Deville Kyle A, Seifert Michael E
Division of Pediatric Nephrology, Department of Pediatrics, University of Alabama Heersink School of Medicine, Birmingham, AL, United States.
Front Pediatr. 2023 Jan 20;10:1087841. doi: 10.3389/fped.2022.1087841. eCollection 2022.
Alloimmune events such as the development of donor-specific antibody (dnDSA), T cell-mediated rejection (TCMR), and antibody-mediated rejection (ABMR) are the primary contributors to kidney transplant failure in children. For decades, a creatinine-based estimated glomerular filtration rate (eGFR) has been the non-invasive gold standard biomarker for detecting clinically significant alloimmune events, but it suffers from low sensitivity and specificity, especially in smaller children and older allografts. Many clinically "stable" children (based on creatinine) will have alloimmune events known as "subclinical acute rejection" (based on biopsy) that merely reflect the inadequacy of creatinine-based estimates for alloimmune injury rather than a distinct phenotype from clinical rejection with allograft dysfunction. The poor biomarker performance of creatinine leads to many unnecessary surveillance and for-cause biopsies that could be avoided by integrating non-invasive biomarkers with superior sensitivity and specificity into current clinical paradigms. In this review article, we will present and appraise the current state-of-the-art in monitoring for alloimmune events in pediatric kidney transplantation. We will first discuss the current clinical standards for assessing the presence of alloimmune injury and predicting long-term outcomes. We will review principles of biomarker medicine and the application of comprehensive metrics to assess the performance of a given biomarker against the current gold standard. We will then highlight novel blood- and urine-based biomarkers (with special emphasis on pediatric biomarker studies) that have shown superior diagnostic and prognostic performance to the current clinical standards including creatinine-based eGFR. Finally, we will review some of the barriers to translating this research and implementing emerging biomarkers into common clinical practice, and present a transformative approach to using multiple biomarker platforms at different times to optimize the detection and management of critical alloimmune events in pediatric kidney transplant recipients.
诸如供体特异性抗体（dnDSA）的产生、T细胞介导的排斥反应（TCMR）和抗体介导的排斥反应（ABMR）等同种免疫事件是导致儿童肾移植失败的主要因素。几十年来，基于肌酐的估计肾小球滤过率（eGFR）一直是检测具有临床意义的同种免疫事件的非侵入性金标准生物标志物，但它存在灵敏度和特异性较低的问题，尤其是在年龄较小的儿童和使用时间较长的移植肾中。许多临床上“稳定”的儿童（基于肌酐水平）会出现被称为“亚临床急性排斥反应”（基于活检）的同种免疫事件，这仅仅反映了基于肌酐的评估对于同种免疫损伤的不足，而不是与伴有移植肾功能障碍的临床排斥反应不同的表型。肌酐作为生物标志物的表现不佳导致了许多不必要的监测和针对特定原因的活检，如果将具有更高灵敏度和特异性的非侵入性生物标志物整合到当前临床模式中，这些情况是可以避免的。在这篇综述文章中，我们将介绍和评估目前小儿肾移植中同种免疫事件监测的最新进展。我们将首先讨论评估同种免疫损伤的存在和预测长期结果的当前临床标准。我们将回顾生物标志物医学的原理以及综合指标在评估给定生物标志物相对于当前金标准的性能方面的应用。然后，我们将重点介绍新型的基于血液和尿液的生物标志物（特别强调儿科生物标志物研究），这些生物标志物已显示出比包括基于肌酐的eGFR在内的当前临床标准更优越的诊断和预后性能。最后，我们将回顾将这项研究转化并将新兴生物标志物应用于常规临床实践的一些障碍，并提出一种变革性方法，即在不同时间使用多个生物标志物平台，以优化小儿肾移植受者中关键同种免疫事件的检测和管理。
