Hospital de Bellvitge, University of Barcelona, Barcelona, Spain
Introduction
The permanent shortage of organs has led to attempts to expand the donor pool. Identifying which kidneys previously considered suboptimal can be safely accepted for transplantation may help to reduce the number of patients on waiting lists. On the other hand, changes in demographic characteristics of developed countries, with an increasing ageing population, makes it more necessary to review donor acceptance criteria to maintain acceptable results even in current transplant activity. In Catalonia in 1990 the proportion of donors older than 50 years was 17%; this had increased to 45% in 1997. During the same period the mean donor age rose from 31.4 years to 45.6 years. Moreover, the proportion of donors dying from cerebrovascular accident, which was less than 40% in 1990, rose to over 50% in 1997 [1]. Similar data have been reported by the United Network for Organ Sharing in the United States [2].
The increasing proportion of suboptimal, marginal, or borderline donors raises several questions. The most important issues regarding these donors are the following: (i) definition of marginal or borderline donors; (ii) acceptance criteria; (iii) techniques of organ preservation for kidneys harvested from these donors to minimize the incidence of delayed graft function; (iv) allocation of such organs, which may be related to the nephron mass provided to the recipient; (v) immunosuppression regimens to prevent rejection and reduce nephrotoxicity; and (vi) the expected graft and patient outcomes.
Viability of kidneys to be transplanted
Advanced age, hypertension, mild diabetes mellitus, acute renal failure during a terminal illness, and death from some poisonings had traditionally been considered exclusion criteria for organ harvesting some decades ago. Donors older than 60 years are currently accepted in living related [3] and in cadaveric [4] transplantation. Advanced donor age is associated with graft survival rates reduced by approximately 2030% at 3 or 5 years after transplantation, and with suboptimal renal function [35]. According to the Catalan Registry [1], only 20% of recipients of renal allografts from donors older than 60 years have a calculated creatinine clearance higher than 59 ml/min; in contrast, 50% of patients have such a creatinine clearance when transplanted with organs from donors younger than 30 years.
Ageing and hypertension may be associated with pre-existing lesions that entail a poor renal function and graft outcome. Considering the limited value of serum creatinine for assessing renal function immediately before harvesting, renal biopsy is the most useful tool for evaluating the viability of a kidney for transplantation. Renal damage assessed with a semiquantitative scale or with a quantitative parameter such as the percentage of sclerosed glomeruli or the expansion of the interstitial space, correlates with the incidence of post-transplant delayed graft function and renal function [68]. Twenty per cent glomerulosclerosis is usually considered the upper limit for accepting kidneys from a marginal donor [4]. However, a more complex score, including glomerular, tubular, interstitial, and vascular lesions, may better reflect the viability of kidneys for transplantation. Such an index has been used to select kidneys for single and double renal transplantation [9].
Problems with kidneys from elderly donors
Transplant recipients of kidneys harvested from older donors have a higher incidence of delayed graft function, which is associated with an increased occurrence of acute rejection. Patients with delayed graft function may double the incidence of acute rejection in comparison with cases with immediate diuresis [10]. Both factors have a severe detrimental effect on graft outcome. However, and regardless of the presence of acute rejection, delayed graft function amplifies the deleterious effect of advanced donor age on long-term graft survival [10]. In addition, recipient age >50 years and prolonged cold ischaemia time are further risk factors for delayed graft function.
Improved kidney preservation strategies
Hence, techniques to shorten cold ischaemia time appear to be vital in older donors to reduce the risk of delayed graft function and to improve transplant outcome. Thus, organ-sharing organizations operating in large geographical areas might consider restricting organ exchange to optimal kidneys. Improved preservation of suboptimal kidneys may also reduce the risk of delayed graft function. Pulsatile perfusion machines are reported to be especially useful in preserving kidneys from older donors. According to the UNOS data [11], the odds of requiring post-transplant dialysis for ice-preserved vs perfused kidneys when the donor age was at least 55 years were 2.33 times greater, and if the cold ischaemia time was 24 h, the odds were also twofold greater. Moreover, pulsatile perfusion preservation also improved the overall outcome of renal allografts from older donors. Pulsatile perfusion machine may also help to assess the viability of suboptimal grafts by measuring vascular resistance, which is an accurate predictor of post-transplant function [12]. An additional approach to improve immediate and long-term graft function would be the use of protective agents able to attenuate reperfusion injury. Scavengers of oxygen free radicals such as recombinant superoxide dismutase failed to decrease the need for haemodialysis after transplantation, but did significantly diminish the incidence of acute rejection and increase the graft half-life [13]. In a single-centre double-blind study we showed a beneficial effect of a platelet-activating factor receptor antagonist in the prevention of delayed graft function, defined as the need for haemodialysis in the immediate post-transplant period [14], although we have not seen such protective effect in a multicentre trial. Nevertheless, and as in the case of superoxide dismutase, we have seen a significant reduction of chronic transplant nephropathy 6 months after transplantation (data not published). These findings suggest that the need for haemodialysis may be a poor parameter for evaluating reperfusion injury, and that the real protective effect of these pharmacological interventions should be assessed in the long-term; this can only add to the complexity of trials to attenuate reperfusion injury in this subset of suboptimal donors.
Which donor kidneys to which recipients?
Ageing is associated with glomerular sclerosis, vascular and tubulointerstitial lesions, and progressive reduction in renal function [6]. Elderly donor kidneys with structural deficits transplanted into young recipients resulted in suboptimal function and reduced long-term graft survival rates [4]. Thus, age-matching kidneys from elderly donors to older recipients, who have both lower metabolic demand and reduced alloimmune response, has been proposed [15]. However, the performance of a suboptimal renal allograft is related to the metabolic demands of the recipient rather than to his/her age per se. Disparity between donor and recipient body surface area greater than 10% is associated with a high incidence of hypertension and proteinuria, both markers of poor graft outcome [16]. Hence, allocation of suboptimal kidneys to recipients with small body surface area might improve graft performance and survival. Despite these proposals, the proportion of kidneys harvested and not implanted has increased in recent years [17]. These data mainly reflect the facts that the proportion of suboptimal donors is increasing and that many teams are reluctant to accept kidneys from such donors.
One or two kidneys for transplantation?
An alternative for reducing the number of discarded kidneys and for offering enough nephron mass with elderly or marginal kidneys to conventional recipients may be the implantation of two marginal kidneys that would otherwise be discarded. This policy would significantly increase the number of older donor kidneys transplanted, reduce the rate of non-use of older donor kidneys, and has resulted in a higher graft survival rate at 1 year after transplantation [18]. The incidence of delayed graft function was low in dual transplantation, especially when cold ischaemia time was shorter than 24 h in a single-centre experience [19]. Data from the first 100 registry patients show that recipients of dual kidneys from donors 54 years of age have a significantly decreased incidence of delayed graft function, and have better renal function and graft survival than recipients of a single kidney harvested from donors of a similar age [20]. In a multicentre, prospective case-control trial [6] comparing the outcome of two marginal kidneys grafts with age- and gender-matched recipients of a single ideal kidney, the incidence and duration of post-transplant anuria and rejection were comparable in cases and controls. Interestingly, diastolic blood pressure was lower in double kidney recipients, and higher donor/recipient body weight and body mass index ratios were both significantly associated with better renal function, suggesting that better outcomes result from more nephrons. Similar physiological considerations may also apply for double kidney transplants from cadaveric infant donors to adult recipients [21].
Modified immunosuppressive drug regimens?
Pre-existent histological lesions make renal allografts more susceptible to cyclosporin nephrotoxicity [7], and calcineurin inhibitor-based immunosuppression in kidney grafts from older donors is associated with poor outcomes [5]. In two preliminary reports [22,23], calcineurin inhibitor-free regimens consisting of mycophenolate mofetil, antithymocyte globulin, and steroids were associated with relatively low incidences of both delayed graft function and acute rejection, with acceptable renal function. These initial data may point the way to controlled studies aimed at avoiding or reducing calcineurin inhibition in recipients of marginal kidneys.
Conclusions
In summary, the utilization of marginal donors may expand the donor pool. Routine renal biopsy to assess the viability of marginal grafts, improved preservation techniques, an allocation policy taking into account the nephron mass provided and the recipients' metabolic demands, and possibly modified immunosuppression regimens designed to minimize calcineurin-inhibitor nephrotoxicity, may optimize graft outcomes.
Notes
Correspondence and offprint requests to: Josep M. Grinyó MD, Department of Nephrology, Hospital de Bellvitge, University of Barcelona, C. Feixa Llarga s/n, L'Hospitalet de Llobregat, E-08907 Barcelona, Spain.
References