In Vivo Assessment of Calcineurin Inhibitor Toxicity in Children

儿童钙调神经磷酸酶抑制剂毒性的体内评估

• 批准号: 8198336
• 负责人: UWE CHRISTIANS
• 金额: $ 37.99万
• 依托单位: UNIVERSITY OF COLORADO DENVER
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-07-20 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8198336
• 关键词: Allografting; Biological Markers; Biopsy; Blood Vessels; Bone Marrow Transplantation; Calcineurin inhibitor; Child; Childhood; Chronic; Clinic; Clinical; Clinical Markers; Clinical Trials; Complex; Creatinine; Data Set; Development; Diagnostic; Disease; Dose; Early Diagnosis; Exposure to; Functional disorder; Homeostasis; Immune; Immunosuppressive Agents; Individual; Inflammation; Inflammatory; Injury; Kidney; Kidney Transplantation; Laboratories; Learning; Longitudinal Studies; Maintenance; Mediating; Metabolism; Methods; Modification; Molecular; Monitor; Nephrotic Syndrome; Nephrotoxic; Organ; Outcome; Oxidative Stress; Patients; Pattern; Perfusion; Pharmaceutical Preparations; Plasma; Play; Population; Population Study; Qualifying; Regimen; Renal function; Research Personnel; Sensitivity and Specificity; Serum; Syndrome; Tacrolimus; Therapeutic immunosuppression; Toxic effect; Uremia; Urine; Vascular Endothelial Cell; Work; base; candidate marker; clinical practice; clinically relevant; improved; in vivo; injury and repair; insight; kidney cell; kidney vascular structure; mitochondrial dysfunction; molecular marker; nephrotoxicity; novel; post gamma-globulins; protein metabolite; tool; urinary; vascular endothelial dysfunction

DESCRIPTION (provided by applicant): Chronic calcineurin inhibitors (CNIs) are toxic to the kidney and cause vascular endothelial dysfunction. Maintenance of kidney function and avoidance of long-term vascular complications are a major challenge especially in pediatric patients treated with CNIs. The key to reducing the damage caused by immunosuppressant toxicity is early detection. Once detected, the damage caused by immunosuppressant toxicity can be reduced by modification/ individualization of the immunosuppressive drug regimen. However, both the diagnostic tools for early detection and the monitoring tools to guide such an individualization of immunosuppressive drug regimens are currently unavailable and clinical practice still relies on relatively late and insensitive markers such as creatinine in serum and on invasive methods such as percutaneous kidney biopsies. We hypothesize that - the negative effects of CNIs on kidney cell and vascular endothelial cell metabolism in pediatric patients with nephrotic syndrome and after kidney transplantation are reflected by changes in plasma and urine metabolite patterns, and - plasma and urine metabolite markers have better sensitivity and specificity compared to markers currently established in the clinic such as creatinine in serum. We will use a unique comprehensive strategy based on metabolite and protein molecular markers established in the investigators' laboratories to assess the toxicodynamic mechanisms of the CNI tacrolimus in pediatric patients. This proposal will be based on two clinical trials: one based on pediatric patients with nephrotic syndrome that require treatment with CNIs (Aim 1, "learning data set") and the other based on pediatric patients after kidney transplantation who receive an immunosuppressive drug regimen based on the CNI tacrolimus (Aim 2, "proof-of-concept" qualification study in a more complex study population). Among others, these studies will answer the following questions: - Are plasma and urine metabolite and protein pattern changes in pediatric patients with nephrotic syndrome sensitive enough to reflect the negative effects of CNIs on the metabolism and function of the proximal tubule and vascular endothelial cells already after the first dose? - Do changes of urinary metabolite and protein patterns reflect CNI-induced mitochondrial dysfunction? - Can children who are more sensitive to CNI nephrotoxicity and vascular endothelial dysfunction already be identified within the first week of exposure and before any noticeable changes in serum creatinine occur? - Will plasma and urine metabolite and protein pattern changes also be a valid diagnostic tool in the more complex kidney transplant children? - Will these metabolite and protein pattern changes be sufficiently specific to distinguish immunosuppressant toxicity from immune and inflammatory kidney injury? - Will plasma and urine metabolite and protein pattern changes be more sensitive and thus predict the increase of less sensitive markers such as creatinine in serum? If successful, our results will not only provide mechanistic insights into CNI renal and vascular toxicity in vivo but will also provide proof-of-concept for the development of candidate markers into clinical diagnostic tools. Utilization of these markers may allow for (A) predicting tolerability of an immunosuppressive drug regimen and individualization of immunosuppressive therapy, (B) monitoring allograft function and CNI toxicity, and (C) improving clinical long-term outcomes. PUBLIC HEALTH RELEVANCE: Calcineurin inhibitors are highly effective immunosuppressants used in children with immune-mediated diseases and after organ and bone marrow transplantation. However, the use of calcineurin inhibitors is limited by their toxic effects on the kidney and the induction of vascular endothelial dysfunction. Current clinical diagnostic markers are known to be insensitive and to only rise after significant damage has already occurred. The proposed study seeks to assess the clinically relevant mechanisms of calcineurin inhibitor toxicity to develop plasma and urine metabolite biomarkers for the early detection of negative effects on kidney and vascular endothelial cells in pediatric patients with the nephrotic syndrome and in pediatric patients who undergo kidney transplantation. We will also determine whether these metabolite biomarkers have better sensitivity and specificity compared to markers in current clinical use such as serum creatinine and/or cystatin C levels.

描述（由申请方提供）：慢性钙调神经磷酸酶抑制剂（CNI）对肾脏有毒性，并导致血管内皮功能障碍。维持肾功能和避免长期血管并发症是一项重大挑战，尤其是在接受CNI治疗的儿科患者中。减少免疫抑制剂毒性造成的损害的关键是早期发现。一旦检测到，免疫抑制剂毒性引起的损伤可以通过免疫抑制药物方案的修改/个体化来减少。然而，用于早期检测的诊断工具和用于指导免疫抑制药物方案的这种个体化的监测工具目前都不可用，并且临床实践仍然依赖于相对较晚且不敏感的标记物（例如血清中的肌酐）和侵入性方法（例如经皮肾活检）。我们假设：-CNIs对肾病综合征患儿和肾移植后肾细胞和血管内皮细胞代谢的负面影响反映在血浆和尿液代谢产物模式的变化上，-血浆和尿液代谢产物标记物与目前临床上建立的标记物（如血清肌酐）相比具有更好的灵敏度和特异性。我们将使用基于研究者实验室建立的代谢物和蛋白质分子标记物的独特综合策略来评估CNI他克莫司在儿科患者中的毒代动力学机制。该提案将基于两项临床试验：一项基于需要CNI治疗的肾病综合征儿科患者（目标1，“学习数据集”），另一项基于肾移植后接受基于CNI的免疫抑制药物方案的儿科患者他克莫司（目标2，在更复杂的研究人群中进行的“概念验证”资格研究）。除其他外，这些研究将回答以下问题：-肾病综合征儿科患者的血浆和尿液代谢物和蛋白质模式变化是否足够敏感，以反映CNI对第一次给药后近端小管和血管内皮细胞代谢和功能的负面影响？ - 尿代谢产物和蛋白质模式的变化是否反映CNI诱导的线粒体功能障碍？ - 在接触CNI的第一周内，血清肌酐发生任何明显变化之前，是否就可以识别出对CNI肾毒性和血管内皮功能障碍更敏感的儿童？ - 血浆和尿液代谢物和蛋白质模式的变化是否也是更复杂的肾移植儿童的有效诊断工具？ - 这些代谢物和蛋白质模式的变化是否足够特异，以区分免疫抑制剂毒性和免疫性和炎症性肾损伤？ - 血浆和尿液代谢产物和蛋白质模式的变化是否更敏感，从而预测敏感性较低的标志物（如血清肌酐）的增加？如果成功，我们的研究结果将不仅提供CNI肾和血管毒性在体内的机制见解，但也将提供候选标记物的发展成为临床诊断工具的概念验证。利用这些标志物可以允许（A）预测免疫抑制药物方案的耐受性和免疫抑制治疗的个体化，（B）监测同种异体移植物功能和CNI毒性，和（C）改善临床长期结果。 公共卫生相关性：钙调磷酸酶抑制剂是一种高效的免疫抑制剂，用于儿童免疫介导的疾病和器官和骨髓移植后。然而，钙调磷酸酶抑制剂的使用受到其对肾脏的毒性作用和诱导血管内皮功能障碍的限制。已知目前的临床诊断标记物是不敏感的，并且仅在已经发生显著损伤后才升高。拟议的研究旨在评估钙调磷酸酶抑制剂毒性的临床相关机制，以开发血浆和尿液代谢物生物标志物，用于早期检测肾病综合征患儿和接受肾移植的患儿对肾脏和血管内皮细胞的负面影响。我们还将确定这些代谢物生物标志物与目前临床使用的标志物（如血清肌酐和/或胱抑素C水平）相比是否具有更好的灵敏度和特异性。