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Background The dramatic shortage of kidney donors has triggered interest in other sources of organs, such as donors without a heartbeat. Accumulating evidence suggests that the short-term survival of cadaveric kidneys from such donors is similar to that of cadaveric kidneys from donors with a heartbeat. However, no data from large, matched studies with long-term follow-up are available. We conducted a matched, single-center study of kidney transplants obtained from donors without a heartbeat and those from donors with a heartbeat, with a 15-year follow-up period.
Methods Between 1985 and 2000, 122 kidney transplantations involving donors without a heartbeat were performed at the University of Zurich, in Switzerland. Outcomes of these procedures were compared with those of 122 transplantations of kidneys from donors with a heartbeat. The recipients were matched according to age, sex, number of transplantations, and calendar period of transplantation.
Results The characteristics of the recipients did not differ significantly between the two groups. We observed a significantly higher incidence of delayed graft function among the patients who received kidneys from donors without a heartbeat (48.4 percent) than among the patients who received kidneys from donors with a heartbeat (23.8 percent) (P<0.001). However, the long-term rate of graft survival was similar in the two groups (P=0.98): at 10 years, the rate of graft survival was 78.7 percent for kidneys from donors without a heartbeat and 76.7 percent for kidneys from donors with a heartbeat.
Conclusions Although the incidence of delayed graft function is significantly higher with kidneys from donors without a heartbeat than with kidneys from donors with a heartbeat, there is no difference in long-term outcome between the two types of graft.
Death in donors without a heartbeat is defined as an irreversible cessation of circulatory and respiratory function,2 whereas brain death in donors with a heartbeat is determined according to neurologic criteria. Therefore, by definition, a donor without a heartbeat has had a prolonged phase of hypotension (one that lasts several minutes) followed by cardiac arrest before organ harvesting. Insufficient perfusion or complete lack of perfusion of such organs has long been thought to cause irreversible damage, resulting in poor short-term and long-term outcomes after grafting.3 With the exception of recent limited experience in liver transplantation,4 the use of organs from donors without a heartbeat has been restricted to the kidneys, since dialysis is available for support in case the graft does not function after transplantation.
Data regarding the use of organs from donors without a heartbeat have remained scarce; data from several centers are often pooled to achieve relevant numbers (Table 1). None of the studies conducted so far have provided long-term follow-up data, and only a few have reported results more than five years after transplantation. In addition, some studies have not included comparison groups (e.g., matched groups of patients receiving grafts from donors with a heartbeat). Thus, the controversy surrounding the outcomes of kidney transplants from donors without a heartbeat has remained unsettled. In 1985, the University Hospital Zurich (Zurich, Switzerland) initiated a kidney-transplantation program involving the use of grafts from donors without a heartbeat. This program continues to operate and uses a well-established protocol. In the current study, we compared the results of the entire series of 122 patients in the Zurich program with the results from a group of 122 matched patients who received grafts from donors with a heartbeat.
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Of 1133 kidneys transplanted at our institution between January 1985 and March 2000, 122 (10.8 percent) were obtained from donors without a heartbeat. From our data base of recipients of kidneys from donors with a heartbeat, 122 randomly identified patients were matched on a one-to-one basis with the patients. Data were collected prospectively during routine follow-up at our institution, and complete follow-up information was available for each patient.
Institutional approval was obtained in accordance with the guidelines of the Swiss Academy of Medical Sciences. Potential recipients of a kidney graft were informed at the time of their acceptance for the waiting list that they might receive an organ from an alternative donor, such as an elderly donor or a donor without a heartbeat, in order to reduce waiting time. With regard to consent from the family of the donor, legislation allowing presumed consent has been enacted in the state of Zurich. Therefore, until 1995, when the Maastricht protocol was established, a few organs from donors without a heartbeat were procured, with presumed consent. Since then, informed consent has routinely been obtained from every donor's next of kin.
Donors and Recipients
A standardized protocol for the transplantation of kidneys from donors without a heartbeat has been used at our institution since this transplantation program was initiated, in 1985. Our initial protocol was similar to the Maastricht protocol (Table 2), 14 established in 1995, with the exception of the waiting period after cardiac arrest. During the first decade of the study, from 1985 until 1995, organ retrieval was initiated 5 minutes after cardiopulmonary arrest; after 1995, organ retrieval was performed according to the Maastricht protocol, which requires a waiting period of 10 minutes after cardiopulmonary arrest. All 122 kidney donors who had a heartbeat fulfilled the criteria for brain death.
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All recipients were chosen according to our local allocation system, which considers HLA matching, age matching, and recipients' waiting time. Beginning in 1989, only primary transplantations were performed with organs from donors without a heartbeat, because of the failure of two such grafts in patients who underwent transplantation at the beginning of the program. The recipients of grafts from donors with a beating heart were treated with standard triple-immunosuppressive therapy consisting of prednisone, cyclosporine (Sandimmune, Novartis), and azathioprine (Imurek, Wellcome); azathioprine was replaced by mycophenolate mofetil (CellCept, Roche) in patients who underwent transplantation after 1996. In the recipients of grafts from donors without a heartbeat, immunosuppression was induced with intravenous antithymocyte globulin (ATG, Fresenius), with overlapping therapy consisting of oral cyclosporine beginning 10 days after surgery.15 Except for the use of antithymocyte globulin in the latter group, the immunosuppressive regimen in the two groups was identical.
Delayed graft function was defined as the need for dialysis during the first week after transplantation, with subsequent recovery of renal function. Primary nonfunction was defined as the absence of renal function during follow-up. When the initial function of the graft was impaired, surveillance biopsy was performed weekly to permit detection of acute episodes of rejection.16 Each episode of acute rejection during a period of delayed graft function was confirmed by biopsy and was graded according to the Banff criteria.17
Data Collection and Statistical Analysis
Data were prospectively collected and stored in a data base. Patients who died were considered either to have had a failed graft or (in the case of those who died of other causes) to have had a functioning graft. Graft survival was recorded for all the patients, including those who died with a functioning graft. In some analyses, data on patients who died with a functioning graft were censored.
To evaluate the natural course of the transplanted grafts, we conducted analyses that included patients whose data were censored after they died with a functioning graft, unless otherwise indicated. Categorical variables were analyzed with the use of the chi-square test or, when appropriate, Fisher's exact test. Continuous variables were analyzed with the use of the Mann–Whitney U test; the results are expressed as means ±SD, unless otherwise stated. Rates of graft survival were computed by the Kaplan–Meier method, and comparisons among groups were calculated with the use of the log-rank test. A P value of less than 0.05 was considered to indicate statistical significance. Variables that were significant in the univariate analysis were included in a Cox proportional-hazards analysis performed to identify independent risk factors for graft failure.
Results
Characteristics of the Donors and Recipients
The characteristics of the donors without a heartbeat and of those with a heartbeat were not significantly different except with respect to the cause of death, the duration of warm ischemia, and the use of diuresis in the hour before organ harvesting (Table 3). The distribution of the 122 donors without a heartbeat according to the categories in the Maastricht protocol14 was as follows. In no case was an organ procured from a donor who was dead on arrival at the hospital (Maastricht protocol category I). In the case of 56 donors (46 percent), resuscitation after cardiac arrest was unsuccessful (category II). In these 56 cases, resuscitation efforts had been performed for a minimum of 30 minutes, in accordance with the guidelines of the Swiss Academy of Medical Sciences. Cardiac arrest was awaited in 57 patients (47 percent) (category III), and cardiac arrest occurred before brain death could be diagnosed in 9 (7 percent) (category IV). For donors in category III, the decision to continue life-support measures was made by physicians who acted strictly independently of the transplantation team. The mean hospitalization time from admission until organ procurement was 28.1±26.4 hours for the "controlled" donations (involving donors in category III or IV) and 5.4±3.0 hours for the "uncontrolled" donations (involving donors in category I or II).
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Outcomes of the Grafts
Primary nonfunction occurred in both groups; the incidence was 5.7 percent among the kidneys from donors without a heartbeat and 4.9 percent among those from donors with a heartbeat (P=0.99) (Table 4). Delayed graft function occurred more frequently with the kidneys from donors without a heartbeat than with those from donors with a heartbeat (48.4 percent vs. 23.8 percent, P<0.001). The higher incidence of delayed graft function in the former group was reflected in their higher serum creatinine levels on postoperative day 7 (4.0 mg per deciliter [354 µmol per liter] vs. 2.6 mg per deciliter [230 µmol per liter], P<0.001). However, the serum creatinine levels among patients with a functioning graft were similar in the two groups at one month (1.8 mg per deciliter [159 µmol per liter] in both groups, P=0.90) and at one year (1.5 mg per deciliter [133 µmol per liter] and 1.6 mg per deciliter [141 µmol per liter] in those with a graft from a donor without a heartbeat and those with a graft from a donor with a heartbeat, respectively; P=0.11).
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50 percent), acute rejection (P=0.01 for the comparison with the absence of such rejection), and corticosteroid-resistant rejection (P=0.006 for the comparison with the absence of such rejection). Acute rejection was also a risk factor for the loss of grafts from donors with a heartbeat (P=0.029 for the comparison with grafts not affected by acute rejection). The following variables had no significant influence on graft survival in either group: trauma or cerebrovascular disease as the cause of death in the donor, the age of the donor (range, 4 to 73 years among those with a heartbeat and 15 to 61 years among those without a heartbeat), diuresis during the hour before death, the age of the recipient (range, 12 to 71 years among those who received a graft from a donor without a heartbeat and 14 to 75 years among those who received a graft from a donor with a heartbeat), sex, and number of HLA mismatches. The duration of cold ischemia did not correlate with graft outcome in either group (grafts from donors without a heartbeat: mean, 17 hours; range, 4 to 35; P=0.47 for the comparison between long [>24 hours] and short periods of cold ischemia; grafts from donors with a heartbeat: mean, 15 hours; range, 3 to 30; P=0.97). The duration of warm ischemia among the grafts from donors without a heartbeat (29±9 minutes; range, 10 to 60) had no significant effect on the survival of the grafts (P=0.56 for the comparison between long [>30 minutes] and short periods of warm ischemia). Finally, the survival of grafts from donors without a heartbeat was not significantly influenced by the Maastricht protocol category14 of the donation ("controlled" or "uncontrolled," P=0.69).
The multivariate analysis conducted to identify independent risk factors revealed a strong and significant association between delayed graft function and decreased graft survival in the grafts that had been obtained from donors with a heartbeat (P=0.03 for the comparison between grafts with delayed function and those without delayed function) but not among the grafts from donors without a heartbeat (P=0.28). In the latter group, risk factors for graft failure that reached statistical significance in the Cox regression analysis were panel-reactive antibody values above 50 percent (P=0.03 for the comparison with values 50 percent) and episodes of corticosteroid-resistant rejection (P<0.001 for the comparison with the absence of such episodes) (Table 5).
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In this single-center, matched-pair study, we found that although the incidence of delayed graft function affecting kidneys from donors without a heartbeat was approximately double that affecting kidneys from donors with a heartbeat, the two groups had similar, low rates of primary nonfunction and similar long-term outcomes. These data support the concept that kidneys from donors without a heartbeat can routinely be included in kidney-transplantation programs, thus decreasing waiting times and mortality rates among patients who are waiting for organs.18
The numbers of patients awaiting organs and the waiting periods before transplantation have increased dramatically during the past decade.19 This situation has triggered interest in seeking alternative strategies for enlarging the donor pool — for example, by retrieving organs from living unrelated donors, elderly brain-dead donors, or donors without a heartbeat. Validation of these alternative approaches is critical if they are to be appropriately recommended by those who make transplantation policy.
Despite its introduction into clinical practice in the early 1980s, the use of organs from donors without a heartbeat has not been popular.20 Numerous issues of concern have been raised about this type of donation, with medical and ethical issues central among them. The poor long-term survival expected of such grafts as a consequence of the high incidence of delayed graft function has been mentioned repeatedly.21,22 The controversy has been sustained by opposing voices that suggest good outcomes with grafts from donors without a heartbeat (Table 1). The absence of properly designed studies with long-term follow-up, particularly the lack of appropriate comparison groups of patients, has prevented the discussion about this type of donation from moving beyond speculation. In addition, multicenter analyses of transplantation programs that make use of organs from donors without a heartbeat suffer from "center effects," since policies regarding the medical and ethical management of donors without a heartbeat vary among institutions and have varied over time.23
The present study is based on the experience at a single center and extends the analysis of outcome beyond a 10-year follow-up period. A standard protocol was used for all the transplantations, and follow-up was complete for all the donors and recipients. Since a randomized trial was not feasible, a matched-pair design using a large data base of patients who received kidneys from donors with a heartbeat at the same center seemed appropriate. As in previous reports,1,12 delayed graft function was more frequent among the recipients of grafts from donors without a heartbeat than among other recipients. However, delayed graft function had no significant negative effect on long-term organ survival in the former group. These results are in contrast to the negative effects of delayed function on graft survival in the recipients of kidneys from donors with a heartbeat. These negative effects have been noted in several other series.24,25,26
In patients with anuria who have delayed graft function, episodes of rejection may be missed because there is a lack of clinical monitoring. Therefore, our protocol included routine biopsy of nonfunctional renal grafts both from donors with a heartbeat and donors without a heartbeat so that rejection would not be missed and left untreated.27 This approach is particularly crucial for recipients of grafts from donors without a heartbeat, since the incidence of delayed graft function is higher in this group than in recipients of grafts from donors with a heartbeat. We also used a distinct protocol for the induction of immunosuppression in patients who received renal transplants from donors without a heartbeat. Because of the nephrotoxic effects of cyclosporine, we used antithymocyte globulin for the first 10 days after transplantation in these patients, so as to avoid additional damage to the transplanted kidney. The decision not to use macrolides such as cyclosporine or tacrolimus for the induction of immunosuppression in these patients is further supported by the recent suggestion that the nephrotoxic effect of these drugs is augmented by coexisting ischemic injury.28 In contrast, antithymocyte globulin contains antibodies to many proinflammatory molecules and may therefore contribute to the attenuation of ischemia–reperfusion injury29 — a property that might be particularly important in the transplantation of organs from donors without a heartbeat.
The type of donor — either controlled or uncontrolled, as defined by the Maastricht protocol14 — has been reported to be a crucial variable affecting the survival of grafts from donors without a heartbeat.1 However, this variable did not influence the outcome of kidney transplantation from donors without a heartbeat in our study. The duration of warm ischemia in our cohort was less than 60 minutes, indicating that uncontrolled donors without a heartbeat who have a short warm-ischemia time can be a useful source of grafts. The cause of the donor's death and the donor's and recipient's ages also had no significant influence on long-term graft survival in our study, in contrast to previous studies.12 Previous recommendations for limiting the use of organs from donors without a heartbeat should be reconsidered.
In situ cooling of the kidneys by intraaortic infusion of cold preservation solution, as performed by many investigators,8,10 was not included in our protocol of organ harvesting. In situ cooling is often started before the consent of the potential donor's family has been obtained. This practice has triggered serious ethical debate,20 rendering the use of organs from donors without a heartbeat unpopular and often unacceptable. Our study shows that excellent results can be obtained without the use of this questionable technique. We also show that a waiting time of 10 minutes after cardiopulmonary arrest, as proposed in the Maastricht protocol,14 does not appear to influence the long-term survival of kidneys from donors without a heartbeat. If these points are considered, ethical concerns regarding the use of grafts from donors without a heartbeat may diminish, and our results may provide a new basis for the reevaluation of this source of organs by transplantation centers and by legislative bodies that have thus far proscribed the use of organs from donors without a heartbeat.
We are indebted to Dr. Burkhardt Seifert (Division of Biostatistics, University of Zurich) for the statistical analyses and to Dr. Ueli Binswanger, Dr. Reto Stocker, Dr. Daniel Candinas, Dr. Rolf Schlumpf, Dr. Marco Decurtins, Julia Hofmann, and Petra Seeburger for important contributions. This article is dedicated to Felix Largiader, who pioneered organ transplantation in Switzerland and who initiated this program in Zurich in 1985.
Source Information
From the Department of Visceral Surgery and Transplantation (M.W., D.D., N.D., P.-A.C.) and the Division of Nephrology (P.M.A.), University Hospital Zurich, Zurich, Switzerland.
Address reprint requests to Dr. Clavien at the Department of Surgery, University Hospital Zurich, Ramistr. 100, CH-8091 Zurich, Switzerland, or at clavien{at}chir.unizh.ch.
References
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Related Letters:
Kidney Transplantation from Donors without a Heartbeat
Evans R. W., Carvalho de Matos A. C., Durão M. S., Pacheco-Silva A., Luan F. L., García-Rinaldi R., Weber M., Dindo D., Clavien P.-A.
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Full Text |
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N Engl J Med 2002;
347:1799-1801, Nov 28, 2002.
Correspondence
This article has been cited by other articles:
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