Dialysis has been the long-established initial choice of treatment for persons with end-stage renal disease. Transplantation before dialysis, or preemptive renal transplantation (PRT), has been controversial because of the paucity of clinical evidence that has clarified the benefits vs. risks of this approach. However, several recent observational analyses indicate that PRT is the optimal strategy to benefit patients requiring renal replacement therapy. This current review will discuss the advantages that are associated with PRT, and will summarize studies that have investigated the impact of the timing of transplantation on outcomes. We will also discuss the utility of PRT from various perspectives, and describe the challenges ahead in expanding the opportunity of PRT for more patients.
Dialysis has been the traditional initial choice of renal replacement therapy for persons who develop end-stage renal disease (ESRD). However, use of this strategy as the standard approach has recently been challenged. Reservations about preemptive renal transplantation (PRT) center around the dearth of evidence demonstrating the benefit of PRT and concerns that these individuals could potentially be exposed sooner to the complications of transplantation and immunosuppression. Recent observational studies support the use of PRT as a more advantageous strategy for the patient than transplantation after dialysis initiation. These data also indicate that most, if not all, patients who undergo PRT have met the criteria for ESRD established by the working group for the Kidney Dialysis Outcomes Quality Initiative (KDOQI) (1). In this review, we contend that the data on clinically meaningful outcomes, such as survival and quality of life, strongly support PRT as the optimal initial form of renal replacement therapy.
Rates of Preemptive Renal Transplantation
Preemptive renal transplantation occurred in 25% of adult recipients of allografts from living donors in the United States in the latter part of the twentieth century (2,3). The lower rate of PRT of cadaveric renal allografts into adult recipients, approaching 10%, is likely attributable to the prolonged waiting times of transplant candidates on the cadaveric list, during which persons become dialysis-dependent. In comparison, children who develop ESRD have increased PRT rates of approximately 34% from living donors and 14% from cadaveric donors (4). The collection of reasons that contribute to the infrequent use of PRT among adults is undefined, but includes donor availability and perhaps an unclear understanding about the advantages of PRT among health care providers leading to delayed referrals to a nephrologist and transplant center (5). The significance to the patient of the under utilization of PRT and the overlooked opportunities for the avoidance of dialysis-associated morbidities and improved transplant survival may be substantial.
Residual Renal Function at the Time of PRT
Concerns that patients who are not yet on dialysis are receiving an organ prematurely are unwarranted. An analysis of 4095 PRT recipients of a renal allograft during 1994 through 2000 in the United States revealed that the estimated glomerular filtration rates (GFRs) averaged 9.9 mL/min [SD (5,3)] at the time of transplantation (6); levels that were significantly less than the suggested threshold of 14 mL/min for dialysis initiation proposed by the KDOQI working group (1). These observations were corroborated by a second study that also demonstrated individuals transplanted preemptively with a cadaveric renal allograft have severe renal insufficiency at the time of transplantation (median serum creatinine level of 8.6 mg/dL), indicating the need for a therapeutic intervention (7).
Avoidance of Dialysis-Associated Morbidities
Preemptive renal transplantation as an alternative strategy for the initiation of dialysis when renal replacement therapy is medically necessary could avoid the morbidities associated with dialysis. For example, 20% of dialysis patients are hospitalized each year for access-related problems; greater than 50% of these admissions are related to infection of the dialysis access. Less certain, because of increased time for risk, is the potential reduction by PRT of other morbidities that are observed more frequently with longer duration on dialysis. However, our experience indicates that the reversibility of cardiac systolic dysfunction by transplantation diminishes with increasing time on dialysis (8). The United States Renal Data System (USRDS) collects the activity of Medicare claims from persons who are on hemodialysis, peritoneal dialysis or who have received a renal allograft. Claims data from persons who are between the ages of 45 and 64 years demonstrate that transplant recipients average 0.79 hospital admissions per patient year at risk in contrast to the mean 1.94 and 1.98 hospital admissions per patient year at risk for individuals who are on hemo- or peritoneal dialysis, respectively (9). This translates into a mean reduction of nine hospital days per patient year at risk associated with transplantation. This assessment, limited by the heterogeneity of persons on dialysis, likely is an upper estimate of this potential effect of PRT. Rigorous evaluation of the effectiveness of PRT and the duration of the economic impact from the reduction of dialysis-related morbidities requires a cost-effectiveness comparison, which has yet to be performed on PRT and transplant-eligible persons on dialysis (8).
Survival Advantages of Preemptive Transplantation
Several investigations utilizing national data from the United States have repeatedLy confirmed the survival advantages of PRT for adults compared with transplantation after dialysis initiation, and that increasing duration of pretransplant dialysis is associated with increasing risks of mortality and allograft failure (Figure 1). Meier-Kreische et al. analyzed data from 73 103 primary adult recipients of renal allografts and demonstrated significantly increased death-censored allograft failure and patient death for nonpreemptive transplantation, and that these rates increased with increasing duration of dialysis (10). Mange et al. examined 8481 recipients of renal allografts from living donors and detected a significant reduction of allograft failure by 52% in the first year for preemptively transplanted persons. This survival advantage was not limited to the short-term but increased over time post-transplant (2). Kasiske et al. corroborated these findings for both cadaveric and living donor transplantations in a study of 38 836 primary adult recipients in the United States (3). In a subsequent investigation, 2405 pairs of renal allografts from a single donor were studied where one recipient underwent dialysis for >24 months and the recipient of the other kidney was exposed to less than 6 months of dialysis (11). Five and 10 years' death-censored allograft survival and patient survival was greater with less exposure to dialysis. The 10-year allograft survival of 69% for recipients of cadaveric renal transplants was only exceeded by survival rates of preemptive transplantation from living donors (75% by 10 years, p < 0.001) (11). Analyses of data collected by the Collaborative Transplant Study and by the Oxford Transplant Centre demonstrate that the salutary impact of PRT on allograft survival is not continent-specific (7,12). These and other observational studies in aggregate demonstrate that PRT is associated with significant allograft and patient survival benefit for adult recipients (13–15).
The survival benefits of PRT compared with transplantation after dialysis have persisted despite substantial improvements in immunosuppression since 1994 (Figure 2) (9). The observation that better educated individuals, Caucasians, and persons with higher incomes in the United States are more likely to be placed on the cadaveric waiting list before dialysis initiation and receive a PRT might suggest that the impact of PRT on survival represents a systematic bias (3,16). Despite these observations, accounting for the measured differences in socioeconomic status, the survival advantage associated with PRT in two large studies was not explained (2,3).
Another process that might contribute to the improved survival associated with PRT is the level of remaining residual function of the native kidneys. Solute clearance, however, is unlikely to simply explain the differences in the rates of long-term allograft survival, as calcineurin inhibitors likely eliminate the mean residual renal function of PRT recipients of <10 mL/min (6) promptly after the institution of these drugs. One study that examined the relationship of native renal function before renal transplantation and allograft survival failed to confirm that higher levels of estimated GFR pretransplant are associated with improved outcomes (6).
There have been several investigations that provide support for a biological dissimilarity in T-cell activity that might contribute to the differential rates of transplant outcomes between persons preemptively transplanted and those who are first exposed to chronic dialysis. Investigations of the function of T cells suggest that the paradigm that combines individuals with renal disease or uremia into a single group irrespective of dialysis exposure is not correct. Kaul and colleagues obtained serial samples of T cells from individuals with severe renal insufficiency as they progressed from nondependence on dialysis to 6 weeks after initiation of dialysis. The responsiveness of T cells to PHA improved, but did not normalize, with increasing exposure to dialysis, indicating that there is a greater degree of suppression of T-cell activity associated with uremia and no dialysis than when one is exposed to dialysis (17). Descamps-Latcha et al. examined various markers of T-cell function and inhibitors of T cells among patients with varying levels of renal function and observed that T-cell reactivity increased with increasing time on dialysis, consistent with the earlier study (18). The activation of the complement system by dialysis membranes may plausibly explain further the observed differences in transplant outcomes, but the contribution from complement activation is unclear at present (19).
The decreased rates of acute rejection that have been observed with PRT might be explained, in part, by these cellular phenomena; rejection rates begin to diverge from the nonpreemptive group early within the first month post-transplant and are unlikely to be explained by disparities in demographic characteristics (20). Further, the increasing risk of acute rejection (20) and reduced allograft survival (10) associated with the increasing time on pretransplant dialysis provides additional support for the plausibility of an alteration of T-cell function during chronic dialysis contributing to the improved outcomes associated with PRT.
Lead Time and Perspectives
Analogous to a lead-time bias in disease screening (21), the equivalent allograft survival gain attributed to PRT compared with the time that an individual receives a transplant before an absolute requirement for dialysis may bias observational studies to findings favoring PRT as the optimal strategy. The magnitude of beneficial effect of PRT on survival (25–52% reduction in the rate of allograft failure) detected in observational studies is not simply explained by a lead-time. How would a lead-time bias impact PRT if it existed? From the perspective of the recipient, if there is a lead-time bias favoring PRT, indicating that there is truth in the no survival advantage, then the avoidance of dialysis-associated morbidities and the observed reduction of acute rejection rates would continue to favor PRT as the preferred strategy. From the perspective of the donor who would donate irrespective of the timing of the procedure, transplantation should be performed at a time that reduces the morbidity of the recipient. The timing of transplantation that provides for minimization of costs and allows for an individual to further contribute to society and in a healthier state would be the dominant strategy according to society's viewpoint.
One arguable point is that there is a subset of persons who may not fully appreciate the privilege of transplantation leading to nonadherence and foreshortened allograft survival. Experience from pediatric transplant centers suggests that adolescents (13–17 years old) have inferior allograft survival to other groups of pediatric recipients attributed to in part poorer compliance with medications (22). A proposed solution to improve allograft survival was to transplant adolescents after high school graduation when they might be more compliant as a result of peer dynamics that are more stable. This viewpoint of requiring persons, adults or children, first experience dialysis in order to improve adherence post-transplant because of a greater appreciation for transplantation entails an unnecessary exposure to life-threatening comorbidities before transplantation. Whether this strategy improves allograft survival or whether these individuals will have persistent personal characteristics of noncompliance despite any intervention is unknown.
Ultimately, the perspective of the individual patient will be the predominant force for PRT to occur. Brand developed a theorem that describes the decision process that an individual with severe renal insufficiency uses to determine the optimal timing of renal transplantation (23). This ‘no-remorse’ theorem assumes that a choice is made about transplantation vs. waiting for a transplant in the present stage of a progressive disease and therefore is independent of the future rate of progression. The formula that represents this decision process requires four factors: the patient's utility of their present health, the probability of surviving the transplant procedure, the probability of allograft survival at a point in the future, and the utility of life when the allograft fails and the person requires dialysis. From the formula, utility functions measured by one of various methods such as a time trade-off can be utilized to construct curves. A utility less than one represents that a person views their present state of health as less than perfect, and lower utility scores reflect that the individual is experiencing a worse state of health. These utility curves, as shown in Figure 3, can be consulted to determine if the present status of renal disease for an individual is of lower utility than the future risks and outcome of transplantation. When the utility of an individual's present state subtends the curves for the utility of the need for dialysis in the future, the transplantation should be performed.
Barriers to PRT
Increasing the rate of PRT in the United States will require surmounting certain barriers. Individuals can only be evaluated with sufficient lead-time to undergo PRT if patients as well as physicians are educated about the detection and recognition of asymptomatic renal disease and the benefits of early referral to a nephrologist (24). This will require more extensive education about utilizing validated formulae to provide an age-, gender- and race-adjusted estimated GFR. Nephrologists should discuss the advantages of PRT with the patient and advocate that these individuals present to a transplant center for evaluation, even at the expense of diminishing the nephrologist's dialysis population and subsequent reimbursement (25). Rates of cadaveric PRT will unlikely vary from the present unless there is a significant increase in the number of consented donors. The increase in PRT is expected to occur among recipients of organs from living-related and unrelated donors; particularly as the advent of laparoscopic procedures for organ removal have diminished organ procurement concerns for the donor.
Numerous studies have provided convincing evidence that PRT is advantageous for patient and allograft survival. Avoidance of dialysis-associated comorbidities further supplements the benefits of PRT. From the perspectives of the recipient, donor and society, PRT is the optimal timing strategy, and should no longer be the minority approach for patients eligible for this surgical procedure with suitable donors. Achieving this goal will require changing the traditional mindset of physicians, a potential change in reimbursement policies for dialysis and transplantation, and the cooperative effort of general practitioners, general and transplant nephrologists, recipients, donors and society.