Looking at the future of solid organ transplants

Looking toward the next 30 years of treating kidney disease

Editor's note: Nephrology News & Issues is celebrating 30 years of publishing this year. In this series, we are looking to the future. How will treating kidney disease change in the next three decades?

In this 30th anniversary issue of Nephrology News & Issues looking at the future of treatment for renal diseases, it should be noted that the Organ Procurement and Transplant Network (OPTN) was also established 30 years ago and been overseen by the United Network for Organ Sharing for this entire time.

The evolution of kidney transplantation over those 30 years has been characterized by a steady improvement in patient and allograft outcomes and in the number of kidney transplants performed in the United States. Thirty years ago the one year kidney allograft survival hovered around 75%. Today the median one-year kidney allograft survival is near 95%. Over the course of those 30 years, kidney transplantation emerged from being regarded by many as a somewhat investigative and risky therapy, to become the treatment of choice for end-stage kidney failure.

The success of kidney transplantation resulted in a steady expansion of the patient populations for whom kidney transplant was felt to be appropriate therapy and which resulted in dramatic increases in the number of patients on the waiting list for kidney transplantation. Over this period of time, however, the number of kidney donors, both deceased and living, failed to keep pace with the growing waiting list. Today there are nearly 100,000 patients on the OPTN kidney transplant waiting list. In 2015, there were 12,250 deceased donor and 5,628 living donor kidney transplants done in the United States. That represents an approximate threefold increase from the number of kidney transplants done 30 years ago. In some portions of the country, however, waiting time for a kidney transplant can approach 10 years and unfortunately patient deaths while on the waiting list are all too common. The waiting time required for many patients to be transplanted now challenges the ability of transplant programs and the OPTN to provide attainable therapy for significant numbers of patents with end-stage kidney disease.

Demand vs. supply

The disparity between the demand for kidney transplantation and supply of transplantable organs is perhaps the defining feature of the current state of kidney transplantation. After 30 years of a steadily increasing gap between the supply of transplantable kidneys and the demand for kidney transplantation, we believe that this gap may have reached its maximum or will soon do so. It is possible that in the near future we may finally see this gap begin to close. The rate of increase in the incidence of kidney disease in the United States appears to be slowing and the past two years has seen significant increases in the number of kidney donors. This may be the result of changing transplant center and organ procurement organization practices as well as demographic changes within the potential donor population. We believe there exists the potential to further accelerate the recent increases in organ donation due to a series of incremental improvements within the transplant system, based on innovative technologic advancements as well as clinical application of basic science advances. Significant changes in the approach to transplantation are currently in clinical trials or on the near horizon. The results of these technologies and scientific advances will be to increase the supply of transplantable organs and to produce transplants that result in longer lasting successes.

Improvements in organ preservation

One set of new technologies in active clinical trials in the United States and entering clinical practice in other countries makes use of a new understanding of the basic mechanisms of organ injury associated with organ procurement. This has resulted in new approaches to organ preservation. The use of cold static organ preservation, which has been the standard approach to solid organ preservation since the 1960s, seems poised to give way to approaches based on normothermic perfusion of oxygenated solutions or blood that maintain procured organs in a near normal physiologically functioning condition. Devices based on this technology in clinical trials in the United States seem likely to be approved for use by the U.S. Food and Drug Administration in the near term. These devices have the potential to extend the tolerable organ ischemic time prior to transplantation which will allow significant changes to the way organ allocation is practiced in this country. These devices also permit the assessment of organ function prior to transplantation which should allow more organs to be transplanted and thus increase the pool of transplantable organs available to recipients.

Organ repair pre-transplant

These perfusion technologies also allow the possibility of pre-transplant repair of organs not previously felt to be transplantable or to pharmacologically or genetically manipulate organs to lessen their immunogenicity. The use of freestanding organ perfusion centers for deceased donor lungs is in an active clinical trial in the United States. These technologies are likely to see widespread clinical use first in lung or heart transplantation where acceptable cold ischemic times and organ supplies impose severe limits on organ allocation and the expansion of transplantation. While the impact of this approach in not yet clear, it does have a potential to be directly applied to kidney transplantation.

Tolerance

These new technologies of organ perfusion and potential organ repair or alteration might be coupled with emerging approaches to induce sustainable immunologic tolerance, long the “holy grail” of transplantation. Kidney transplantation protocols which couple donor bone marrow transplantation with kidney transplantation have shown dramatic results in small numbers of patients. While not increasing the number of donors, such techniques may result in substantial improvement in long term allograft survival which would decrease pressure on the strained donor supply.

Combinations of these techniques which are now in clinical trials, we believe, can be expected to change clinical kidney transplantation in the relatively near term and begin to close the gap between supply and demand that currently exists.

On the 30-year horizon there exist a variety of therapies and technologies that seem likely to substantially change the transplantation paradigm under which we currently operate. The constraints imposed on transplantation by the supply of deceased donor organs and the limitations of living organ donation may in the future cease to define kidney transplantation.

It appears possible to contemplate the development of successful long term preservation of donor organs. Super cooling or even vitrification of organs, analogous to what is known to occur in certain amphibian species such as the wood frog, have been successfully demonstrated as a proof of concept using animal models. Basic science advances in the properties of materials and complex cellular structures at low temperatures, along with the re-warming of vitrified materials, suggest that this could be applied to solid organs. If this is proven successful, biologic time becomes non-relevant and the current concept of organ allocation within the OPTN could evolve into true organ banking similar to blood banking.

Bio-artificial organs

The ultimate approach to the shortage of donor organs is likely to be some version of the manufacture and transplantation of bio-artificial organs. This has already been achieved in simple systems such as the production of bio-artificial trachea and urinary bladders. The re-cellularization of organ scaffolds using stem cells or more differentiated cell precursors has great potential for the production of transplantable organs that could be tailored to a specific patient’s needs. This approach has been already applied to a limited model of kidney transplantation in animals and is an area of intense clinical investigation. The potential to produce organ scaffolds and populate scaffolds with cells using 3D printing technology is also actively being investigated and has been frequently featured in popular press accounts of future therapies. A somewhat similar approach is currently being investigated in a clinical trial using encapsulated stem cell-derived insulin secreting cells implanted into diabetic patients. Devices, designed to be implanted in patients that incorporate human renal tubular cells and function as a bio-artificial kidney capable of many of the physiologic functions of a native kidney, are currently being investigated.

The future with many possibilities in transplant

If one is willing to project our current state of knowledge 30 years into the future, we think that clinical kidney transplantation will have evolved into a field not defined by issues of supply and demand for transplantable organs, or by the policy debates around issues of geography and equity, and limited by the constraints of immunology and immunosuppression. Instead, transplantation and the therapy of kidney diseases will be a field of organ repair and regeneration or manufacture that will be widely available and widely applied. -by David K. Klassen, MD; Brian M. Shepard, MBA