Background Attempts have recently been made to expand the numberof cadaveric kidneys available for transplantation by usingkidneys from donors without heartbeats in addition to thosefrom brain-dead donors with beating hearts. We studied the efficacyof transplanting kidneys from donors without heartbeats on thebasis of aggregate results from the Kidney Transplant Registryof the United Network for Organ Sharing.
Methods We compared the early function and survival rates of229 kidney grafts from donors without heartbeats with thoseof 8718 grafts from cadaveric donors with heartbeats. All transplantationswere performed at 64 U.S. transplantation centers. Cox proportional-hazardsanalysis was used to evaluate 10 major risk factors for graftfailure.
Results The survival rate at one year was 83 percent for kidneygrafts from donors without heartbeats, as compared with 86 percentfor grafts from donors with heartbeats (P = 0.26). Among thekidneys from donors without heartbeats, the survival rate atone year was 89 percent for grafts from donors who had diedof trauma, as compared with 78 percent for grafts from donorswho had died of other causes (P = 0.04). The survival rateswere high for grafts from donors without heartbeats despitethe poorer early function of these grafts; 48 percent of therecipients required dialysis within the first week after transplantation,as compared with 22 percent of the recipients of grafts fromdonors with heartbeats. The primary-failure rate for kidneysfrom donors without heartbeats was 4 percent, as compared with1 percent for kidneys from donors with heartbeats.
Conclusions Transplantation of kidneys from donors whose heartshave stopped beating, especially those who have died of trauma,is often successful, and the use of kidneys from such donorscould increase the overall supply of cadaveric kidney transplants.
At the end of 1996, more than 34,000 patients undergoing dialysiswere on the national waiting list for kidney transplants, butonly about 8600 cadaveric kidneys were transplanted in thatyear.1 The number of patients awaiting cadaveric kidneys hasincreased progressively in recent years, and by the year 2000,more than 42,000 patients will be on the waiting list. Asidefrom the social costs of an inadequate supply of kidney transplants,the inability to treat patients optimally is frustrating forboth the patients and the physicians who perform transplantation.
Use of kidneys from donors whose hearts have stopped beatingcould increase the supply of kidney transplants by a factorof 2 to 4.5.2 Currently, more than 99 percent of cadaveric kidneysavailable for transplantation come from donors whose heartsare beating but who are brain-dead and in the hospital. Mostof the early kidney transplantations, performed during the 1960s,used kidneys from donors whose hearts had stopped beating.3,4Under some circumstances, such kidneys can withstand warm ischemiafor up to one hour,5,6 and kidneys removed from patients aftertheir hearts have stopped beating can function well.7,8,9,10,11,12,13,14,15,16,17,18,19,20,21,22To determine the efficacy of transplanting kidneys from donorswithout heartbeats, we compared 229 transplants from such donorswith 8718 transplants from cadaveric donors with beating hearts.
Methods
Study Population
Since 1994, the United Network for Organ Sharing (UNOS) hascollected information from organ-procurement organizations oncadaveric organs procured from donors without heartbeats inwhom life support was withdrawn after family members had givenconsent for donation. Transplantation centers that accept kidneysfrom donors without heartbeats notify UNOS of their willingnessto do so, and kidneys from such donors are allocated accordingto the same point system used to distribute kidneys from brain-deaddonors with heartbeats.
From 1994 to 1996, a total of 229 kidneys from donors withoutheartbeats were collected by 30 of the 63 U.S. organ-procurementorganizations (range, 1 to 38 kidneys per organization) andtransplanted at the 64 U.S. transplantation centers (range,1 to 31 kidney transplantations per center) that accepted kidneysfrom donors without heartbeats. A total of 8718 cadaveric kidneysfrom donors with heartbeats were transplanted by the same 64centers during the same period. The graft-survival rates atthe 64 centers did not differ significantly from those at the186 centers that did not accept kidneys from donors withoutheartbeats. The analysis included follow-up information providedon UNOS survey forms at scheduled intervals after transplantationand received at the UNOS Kidney Transplant Registry throughJune 1997.
Statistical Analysis
Graft-survival rates were estimated with the use of the Kaplan–Meierproduct-limit method. The log-rank test was used to evaluatedifferences in the survival curves for the two groups of grafts.The death of a recipient was documented as a graft failure.The Wilcoxon rank-sum test was used to compare continuous variables,and the chi-square test was used to compare categorical variables.Variables that significantly influenced graft failure in univariateanalyses were included (along with the dichotomous variablefor the presence or absence of a heartbeat in the donor) ina multivariate Cox regression analysis. Less than 5 percentof values were missing for any covariate. Missing data for thisanalysis were replaced with modal values for categorical variablesand mean values for continuous variables. In addition, continuousvariables such as age, weight, cold-ischemia time, and the peakvalue for panel-reactive antibodies were categorized, sincetheir effects on the hazard function were nonlinear. Plots oflog[-log(survival function)] against time were used to checkthe validity of the proportionality assumption in the Cox model.Since the curves were parallel, this assumption was judged tobe appropriate. Relative risks and their 95 percent confidenceintervals were calculated with the use of the estimated regressioncoefficients and their standard errors in the Cox regressionanalysis. All statistical tests were two-tailed.
Results
The characteristics of the recipients and the donors are shownin Table 1. The proportions of female and white patients weresignificantly higher in the group receiving grafts from donorswithout heartbeats than in the group receiving grafts from donorswith heartbeats. For donors without heartbeats, the averagewarm-ischemia time associated with the procurement surgery was14 minutes, whereas for donors with heartbeats, there was norecord of warm-ischemia time because it was close to 0 minutes.The second warm-ischemia time, or the time required to restorecirculation in the recipient, was only three minutes longerfor the recipients of kidneys from donors without heartbeatsthan for the recipients of kidneys from donors with heartbeats.Pump perfusion was used more frequently for kidneys from donorswithout heartbeats (50 percent vs. 20 percent).
Table 1. Characteristics of Renal-Transplant Recipients, Donors, and Renal Grafts.
The outcome of transplantation in the two groups of recipientsis shown in Table 2. Anuria occurred on the first day in 11percent of grafts from donors with heartbeats, as compared with21 percent of grafts from donors without heartbeats (P<0.001).Twenty-two percent of the recipients of kidneys from donorswith heartbeats required dialysis during the first week aftertransplantation, as compared with 48 percent of the recipientsof kidneys from donors without heartbeats. The less-than-optimalstate of the kidneys from donors without heartbeats was reflectedin the proportion of recipients with high serum creatinine concentrationsat the time of discharge. Primary graft failure (defined asa graft that never functioned) was reported in 4 percent ofthe recipients of kidneys from donors without heartbeats, ascompared with 1 percent of the recipients of kidneys from donorswith heartbeats.
Table 2. Early Function of Kidney Grafts from Donors without Heartbeats and Donors with Heartbeats.
The graft-survival rate at one year for kidneys from donorswithout heartbeats was 83 percent, as compared with 86 percentfor kidneys from donors with heartbeats (P = 0.26) (Figure 1).The difference of three percentage points occurred within thefirst month, suggesting that it was due to a difference in ischemicdamage. There were no longer-term consequences of ischemia;the loss rate between one month and one year was the same forthe two groups of kidneys. Five recipients of kidneys from donorswithout heartbeats (2 percent) and 312 recipients of kidneysfrom donors with heartbeats (4 percent) died with functioninggrafts during the study period. Less than 1 percent of patientswere lost to follow-up during the study period (1 who receiveda kidney from a donor without a heartbeat and 72 who receivedkidneys from donors with heartbeats). One year after transplantation,the mean (±SD) serum creatinine concentration in thepatients with functioning grafts was 1.9±0.9 mg per deciliter(170±80 µmol per liter) in the 91 recipients ofkidneys from donors without heartbeats and 1.8±0.8 mgper deciliter (160±70 µmol per liter) in the 3598recipients of kidneys from donors with heartbeats.
Figure 1. Graft-Survival Rates for Kidney Transplants from Donors with Heartbeats and Donors without Heartbeats.
Data are from the United Network for Organ Sharing for the period from 1994 to 1996.
The graft-survival rate at one year for kidneys from donorswithout heartbeats who had died of trauma was 89 percent, ascompared with 78 percent for kidneys from donors without heartbeatswho had died of other causes (P = 0.04) (Figure 2). We consideredthe possibility that this effect might be the result of theyounger age of donors who had died of trauma, but when the analysiswas stratified according to the donor's age, the cause of deathwas still correlated with the graft-survival rate. The survivalof grafts from donors without heartbeats who had died of traumawas similar to that of grafts from donors with heartbeats. Survivalwas significantly poorer for kidneys from donors without heartbeatswho had died of other causes (P = 0.02). However, the survivalof grafts from donors without heartbeats who had died of nontraumaticcauses did not differ significantly from the survival of graftsfrom donors with heartbeats who had died of similar causes (P= 0.23, data not shown).
Figure 2. Graft-Survival Rates for Kidney Transplants from Donors with Heartbeats and Donors without Heartbeats, According to the Cause of Death in the Donors without Heartbeats.
P = 0.02 for the comparison between donors with heartbeats and those without heartbeats who died from causes other than trauma. P = 0.04 for the comparison between donors without heartbeats who died from trauma and those without heartbeats who died from other causes.
Multivariate regression analysis of 10 potential risk factorsshowed that all factors except the presence or absence of aheartbeat in the donor were significantly associated with therisk of graft failure, after adjustment for the remaining factors(Table 3). In view of the effect of all the listed factors ongraft survival, the difference between kidneys from donors withoutheartbeats and those from donors with heartbeats was small.
Table 3. Risk Factors for Graft Failure According to the Regression Analysis.
Discussion
Although the initial experience in transplanting kidneys fromdonors without heartbeats was in the United States,3,4 muchof the recent experience has been in Europe,6,7,9,10,11,15,16,18,20,21led by the Netherlands15 and Japan,8,12,19,22 where kidneysfrom cadaveric donors with heartbeats have been difficult toobtain. Interest in the use of grafts from donors without heartbeatshas increased in the United States recently, with several encouragingstudies.13,14,16,17 Our study of the results of 229 transplantationsperformed at 64 centers in the United States largely confirmsthe previous reports from single centers.
The most important finding of our study was that the survivalof kidney grafts from donors without heartbeats was similarto that of grafts from donors with heartbeats. One year aftertransplantation, the kidneys from donors without heartbeatsfunctioned well (as indicated by the mean serum creatinine concentration),suggesting that long-term survival rates for these kidneys willbe similar to those for kidneys from donors with heartbeats,despite the poorer early function of the grafts from donorswithout heartbeats. Kidneys from donors without heartbeats whohad died of trauma survived as well as those from donors withheartbeats. We do not know whether the small difference in survivalassociated with the cause of death in the donors without heartbeatsreflects differences in their care before their hearts stoppedbeating.
In the early period after transplantation, kidneys from donorswithout heartbeats did not function as well as those from donorswith heartbeats, a finding reported in several previous studies.2,6,8,9,12,14,15Nearly half the recipients of kidneys from donors without heartbeatsrequired dialysis during the first week after transplantation,and 4 percent of the kidneys in this group never functioned.The survival curves show that the difference between the survivalof kidneys from donors without heartbeats and the survival ofthose from donors with heartbeats was entirely due to graftfailure in the first month after transplantation. This meansthat the disadvantage of using kidneys from donors without heartbeatscould be reduced considerably or eliminated if a kidney-viabilitytest were available to exclude poor kidneys, particularly thosethat will never function. Several such tests have been developed:the tetrazolium test, which measures the metabolic activityof tubules either by visual timing of the color change23 orby spectrometric measurement,24 proton magnetic resonance spectroscopy,25and measurement of alpha glutathione S-transferase activity.26However, none of those tests have yet been validated for thepurpose of documenting the viability of human kidneys.
The number of patients waiting for cadaveric kidney transplantshas increased by about 2400 per year since 1988. If 2400 morekidneys from 1200 donors without heartbeats could have beenprocured each year, the waiting list would not have increased.Even today, the waiting list would not increase if each of the63 organ-procurement agencies in the United States obtainedkidneys from two donors without heartbeats each month. A programfor procuring kidneys from donors without heartbeats has beenreported to result in a 40 percent increase in the overall supplyof cadaveric kidneys,2 and there may be twice as many donorswithout heartbeats as donors with heartbeats. A 40 percent increasein the supply of cadaveric kidneys in the United States wouldmean that there would be 3440 more kidneys available for transplantationthan in 1995, an increase that (if maintained) might begin toreduce the number of patients on the waiting list for cadaverickidney transplants each year.
In conclusion, the early results from 64 U.S. centers suggestthat graft survival at one year is not adversely affected bytransplanting kidneys from donors whose hearts have stoppedbeating. The supply of cadaveric grafts could be increased byusing kidneys from these donors.
Supported in part through a subcontract with the United Networkfor Organ Sharing. The opinions expressed in this article arethose of the authors and are not necessarily approved or endorsedby the network.
Source Information
From the Department of Surgery, University of California at Los Angeles School of Medicine, Los Angeles.
Address reprint requests to Dr. Cho at the UCLA Tissue Typing Laboratory, 950 Veteran Ave., Los Angeles, CA 90095-1652.
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