An analysis of 1-year transplant outcome in the more recent subcohort of 2440 transplants showed a 1-year transplant survival rate of 88% (95% CI, 87-89). All factors found to have a significant influence on the 5-year survival model were retained in this analysis, and in addition, the influence of recipient ethnicity, recipient sensitization to HLA antigens, and CIT were considered.
Effects of factors analyzed in the full cohort were found to be comparable in this shorter term analysis. Although no significant effect of degree of sensitization was identified, recipient ethnicity and CIT were both found to be influential factors. There was no evidence of an increasing risk of transplant failure for CIT up to 21 hr, but beyond this, the risk of failure increased by 4% for each additional hour of ischemia time (RR=1.04; 95% CI, 1.02-1.06). Results for recipient ethnicity showed that relative to white patients (n=2151), black patients (n=65) had the poorest transplant outcomes (RR=1.84; 95% CI, 0.94-3.60), whereas Asian (n=192) and other patients (n=32) had comparable outcomes.
A number of clinically relevant interaction effects were considered—HLA mismatch by each of recipient age, blood group, and CIT; CIT by donor and recipient age groups; waiting time by recipient primary renal disease and ethnicity; donor by recipient age. None of these was significant, although there was some evidence (P<0.15) that both HLA mismatch and older donor age had decreasing importance with increasing recipient age at transplant, whereas waiting time seemed to have an exaggerated detrimental effect on transplant survival for diabetic patients. No significant effects on outcome were seen for other factors, including donor-recipient gender match and CMV match.
Death-censored graft survival analyses were also undertaken, but results are not shown because of similarity of effects for most factors of interest: the only differences related to recipient age, diabetes, and waiting time. These factors were more strongly associated with patient death than graft failure. In fact, the risk of graft failure was significantly lower for patients older than 40 years at time of transplant than for those who are 18 to 39 years old.
Transplant Survival—Primary Transplants in Pediatric Recipients
Five-year analysis of pediatric kidney-only transplants from DHB donors considered a cohort of 596 primary grafts. Patients were defined as younger than 18 years at time of transplant.
Investigation of all the risk factors showed only year of graft, donor age, and recipient primary renal disease to have a significant influence on 5-year transplant survival of pediatric patients. HLA mismatch was nonsignificant in this small cohort, but the magnitude of the effects was similar to those in adult patients.
Five-year transplant survival improved year-on-year for pediatric recipients in the period analyzed (RR=0.89 for each successive year; 95% CI, 0.80-0.98). Young donors conferred a nonsignificant increased risk of failure compared with donors aged 18 to 29 years (baseline group), whereas donors older than 40 years were associated with the greatest risk of transplant failure for pediatric patients (RR=2.23; 95% CI, 0.97-5.14). Grafts in patients with glomerulonephritis (GN) were almost twice as likely to fail within 5 years compared with other renal diseases (P<0.05).
Transplant Survival—Combined Adult and Pediatric Data
Combining pediatric and adult patient data enabled 5-year transplant survival to be compared across all donor and recipient age groups. Results are shown in Table 3. In terms of donors, those aged 11 to 39 years were associated with the best graft outcomes, with both younger and older donors conferring an increased risk. For recipients, inferior graft outcomes were apparent for patients aged 11 to 17 years and for those aged 60 years and more. When censoring for patient death, analysis showed that the risk of graft failure was greatest for pediatric patients and, in particular, those aged 11 to 17 years (RR 1.6; 95% CI, 1.2-2.2, compared with patients aged 18-39 years).
Transplant Survival—Secondary Transplants in Adult Recipients
Five-year transplant survival for second grafts was 71% (95% CI, 68-74) based on 1165 adult secondary transplants. There were insufficient third and subsequent transplants for meaningful risk-adjusted analysis (n=239).
Investigation of the effects of the same factors considered for first grafts showed only minor differences. The effect of donor age appeared stronger on outcome of second transplants, and an adverse effect of renal vascular disease relative to GN was present that was not apparent in first transplants. Although nonsignificant for first transplants, any form of organ damage, as reported by retrieving and transplanting centers, had a significantly adverse effect on 5-year transplant survival of second transplants. The organ was classified as damaged with any of the following: capsule stripped or torn, small hematomas, cut polar artery, cut to renal vein, cut to renal artery, patch removed, patch excluding an additional artery, ureter cut short, or other notable damage.
Two additional factors not applicable to analysis of first grafts were also considered. HLA mismatch at first transplant was nonsignificant, but there was evidence that, compared with first grafts surviving <3 months, first grafts surviving 3 to 12 months were associated with a greater risk of failure for the second graft (RR=2.12; 95% CI, 1.33-3.37; P<0.01). No such increased risk was associated with first grafts surviving more than 12 months.
One-year transplant survival of second transplants in the later cohort was 85% (95% CI, 82-89). In this smaller cohort of 360 grafts, only year of graft (RR for year-on-year improvement=0.62; 95% CI, 0.42-0.92; P<0.05) and donor age reached statistical significance.
Patient Survival—Primary Transplants in Adult Recipients
Five-year patient survival of the cohort of 7350 primary adult kidney-only transplants was 85% (95% CI, 84-86). Patient survival effects were similar to transplant survival effects (although HLA mismatch and donor cause of death did not reach statistical significance) with three notable (and not unexpected) exceptions: recipient age, waiting time, and diabetes had a much stronger influence on patient survival. Results are shown in the final columns of Table 1.
One-year patient survival was 95% (95% CI, 94-96%) based on 2440 patients in the more recent cohort of primary adult transplants. Significant factors affecting outcome of this cohort were recipient age, primary renal disease (polycystic kidney disease associated with less risk of patient death and diabetes associated with greater risk of patient death compared with GN), waiting time, donor cause of death, and HLA mismatch.
Factors Contributing to CIT
Having found that CIT has a significant influence on posttransplant outcome, it was important to understand the factors that contribute to prolonged CIT in order that a new allocation scheme could seek to avoid prolonging cold storage times.
Analysis showed that each time a kidney was offered to a transplant center and was declined by that center, the CIT increased by an average of 30 min. This reflects the time allowed to make a decision about an offer of a kidney for transplant in the United Kingdom.
Furthermore, a kidney offered through the national allocation scheme and accepted by a transplant center, but subsequently not used in the intended patient and therefore reallocated to another patient, added an average of 7 hr to the total CIT of the kidney.
Further analysis showed that only when kidneys were transported between distant transplant centers within the United Kingdom was there an effect on CIT (average 2 hr longer).
This analysis of the factors influencing deceased donor kidney transplant outcomes was undertaken to inform the development of a new kidney allocation scheme in the United Kingdom. The analysis was based on a robust data set with excellent levels of follow-up information and incorporating all transplant centers in the United Kingdom. Transplant and patient survival of adult and pediatric patients were investigated, and primary and secondary kidney-only transplants were analyzed separately. The results confirmed the continued relevance of HLA matching between donor and recipient but showed that the influence of HLA matching on outcome had changed from that reported in the United Kingdom a decade ago (8). This change was such that only the most poorly matched grafts, such as those with two HLA-DR mismatches, were associated with significantly inferior graft survival relative to 000 HLA-A, B, DR mismatched grafts. The change is likely to reflect improvements in immunosuppression in the United Kingdom over the last 10 years. As observed previously, recipient and donor age, donor cause of death, CIT, recipient waiting time to transplant, and recipient diabetes were all identified as significant factors influencing transplant outcome. Patient ethnicity was also found to be a factor influencing transplant outcome with poorer outcomes for black patients compared with white and Asian patients, as reported previously in the United Kingdom (10). It was interesting to note that after adjusting for all of the relevant factors shown to influence transplant survival, transplant outcome during the first 3 years improved progressively during the study period. The explanation for this finding is not clear, but it may reflect continuing developments in immunosuppression and patient management.
This analysis of registry data is limited by the availability of relevant data for risk adjustment, and it is acknowledged that there will be other factors influencing outcome that cannot be taken in to account. Time on dialysis/preemptive transplant is now routinely reported to the UK Transplant Registry, but is not available for the cohort analyzed in this report. Recipient weight is another such example in that it is not routinely collected for the registry, although donor/recipient body weight ratio has been associated with renal transplant outcome in other studies (11).
The previously defined “favorable matching” for HLA-A, B, DR mismatch levels (9) formed the basis of the 1998 NKAS but was shown here to no longer reflect significant differences in transplant outcome. Instead, grafts with two HLA-DR mismatches or two HLA-B and one HLA-DR mismatch fared significantly less well than 000 mismatched grafts, with degrees of difference between a total of four newly defined levels of mismatch. This finding is particularly relevant to development of a new kidney allocation scheme, suggesting that although the effect of HLA mismatch may be different in more recent years, the influence on outcome remains significant, as also shown in an analysis of data reported to the Collaborative Transplant Study (3).
Increasing donor age was one of the most significant factors adversely affecting transplant outcome, and this observation is entirely consistent with other multicenter and single-center studies (5, 12). However, there was no evidence from the current analysis to suggest that the adverse effects of older donor age could be minimized by allocation to recipients selected, for example, on the basis of age, HLA mismatch, or CIT. This study also showed that kidneys from young donors (<11 years) did not fare as well as those from donors aged 11 to 39 years, questioning the rationale under the 1998 NKAS for preferentially offering such kidneys to pediatric recipients.
As shown by others (13, 14), older recipients fare less well after transplantation. Recipients older than 40 years and especially those older than 60 years faced a significantly increased risk for death within 5 years, although there was no increased risk of graft failure after censoring for patient death. The inferiority of the graft survival in adolescent patients (11-17 years old) in this study was of particular concern and has been noted previously (15), an effect often attributed, at least in part, to nonadherence with immunosuppressive therapy.
The influence of waiting time to transplant on subsequent outcome was an important finding given the potential to influence waiting time through an organ allocation scheme. A waiting time longer than 6 months conferred an increased risk of transplant failure, although reassuringly the effect seemed to be transient, and the risk was found not to increase significantly as waiting time extended beyond 2 years. An analysis of the United States Renal Data System Registry reported in 2000 showed an increased risk associated with longer waiting times on dialysis, but unlike the results in this study, the risk was seen to increase with increasing waiting times beyond 2 years (16).
CIT more than 21 hr was found to have a significant influence on short-term graft outcome, with a 4% increase in risk of failure for each additional hour of CIT. The influence of prolonged cold ischemia has long been recognized in the United Kingdom (17), and similar effects have been reported elsewhere (18, 19). CIT is of particular relevance to allocation because organ exchange over long distances will increase CIT, and this study confirmed that reallocation of kidneys and long-distance exchanges between centers are associated with increased CIT.
The factors and influences on outcomes of secondary transplants were largely comparable with those for primary transplants, although kidney damage incurred during organ retrieval was additionally identified as a risk factor for inferior outcome. Survival time of the first transplant was also relevant, and similar findings were reported by a recent single-center study (20).
The findings for pediatric patients are rather limited because of the much smaller cohort, but it was important to establish whether results were comparable with those for adults in forming an evidence base on which a new allocation scheme could be developed. Results were found to be consistent, although only year of graft, donor age, and recipient primary renal disease reached statistical significance. Five-year transplant outcome was as poor for patients aged 11 to 17 years at time of transplant as it was for patients aged 60 years and over, and when censoring for patient death, the risk of graft failure was greatest for pediatric patients and, in particular, those aged 11 to 17 years. An analysis of more than 8000 pediatric transplants reported to the United Network for Organ Sharing Kidney Transplant Registry identified recipient age, ethnicity, sensitization and year of transplant as significant factors influencing long-term outcomes, with graft outcome for teenagers a particular concern (21) as seen in earlier UK data (22).
Recipient age, waiting time, and diabetes had a much stronger influence on patient survival than on transplant survival, whereas other factors had a similar influence on survival of the patient.
In conclusion, this study has identified a variety of factors that influence transplant outcome after DHB donor transplant in the United Kingdom. The findings suggest that the influences of HLA mismatch and CIT are of most relevance in considering a revised organ allocation scheme. The “favorable matching” model for HLA mismatch that was central to the 1998 NKAS is no longer relevant in an era of improved immunosuppression, and only the poorest of four newly defined levels of HLA mismatch have inferior outcome compared with 000 mismatched grafts. CIT has a strong influence on transplant outcome and is prolonged by reallocation of kidneys and long-distance exchanges between transplant centers.
The authors are grateful to all the kidney transplant centers in the United Kingdom that contributed data to the United Kingdom Transplant Registry on which this article is based.
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Keywords:© 2010 Lippincott Williams & Wilkins, Inc.
Outcome; Kidney transplant; Allocation scheme; Multivariate analysis