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Background The effect on allograft survival of the transplantation of kidneys from living donors without the previous initiation of long-term dialysis is controversial.
Methods Using data from the U.S. Renal Data System, we performed a retrospective cohort study of 8481 patients who were or who were not treated by long-term dialysis before receiving a kidney transplant from a living donor. The relative rate of allograft failure for patients who received a transplant without previously undergoing long-term dialysis, as compared with patients who underwent long-term dialysis before transplantation, was assessed by proportional-hazards analysis, with adjustment for potential confounding variables, including the transplantation center and median household income. The association between the receipt of a kidney transplant from a living donor without previous dialysis ("preemptive" transplantation) and the risk of biopsy-confirmed acute rejection within six months after transplantation was evaluated by conditional logistic-regression analysis, with adjustment for the transplantation center.
Results Transplantation of a kidney from a living donor without previous long-term dialysis was associated with a 52 percent reduction in the risk of allograft failure during the first year after transplantation (rate ratio, 0.48; P=0.002), an 82 percent reduction during the second year (rate ratio, 0.18; P=0.001), and an 86 percent reduction during subsequent years (rate ratio, 0.14; P=0.001), as compared with transplantation after dialysis. The reduction in the rate of allograft failure during the first year was attenuated when adjustment was made for the timing of acute rejection within the first year (rate ratio, 0.69; 95 percent confidence interval, 0.44 to 1.10; P=0.10). Increasing duration of dialysis was associated with increasing odds of rejection within six months after transplantation (P=0.001).
Conclusions Preemptive transplantation of kidneys from living donors without the previous initiation of dialysis is associated with longer allograft survival than transplantation performed after the initiation of dialysis.
The results of studies of the timing of transplantation relative to the initiation of dialysis, predominantly for cadaveric kidney transplantation, have been conflicting.6,7 In the largest study of the timing of transplantation of kidneys from living donors, the rate of allograft survival was approximately 10 percent higher for recipients who underwent transplantation without previously undergoing long-term dialysis than for those who underwent transplantation after long-term dialysis, but the result was not adjusted for potential confounding factors.8 Among adult recipients in the United States, approximately 25 percent of transplantations of kidneys from living donors are performed before the initiation of long-term dialysis.9 At present, the relation between prior long-term dialysis and allograft survival remains unclear. We conducted a retrospective cohort study using national data to examine the relation between prior dialysis and the survival of kidney allografts from living donors. In a secondary analysis, we investigated the effect of prior dialysis on the probability of biopsy-confirmed rejection within six months after transplantation.
Methods
Patients
Eligible patients were 18 years of age or older, had received a first kidney transplant from a living donor in the United States between January 1994 and June 1997, and had a known date of first treatment for end-stage renal disease. Patients were followed through June 1998.
Study Design
The study design was approved by the institutional review board of the University of Pennsylvania. All demographic information and follow-up data were supplied by the U.S. Renal Data System and collected by the United Network for Organ Sharing. Data on median household incomes in 1989 as linked to residential ZIP Codes were obtained from the 1990 U.S. Census. The potential confounders considered were the age, sex, and race of the recipient and the donor (race was classified as white, black, or other); the relationship of the donor to the recipient (parent, child, sibling, spouse, or other); the number of HLA haplotype matches (zero, one, or two); the most recently determined serum levels of panel-reactive antibodies (0 to 100 percent); the cause of kidney disease (diabetes mellitus, hypertension, glomerulonephritis, cystic kidney disease, interstitial disease, unknown or other causes, or data missing); the use or nonuse of antibody-induction therapy; the use or nonuse of hemodialysis or peritoneal dialysis; the duration of dialysis before transplantation (in days); the average number of transplantations of kidneys from living donors performed annually at each transplantation center; and the median household income (in 1989 dollars) for the ZIP Code of the recipient's residence. The covariates considered after transplantation were the presence or absence of delayed allograft function (necessitating dialysis treatment in the first week) and the presence or absence of biopsy-confirmed rejection within 6 and 12 months, as indicated by codes from the International Classification of Diseases, Ninth Revision (code 996.80 for transplant rejection or 996.81 for kidney rejection and 55.23 for kidney biopsy). "Preemptive" kidney transplantation was defined as the absence of exposure to dialysis before transplantation, and "nonpreemptive" transplantation was defined as exposure to dialysis of any duration before transplantation. The primary outcome, allograft failure, was defined by the institution of long-term dialysis after transplantation, repeated transplantation, or death.
Statistical Analysis
Proportional-hazards analysis was used to investigate the effect of preemptive transplantation of kidneys from living donors on allograft function.10 The proportional-hazards assumption was tested by graphical and weighted residual analyses.11 Potential confounding variables were screened in unadjusted models, and if they were associated with allograft survival (P
0.10), they were eligible for inclusion in multivariable models used to adjust the relation between preemptive transplantation and allograft survival.12 Multivariable models were fitted by adding covariates in a forward, stepwise manner and then removing those that did not retain statistical significance according to the Wald statistic (P0.05).12 To account for potential confounding by the transplantation center, an indicator variable representing the number of preemptive transplantations of kidneys from living donors performed annually at the center was included in separate models. We accounted for the potential underestimation of the standard errors of rate ratios as a result of the nonindependence of observations within a center by using robust estimates of variance.13 We replaced the dichotomous variable (preemptive vs. nonpreemptive transplantation) in the models with a series of indicator variables representing the duration of dialysis before transplantation in order to explore the relation between the duration of dialysis and allograft survival.
In a secondary analysis, we explored the association between preemptive transplantation and the risk of biopsy-confirmed acute rejection during the first six months after transplantation, using conditional logistic-regression analysis adjusted for transplantation center. Potential confounding variables were included in the multivariable model according to a stepwise selection procedure in which terms that were significant at the 0.05 level were retained. To characterize further the relation between the duration of prior dialysis and acute rejection, we replaced the dichotomous variable (preemptive vs. nonpreemptive transplantation) in the multivariable model with a series of indicator variables representing the duration of dialysis before transplantation.
All analyses were performed with Stata software (version 6.0, Stata, College Station, Tex.). All reported P values are two-sided.
Results
Patients' Characteristics at the Time of Transplantation
From January 1994 to June 1997, 9130 patients 18 years of age or older received kidney transplants from living donors in the United States. Six hundred forty-nine patients were excluded because the date of first treatment for end-stage renal disease was unknown or because of prior transplantation. A total of 1819 patients underwent transplantation without prior exposure to dialysis, and 6662 patients underwent transplantation after dialysis was initiated. Five percent of the total number of eligible patients had allograft failure, the primary outcome, by the end of the study (mean [±SD] follow-up, 406±290 days) (Table 1). Most allograft failures were defined by the initiation of long-term dialysis.
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The proportions of all allografts surviving at one, two, and three years after transplantation were 96.3 percent, 93.4 percent, and 82.9 percent, respectively. These rates of allograft survival are consistent with those published for first renal transplants from living related donors.14 The unadjusted rates of allograft survival for patients undergoing preemptive and nonpreemptive transplantation are shown in Figure 1 (P=0.009). By three years after transplantation, the patients who underwent preemptive transplantation had a rate of allograft survival of 90 percent, as compared with 81 percent for patients who underwent transplantation after the initiation of long-term dialysis. Both graphical and weighted residual analysis demonstrated a departure from the proportional-hazards assumption.
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The magnitude of the unadjusted association between preemptive transplantation and the rate of allograft failure is shown in Table 3 for each of the three intervals after transplantation. Preemptive transplantation of kidneys from living donors was associated with a 34 percent reduction in the rate of allograft failure during the first year (P=0.01), a 44 percent reduction during the second year (P=0.07), and a 62 percent reduction thereafter (P=0.002). Other potential predictors that had significant associations with allograft survival in the unadjusted analysis are also shown in Table 3.
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Because of the changing rate of allograft survival in the two groups over time, we fitted three multivariable proportional-hazards models for yearly intervals after transplantation: the first year, the second year, and the third and subsequent years (Table 4). Acute rejection was not initially included in these models, because of the hypothesis that the effect of preemptive transplantation was mediated through acute rejection. The serum level of panel-reactive antibodies was no longer significantly associated with allograft failure after adjustment in any of these models. After adjustment for the cause of the kidney disease, the racial relationship of the donor and the recipient (both nonblack [defined as white or other], both black, or one nonblack and one black), and the presence or absence of delayed allograft function, preemptive transplantation continued to have a strong relation with allograft survival. Preemptive transplantation was associated with a reduction of 52 percent in the rate of allograft failure during the first year after transplantation (P=0.002), a reduction of 82 percent during the second year (P=0.001), and a reduction of 86 percent during subsequent years (P=0.001).
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To explore whether a decreased incidence of acute rejection is one mechanism by which preemptive transplantation improves allograft survival, we adjusted our multivariable models for the first episode of biopsy-confirmed acute rejection in the first year after transplantation. A reduction in the rate ratio for preemptive transplantation after adjustment for acute rejection would be consistent with this mechanism. During the first year after transplantation, adjustment for acute rejection (as a time-varying covariate) attenuated the effect of preemptive transplantation (P=0.10) (Table 4). When a fixed variable indicating the occurrence of biopsy-confirmed acute rejection in the first year was included in models for the second and third years, the effect of preemptive transplantation was essentially unchanged.
Finally, we examined the relation between preemptive transplantation and acute rejection, using conditional logistic-regression analysis with adjustment for the transplantation center (Table 5). After other predictors that had significant unadjusted associations with acute rejection were accounted for, there was a significant linear increase in the odds of rejection with an increasing duration of long-term dialysis (adjusted odds ratios, 1.6, 2.3, 3.0, and 4.2 for the first, second, third, and fourth quartiles, respectively, as compared with preemptive transplantation; P=0.001 for all comparisons with the preemptive-transplantation group). These observations persisted when this analysis was limited to patients who had Medicare as their primary payer.
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This study of a national sample of renal-transplant recipients demonstrates that transplantation of a kidney from a living donor performed without the previous initiation of long-term dialysis is associated with a 52 percent reduction in the rate of allograft failure in the first year after transplantation and larger reductions in subsequent years, independently of the transplantation center. This association of greater allograft survival with preemptive transplantation may be mediated, in part, by a reduction in the occurrence of acute rejection.
The results of this study are consistent with previous research. In a single-center study involving 148 children, Schurman and McEnery found that preemptive transplantation of kidneys from living donors, as compared with transplantation performed after the initiation of long-term dialysis, was associated with a greater rate of allograft survival during the first year (85 percent vs. 74 percent) and with a significantly longer allograft half-life (16.9 years vs. 8.0 years).15 Donnelly et al. evaluated 11,913 patients and reported an increase of approximately 10 percent in the unadjusted rate of allograft survival among patients who received kidneys from living donors without the previous initiation of dialysis.8 Neither group of investigators reported multivariable analyses adjusted for potential confounding.
The attenuation of the relation between preemptive transplantation and allograft survival, after adjustment for acute rejection, suggests that the association may be mediated at least in part through an immunologic mechanism. The relation between an increased duration of dialysis before transplantation and increased odds of acute rejection by six months further supports the concept of an immunologic effect of dialysis. These findings are consistent with those of Cacciarelli et al.,16 who examined 325 recipients of cadaveric kidneys; the incidence of acute rejection was lowest among the patients who had the shortest duration of long-term dialysis (less than six months).
The biologic plausibility of our findings is further supported by in vitro data on immune dysfunction among patients with chronic renal failure.17,18,19,20 Descamps-Latscha et al.21 provided evidence of a greater degree of impairment in the immune system in patients not undergoing dialysis as compared with patients undergoing long-term dialysis. Kaul et al. recently confirmed that the initiation of hemodialysis leads to a significant improvement in T-cell proliferation.22 These findings suggest that exposure to dialysis may diminish the severity of immune dysfunction and thus increase the risk of acute rejection.
There are several potential limitations to this study. First, the patients who underwent preemptive transplantation probably had a higher level of residual function of the native kidney. We were unable to examine directly the contribution of this factor to our findings. However, episodes of delayed allograft function may have been missed in the preemptive-transplantation group because the better-preserved function of the native kidney in these patients may have made dialysis unnecessary even when allograft function was markedly delayed. Nonetheless, the exclusion of delayed allograft function from the multivariable model did not appreciably modify the observed association of preemptive transplantation with improved allograft survival.
Second, the indicators of socioeconomic status were limited to race and the median household income for the ZIP Code of the recipients' residence. Although socioeconomic status may confound analyses of allograft survival, particularly in studies comparing transplantation from cadavers and living donors, our comparison groups most likely had substantial similarities, given their uniform access to a living donor. Third, notwithstanding the inclusion of recipients of kidneys from living donors only and the use of multivariable analyses to minimize confounding, we cannot exclude the possibility that patients who underwent preemptive transplantation were healthier and more compliant with therapy and that these characteristics contributed to the higher rates of allograft survival in these patients.
Finally, our study was not able to answer the policy question of whether preemptive transplantation of kidneys from living donors is a more beneficial strategy than such transplantation after the initiation of dialysis. A trial designed to address this question would randomly assign patients eligible for preemptive transplantation to either preemptive kidney transplantation from living donors or kidney transplantation from living donors after dialysis had been initiated.
In summary, using nationally representative data, we have demonstrated that preemptive transplantation of kidneys from living donors was associated with improved allograft survival. The reduction in the rate of acute allograft rejection suggests that preemptive transplantation may modulate immune mechanisms that shorten allograft survival.
The interpretation and reporting of these data are the responsibility of the authors and should in no way be seen as reflecting the official policy or interpretation of the U.S. government.
Supported in part by a training grant (DK-07006) and a center grant (DK-45191) from the National Institutes of Health. Portions of this study were completed while Dr. Feldman was an Established Investigator of the American Heart Association.
We are indebted to John Holmes, Ph.D., and Jill Santana, M.S., for their technical expertise and assistance.
Source Information
From the Center for Clinical Epidemiology and Biostatistics and the Department of Biostatistics and Epidemiology, University of Pennsylvania (K.C.M., M.M.J., H.I.F.); and the Renal-Electrolyte and Hypertension Division, Department of Medicine, Hospital of the University of Pennsylvania (K.C.M., H.I.F.) — both in Philadelphia. Presented in part at the annual meetings of the American Society of Nephrology, Philadelphia, October 25–28, 1998, and Miami, November 1–8, 1999.
Address reprint requests to Dr. Mange at 700 Clinical Research Bldg., 415 Curie Blvd., Philadelphia, PA 19104, or at kmange{at}cceb.med.upenn.edu.
References
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and their specific inhibitors in chronic renal failure and maintenance dialysis: relationships with activation markers of T cells, B cells, and monocytes. J Immunol 1995;154:882-892. [Abstract]
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