The Importance of Innovative Efforts to Increase Organ Donation

In the United States, patients with end-stage renal disease have 2 treatment options: dialysis or a kidney transplant. Those choosing a transplant have 2 donor choices: a living donor or a deceased donor.

Considerable information has been accumulated to help guide patient choices. Compared with dialysis, a transplant leads to a longer life,¹ enhances quality of life,² and is cost-effective for the health care system.³ Moreover, a living donor transplant (either related or unrelated) leads to better outcomes (patient and graft survival) than a deceased donor transplant.⁴ Thus, for patients with end-stage renal disease who are medically eligible for a transplant, the best treatment choice is a living donor transplant. In the last 2 decades, it has been recognized that unrelated living donor transplants have results equivalent to related living donor transplants. In 2004, unrelated living donor transplants accounted for more than 34% of living donor transplants performed in the United States.⁵

But what if no living donor is available? A transplant candidate might not have an eligible living donor for many reasons. First, the donor operation is associated with morbidity and mortality,⁶ so philosophically, many transplant personnel and community physicians do not encourage use of a living donor. For the same reason, eligible donor candidates may not volunteer. Second, the donor operation requires time off work, and some willing candidates without health or disability insurance may not be able to afford donating. Third, a donor must be in good health, have 2 normal kidneys, have normal kidney function, and not have any disease that would be transmitted with the transplanted kidney. Many transplant candidates have no family or friends who meet these criteria. Fourth, the donor must be compatible by blood type and immunologically compatible with the recipient. Blood type compatibility follows the same rules as for blood transfusions (eg, an individual with blood type O is a universal donor, but can only receive a kidney from a blood type O donor). Immunologic compatibility is determined by mixing recipient serum (containing antibodies), complement, and donor white blood cells (the test is called a crossmatch); if recipient antibody kills the donor cells (a positive crossmatch), the transplant is not performed.

If, for any reason, a living donor transplant is not possible, the transplant candidate must go on the waiting list for a deceased donor transplant. In the last 2 decades, the number of candidates annually on the waiting list for a deceased donor transplant has exceeded the number of available kidneys (with little increase in deceased donation during this same period).⁷ As a consequence, waiting time has steadily lengthened. In 1980, a candidate on the waiting list could expect a transplant within 1 year. Currently, more than 62 000 candidates are on the national kidney waiting list,⁵ and the average waiting time in many parts of the country is longer than 5 years.⁵ This increased waiting time has significant negative consequences. Annually, about 7% of the candidates on the waiting list die.⁸ These deaths are not limited to older patients with extrarenal morbidity, but also occur in young (<40 years) primary transplant candidates (V. Casingel, MD, unpublished data, 2005). The mortality rate decreases dramatically following transplantation.⁹ In addition, longer waits while continuing to undergo dialysis are associated with worse posttransplantation outcomes.¹⁰ For many years, immunologic barriers were thought to be the major hurdle in transplantation; today, many cite the organ shortage as the major limitation.

Efforts to increase deceased organ donation have included public relation campaigns, improvements in the consent process, the use of expanded-criteria donors (ie, donors with characteristics associated with worse transplant outcomes),¹¹ and the use of nonheartbeating donors.¹² These efforts have resulted in a small increase in deceased donor transplants in the United States in the last 2 years. Unfortunately, as noted in a recent study by Sheehy et al,¹³ even if all potential deceased donors became actual deceased donors, there would still be a shortage of organs.

During the last decade, the largest expansion of donation has been in the use of living donors, particularly unrelated living donors. The use of unrelated living donors has the greatest potential for increasing the number of donors in the future.

More recently, some centers have expanded acceptance criteria for living donors (eg, to include those with single-drug hypertension).¹⁴ Others have begun to use nondirected donors (ie, individuals who call the transplant center and offer to donate to anyone on the list).¹⁵ For each of these approaches, the numbers of available organs are small.

Another strategy for increasing the use of living donors has been an attempt to overcome the blood type and immunologic compatibility barriers. If the potential donor is incompatible by blood type or is crossmatch positive, successful transplants have been performed in association with extensive recipient desensitization protocols (pretransplant and posttransplant plasmapheresis, administration of high-dose immunoglobulin, pretransplant immunosuppression, and, in some cases, splenectomy).^{16 - 17} These protocols are expensive and labor intensive, and in the United States, have been implemented only for small numbers of patients.

In this issue of JAMA, Montgomery et al¹⁸ report the success of another option: paired organ exchange. A potential willing donor (donor 1) who is blood type or immunologically incompatible with the intended recipient (recipient 1) instead is compatible with recipient 2; simultaneously, donor 2 is incompatible with recipient 2, but compatible with recipient 1. Thus, donor 1 can provide an organ for recipient 2 while donor 2 provides an organ for recipient 1, without crossing blood type or immunologic barriers. Given the success of unrelated living donor transplants in general, paired exchanges should have excellent long-term outcomes. However, as with other approaches, only a limited number of paired exchange transplants can be performed.¹⁹ Most blood type exchange transplants will be between blood type A and B pairs; yet most blood type incompatibilities occur when the donor is blood type A or B and the recipient is blood type O.

In addition to the traditional paired exchanges, Montgomery et al show how blood type O recipients can benefit from an exchange program when a willing donor is immunologically incompatible. With the help of extensive laboratory testing (to determine which donor candidates are compatible with which recipients), multiple exchanges can be performed. Montgomery et al report two 3-way exchanges (3 donor/recipient pairs involved). In Korea, Park et al²⁰ have performed 6-way exchanges. Some paired exchange recipients, as reported by Montgomery et al, might still require expensive desensitization protocols. Even with multiple exchanges, numbers are limited. Park et al, whose program has been performing exchange transplants since 1991, recently reported a total of 101 cases.²⁰

While these approaches have limited application, they are still exciting advances. The individual organ recipients who undergo a successful transplantation have greatly improved expectations compared with those individuals who continue to undergo dialysis. Removing candidates from the transplant waiting list shortens the waiting time for the remainder of patients. One of the limitations of paired exchange is the small number of eligible donor/recipient pairs at each center, making finding a matched pair difficult. Regional or national matching programs would make finding pairs more probable,^{21 - 22} but including the highly sensitized blood type O candidates would require extensive laboratory testing.

However, there are several important cautions. While transplant physicians see the tremendous benefit that organ recipients derive from a successful transplant, organ transplantation raises numerous ethical issues involving protection of the donor, informed consent, and equity in organ allocation. To date, only a limited number of long-term outcome and quality-of-life follow-up studies have been performed concerning conventional donors. Paired exchange leads to additional concerns. For example, what if 1 kidney fails early but the other functions well? Those involved in such programs must pay careful attention to the informed consent process and should be conducting formal follow-up studies of donors.

For an organ recipient who has an incompatible donor, the first option should be to look for another donor. Only after such attempts have failed should the recipient be considered for an exchange program. In addition, some proponents of paired exchange have also advocated a list-paired exchange (ie, the incompatible donor donates to a patient on the deceased donor waiting list, and the intended recipient jumps to the top of the list); yet such transplants will disadvantage blood type O candidates already on the list.²³ Informed consent is also critical. For instance, in 1 of the exchanges described by Montgomery et al¹⁸ and in the study by Park et al,²⁰ the benefit noted was a better antigen match for the recipient; yet there is little evidence that antigen matching improves the patient’s outcome after a kidney transplant with an unrelated living donor.

Kidney transplantation remains a success story, but its promise and future continue to be threatened by the ongoing lack of suitable organ donors. While new methods to overcome this problem are welcome, the transplant community must face up to the new ethical issues that surround every advance.