Issues in solid-organ transplantation in children: translational research from bench to bedside

Abstract

In this review, we identify important challenges facing physicians responsible for renal and cardiac transplantation in children based on a review of the contemporary medical literature. Regarding pediatric renal transplantation, we discuss the challenge of antibody-mediated rejection, focusing on both acute and chronic antibody-mediated rejection. We review new diagnostic approaches to antibody-mediated rejection, such as panel-reactive antibodies, donor-specific cross-matching, antibody assays, risk assessment and diagnosis of antibody-mediated rejection, the pathology of antibody-mediated rejection, the issue of ABO incompatibility in renal transplantation, new therapies for antibody-mediated rejection, inhibiting of residual antibodies, the suppression or depletion of B-cells, genetic approaches to treating acute antibody-mediated rejection, and identifying future translational research directions in kidney transplantation in children. Regarding pediatric cardiac transplantation, we discuss the mechanisms of cardiac transplant rejection, including the role of endomyocardial biopsy in detecting graft rejection and the role of biomarkers in detecting cardiac graft rejection, including biomarkers of inflammation, cardiomyocyte injury, or stress. We review cardiac allograft vasculopathy. We also address the role of genetic analyses, including genome-wide association studies, gene expression profiling using entities such as AlloMap®, and adenosine triphosphate release as a measure of immune function using the Cylex® ImmuKnow™ cell function assay. Finally, we identify future translational research directions in heart transplantation in children.

Identifying low-grade cellular rejection after heart transplantation in children by using gene expression profiling

“…The longitudinal design of our study allowed us to minimize gene variability within individual patients to some extent by subtracting each individual patient's baseline GEP from pretransplantation blood samples. The identification of novel cardiac biomarkers to better diagnose early cellular rejection in children after heart transplantation is of paramount importance (16). The algorithm for such diagnosis is the kNN analysis.…”

“…In addition, EMB is also subject to interobserver variability (18). Consequently, the identification of cheaper, more reliable, and less-invasive cardiac investigations to improve prediction of the clinical course of children after heart transplantation is of paramount importance (16).…”

An Integrated Transcriptomic Approach to Identify Molecular Markers of Calcineurin Inhibitor Nephrotoxicity in Pediatric Kidney Transplant Recipients

“…Previously, our group reported the molecular profile of CNIT in adult KT recipients [ 28 ]. There is reason to believe that age-related and developmental differences in host immune system responses, drug handling (both pharmacokinetics and pharmacodynamics), primary kidney disease, and presence of concurrent cardiovascular co-morbidities may impact gene expression [ 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ]. For instance, KT recipients less than 5–6 years of age often require higher CNI doses than older patients, which were potentially related to CYP3A maturation and activity [ 37 , 38 , 39 , 40 ].…”

Towards novel theranostic approaches in cardiac transplantation medicine

“…In addition to postoperative care, another area where improvement is needed is in evaluation, monitoring and decision-making regarding the listing of patients, especially children. 23 Current policies on the selection of candidates and the allocation of hearts for transplantation give priority to patients who are at greatest risk if they do not receive a transplant. 24 Further refinement of allocation will be possible, based on solid evidence from large-scale, longitudinal, randomized clinical trials using validated biomarkers.…”