Preserving physical function in patients with kidney disease

项目摘要/摘要 骨骼肌功能障碍导致慢性阻塞性肺疾病患者的虚弱、残疾和死亡 肾病(CKD)。这项建议试图确定CKD患者的肌肉功能障碍是否可以 通过透析(肾功能衰竭时的血液滤过)缓解。我们最近发现，患者 随着慢性肾脏病的症状逐渐恶化，肌肉纤维化的严重性更大 纤维化与肌肉力量和身体功能的降低有关。在患有 重度CKD，纤维化改变广泛。然而，尽管表面上看起来很先进 在这种纤维化转化中，开始透析的患者在 纤维化症。这表明，在患有严重慢性肾脏病和肌肉纤维化的患者中， 透析可改善患者的身体功能。因此，这一建议考验着高度创新的 假设重症慢性肾脏病患者开始透析可逆转肌肉纤维化和 改善身体机能。我们将使用翻译方法来实现这一目标 将临床相关的功能终端与包括肌肉在内的最先进方法相结合 组织力学，定量磁共振成像(QMR)，转录和 人类骨骼肌的蛋白质组学研究。拟议的人体研究将(1)定义 透析开始通过检测肌肉胶原含量的变化对肌肉纤维化的影响， 胶原蛋白交联、组织被动僵硬和QMR测量；(2)确定 透析开始后纤维化的消退通过以下哪一种方式转化为功能改善 测试来自目标1的结构参数的变化与 肌肉力量、耐力和下肢功能；以及(3)识别分子和 转录组和蛋白质组学分析对纤维化消退的细胞预测因子 骨骼肌。如果我们的假设是正确的：(1)肌肉纤维化可能是 医生开始透析治疗；以及(2)这项提议将确定一种干预措施，以缓解 慢性肾脏病患者的肌肉功能障碍。

Project Summary/Abstract Skeletal muscle dysfunction contributes to frailty, disability, and mortality in patients with chronic kidney disease (CKD). This proposal seeks to determine if muscle dysfunction in CKD can be alleviated by dialysis (blood filtration for kidney failure). We recently discovered that patients with CKD experience progressively worsening muscle fibrosis, and that greater severity of fibrosis is associated with reduced muscle strength and physical function. In patients with severe CKD, fibrotic changes are extensive. However, despite the seemingly advanced nature of this fibrotic transformation, patients starting dialysis experienced marked improvement in fibrosis. This suggests that, in patients with severe CKD and muscle fibrosis, the initiation of dialysis could improve physical function. Therefore, this proposal tests the highly innovative hypothesis that the initiation of dialysis in patients with severe CKD reverses muscle fibrosis and improves physical function. We will accomplish this objective using a translational approach that integrates clinically relevant functional endpoints with state-of-the-art methods including muscle tissue mechanics, quantitative magnetic resonance imaging (qMR), and transcriptomic and proteomic studies of human skeletal muscle. The proposed human studies will (1) define the effect of dialysis initiation on muscle fibrosis by examining changes in muscle collagen content, collagen cross-linking, tissue passive stiffness, and qMR measures; (2) determine the extent to which regression of fibrosis after dialysis initiation translates into functional improvements by testing the association of alterations in the structural parameters from Aim 1 with changes in muscle strength, endurance, and lower extremity performance; and (3) identify molecular and cellular predictors of the resolution of fibrosis using transcriptomic and proteomic analyses of skeletal muscle. If our hypotheses are correct: (1) muscle fibrosis could be an indicator for physicians to start dialysis therapy; and (2) this proposal will identify an intervention to alleviate muscle dysfunction in patients with CKD.