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Does cadaveric donor renal transplantation ever provide better outcomes than live-donor renal transplantation?1,2

Mandal, Aloke K.3; Snyder, Jon J.4; Gilbertson, David T.4; Collins, Allan J.4 5; Silkensen, John R.5

doi: 10.1097/01.TP.0000048381.48473.D1
Clinical Transplantation
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SDC

Background.  Live donor renal transplantation (LRT) now comprises more than 40% of all kidney transplants performed in the United States. Many patients on the cadaveric waiting list have a prospective live kidney donor. This study determines whether cadaveric donor renal transplantation (CRT) can demonstrate better outcomes than LRT.

Methods.  From the United States Renal Data System registry, 31,909 adult recipients of a first-time kidney transplant from 1995 to 1998 were analyzed. Recipients were followed until December 31, 2000.

Results.  CRT, more human leukocyte antigen (HLA) mismatches, increased donor age, cold ischemia time greater than 24 hr, African American recipient, and a history of diabetic nephropathy all increased the risk of graft failure, return to dialysis, and death. Nevertheless, in specific circumstances, CRT could provide better outcomes than LRT. For example, in recipients aged 18 to 59 years with a hypothetical live kidney donor aged 50 years and four HLA mismatches, the relative risk of graft loss with LRT is comparable or increased compared with CRT if the cadaveric kidney donor is much younger or with fewer HLA mismatches. On the other hand, for recipients aged 60 years or older, CRT never provides better outcomes than LRT. All analyses were adjusted for recipient race, gender, and history of diabetic nephropathy. There were no significant interactions among donor type, HLA mismatches, donor age, and cold ischemia time.

Conclusions.  The elderly recipient with an imminent LRT should never be offered CRT. A combination of recipient and donor factors can make CRT preferable to LRT in younger patients.

3 Division of Abdominal Organ Transplantation, Department of Surgery, Oregon Health and Science University, Portland, OR.

4 United States Renal Data System Coordinating Center, Minneapolis, MN.

5 Division of Nephrology, Department of Medicine, Hennepin County Medical Center, Minneapolis, MN.

Address correspondence to: Aloke K. Mandal, M.D., Ph.D., Division of Abdominal Organ Transplantation, Department of Surgery, Oregon Health & Science University, 3181 S.W. Sam Jackson Park Road, Mail Code L590, Portland, OR 97201–3098. E-mail: mandala@ohsu.edu.

1 Portions of this work were presented at the American Transplant Congress: Transplant 2002, Washington, DC, April 26 to May 2, 2002.

2 The United States Renal Data System has supplied the data reported here. The interpretation and reporting of these data are the responsibility of the authors and should in no way be interpreted as official policy or interpretation of the U.S. government.

Received 1 July 2002.

Revision requested 27 August 2002.

Accepted 8 October 2002.

Renal transplantation remains the treatment of choice for end-stage renal disease (ESRD). Survival, economic, and quality of life data have demonstrated a clear preference for transplantation compared with dialysis (1–4). Over the years, the number of cadaveric organs has remained static, whereas the cadaveric donor age has increased (5). On the other hand, live donor renal transplantation (LRT) is increasing in frequency. For example, within the United States in 2001, 14,152 kidney transplants were performed, of which 5,949 (42%) were LRTs (6). Living unrelated kidney transplantation has shown the greatest increase among types of LRT (7). For example, in 1989, 70 LRTs (3%) were from unrelated donors. By 1999, 1,061 LRTs (23%) were from unrelated donors (8). The development of minimally invasive live donor nephrectomy procedures and the demonstration of similar or better graft survival with LRT compared with cadaveric donor renal transplantation (CRT) have been the catalysts for the increase in live kidney donation (9–12).

Most patients scheduled for elective LRT remain on the cadaveric waiting list and may receive a CRT offer. A reported live donor mortality of 0.03% and morbidity rate between 10% and 20% must also be considered (11,12). In fact, two donor deaths were recently reported after laparoscopic live donor nephrectomy (13). With the progressive decline in acute rejection, nonimmunologic variables, such as donor and recipient comorbidities, are becoming important factors affecting long-term survival. Finally, from 1988 to 1996, both CRT and LRT showed substantial increases in short-term and long-term graft survival (14). Therefore, the assumption that an LRT is always the better choice (compared with CRT) may no longer apply. This study determines whether there are any specific instances when CRT may provide equivalent or better graft survival rates than LRT.

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MATERIALS AND METHODS

Patient Population

The United States Renal Data System (USRDS) was used to identify patients for the study. All adult patients who received a first-time, kidney-only transplant between 1995 and 1998 and with no history of other organ transplants were considered (n=38,284). Through the USRDS Coordinating Center, the primary cause of renal failure was obtained from the “Primary Diagnosis Field” of the United Network for Organ Sharing Kidney Transplant Recipient Registration Form. Transplant events with known cold ischemia time (CIT) and number of human leukocyte antigen (HLA) mismatches were included in the final set (n=31,909). Patient outcomes were assessed through December 31, 2000.

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Analysis of Outcomes

Outcomes of interest included graft failure (including death), return to dialysis (death-censored graft failure), and death. A Cox proportional hazards model was used to approximate the risk associated with CRT and LRT with respect to the number of HLA mismatches, donor age, and CIT. The Cox model was adjusted further for recipient age, gender, race, and diabetic nephropathy as the primary cause of ESRD. Separate models were developed for adult recipients aged between 18 and 59 years and for elderly recipients who were defined as aged 60 years or older. Statistical significance was determined by P <0.05, using the chi-square test.

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RESULTS

General Characteristics

The general characteristics of all renal allograft recipients are summarized in Table 1. Among the recipient age groups reviewed, there were no differences in gender or race. As would be expected, a higher percentage of the elderly patients (aged ≥60 years) demonstrated type 2 diabetes mellitus as the primary cause of renal failure, whereas type 1 diabetes mellitus was more common in the younger adult recipients. For donor characteristics, the percentage of cadaveric allografts with CIT less than or equal to 24 hr and the distribution of HLA mismatches were similar between the two recipient groups. Elderly recipients were more apt to undergo CRT rather than LRT. Moreover, regardless of CRT or LRT, a higher percentage of donors for elderly recipients also were aged 60 years or older.

Table 1

Table 1

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Recipients Aged 18 to 59 Years

For younger adults undergoing renal transplantation, the relative risks of graft failure and patient survival for various donor and recipient characteristics are summarized in Table 2. CRT, increasing number of HLA mismatches, CIT of greater than 24 hr, increasing donor age, African American recipient race, and diabetic nephropathy as the cause of ESRD all adversely affected graft survival (not censored for death), death-censored graft survival, and patient survival. Increasing recipient age and recipient male gender increased the risk of death but not of graft failure per se.

Table 2

Table 2

In general, LRT resulted in improved graft and patient survival. Nevertheless, in certain circumstances, a CRT could provide better outcomes than LRT. For recipients aged 18 to 39 years, Figure 1 lists various combinations of cadaveric donor age and HLA mismatch that may provide better death-uncensored graft survival than LRT, assuming CRT with CIT less than 24 hr. For example, with a prospective live kidney donor aged between 50 and 59 years and with two HLA mismatches, if available, a cadaveric donor younger than 20 years of age with no or only one HLA mismatch (less than two mismatches) would be a better choice. As the age of the live donor or the number of HLA mismatches between the recipient and prospective live donor increases, the number of potential cadaveric renal allograft options that would provide improved graft survival also increases. On the other hand, as CIT increases past 24 hr, the CRT options for providing better outcomes decrease considerably (Fig. 2). All analyses were adjusted for recipient race, gender, and diabetic nephropathy. There were no significant interactions among donor type (CRT or LRT), HLA mismatches, donor age, or CIT.

Figure 1

Figure 1

Figure 2

Figure 2

Figures 3 and 4 summarize when CRT is more advantageous than LRT for recipients aged between 40 and 59 years when CIT is less than or greater than 24 hr, respectively. In comparing Figure 1 with Figure 3, older recipient age reduces the number of options for improved survival with CRT. In this older age group, CIT greater than 24 hr further reduces the number of instances when CRT shows a better outcome than LRT (Fig. 4).

Figure 3

Figure 3

Figure 4

Figure 4

All of these figures demonstrate when CRT provides better survival than LRT. In addition, equivalent survival with CRT and LRT also was analyzed. To this end, a recipient aged 18 to 59 years with a hypothetical live kidney donor aged 50 years and with five HLA mismatches was analyzed. This hypothetical donor would be fairly common (Table 1). Assuming CIT less than 24 hr, equivalent graft survival with a CRT was identified for cadaveric donors with the following characteristics: zero HLA mismatches between 40 and 59 years of age, one mismatch between 30 and 49 years of age, two to three mismatches between 30 and 39 years of age, four mismatches between 10 and 29 years of age, and five to six mismatches between 10 and 19 years of age. With this hypothetical live donor, CRT would be advantageous with the following cadaveric donor characteristics: zero mismatches between 10 and 39 years of age, one to two mismatches between 10 and 29 years of age, and three mismatches between 10 and 19 years of age. For CIT greater than 24 hr, only a cadaveric donor with zero HLA mismatches between 10 and 19 years of age would be advantageous compared with the hypothetical live donor. Similarly, the number of cadaveric options that afforded equivalent graft survival was decreased when CIT was greater than 24 hr: zero mismatches between 20 and 39 years of age, one to two mismatches between 10 and 29 years of age, and three to four mismatches between 10 and 19 years of age.

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Recipients Aged 60 Years or Older

Table 2 also summarizes the various donor and recipient characteristics that affected graft and patient survival in elderly kidney transplant recipients. CRT, increasing number of HLA mismatches, and increasing donor age increased the risk of graft failure not censored for death, return to dialysis, and death. African American race and CIT greater than 24 hr primarily affected graft survival per se but not patient survival. Recipient age and diabetic nephropathy adversely affected patient survival rather than graft survival per se. As suggested in Figures 1 and 3, increasing recipient age decreases the opportunities when CRT may have better outcomes than LRT even when CIT is less than 24 hr. For recipients aged 60 years or older, it never was advantageous to perform a CRT rather than an LRT. Therefore, in this group of patients, if a prospective live kidney donor is available, LRT should always be performed rather than CRT.

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DISCUSSION

On the basis of the previous findings, the following conclusions can be made about LRT and CRT. First, although LRT generally is considered to provide better outcomes than CRT, there are instances when a CRT may have favorable outcomes compared with LRT. Second, greater CIT reduces the number of instances when CRT may be advantageous compared with LRT. Third, increasing recipient age also reduces the number of instances when CRT may be advantageous compared with LRT. Fourth, if an elderly patient is scheduled for imminent LRT, then CRT should not be offered.

As shown in Table 2, CRT increases the relative risk of graft failure and patient death when compared with LRT. Explanations for advantages of LRT compared with CRT include better “quality” of organ and reduced CIT (7,10–12). Recent reports on the effect of greater CIT and HLA-matching on shipped and locally transplanted cadaveric renal allografts are confounding (15,16). On the one hand, CIT on HLA-mismatched CRT demonstrates a detrimental effect but may not be as important a factor with HLA-matched CRT. In the most recent years of renal transplantation, graft survival rates have improved considerably for both CRT and LRT (14). With these improvements in overall graft survival and the panoply of recipient and donor factors affecting graft survival, the assumption that LRT is always favorable to CRT may not be valid.

Indeed, in the current analysis, there are instances when CRT may have equivalent or better graft and patient survival rates than LRT. For this to occur, certain requirements need to be met. First of all, the recipient must be aged between 18 and 59 years. Second, the cadaveric donor age and number of HLA mismatches must be less than that for the live kidney donor. These data are consistent with the current observation that with the progressive decline in acute rejection rates, nonimmunologic variables, such as recipient age, recipient comorbidities, time on the waiting list, pretransplant dialysis exposure, donor age, donor comorbidities, CIT, and delayed graft function (DGF), are becoming more important in affecting long-term survival.

As shown in Figures 2 and 4, CIT of greater than 24 hr decreases the number of instances when a CRT may perform better than an LRT regardless of the degree of HLA mismatch or donor age. These observations were based on an analysis of CRT and LRT with respect to the number of HLA mismatches, donor age, and CIT. Unfortunately, DGF was not included in this analysis because there is no way of predicting definitively which allografts will experience DGF. In this regard, such an analysis from the USRDS database may be limited. Nevertheless, because cadaveric renal allografts with greater CIT would be more likely to experience DGF and thus poorer outcomes, it is not surprising that our study noted that CIT greater than 24 hr provided fewer acceptable cadaveric organs from which to choose.

For this analysis, the Cox model was adjusted for recipient age, gender, race, and diabetic nephropathy as the primary cause of ESRD. The cause of donor death, preterminal creatinine, and other cadaveric donor characteristics were not included in the modeling. The length of pretransplant dialysis exposure also adversely affects graft and patient survival (17–19). One theoretical advantage of accepting a CRT while awaiting an LRT is that the length of dialysis exposure may be shortened by several months, depending on the transplant center’s ability to evaluate and schedule LRT. Indeed, the current analysis was stimulated by our observation that many patients with an imminent LRT also were being offered suitable cadaveric renal allografts because of the current policy for nationwide sharing of HLA-identical kidneys. The current study also does not address whether there are any adverse consequences of continued dialysis exposure after refusing a cadaveric allograft offer while awaiting LRT. Preliminary data have suggested that, when pretransplant dialysis exposure exceeds 3 years, the survival benefit of CRT compared with continued dialysis is lost, especially in elderly recipients (19). Conceivably, the longer the waiting time, the poorer the outcome will be regardless of the donor type and the less likely the patient will have a potential live donor. On the basis of these statements, therefore, it is unlikely that the inclusion of waiting time in the current analysis would alter these conclusions.

Within the group of younger recipients, as the recipient age increased from 18 to 39 years to 40 to 59 years, there were fewer instances when CRT was associated with better outcomes than LRT. By the time the recipient reached the age of 60 years or older, an imminent LRT is always preferable to CRT. Currently, elderly patients account for the fastest rising group of patients being placed on the kidney transplant waiting list, with an increase of 680% from 1990 to 1998 (8). Because this population is at high risk for morbidity and mortality associated with renal transplantation and is rapidly growing on the transplant waiting list, current analysis should include how best to manage this group of patients. As demonstrated in this and other studies (19), elderly patients seem to experience better outcomes with LRT than with CRT. For whatever reason, however, this practice currently is not advocated in the United States. As shown in Table 1, a significantly higher percentage of elderly recipients undergo CRT than LRT when compared with younger recipients. Moreover, although increasing donor age adversely affects patient and graft survival in this group of patients (Table 2), the elderly recipient is more apt to receive a kidney from an older donor regardless of whether it was a CRT or an LRT (Table 1). That this combination of older donor and older recipient would provide the poorest outcomes is not surprising (20). Indeed, recent data suggest that the dictum of “elderly kidneys for elderly patients” no longer should be dogma (21,22). On the basis of these data and in reviewing current practices, LRT should be emphasized increasingly in the elderly patient with ESRD (19). This change in practice not only would provide better outcomes for this high-risk population but also would increase resource use of the scarce supply of cadaveric renal allografts.

In regard to donor allocation policies, most transplant centers continue to list a recipient for CRT even after a live kidney donor has been identified. Arguments in favor of continuing to list patients on the list include (1) the continued accrual of waiting list time in case the prospective LRT is canceled, and (2) the possibility of receiving an HLA-identical CRT and thereby avoiding the risks to the live kidney donor while still providing an excellent renal allograft to the recipient. On the other hand, others advocate removal from the waiting list of patients about to undergo LRT because patients with live kidney donors should not have access to CRT because of limited resources. Finally, it has been suggested that whenever possible, every ESRD patient is managed best with CRT, reserving LRT for those patients unable to obtain CRT. This last statement is in direct opposition to what is practiced in the United States. During the past several years, the number of LRTs has continued to increase. As of 2001, 53,560 patients were placed on the cadaveric kidney transplant waiting list, and only one quarter of them underwent transplantation. Of the patients receiving transplants, 42% obtained renal allografts from live kidney donors. Therefore, to provide more kidneys for transplantation, live kidney donation continues to play an increasingly important role. Nevertheless, as shown in certain circumstances, CRT may provide better outcomes than LRT. The potential morbidity and mortality of live donor nephrectomy cannot be disregarded (10–12). Therefore, a combination of recipient, live kidney donor, and cadaveric kidney donor characteristics needs to be considered when a CRT is offered to a patient with a prospective live kidney donor. Finally, the benefits of LRT compared with CRT in the elderly recipient should be emphasized further. Changing the current use of LRT and CRT in elderly patients would improve patient and graft survival in this high-risk population and also improve use of scarce cadaveric renal allografts.

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