is very encouraging. Knowing that, however, are there actions we can take in the meantime to increase the number of available organs to shorten the waiting list time and decrease the mortality and lost opportunities that characterize the situation today? The answer to this question is a definite “yes.”

Previous articles in Kidney News have focused on a multitude of ideas to increase the rate of kidney transplantation (Table 1).

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Discarding old assumptions about willingness to donate

An important point is that one potential solution does not fit every situation. For example, a northeastern urban African American community has not been known to have a high rate of living or deceased kidney donation. One might assume that the residents of that community would not be willing to donate. Yet, a community-implemented survey carried out by leaders and volunteers in the Central Brooklyn Health Movement in collaboration with The Rogosin Institute found that 62% of residents were willing to consider giving a kidney as a living donor and a somewhat smaller percentage (56%) were willing to consider giving a kidney as a deceased kidney donor. Although one must be very cautious in interpreting these data (e.g., many of those willing to be living kidney donors would not prove to be medically suitable or might ultimately decide not to follow through), it is also true, as some residents contacted in the survey stated, that they had never been asked the question. These findings indicate that we need to be very careful about the assumptions we make about the willingness to donate organs in any given community.

It is also important that people in the community who are trusted ask the questions about willingness in the “language” of the community. Put another way, different communities need to be asked in ways that are meaningful to them, and their concerns, cultural norms, and mores must be taken into account. In this way, more reliable information can be obtained, and more importantly, the donation of kidneys and other organs can be increased.

These observations lead to other questions about how to best increase organ donation in a given community in a fashion that is sustainable over the long term. The desired changes will not happen all at once. Education about both living and deceased organ donation needs to begin in schools (middle and high schools), and it needs to be carried out where people live, work, play, and worship. The information needs to be provided repeatedly and pervasively in the community, such that it becomes a part of the fabric of the community. The desired message is, “We are a community whose residents care for each other.”

Much of this message can and should be conveyed by community leaders and residents themselves because theirs is the voice that will be listened to in the community. The creation of a culture of organ donation must arise within and be fostered by the community itself. Health professionals have an important role to play in all of this, but it is most often a supportive and reinforcing one that ensures the supply of correct information. The Central Brooklyn Health Movement, mentioned above in relation to the kidney transplantation survey, is a movement of just this sort—a movement for better health of, by, and for the people of eastern New York and Brownsville, Brooklyn, NY—places where the health indices for hypertension, diabetes, and kidney disease, for example, are far higher than they should be and the need for kidneys for transplantation is great.

Advances in newly built kidneys

Even with all these efforts, it is unlikely there will ever be enough living and deceased donor kidneys to meet the need. So how can we address that need? This requires that we consider the prospects for “newly built” kidneys. What are the prospects?

Recent years have seen an explosion of activity in the development of stem cell–based strategies to build new tissues. Because of its structural complexity, the kidney is a relative latecomer to this aspect of regenerative medicine. However, work in the past 5 years has highlighted the feasibility of this approach as a potential long-term solution to the organ shortage crisis, resulting in a surge of research activity.

Before going into more detail regarding research strategies being pursued to generate new tissue, the tenacious work over the past decades on xenografting should be discussed. Although many obstacles have been encountered along the road to developing the pig xenografting strategy, such as the discovery of unforeseen layers of immune protection against cross-species engraftment and the identification of porcine endogenous retroviruses as a significant risk to human recipients, this field has undergone a revitalization with the discovery of new tools for genome modification. Outcomes of grafting tissues from new generations of multigene knockout pigs into primates show increasing tolerability, and there is good reason to be optimistic about this approach.

The possibility to generate entirely new and patient-specific kidney tissue gained traction when it was shown that pluripotent stem cells derived from adult humans could be directed to form the major cell types required for a fetal kidney: nephron progenitors; collecting duct progenitors; interstitial, mesangial, and pericyte progenitors; and endothelial progenitors. This mix of fetal progenitor cells can be induced to differentiate in vitro, and through their intrinsic self-organizing properties, they form small aggregates of tissue containing rudimentary patterned nephrons, collecting ducts, and structures resembling glomeruli. Although these remarkable in vitro-generated organoids display characteristics of fetal rather than adult tissue, the potential of this approach is clear, and many research groups are pursuing key aspects of its development. Ongoing research is addressing issues such as the maturity of this synthetic tissue, its ability to be vascularized by a host into which it is engrafted, and how it may be assembled on a biological scaffold that would encourage its integration into a recipient. Although many difficult hurdles remain, the potential of this approach to generate patient-specific tissue, minimizing or perhaps eliminating the need for immunosuppression, is very exciting.

Simultaneous pursuit of distinct strategies such as xenografting and the generation of laboratory-grown tissue ensures vigorous and dynamic activity in the area of alternative sources of tissue for renal replacement. With the recent injection of optimism into this research field, we are seeing an increase in resources, for example, the (Re)Building a Kidney Consortium established by the National Institute of Diabetes and Digestive and Kidney Diseases. With resources come new investigators with fresh ideas, and, if the current momentum is maintained, it is realistic to predict both an acceleration of ongoing work and the development of brand new approaches that may complement or supersede current strategies. Now that we can clearly see a way forward for kidney regenerative medicine, it is essential to designate resources for the long term. Strategic thinking and realistic expectations of progress are essential to avoiding the hype and boom/bust economies that have been obstacles to progress in so many fields of biomedicine. Perhaps by being a relative latecomer to this field, kidney regenerative medicine can learn from past mistakes and avoid these traps (14).

February 2018 (Vol. 10, Number 2)

References

1. Cooper DK, et al. The pathobiology of pig-to-primate xenotransplantation: A historical review. Xenotransplantation 2016; 23:83–105.

2. Little MH, Kairath P. Regenerative medicine in kidney disease. Kidney Int 2016; 90:289–299.

3. Morizane R, Bonventre JV. Kidney organoids: A translational journey. Trends Mol Med 2017; 23:246–263.

4. Oxburgh L, et al. (Re)building a kidney. J Am Soc Nephrol 2017; 28:1370–1378.