The Clinical Impact of Humoral Immunity in Pediatric Renal Transplantation

The development of anti-donor humoral responses after transplantation associates with higher risks for acute rejection and 1-year graft survival in adults, but the influence of humoral immunity on transplant outcomes in children is not well understood. Here, we studied the evolution of humoral immunity in low-risk pediatric patients during the first 2 years after renal transplantation. Using data from 130 pediatric renal transplant patients randomized to steroid-free (SF) or steroid-based (SB) immunosuppression in the NIH-SNSO1 trial, we correlated the presence of serum anti-HLA antibodies to donor HLA antigens (donor-specific antibodies) and serum MHC class 1-related chain A (MICA) antibody with both clinical outcomes and histology identified on protocol biopsies at 0, 6, 12, and 24 months. We detected de novo antibodies after transplant in 24% (23% of SF group and 25% of SB group), most often after the first year. Overall, 22% developed anti-HLA antibodies, of which 6% were donor-specific antibodies, and 6% developed anti-MICA antibody. Presence of these antibodies de novo associated with significantly higher risks for acute rejection (P=0.02), chronic graft injury (P=0.02), and decline in graft function (P=0.02). In summary, antibodies to HLA and MICA antigens appear in approximately 25% of unsensitized pediatric patients, placing them at greater risk for acute and chronic rejection with accelerated loss of graft function. Avoiding steroids does not seem to modify this incidence. Whether serial assessments of these antibodies after transplant could guide individual tailoring of immunosuppression requires additional study.Kidney transplantation is the modality of choice for children with ESRD. Despite an improvement in early outcomes, long-term allograft survival remains restricted^1,2; chronic graft injury is the prime limiting survival factor and largely driven by the development of antidonor humoral responses.^3,4 Anti-human leukocyte antigen (anti-HLA) antibodies (Abs) are a major cause of acute antibody-mediated rejection and also may damage the kidney in a more indolent process, leading to chronic antibody-mediated rejection and eventual allograft loss.⁵ Nevertheless, ongoing allograft rejection in HLA identical transplant recipients and patients without detectable anti-HLA Abs to donor HLA antigens (DSA) supports an additional pathogenic role for graft injury by non-HLA antigens, such as protein kinase-ζ, and MHC class 1-related chain A (MICA).^6–9In adult renal transplantation, Terasaki¹⁰ and Terasaki and Cai¹¹ have shown that preformed and de novo post-transplant production of DSAs correlates with a higher risk of acute rejection (AR) and reduced 1-year graft survival. The impact of the humoral response has not been well studied in the pediatric transplantation. We performed quantitative analysis of post-transplant de novo Abs to HLA and MICA in children undergoing kidney transplants and questioned differences in Ab profiles with steroid avoidance.^12–14 To this end, we compared the measured humoral immune responses of pediatric kidney transplant patients in a randomized, multicenter, open-labeled study for a steroid-based (SB) or steroid-free (SF) immunosuppression protocol (SNSO1).^15,16 We conducted serial monitoring of quantitative titers of circulating for MHC classes I and II and Abs to MICA in patients with stable graft function, acute graft rejection, and chronic graft injury as evaluated by matched protocol or indicated renal allograft biopsies (Figure 1). We intended to find if there were differences in the detection of these Abs with steroid avoidance, the average time for de novo Ab detection post-transplantation, and the correlation of Ab levels with graft injury and function. Correlation of the negative impact of the peripheral and intragraft humoral responses and their specificities with adverse graft outcomes in children could develop a novel means of monitoring and titrating immunosuppression in pediatric renal transplantation.Open in a separate windowFigure 1.Study outline. This study used 440 serum samples and 440 matched blinded biopsy scores for CADI, CNIT, Banff rejection grading, and C4d stains on 440 matched protocol biopsies from the SNSO1 multicenter randomized trial of SF and SB immunosuppression in pediatric renal transplantation.^15,16 Samples and biopsies were assayed at 0 (pretransplant), 6, 12, and 24 months post-transplantation. Of 130 patients in the trial, 124 patients had at least three of four sera samples collected and were included in the analysis.