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: 8660315
• 负责人: UWE CHRISTIANS
• 金额: $ 36.92万
• 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/8660315
• 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; endothelial dysfunction; 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.

描述（由申请人提供）：慢性钙调神经磷酸酶抑制剂（CNI）对肾脏有毒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，尤其是对于接受 CNI 治疗的儿科患者。减少免疫抑制剂毒性损害的关键是早期发现。一旦检测到，免疫抑制剂毒性造成的损害可以通过免疫抑制药物治疗方案的修改/个体化来减少。然而，用于早期检测的诊断工具和指导免疫抑制药物治疗方案个体化的监测工具目前尚不可用，临床实践仍然依赖于相对较晚且不敏感的标志物（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 - CNI 对肾病综合征儿科患者和肾移植后肾细胞和血管内皮细胞代谢的负面影响通过血浆和尿液代谢模式的变化反映出来，并且 - 血浆和尿液代谢标志物与目前临床上建立的标志物（如血清肌酐）相比具有更好的敏感性和特异性。我们将使用基于研究人员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 他克莫司的免疫抑制药物治疗方案的儿科患者（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血浆和尿液代谢物和蛋白质模式的变化是否足够敏感，足以反映首次给药后 CNI 对近端肾小管和血管内皮细胞的代谢和功能的负面影响？ - 尿液代谢物和蛋白质模式的变化是否反映了 CNI 诱导的线粒体功能障碍？ - 在接触的第一周内以及血清肌酐发生任何明显变化之前，是否可以识别出对 CNI 肾毒性和血管内皮功能障碍更敏感的儿童？ - 血浆和尿液代谢物以及蛋白质模式的变化是否也可以成为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具有足够的特异性来区分免疫抑制剂毒性与免疫和炎症性肾损伤？ - 血浆和尿液代谢物和蛋白质模式的变化是否会更敏感，从而预测血清中肌酐等不太敏感的标志物的增加？如果成功，我们的结果不仅将为体内 CNI 肾脏和血管毒性提供机制见解，还将为临床诊断工具候选标记物的开发提供概念验证。利用这些标志物可以实现 (A) 预测免疫抑制药物治疗方案的耐受性和个体化免疫抑制治疗，(B) 监测同种异体移植物功能和 CNI 毒性，以及 (C) 改善临床长期结果。