Extending the selection criteria for living donors
The persistent shortage of organs has forced the transplant community to consider newer, more-controversial options. A wider range of potential living donors is being evaluated than ever before, and selection criteria have been extended to include donors who traditionally would not have been considered. Older people and those with mild hypertension and obesity are being accepted as donors more frequently.
Hypertension, most often defined as blood pressures above 140/90 mmHg or the need for antihypertensive medications, is one of the most common reasons for excluding donors who are otherwise eligible.47 The primary concern is that hypertensive donors might have increased postoperative risks of worsening hypertension and of developing kidney failure. African American donors and those with a family history of hypertension and/or kidney disease are regarded as particularly susceptible.19 It is unclear whether or not moderately hypertensive white donors are at appreciable risk in the absence of associated kidney disease. Thresholds for defining hypertension have been constantly lowered over the past two decades. Many donors classified as having normal blood pressure 25 years ago would now be categorized as hypertensive and excluded from kidney donation; however, relatively benign donor outcomes have been reported during follow-up of at least 20 years following kidney donation.16, 17, 18
The Mayo Clinic has implemented a structured program of accepting moderately hypertensive white kidney donors who satisfy other criteria (e.g. >50 years of age, glomerular filtration rate [GFR] >80 ml/min and urinary albumin excretion <30 mg/day).47 Twenty-four donors have been followed for between 6 and 12 months, and no adverse effects have been detected on blood pressure, GFR or urinary protein excretion. Notwithstanding encouraging short-term results, it should be emphasized that only individuals with moderate hypertension and no other adverse risk factors (e.g. African American race, family history of hypertension and/or renal disease, and glucose intolerance) may be considered for kidney donation.
Donor obesityObese donors, previously discouraged from living organ donation, are now being considered under expanded criteria. Obesity (BMI >30 kg/m2) is associated with health problems (hypertension, proteinuria and diabetes) and has a negative impact on renal .20, 48, 49 Being overweight could, therefore, increase the risk of a donor developing proteinuria and renal disease. Obesity also increases the risk of perioperative infections and death for patients undergoing a variety of surgical procedures. Nonetheless, as pressure to expand the living donor pool has grown, prudently selected obese donors have been used, with relatively good short-term outcomes.48 Fasting blood sugar and 75 g 2 h oral glucose tolerance tests should be performed on all obese potential donors. Other comorbidities should be evaluated. Weight reduction programs and education about healthy lifestyle should both be included in the plan for donation.20
Elderly donorsReluctance to use organs from elderly donors has decreased with the increase in demand. Until fairly recently, age greater than 55 or 60 years was often considered sufficient grounds to reject a donor organ, as survival of older grafts is inferior to that of kidneys from younger donors. In most large studies of kidney transplant outcomes, deceased donor age greater than 50 or 60 years has been identified as a strong independent predictor of poorer graft survival.50, 51, 52, 53 The use of kidneys from older donors is associated with increased risk of delayed graft , acute rejection, chronic allograft nephropathy, increased baseline creatinine and, consequently, increased rates of early and late allograft failure. It is worrying that donor age has recently been identified as a significant risk factor for patient death with ing graft.54 The authors of that study speculated that poor of the aged graft might lead to hypertension and an increased incidence of cardiovascular events.
Concerns regarding the effects of older donor age on deceased donor renal transplant outcome have influenced the assessment of potential living donors at many centers. It is not uncommon for elderly individuals to be discouraged from donation in favor of a younger living donor or placement of the intended recipient on the waiting list for a deceased donor organ. The influence of donor age on the outcome of living donor kidney transplantation is, however, unconfirmed. Both equivalent, as well as reduced, graft survival (as compared with transplantation from younger donors) have been reported.
Kumar and co-workers retrospectively compared the long-term outcomes of 112 recipients of kidneys from elderly (>55 years) living related donors with 87 recipients who had younger donors (<45 years).55 No differences in graft and patient survival between the two groups were detected at either 1 year or 5 years after transplantation. No additional morbidity or deterioration of preoperative blood pressure and renal were observed at 1 year in the group with elderly donors. These observations are supported by a study from the Mayo Clinic, which compared the outcomes of 52 recipients of older (>50 years) living donor grafts with a matched group of 103 recipients of younger (<50 years) donor kidneys.56 Overall graft survival, patient survival and death-censored graft survival, up to 3 years post-transplantation, did not differ significantly between the two groups.
In contrast to the above findings, significantly poorer survival of grafts from 5 years post-transplantation onwards was detected in a Japanese series of 343 older (>60 years) living donor allografts.57 Similarly, Prommool et al. found donor age to be the most important risk factor for graft loss after the first 5 years.58 In an analysis of their entire living donor population of 2,540 kidney transplants at the University of Minnesota, Matas and colleagues identified donor age greater than 55 years to be a significant risk factor for late graft loss. This finding was in contrast to a previous study by the same group that showed that increased donor age was not a risk factor for poor outcomes from living donor transplants.59, 60 Nevertheless, long-term survival of grafts from older living donors has been shown to be significantly better than that of organs from elderly deceased donors and similar to that of grafts from younger deceased donors.60
The inferior outcomes of an older kidney graft might be a of the anatomical and physiological changes that occur during aging.61 Halloran et al. have proposed a role for cellular senescence in the decline of renal transplant over time, pointing out the similarities between some histological features of chronic allograft nephropathy and those of the aging kidney.62 al changes in aging kidneys might be compounded by adverse events in the post-transplantation period (such as warm ischemia, allograft rejection and exposure to nephrotoxic immunosuppression) resulting in a poor graft outcome. The hallmark of renal aging is increased basal renovascular tone accompanied by reduced perfusion, thought to be secondary to glomerulosclerosis.
In individual cases, however, the association between donor age and graft is weak. Results from the seminal Baltimore Longitudinal Study of Aging have shown that the magnitude of the decline in GFR experienced by healthy elderly subjects was less than was previously estimated. In some elderly subjects, no change in GFR was documented over at least 25 years.63 So, for a substantial proportion of healthy elderly individuals, GFR remains within the (lower) normal range. GFR is only modestly decreased at the expense of an increased filtration fraction and postglomerular vasoconstriction. Age-related renal changes are exacerbated by comorbidities such as hypertension, atherosclerosis and heart failure.64 Not surprisingly, therefore, the medical history of the potential kidney donor yields information useful for prediction of post-transplantation outcomes, independent of donor age. Kidneys from patients dying of cardiovascular events or stroke fail more often than organs from donors dying of subarachnoid hemorrhage.65 Pre-existing donor hypertension and diabetes negatively influence transplant outcome.66, 67
Another important factor when considering older living donors is the likelihood of an increased complication rate during procurement of organs. Advances in surgical techniques and anesthesia, and improvements in perioperative care, have made nephrectomy a safe procedure, even for the elderly.55, 60, 68 Rates of short-term morbidity and mortality do not seem to be higher for elderly donors, but no data on long-term outcomes for this specific group are available.
It is clear that older potential donors should be accepted only after thorough evaluation and careful screening for conditions that are likely to produce unacceptable operative risk. Healthy donors should not be rejected on the basis of age alone. General health of the donor and al renal reserve should determine the upper age limit for donation. Donor kidney , which tends to decline with age, should be balanced against the needs of the recipient. Older living donors and the recipients of their organs should be made aware that allograft and possibly even graft survival might be compromised by donor age; however, this should not necessarily preclude use of older living donors, as transplantation provides significant advantages over remaining on dialysis while awaiting deceased organ donation.
Elderly recipients
The life expectancy of the general population is increasing consistently, as is the average age of the dialysis population.3 In most Western countries, the median age of patients on dialysis is approximately 60 years. Advanced recipient age should no longer be a contraindication for renal transplantation, as successful transplantation improves quality of life and survival and reduces costs, even in older recipients.1, 68, 69, 70 For patients older than 60 years who are on transplant waiting lists, the annual death rate is 10%; this rate is 7.4% in transplant recipients. The absolute benefit to patients in this age-group is, therefore, even greater than that observed for 20–39-year-olds, even though more projected life years are gained by transplantation of the latter cohort (17 vs 4 years).1 Transplant candidates older than 60 years have a fivefold greater likelihood of dying while waiting for a donor kidney than patients under 50 years of age.3 Prolonged waiting time on dialysis dramatically decreases the clinical and economic benefits of transplantation of older recipients.71 Early transplantation should, therefore, be strongly encouraged in this group of patients.
In spite of the above data, there is still great reluctance to transplant kidneys in elderly recipients, mainly because of their limited life expectancy. Additionally, in the context of the persistent deceased donor shortage, priority is given to younger patients. Living donor transplantation might, therefore, be particularly beneficial in elderly recipient populations, as it decreases waiting time and enhances patient and allograft survival compared with deceased donor transplantation—effects similar to those observed in younger recipients.61 Using a living donor negates the argument of organ wasting, and can be a valuable therapeutic option even in the very old. Healthy spouses, siblings and children are potential living donors. (Genetic renal diseases must be ruled out when considering children or siblings as donors.) Furthermore, the selection process for a living donor should include discussion of possibly increased operative and long-term risks in the context of potentially limited benefit to the recipient owing to their short projected life expectancy.
The most common cause of graft loss in elderly recipients is patient death, which is almost four times as likely to occur in recipients older than 65 years than in recipients aged 18–49 years.70, 72 After receipt of an organ from a living donor, survival at 5 years is 93% for younger patients, but only 72% in those older than 60 years. By contrast, death-censored graft survival seems to be better in elderly recipients. In the elderly, the two main causes of post-renal-transplantation morbidity and mortality are cardiovascular disease and infection. Before being accepted onto a transplant waiting list, all older patients should be screened intensively for pre-existing comorbidities. Careful follow-up is mandatory in order to minimize immunosuppression and the occurrence of surgery-related complications.
Elderly recipients seem to have a relatively low risk of acute rejection resulting from age-related deterioration of the immune system. Clinical and experimental studies have shown, however, that recipient age is a strong and independent predictor of the development of chronic allograft failure.72, 73, 74 These findings were reinforced by an analysis restricted to living donor transplants that were not acutely rejected.72 The pathogenic mechanisms underlying the increased likelihood of chronic allograft failure in elderly patients are not well understood, but probably encompass age-related changes of both immunological and nonimmunological mediators in the recipient, and increased susceptibility to calcineurin inhibitor nephrotoxicity. Tailoring immunosuppressive regimens to account for altered immune responses and increased risks of drug toxicity, infections and cardiovascular disease seems to be the best strategy for improving graft and patient survival in the elderly transplant population.75
Conclusions
Renal transplantation is established as the treatment of choice for ESRD patients in all age-groups. To overcome the organ shortfall, vigorous multipronged strategies to increase the availability of living donors are imperative. These endeavors should include acceptance of genetically unrelated donors (including altruistic donors), development of exchange programs, transplantation across ABO and HLA barriers, and use of expanded-criteria donors, particularly elderly volunteers. It is expected that transplantation of a kidney from an expanded-criteria living donor will be associated with inferior outcomes. It should be emphasized, however, that receiving an allograft from such a donor is preferable to remaining dialysis-dependent on a transplant waiting list. Worldwide, ongoing education of patients and providers, the broadening of regulations to include unrelated living donation, and legislative initiatives removing financial barriers to living donation are required to enhance the potential of this organ source. To minimize the risk to the living donor, ensuring the highest possible standards of clinical care for living donor transplantation has to be our aim. Only then can the enormous benefit of living donor transplantation be maintained for all.
Key points
- Compared with deceased donor transplantation, transplantation of a kidney from a living donor is associated with superior graft and recipient survival, facilitates pre-emptive transplantation, and expands the total donor pool
- Potential risks to living kidney donors include perioperative morbidity and mortality, renal dys in the long-term, and financial loss
- Strategies to increase the number of living kidney donors include using donors that are genetically unrelated to the recipient, obese, hypertensive or elderly-paired-donor kidney exchanges, and transplantation across ABO and HLA barriers
- Successful promotion of living kidney donation requires legislative reform, education of patients and providers, and commitment to high-quality, long-term follow-up of living donors
