The Risk of Failure With HLA Mismatch and Recipient Age in First Pediatric (<18 years) Kidney Transplants

Abstract

Background: Even in the modern era of kidney transplantation with improved surgical techniques, immunosuppression, and clinical care, HLA matching has been shown to be important in allograft survival in adults who receive an organ from either a deceased or living donor. We now explore the impact of genetic matching in pediatric first-kidney transplants.

Methods: Using the United Network for Organ Sharing data, we identified 18 602 first pediatric (<18 years) kidney transplants between October 1, 1987, and December 31, 2016. Recipients were classified by number of HLA mismatches and donor origin. Cox proportional hazard analyses, adjusting for recipient and donor transplant covariates, were performed to study the impact of HLA on kidney allograft survival.

Results: For the fully adjusted Cox model there was a 30% increase in the hazard of allograft failure for 1 HLA mismatch, when compared with 0 mismatched recipients, and a 92% increase in risk for 6 mismatches. Although pediatric allografts from living donors survive as long or longer than those from deceased persons, they have a higher hazard of failure as a function of HLA mismatch. Kidney allografts from deceased donors HLA mismatched 0 to 3 were found to survive as long as organs from living donors HLA mismatched 4 to 6. In the full Cox model, there was a strong, linear effect on the hazard of allograft failure with quartile of age such that the youngest patients at age of transplant had the longest surviving grafts.

Conclusions: HLA plays an important role in the survival of first pediatric kidney transplants. The better the match, and the earlier the transplant is performed in the child's life, the lower is the risk that the organ will fail.

FIGURE 1

KM curves were fitted to the unadjusted survival data for 18 602 pediatric (<18 years) first kidney transplants when stratified by HLA mismatch. Median survival times and their 95% CIs were, for 0 mismatches, 24.8 (19.9, NA); 1 mismatch, 19.6 (18.3, NA); 2 mismatches, 18.3 (16.3-21.0); 3 mismatches, 14.7 (13.9-15.4); 4 mismatches, 12.5 (11.6-13.7); 5 mismatches, 12.5 (11.6-13.2); and for 6 mismatches, 12.2 (11.1, 13.4). The log rank statistic for equality over strata was 200.8 with 6 df (P < 0.0001).

FIGURE 2

A bar graph emphasizes the differences in the HRs of Cox multivariate, fully adjusted models, with HLA mismatch as the primary explanatory variable, for deceased (blue bars) and living (red bars) donors in 18 602 first kidney pediatric (<18 years) transplants (Table 2). For each mismatch category, the HR for the living donor data was larger than for the deceased donor stratum. For mismatches 4 and 5, the 95% CIs exclude one another.

FIGURE 3

The percent HLA mismatch for deceased as compared with living donors is presented. The predominance of “good” mismatches, 0 to 3, in the living donor stratum was the result of these being primarily living-related organs (Table 2). Despite the large differences in mismatch categories 4 to 6, in which the deceased donors have a much higher proportion of mismatches, the respective HRs for the living donors in these categories is always larger in the fully adjusted Cox proportional hazard regression (Table 2).

FIGURE 4

Weighted linear regressions were performed for the fully adjusted Cox multivariate regression HRs for the deceased and living donors for all pediatric transplants in the UNOS STAR data set, 1987-–2016 (Table 2). The relative slopes of the lines can be used to graphically compare the strength of the HLA mismatches in the failure of pediatric transplants. The slope of the living donor line was more than 4 times larger, 0.32 (0.14-0.50; P = 0.0055) compared with 0.07 (0.02-0.13; P = 0.0208) for the deceased stratum.

FIGURE 5

An unadjusted KM analysis was performed for 18 602 pediatric transplants from the UNOS STAR data files from 1987 to 2016 when stratified by quartile of age. Survival was significantly related to quartile with Q1 > Q2 > Q3 > Q4. The log-rank test statistic for equality over strata is 382.0 with 3 df (P < 0.0001).

FIGURE 6

A, Weighted linear regression (black line) performed with the median survival times from KM curves (red squares) for all pediatric transplants when stratified by quartile of age at transplant. The line has a slope of −2.69 (−4.33 to −1.06), P = 0.0193. Therefore, kidney survival time decreases at a rate of 2.7 years per quartile of increasing age. B, Weighted linear regression (green line) of the fully adjusted HRs from a Cox proportional hazards analysis (blue squares) by quartile of recipient age (Table 5). The slope of the line is 0.26 (0.21-0.31), P = 0.0020. The hazard of pediatric kidney failure increases by 0.26 hazard unit per quartile of recipient age. Our hypothesis is that this reflects the loss of immunological malleability as the children become older.