Background: Antibodies to mismatched donor HLA antigens (DSA) have been associated with poor long-term outcomes in adult kidney recipients. We recently demonstrated a high prevalence of early subclinical inflammation, primarily vascular injury, in pediatric kidney recipients that was associated with rejection and graft failure. Whether this subclinical vascular injury increases the development of subsequent DSA to influence long-term pediatric outcomes is unknown.

Objective: We tested the hypothesis that children with subclinical vascular injury subsequently develop de novo DSA that are associated with poor transplant outcomes. We also examined determinants of de novo DSA in pediatric kidney recipients using molecular HLA typing methods.

Design/Methods: We reviewed 120 consecutive pediatric kidney transplants at our center from August 2008 to December 2014. Median (IQR) clinical follow-up was 35 (21-62) months. The primary outcome was a composite of acute rejection or graft loss by 5 years. The primary exposure was de novo class I or II DSA, which was also modeled as a secondary outcome. Secondary exposures included demographics, surveillance Banff scores, mismatches at HLA loci, and early non-adherence. Outcomes were analyzed with Fisher's exact test, student's t test, and Kaplan-Meier methods.

Results: We analyzed 95/120 (79%) recipients that had surveillance biopsies at 3 and/or 6 months with donor-recipient HLA molecular typing data. The composite outcome occurred in 28% of subjects. DSA were measured in 80/95 (84%) subjects, and 33/80 (41%) had de novo class I and/or II DSA. Critical risk factors for DSA development were the number of HLA-A and -DQ mismatches, black race, deceased donors, and early non-adherence (all P<0.05), with a trend for subclinical vascular injury (g+ptc+v>0; P=0.05). DSA development was associated with a higher incidence of the composite outcome [64% vs. 13%, P<0.001; adjusted HR 7.7 (2.6, 22.6)], as was the number of HLA-C mismatches (1.7 ± 0.5 vs. 1.3 ± 0.6, P<0.01).

Conclusions: DSA were frequently detected in pediatric kidney recipients and were associated with a nearly 8-fold increase in acute rejection and graft failure by 5 years. HLA-C mismatches, routinely ignored in donor allocation, were also associated with poor long-term outcomes. These data highlight the need for improved ascertainment of immunological risk to reduce graft failure in pediatric recipients.

CITATION INFORMATION: Seifert M, Yanik M, Hauptfeld-Dolejsek V, Mannon R. HLA-C Mismatching and Humoral Alloimmune Responses in Pediatric Kidney Recipients with Subclinical Vascular Injury. Am J Transplant. 2017;17 (suppl 3).

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