Kidney transplant is the optimal treatment for end-stage kidney disease as it offers significant survival and quality of life advantages over dialysis. While recent advances have significantly improved early graft outcomes, long-term overall graft survival has remained largely unchanged for the last 20 years. Due to the young age at which children receive their first transplant, most children will require multiple transplants during their lifetime. Each subsequent transplant becomes more difficult because of the development of donor specific HLA antibodies (dnDSA), thereby limiting the donor pool and increasing mortality and morbidity due to longer time on dialysis awaiting re-transplantation. Secondary prevention of dnDSA through increased post-transplant immunosuppression in children is constrained by a significant risk for viral and oncologic complications. There are currently no FDA-approved therapies that can meaningfully reduce dnDSA burden or improve long-term allograft outcomes. Therefore, primary prevention strategies aimed at reducing the risk of dnDSA formation would allow for the best possible long-term allograft outcomes without the adverse complications associated with over-immunosuppression. Epitope matching, which provides a more nuanced assessment of immunological compatibility between donor and recipient, offers the potential for improved donor selection. Although epitope matching is promising, it has not yet been readily applied in the clinical setting. Our review will describe current strengths and limitations of epitope matching software, the evidence for and against improved outcomes with epitope matching, discussion of eplet load vs. variable immunogenicity, and conclude with a discussion of the delicate balance of improving matching without disadvantaging certain populations.

<p><strong>BACKGROUND AND OBJECTIVES: </strong>Acute kidney injury (AKI) is nearly universally associated with worse outcomes, especially among children after hematopoietic stem cell transplant (HCT). Our objective was to examine urinary immune biomarkers of AKI after HCT to provide insights into novel mechanisms of kidney injury in this population. Studying patients undergoing allogeneic (HCT) provides a unique opportunity to examine immune markers of AKI because the risk of AKI is high and the immune system newly develops after transplant.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS: </strong>Children (&gt;2 years old) and young adults undergoing their first allogeneic HCT and enrolled in a prospective, observational cohort study at two large children's hospitals had urine collected pre-HCT and monthly for the first 4 months after HCT. Urine samples at each monthly time point were assayed for 8 immune-related biomarkers. AKI was defined as a 1.5-fold increase in the monthly serum creatinine value which was recorded ±1 day from when the research urine sample was obtained, as compared to the pre-HCT baseline. Generalized estimating equation regression analysis evaluated the association between the monthly repeated measures (urinary biomarkers and AKI).</p>

<p><strong>RESULTS: </strong>A total of 176 patients were included from two pediatric centers. Thirty-six subjects from one center were analyzed as a discovery cohort and the remaining 140 subjects from the second center were analyzed as a validation cohort. AKI rates were 18-35% depending on the monthly time point after HCT. Urine CXCL10 and CXCL9 concentrations were significantly higher among children who developed AKI compared with children who did not (p&lt;0.01) in both cohorts. In order to gain a better understanding of the cellular source for these biomarkers in the urine, we also analyzed in vitro expression of CXCL10 and CXCL9 in kidney cell lines after stimulation with interferon-gamma and interferon-alpha. HEK293-epithelial kidney cells demonstrated interferon-induced expression of CXCL10 and CXCL9, suggesting a potential mechanism driving the key finding.</p>

<p><strong>CONCLUSIONS: </strong>CXCL10 and CXCL9 are associated with AKI after HCT and are therefore promising biomarkers to guide improved diagnostic and treatment strategies for AKI in this high-risk population.</p>