Seema Baid-Agrawal and Ulrich A Frei* About the authors
Correspondence *Department of Nephrology and Medical Intensive Care, Campus Virchow-Klinikum, Charité Universitaetsmedizin Berlin, Augustenburger Platz 1, 13353 Berlin, Germany
Email ulrich.frei@charite.de
Summary
Renal transplantation is the optimal treatment for patients of all ages with end-stage renal disease. Life expectancy of the population in general is increasing consistently, as is the age of the dialysis population. Consequently, the average ages of kidney donors and recipients are rising. The combination of a growing number of patients with end-stage renal disease and a shortage of organs poses a significant challenge to the transplant community. Donor shortage is associated with unfavorable consequences (e.g. prolonged waiting time, and compromised graft and patient survival). As such, multidirectional efforts are required to expand the donor pool. Increasing the frequency of living donation seems to be an efficient solution. Living donation is associated with superior results for the recipient, and relatively benign long-term outcomes for donors. Reluctance to use organs from living donors whose eligibility was previously considered marginal (e.g. elderly donors) is declining. Although increased donor age is associated with reduced graft survival rates, this should not preclude use of older living donors; transplantation is definitely superior to remaining on dialysis. Thorough, standardized evaluation and careful screening for premorbid conditions in both elderly donors and elderly recipients are essential. Here, we present various options for expanding the living donor pool, with emphasis on the utilization of elderly living donors and transplantation in elderly recipients.
Review criteria
We focused our literature search on the PubMed and MEDLINE databases, and used the following search terms in different combinations: "renal transplantation", "living related", "living unrelated", "living donors", "elderly donors", "elderly recipients", "expanded criteria donors", "preemptive transplantation", "paired exchanges", "altruistic donation", "ABO-incompatible transplantation" and "HLA-incompatible transplantation". We concentrated on English-language articles and abstracts that have appeared in nephrology and transplantation publications in the past 5 years. We also searched article bibliographies for other relevant papers.
Keywords:
elderly donor, elderly recipient, expanded criteria donor, living donor, renal transplantation
Introduction
The first successful living donor renal transplant, performed in Boston in 1954 between identical twins, is a notable landmark in medical history. Remarkable medical and surgical advances in renal transplantation over the subsequent half century have advanced this modality so that it is now the optimal treatment for end-stage renal disease (ESRD). Renal transplantation improves patient survival and quality of life; it is also cost-effective when compared with hemodialysis and peritoneal dialysis.1 The long-term mortality rates among transplant recipients are 49–82% lower than those of patients on transplant waiting lists (depending on comorbidities).1 The survival and economic benefits of transplantation are evident across all age-groups.
The ESRD population is growing worldwide and has doubled in the Western world during the past decade.2 The elderly comprise the most rapidly expanding segment of the ESRD population.3 Consequently, the number of patients on transplant waiting lists has increased steadily, but there has been no concomitant increase in organ supply. This increasing disparity has resulted in a serious shortage of kidneys, leading to prolonged periods of dialysis and increased death rates for patients on waiting lists.1 Prolonged dialysis is associated with poor post-transplantation graft and patient survival.4, 5, 6
Increasing the number of donor kidneys is a major contemporary challenge. Recent evidence indicates that only 42% of potential deceased donors become actual donors in the US, and even if the organs of all potential brain-dead donors were utilized, the supply of kidneys would still be insufficient to meet the escalating demand.7 One potential solution to expand the donor pool is to increase the number of living donors. Transplantation from both living related and living unrelated donors is now widely accepted as a highly effective method of treating ESRD in selected recipients. Besides combating the increasing gap between organ supply and demand, living donation is associated with superior long-term outcomes when compared with renal transplants using organs from deceased donors. A disadvantage of living donation is that it requires a major surgical procedure with associated risks of morbidity and mortality. Living with a single kidney can also confer long-term risks. Consideration of living donation, therefore, involves weighing the benefits to the recipient against the risks to the donor.
Living versus deceased donor transplants: benefits and risks
Over the past few years, the benefits of living donor transplantation—compared with all forms of deceased donor transplantation—have been well recognized (Box 1). Use of living donors is associated with better graft and patient survival rates and a reduction in the time patients spend on dialysis. The half-life of renal allografts from living donors is 21.6 years, compared with 13.8 years for deceased donor organs.8
Box 1 Potential benefits and risks of living kidney donation.
Potential benefits
- Improved graft and patient survival, primarily due to superior organ quality, better HLA matching, shorter cold ischemia time, negation of negative donor-related factors (e.g. brain death, cardiovascular instability, use of vasopressins), short waiting time on dialysis, and feasibility of pre-emptive transplantation
- Facilitation of pre-emptive transplantation, which allows avoidance of dialysis-related complications, provides optimal medical and psychological condition of the recipient at the time of surgery, reduces risk of acute rejection, and improves graft and patient survival
- Expansion of total donor pool
Potential risks (to the donor)
- Perioperative morbidity and mortality
- Renal dys in the long-term
- Financial penalties from loss of work-time
The availability of a living donor also facilitates pre-emptive transplantation (i.e. transplantation prior to initiation of dialysis). The advantages of using a living donor (outlined above) are more pronounced in pre-emptively transplanted patients. Pre-emptive transplantation negates dialysis-related complications, and is associated with reduced risk of acute rejection as well as better allograft and patient survival.5, 9, 10, 11 Furthermore, recipients are generally in better medical and psychological condition at the time of pre-emptive transplantation than following dialysis. In an analysis of data from the United States Renal Data System (USRDS) database, Meier-Kriesche and Kaplan showed that 10-year graft survival was 78% for patients receiving pre-emptive transplants from living donors versus 48% for those who underwent transplantation after 24 months on dialysis.5 Living donor transplantation after recipients had been on dialysis for more than 24 months resulted in the same graft survival rates as transplants from deceased donors performed within 6 months of joining waiting lists.5 This phenomenon might account for a large proportion of the advantage of living donor transplantation over deceased donor transplantation. Other reasons for improved outcome could include superior organ quality, shorter cold ischemia time, negation of donor-related factors (e.g. brain death, cardiovascular instability, use of vasopressins) and a better human leukocyte antigen (HLA) match.12 Excellent outcomes have been observed, even in cases of unrelated living donation in which there is poor matching for HLA antigens.13, 14
The fundamental principle of 'first, do no harm' to the donors must be the primary consideration when contemplating living donation. Donors undergo a major operation with potential risks of perioperative morbidity and mortality, and renal dys in the long-term. Perioperative mortality for living kidney donors (donation by both open and laparoscopic methods) is 0.03%.15 Despite this relatively low mortality rate, there is a need for accurate ongoing reporting of donor operative outcomes. Existing evidence, mainly from retrospective surveys, indicates that there is little long-term medical risk to a healthy donor after unilateral nephrectomy.16, 17, 18 Most donors had normal renal 20–37 years after donation.18 Rates of proteinuria and hypertension were similar to those of the age-matched general population. Nevertheless, five (1%) donors developed ESRD and three others had abnormal renal .18 Ellison and colleagues identified 56 living kidney donors in the Organ Procurement and Transplantation Network database who were themselves listed for a kidney transplant.19 ESRD affected 0.04% of donors, a rate comparable to that of the general US population. To ensure their safety, all donors must undergo a complete and standardized predonation medical and psychosocial evaluation, receive appropriate instruction on providing informed consent, and be capable of understanding the information presented such that a voluntary decision to donate organs can be made.20
Strategies to expand the living donor pool
Enhanced public and provider awareness of living donor kidney transplantation has promoted increases of 68% and 1,000%, respectively, in the numbers of living related and unrelated donors in the US over the past decade.21 The number of living donors has actually surpassed that of deceased donors in some countries, including the US (Figure 1). The advent of laparoscopic donor nephrectomy has further propelled this change in practice. Despite this improvement, demand for organs still surpasses supply. Further increasing the number of living donors will require both innovative approaches and continued public education. Various strategies that are currently used to expand the living donor pool are summarized in Box 2.
Figure 1 Number of living and deceased kidney donors in the US from 1994 to 2003.
Data from the 2004 Organ Procurement and Transplantation Network/Scientific Registry of Transplant Recipients Annual Report 1994–2003 (www.optn.org/ar2004). These data have been supplied by the United Network for Organ Sharing (UNOS) and the University Renal Research and Education Association (URREA) under contract with the Department of Health and Human Services (HHS). The authors alone are responsible for reporting and interpreting these data; the views expressed herein are those of the authors and not necessarily those of the US Government.
Full figure and legend (19K)Figures & Tables indexDownload Power Point slide (104K)Box 2 Strategies to expand the living donor pool.
- Use of genetically unrelated donors such as a spouse, friend or acquaintance (emotionally related donors) or a stranger (altruistic or living nondirected donors [LNDs])
- Paired-donor kidney exchanges, either direct (living-donor–living-donor) exchanges (kidney-paired donation) or indirect (living-donor–deceased-donor) exchanges (list-paired donation)
- Integration of paired exchanges with LND donation, as either domino-paired donation (LND donation plus direct exchanges) or chain-paired donation (LND donation plus direct and indirect exchanges)
- Transplantation across ABO or HLA barriers using desensitization techniques
- Use of expanded-criteria living donors including hypertensive donors, obese donors and elderly donors
Genetically unrelated donors
In the past, 'living donation' meant donation by a sibling, parent or, sometimes, a child of the recipient (genetically related). Now, 'living donation' encompasses donation by a spouse, friend, acquaintance ('emotionally related') or even a complete stranger ('altruistic' or 'nondirected'). New immunosuppressive agents have permitted expansion of the living donor pool to include such emotionally related and nondirected donations. Data indicate that outcomes of living donor kidney transplants between genetically unrelated donors and recipients are superior to those using deceased organs with closer HLA matching (Figure 2).13 Further, the results of unrelated living donor transplantation are similar to those of living donor transplantation matched for one haplotype—a better outcome is achieved only by using an HLA-identical kidney.13, 14, 22, 23 As a result of these findings, interest in living unrelated transplantation has increased and protocols for nondirected living donation have been developed (see below).
Figure 2 Survival of first kidney grafts.
The survival rates of both spousal grafts and grafts from other living unrelated donors were similar to that of grafts from living donors with one haplotype match (parental donors) and superior to that of grafts from deceased donors. The grafts from HLA-identical siblings had the highest survival rates. Abbreviation: HLA, human leukocyte antigen. Permission obtained from Massachusetts Medical Society ? Terasaki PI et al. (1995) N Engl J Med 333: 333–336.
Full figure and legend (41K)Figures & Tables indexDownload Power Point slide (150K)Altruistic or nondirected donation
The success of living unrelated transplantation has led transplant physicians to consider the requests of individuals who volunteer as kidney donors but do not specify a recipient. Currently, such donors are dubbed living 'nondirected' (LND) or 'altruistic' donors. LND donation must be distinguished from directed donation, which involves designation of a donor organ for a specific individual. Any person who is competent, willing to donate, free of coercion, and found to be medically and psychosocially suitable, can be a living kidney donor in the US.24 In most other regions of the world, acceptance of such unconventional LND donors, however, has not occurred because of the difficult legal and ethical issues raised by this practice. Transplant centers that accept donors in this category should document an informed consent process that details donor risks and ensures donor safety. Motives for donation should also be established, with care taken to avoid donors who intend to remedy a psychological disorder via donation. Benefits to both donor and recipient must outweigh the risks.
At the University of Minnesota, a nondirected protocol has resulted in 23 successful donations.25 Such a program is, however, highly labor-intensive, as underscored by the fact that telephone screening interviews of the 362 potential LND donors led to only 53 comprehensive evaluations at the center and 23 transplants. Staff at this center emphasize the importance of a highly dedicated donor management team and the need for additional time and resources, given the number of practical, logistical and ethical issues inherent in LND donation.
Paired-donor kidney exchanges
Over the past few years, paired-donor kidney exchange programs have generated considerable international interest. A paired exchange program between two living-donor–recipient pairs was developed in Korea by Park and co-workers as a therapeutic option for ESRD patients whose only available living kidney donor is willing to donate, but is ABO blood- type incompatible or HLA incompatible.26, 27 At the time of their latest report, 101 exchanges had been performed. Five-year graft and patient survival were comparable to those for living unrelated donor transplants.28 Exchange programs increase the likelihood of resolving ABO and crossmatch incompatibility without exposing recipients to the risks associated with additional immunosuppression; which is necessary for desensitization programs. Paired-donor kidney exchanges might prevent loss of a significant number of suitable living kidney donors, and thereby have a positive impact on the current acute shortage of organs for transplantation. These programs are now classified as either direct or indirect.29
Direct (living-donor–living-donor) exchanges (or kidney-paired donation)In a direct paired exchange program, kidneys from living ABO-incompatible or lymphocyte-crossmatch-incompatible donors are available via arrangement between two living-donor–recipient pairs. Swapping donors makes possible two compatible living donor kidney transplants. In most instances there are no ethical obstacles to direct exchange, as the net gain for the two pairs does not differ from that of direct living donation and the exchange occurs on the basis of equality. There is no negative impact on the deceased donor list.
Despite the increasing popularity of direct exchanges, these transplantations are currently being performed at only a few centers, with matches identified through local or regional patient databases. To expand the opportunity for such exchanges, it is crucial to determine the most cost-effective method, optimal allocation priorities, and algorithms for matching patients and donors at the outset. Various computerized models using simulated pools of incompatible donor–recipient pairs have been designed to facilitate identification of the maximum number of compatible donor–recipient pairs from registries of incompatible pairs.30, 31, 32 It has been suggested that, using such a mathematically optimized matching algorithm, the nationwide pool of incompatible patients (predicted to be 2,500–4,000 registrants per year in the US) could achieve a match rate of 47%.30
Indirect (living-donor–deceased-donor) exchanges (or list-paired donation)The exchange program between living-donor–recipient pairs has been further evolved by the United Network for Organ Sharing Region 1 to include living-donor–deceased-donor exchange.29 This system helps patients who have an incompatible living donor available but are unable to participate in a living donor paired exchange. The exchange involves the donor of an incompatible pair giving a kidney to a patient at the top of the deceased donor waiting list, after which the living donor's original intended recipient is given 'priority points' so that they will receive the next ABO-identical or O type (T-cell crossmatch negative) deceased donor kidney available within the region; the original intended recipient does not take priority over candidates who are zero mismatch or sensitized, or over children. Offering the exchange-participant priority for an O blood type kidney seriously disadvantages O type candidates on the already long deceased donor waiting list. As such, indirect exchanges have been challenged on ethical grounds and have not been globally acclaimed.
Integration of paired exchanges with living nondirected donation
Recently, a new type of paired donation—'domino-paired donation'—has been proposed to improve the qualitative and quantitative benefit of each LND donation.33 In this strategy, the LND donor is allocated to a pool of direct-exchange pairs. First, the LND donor's kidney is matched to a recipient who has a willing but incompatible donor. The recipient's incompatible donor can, in turn, agree to give a kidney to the next compatible patient on the transplant waiting list, generating a 'domino' effect. In this way, two living donor kidney transplantations result, multiplying the impact of the donor's gift. Furthermore, integrating direct and nondirect exchanges with LND donation (through chain exchanges) has been shown to increase the number of individuals who receive a transplant without creating any further adverse effect on O blood type candidates on the deceased donor waiting list.34
Transplantation across ABO or HLA barriers
ABO blood type incompatibility or T-cell crossmatch reactivity between donor organs and recipients would result in an accelerated rejection of the allograft. Historically, therefore, these factors have been considered as absolute contraindications to transplantation.35, 36, 37 In most centers, between 30% and 40% of all otherwise-acceptable living donors are presently rejected because of ABO incompatibility. Moreover, approximately 20–30% of patients on transplant waiting lists in the US are highly sensitized against HLA antigens and cannot find a compatible living donor. Until recently, therefore, ABO and HLA incompatibility have been two of the greatest barriers to optimal utilization of kidneys from living donors.
Performing the transplant despite incompatibility is another recent exciting advance for ABO-incompatible or HLA-incompatible living-donor–recipient pairs, besides paired-donor kidney exchanges. Successful desensitization of some of these patients has been possible, allowing living donor transplantation or deceased donor transplantation across these biological barriers.36, 37, 38, 39, 40, 41, 42, 43, 44, 45 The overall goal of desensitization is to reduce antibodies against donor ABO or HLA before and after transplantation. Two desensitization protocols have shown great promise in accomplishing this goal: first, plasmapheresis or extracorporeal immunoadsorption, and second, intravenous immunoglobulin (IVIG), both in conjunction with maintenance immunosuppression using mycophenolate mofetil and tacrolimus with or without steroids.
IVIG is used in high doses (2 g/kg body weight) for patients awaiting either a deceased or living donor transplantation, and in low doses (cytomegalovirus hyperimmune globulin [CMVIG] 100 mg/kg body weight) in combination with plasmapheresis for patients with living donors only.37 IVIG has well-recognized but poorly understood immunomodulatory effects. Rituximab, a high affinity CD20-specific monoclonal antibody, has become an important (off-label) adjunct in desensitization protocols. This agent is a rational choice for desensitization, as it attenuates alloimmune responses by abrogating B-cell-mediated events.
The persistence or reappearance of antibodies, resulting in antibody-mediated rejection (AMR) of the graft, are potential risks of transplantation across ABO or HLA barriers. The risk of AMR is highest during the first 10 days following transplantation. Acute AMR should be diagnosed on the basis of allograft dys, rising antibody titers and the presence of deposits of the complement component C4d in peritubular capillaries.35, 37 Recently, the identification of C4d deposits was found to be an important indicator of AMR in HLA-incompatible grafts; identification did not, however, correlate with injury in most ABO-incompatible grafts.46 Treatment of acute AMR includes lowering antibody levels with pulse steroids, plasmapheresis plus CMVIG for mild cases, and rituximab and/or urgent splenectomy for severe cases.37
ABO-incompatible transplantationABO-incompatible transplantation has become relatively common in Japan over the past 20 years because of the very limited number of deceased donors in that country. Excellent outcomes at 9 years, comparable to those following ABO-compatible transplantation, were reported in a large Japanese series of 441 ABO-incompatible living donor renal transplants with splenectomy.43 Splenectomy, however, remains a major impediment to wider acceptance of ABO-incompatible transplantation. The need for splenectomy has recently been questioned, as substitution of splenectomy with rituximab has been associated with good results.44, 45 Extending their previous observations, Tyden et al. have reported successful ABO-incompatible transplantation without splenectomy in 21 patients using antigen-specific immunoadsorption, one dose each of rituximab and low-dose IVIG (0.5 g/kg body weight), and a conventional triple-drug immunosuppressive protocol.44 These results have been reproduced by Sonnenday et al. in six ABO-incompatible recipients.45
HLA-incompatible transplantationSuccessful desensitization overcoming positive T-cell crossmatches has been achieved by various centers, allowing safe transplantation with good 1-year and 3-year graft survival rates.37, 38, 39, 40, 41 Using the Hopkins protocol of plasmapheresis and low-dose CMVIG, Montgomery and Zachary have successfully transplanted more than 80 sensitized patients, including some with very highly positive baseline crossmatches.37 Rituximab or splenectomy are reserved for those at highest risk of severe AMR in this protocol. Rituximab has also been used successfully in a series of 14 patients with a positive pretransplantation living donor crossmatch, in conjunction with an intensive regimen including splenectomy and plasmapheresis; 11 patients maintained their grafts for more than 1 year.41 Such an intensive protocol has also been used to overcome simultaneous HLA and ABO incompatibility in three patients, with excellent short-term outcomes.42
ABO-incompatible and HLA-incompatible living donor kidney transplantation have the potential to increase the size of the living donor pool without disadvantaging candidates on the deceased donor waiting list. Nevertheless, these conditioning regimens are relatively expensive and are still associated with unpredictable rates of biological graft loss and potential risks of intensive immunosuppression. It should also be emphasized that long-term outcomes are not yet known. Randomized, controlled clinical trials are needed to establish optimal peritransplantation management protocols and to confirm their long-term efficacy.
