Delayed function of a kidney transplant is the most common allograft complication in the immediate posttransplant period, affecting 8-50% of primary cadaveric renal transplants in the United States (1-6). The clinical manifestations of delayed graft function (DGF*) vary along a spectrum of severity, from a subtle slowing of the expected decline in serum creatinine to prolonged oliguria requiring dialytic support for a number of days after transplantation. The most benign consequences of DGF are still quite significant, and include prolonged hospitalization, higher cost of transplantation, increased complexity of management of immunosuppressive drugs, and an adverse effect on the rehabilitation potential of transplant recipients (7-10). However, it is becoming increasingly apparent that DGF may also be associated with more ominous consequences, particularly poor long-term survival of the renal transplant.
Decreased graft survival has been correlated with DGF in a number of recent studies (7, 8, 11-13). However, there are conflicting reports on several aspects of the relationship between DGF and the outcomes of kidney transplantation. Some reports suggest limited or no impact of DGF on graft survival (13-19). In a recent report, Troppmann et al. (20) showed that DGF has no compelling, independent effect on 5-year graft survival once the role of acute transplant rejection has been taken into account. However, this study implicated DGF as a predisposing factor for acute rejection and also suggested that DGF can interact in synergy with rejection to result in decreased long-term graft survival. Thus, although the strength and significance of the effect of DGF on long-term graft function are contested, there is increasing evidence that DGF may be a powerful independent predictor of poor long-term renal graft survival.
In view of the profound effect that DGF may have on both health care utilization and renal graft survival, we undertook a cohort analysis of over 37,216 primary cadaveric renal transplants (1985 to 1992) in the U.S. Renal Data System database. The primary goal of the study was to determine whether DGF is an independent prognostic factor for short-and/or long-term graft survival. Our second objective was to clarify the magnitude of the relationship that exists between delayed function and early acute rejection among transplant recipients. Third, we calculated the risk of DGF according to the duration of organ preservation or cold ischemia time. Finally, we offer a comparative analysis of the benefit of optimal HLA matching versus immediate graft function.
MATERIALS AND METHODS
The U.S. Renal Data System prospectively compiled data on 44,703 primary renal allografts transplanted between January 1985 and December 1992. We identified a study population of 38,966 transplants (87.2%) with complete transplant characteristics and adequate follow-up data. Of the latter, cold ischemia time was missing on 1750 transplants (4.5%) and these were excluded. Apart from missing cold ischemia time, no other exclusion criterion was imposed. The analysis was based on the final sample of 37,216 first cadaveric kidney transplants from 249 U.S. transplant centers. Allograft status was followed until recipient death, return to dialysis, transplant nephrectomy, or December 31, 1993. Data were extracted from the transplant follow-up form, which was completed for all transplants at discharge. DGF was defined as a requirement of at least one dialysis treatment during the first postoperative week. The definition of acute rejection was based on the conventional histologic and clinical criteria of the reporting centers.
Baseline characteristics among groups were compared by chi-square statistics and analysis of variance for unbalanced design for categorical and continuous variables, respectively. Unconditional logistic regression was used to calculate the adjusted odds ratio of DGF, and the association between DGF and graft survival was analyzed with the Cox regression model. Apart from cold ischemia time, DGF, and acute transplant rejection, 22 factors were incorporated into the regression models. These explanatory covariates included donor characteristics (age, gender, and race), recipient variables (age at transplantation, race, gender, original etiology of end-stage renal disease, pretransplant duration of dialysis, pretransplant blood transfusions, pretransplant medical/rehabilitation status, current panel-reactive antibody level, type of end-stage renal disease care coverage [Medicare±private insurance]), and transplant variables (warm ischemia time, HLA-A,B mismatches, HLA-DR mismatches, zero-HLA-mismatch status, cytomegalovirus match status, organ disposition [local or shared], ABO compatibility, immunosuppression at discharge, and year of transplantation). The fitted Cox regression model was deemed adequate by visual inspection of the plots of deviance and martingale residuals, and the logistic regression model was judged to be robust by the Hosmer and Lemeshow goodness-of-fit test. All tests of significance were two-sided with an α of 0.05. Statistical analysis was performed with SAS version 6.11 (SAS, Cary, NC).
RESULTS
Baseline characteristics. During the initial transplant hospitalization, 58.4% of recipients had neither DGF nor acute transplant rejection (group 1, n=21,726), 14.1% had DGF only (group 2, n=5,246), 17.8% had acute rejection (group 3, n=6,620), and 9.7% had both DGF and predischarge rejection (group 4, n=3,624). The distribution of donor and recipient characteristics among the study groups is tabulated in Table 1.
Risk factors for DGF: trend, risk factors, and relationship to acute transplant rejection during the initial hospitalization. The overall incidence of DGF and early rejection was 26.2% and 24.8%, respectively. By chi-square analysis, predischarge acute rejection occurred twice as frequently in grafts with delayed function compared with those with immediate function (37% vs. 20%; odds ratio [OR] =2.25, P=0.001). In the period covered by the study, the incidence of DGF declined gradually from 30.7% in 1985 to 23.4% in 1992. However, the incidence of DGF remained relatively constant during the most recent 2 years of the study (1991 and 1992).
The risk factors and associated adjusted odds ratios of DGF are shown in Table 2. Among these predictive factors, the strongest association was observed for cold ischemia time (OR=1.38-3.48), donor age >50 years (OR=2.07), and African-American recipient (OR=1.63).
Influence of cold ischemia time on DGF and graft survival. When cold ischemia time was analyzed as a linear variable, the adjusted odds of DGF were higher by 23% for every 6-hr increase in cold ischemia time (OR=1.23 per 6 hr, P<0.001). Using 12-hr intervals of cold ischemia time in a separate analysis, with the ≤12-hr interval as the reference group (OR=1.00), the risk of DGF increased monotonically with increasing duration of cold ischemia time. The risk of DGF increased by more than twofold when cold ischemia time exceeded 24 hr (OR=2.28, P<0.001) and was substantially higher with cold ischemia time >36 hr (OR=3.48, P<0.001). Although mandatory shipping is not required for 96% of transplants with one or more HLA mismatches, we found that 36% of these kidneys experienced cold ischemia time >24 hr.
Does cold ischemia time independently compromise long-term graft survival, irrespective of DGF? A Cox survival analysis stratified according to four intervals of cold ischemia time revealed a similar 5-year survival for allografts with cold ischemia time of ≤12 and 13-24 hr (60% vs. 61%). However, even after controlling for delayed function and acute rejection, allografts had an inferior 5-yr graft survival rate compared with those with cold ischemia time ≤12 hr (52% vs. 61%, P<0.001). Thus, it appears that excessively prolonged cold ischemia may directly and independently compromise long-term graft survival.
The influence of DGF on short- and long-term graft survival. To measure the influence of delayed function on graft survival, we calculated graft loss for the overall study period (0-5 years) and for two distinct posttransplant intervals: 0-1 year (short-term survival) and 1-5 years (long-term survival). In the latter category, the long-term graft survival was conditional on transplant function on the first anniversary.
The adjusted 1-year graft survival rate was 88%, 74%, 72%, and 56% for groups 1, 2, 3, and 4, respectively. Delayed function alone (group 2) was associated with significantly lower 1-year graft survival compared with no DGF + no acute transplant rejection (group 1; 88% vs. 74%; P<0.001). Similarly, 1-year graft survival was diminished in the presence of acute transplant rejection alone (group 3) (88% vs. 72%, group 1 vs. group 3, P<0.001). Simultaneous occurrence of both delayed function and acute rejection (group 4) was associated with a dramatically poorer 1-year survival rate of 56% (P<0.01 compared with each of groups 1, 2, and 3).
Stratified Cox-adjusted cumulative functional 5-year graft survival curves are shown in Figure 1. The cumulative 5-year graft survival rate was 66%, 53%, 48%, and 35% for groups 1, 2, 3, and 4, respectively. Delayed function alone (group 2) and acute rejection alone (group 3) independently yielded a poor 5-year cumulative graft survival rate (P<0.001 compared with group 1, no DGF + no acute rejection). Moreover, these two early posttransplant events occurring together (group 4) was associated with a dismal 5-year graft survival rate of only 35% (P<0.001 compared with groups 2 and 3).
From a cursory examination of Figure 1, it may appear that the survival curve trajectories are parallel after the initial, precipitous loss of grafts during the first year. However, we found that this was not the case. As shown in Figure 2, the 5-year graft survival rate given graft function at 1 year was 76%, 72%, 67%, and 65% for groups 1, 2, 3, and 4, respectively. Notably, graft survival was significantly lower for recipients who had DGF with or without acute rejection (groups 4 and 2, respectively) compared with recipients who were spared either adverse event (group 1) during their early transplant hospitalization (P<0.001). The adjusted 5-year relative risk of graft loss was 1.53 (P<0.001) for DGF alone (Table 3). In a subanalysis of allografts functioning at 1 year, transplants with DGF but no rejection episode (group 2) during the first year still demonstrated a significantly lower 5-year survival rate compared with grafts with neither DGF nor a 1-year rejection episode (group 1) (72% vs. 79%, P=0.0001). Thus, DGF alone is a significant independent predictor of both cumulative and conditional long-term graft survival.
DGF may offset the potential benefits of HLA matching. The balance of possible cost of increased cold ischemia time versus the benefit of HLA matching was studied by comparing the graft survival for zero-antigen-mismatched kidney transplants versus higher grade mismatched transplants (mean HLA mismatch=3.5) in the context of whether or not DGF was present. Table 4 shows the 1-year and 5-yr graft survival rates of this comparative analysis. Regardless of the early functional status of the allograft, zero mismatch was associated with a 10% and 15% improved graft survival at 1 and 5 years, respectively. Notwithstanding the modest benefit of zero mismatching, the 1-year graft survival rate for higher grade mismatched kidneys without DGF was significantly higher than that of zero-antigen-mismatched kidneys with DGF (85% vs. 75%; P=0.009). The corresponding figures for the 5-year graft survival were 63% and 51% (P<0.001). Thus, the potential benefit of receiving a zero-mismatched kidney was inferior to that of early graft function.
Estimate of the number of graft losses due to delayed graft function. To estimate the number of cadaveric renal transplants that are lost due to the occurrence of DGF, we calculated the attributable risk for 5-year graft survival. Using the composite adjusted 5-year relative risk (RR) of graft loss due to delayed function in Table 4 (RR=2.54), in conjunction with the overall incidence of DGF of 26%, we calculated a population attributable risk of 0.29. Thus, we estimated that 2280 transplants were lost due to the influence of DGF, representing one third of failed kidney transplants in the study cohort.
Impact of DGF on length of hospital stay. The occurrence of DGF and/or acute transplant rejection had a significant impact on the length of stay during the initial transplant hospitalization. The median length of stay was 10, 17, 15, and 21 days for groups 1, 2, 3, and 4, respectively. Multiple comparisons by analysis of variance showed that the difference in length of stay was significant among the four groups (overall P=0.05). Based on median length of stay for each study group, we estimated that DGF accounted for an additional 9115 inpatient days during the initial transplant admission per year.
DISCUSSION
The results of this study strongly argue that the short- and long-term fate of a renal allograft can, in large part, be predicted by two events that occur early in the life of that allograft: DGF and acute rejection. The occurrence of either of these events in the initial posttransplant hospital course is independently predictive of 48-52% 5-year graft survival, compared with 66% in the absence of these early events. Both events occurring simultaneously in the early posttransplant period portend a dismal graft survival at 5 years of only 35%. Compared with all other factors potentially associated with poor long-term graft survival studied in this report, none begin to approach the independent and additive adverse effects of DGF and early acute rejection.
That DGF is an independent risk factor for long- and short-term graft survival is in contrast to the results of a single-center study in which DGF was associated with acute rejection episodes, but was not a significant risk factor for diminished 5-year graft survival (20). We found that the relative risk of 5-year graft loss in transplants with DGF in the absence of acute allograft rejection was 1.53 (P<0.001). Although the corresponding excess risk in the single-center study was also high (30%), it did not reach statistical significance (RR=1.30, P=0.42). It is likely that the lack of statistical significance in the presence of an effect size of 30% was due to the relatively smaller sample size in that study.
Our own findings are limited by the fact that not all cases of acute rejection were biopsy proven and the “time at risk” for acute rejection (i.e., duration of transplant hospitalization) was longer for grafts with delayed function. A recent report without these limitations reached conclusions similar to ours (21). In our main analysis, we evaluated the relationship between DGF and acute rejection occurring during the initial transplant hospitalization because rejection episodes occurring later may have been precipitated by other intervening variables not attributable to DGF. This may explain the disparity between our finding and that of Troppmann et al. (20), who studied late rejection episodes. A more recent study in recipients with serum creatinine ≤2.0 mg/dl on the first transplant anniversary was also reported by Troppmann et al. (22). They showed that DGF alone had no significant import for long-term graft survival. Their study population may represent a highly select group with mild DGF whose residual nephron mass after recovery from DGF is favorably balanced with the recipient's metabolic and chronic hemodynamic burden.
Why should DGF and early rejection have such a profound negative effect on long-term graft survival? Although inflammatory events directed against the renal allograft in the form of anti-alloantigen-specific immunity have classically been implicated in graft loss, the role of nonspecific inflammation in graft loss has recently become a focus of great interest (23-27). Acute allograft rejection and DGF may represent the two poles of this continuum between specific and nonspecific inflammation, respectively. In the early course of a renal allograft, the occurrence of acute allograft rejection clearly demonstrates that the recipient's immune system has acquired and effectively utilized the targeting information that is necessary and sufficient to continue specific immunologic attack(s) on the allograft. Thus, the negative and independent predictive role of acute allograft rejection in long-term graft survival, as again demonstrated in this study, is intuitive.
How can DGF, independent of early acute rejection, negatively effect renal allograft survival? First, severe acute tubular necrosis may be associated with actual nephron destruction (28, 29). The development of severe acute tubular necrosis may be further exacerbated by either cytokine-releasing induction therapy and/or cyclosporine therapy if cyclosporine is used before graft function is established (30-32). This early pruning of renal nephron mass may predispose to hyperfiltration injury of the remaining nephron mass of the allograft (33). Second, DGF may be associated with a rich tubular-interstitial milieu of proximal proinflammatory agonists, including interferon-γ, interleukin 2, transforming growth factor-β, and interleukin 4 (25, 26), which may stimulate non-antigen-dependent inflammation and scarring (24, 27, 34, 35).
Long-term graft survival is most seriously compromised by the association of DGF with acute rejection. This is likely mediated by mechanisms including the following. First, initial nonfunction of the renal allograft eliminates the use of serum creatinine as a means of detecting early, treatable rejection episodes. Second, the nonspecific inflammatory events associated with DGF may enhance both recipient inflammatory cell migration into the allograft and alloantigen presentation with activation of specific immunity. Finally, the combination of fibrosing events from both antigen-specific and nonspecific inflammation may collectively encroach upon graft function. The combined insult of the latter two events may place the allograft in the host immune-independent phase of progressive injury (23).
Higher grade HLA mismatch has previously been reported to be associated with an increased risk of DGF (3, 14, 17, 18). Terasaki et al. (36) recently showed that graft survival in cadaveric transplants with immediate function is superior to that in zero-HLA-mismatched transplants compromised by DGF. The current study showed that zero-mismatched kidneys yielded better graft survival within each category of graft function, but on a comparative basis, the modest benefit of HLA matching is smaller than that early graft function. Thus, it may be better to receive a “fresh” kidney than a well-matched one. Previous reports support this concept (37-39). Indeed, some investigators have argued for omitting HLA matching altogether in an attempt to decrease cold ischemia time (40).
We cannot state that the shipping of zero-HLA-mismatched organs is responsible for prolonged cold ischemia time. To the contrary, our data showed that the mean cold ischemia time is remarkably close at 22.6 hr and 20.1 hr for zero- and higher grade-mismatched kidneys. The 2.5-hr difference agrees with a previous study (41) and may contribute minimally to the risk of DGF. In essence, the small increased risk of DGF (≈3.9% per hr) is a small price to pay for the significantly improved outcome of zero-mismatched allografts. However, two studies (41, 42) have shown that under a maximal achievable matching strategy, zero mismatching would be accomplished in no more than 20% of kidneys. This would still leave a majority of organs in the mismatched pool that could potentially benefit most from a reduction in the overall cold ischemia time. It is even more germane to note that cold ischemia time exceeded 24 hr in 35.7% of U.S. non-zero-HLA-mismatched transplants, of which 38% suffered DGF. This leads us to suggest that reasons unrelated to shipping of zero-mismatched organs are responsible, in the most part, for prolongation of cold ischemia time in the majority of kidney transplants. It is these other potentially remediable causes of longer preservation time that should command the attention of the reader. The economic consequences of DGF are enormous. Based on the 6500 primary cadaveric renal transplants performed in the United States in 1992 (43, 44), we estimated that the annual incremental cost associated with DGF was $54 million. The persuasive results in our study and others (20, 21, 36) should heighten the sensitivity to the outcomes and cost consequences of prolonged cold ischemia time.
The incidence of DGF has been relatively stable at 23% since 1991. We identified prolonged cold ischemia time as the single most important factor that predicts DGF. Thus, efforts by both organ procurement organizations and transplant centers to decrease this time period to consistently less than 18-24 hr would be the single most effective means to further decrease the incidence of DGF.
In conclusion, we have described a significant and robust relationship between DGF and decreased cadaveric renal allograft survival. The most compelling predictor of DGF was cold ischemia time. Although the recent years have marked many advances in renal transplantation, the rate of DGF necessitating dialysis therapy has recently remained constant, complicating greater than 20% of cadaveric renal transplants. DGF can potentially compromise long-term graft function both by indirectly predisposing transplant recipients to acute rejection and by directly and independently contributing to ongoing long-term graft loss. In addition to the incalculable costs of premature graft loss to patients and society, DGF increases the already high postoperative hospitalization cost of transplantation by more than threefold (10, 44). Our data argue that further effort must be made to reduce cold ischemia time, which is clearly the strongest predictor of DGF.
Footnotes
This work was supported by in part by NIDDK grant RO3 DK50936 01 (to A.O.O.) and the Department of Veterans Affairs research associate award (to R.L.S.).
Abbreviations: DGF, delayed graft function; OR, odds ratio; RR, relative risk; USRDS, United States Renal Data System.
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