Testosterone Replacement Therapy in Advanced Chronic Kidney Disease

描述（由申请人提供）：肌肉萎缩在晚期慢性肾脏病（CKD）中很常见，对发病率和死亡率有不利影响。在2/3的晚期CKD男性中，血清睾酮（TT）水平降低，可能导致消瘦。由于TT在相对安全的生理替代剂量下增加了其他正常TT缺乏受试者的肌肉质量，我们假设生理TT替代将有效预防和治疗CKD患者的肌肉质量和功能丧失，将改善生活质量，并可能减少一些心血管疾病（CVD）风险因素。TT影响尿毒症肌肉反应的机制知之甚少;我们推测骨骼肌受益是通过雄激素受体上调、IGF-1和肌生长抑制素之间平衡的变化、泛素-蛋白酶体和钙蛋白酶蛋白水解系统的变化以及炎症细胞因子的抑制来实现的。我们的具体目标是：1.确定生理性TT替代是否能有效改善低血清TT水平和晚期CKD男性的肌肉质量、力量和生活质量。2.阐明TT刺激CKD患者肌肉肥大的机制。3.确定TT是否可以改善CKD患者的某些CVD危险因素。将研究55-75岁的男性，其患有晚期稳定或缓慢进展的CKD（GFR 15-29 ml/min/ 1.73m2）和低血清TT水平（<300 ng/ml）。受试者（18/组）将接受生理替代剂量的安慰剂或TT治疗，并在16周内进行研究，同时监测任何副作用。TT水平正常的健康久坐男性将作为正常基线对照，不接受治疗。治疗前后将测量以下指标：通过DEXA测量瘦体重和脂肪量，通过MRI测量大腿肌肉体积和组成，肌肉力量和功能生活质量，脂质，炎症标志物和胰岛素敏感性。将在基线和治疗后进行股外侧肌活检，并检查肌纤维类型、横截面积、肌核和卫星细胞数量、肌肉质量关键阳性和阴性调节因子（IGF-1、肌生长抑制素及其受体、雄激素受体、选定的炎性细胞因子）的mRNA和蛋白表达以及泛素-蛋白酶体和钙蛋白酶蛋白水解系统的关键组分。这项研究测试了生理性TT替代疗法是否能有效预防和治疗CKD患者的肌肉质量和功能丧失，以及它是否还能改善生活质量并减少一些CVD风险因素。此外，这项研究将为尿毒症肌肉萎缩的分子机制提供新的见解。如果如预期的那样有效，这种TT替代策略将成为TT治疗更广泛研究的基础。这可以与运动或其他合成代谢药物相结合，并扩展到包括女性和年轻的CKD受试者。肌肉萎缩在晚期慢性肾病（CKD）中很常见，并对发病率和死亡率产生不利影响。这也适用于其他疾病，如肺和心脏病。在2/3的晚期CKD男性中，血清睾酮水平降低，可能导致消瘦。我们计划测试使低睾酮水平正常化是否能有效预防和治疗CKD患者的肌肉质量和功能丧失，并改善生活质量。如果在这些患者中有效，那么这不仅有可能改善CKD患者的管理，而且还有可能改善其他肌肉萎缩性疾病患者的管理。

DESCRIPTION (provided by applicant): Muscle wasting is common in advanced chronic kidney disease (CKD) and adversely affects morbidity and mortality. In 2/3 of males with advanced CKD, serum testosterone (TT) levels are reduced and likely contribute to the wasting. As TT in relatively safe physiologic replacement doses, increases muscle mass in otherwise normal TT deficient subjects, we hypothesize that physiologic TT replacement will be effective in preventing and treating the loss of muscle mass and function in CKD patients, will improve quality of life and may reduce some cardiovascular disease (CVD) risk factors. The mechanisms whereby TT affect its response in uremic muscle is poorly understood; we postulate that skeletal muscle benefit occurs through androgen receptor upregulation, changes in the balance between IGF-1 and myostatin, changes in the ubiquitin-proteasome and calpain proteolytic systems, and suppression of inflammatory cytokines. Our specific aims are: 1. To determine whether physiologic TT replacement is effective in improving muscle mass, strength and quality of life in males with low serum TT levels and advanced CKD. 2. To elucidate the mechanisms whereby TT stimulates muscle hypertrophy in CKD. 3. To determine whether TT can improve some CVD risk factors in CKD. Males 55-75 years of age with advanced stable or slowly progressive CKD (GFR 15-29 ml/min/ 1.73m2) and low serum TT levels (<300 ng/ml) will be studied. Subjects (18/group) will be a treated with placebo or TT in physiologic replacement doses and studied over 16 weeks with monitoring for any side effects. Healthy sedentary men, with normal TT levels, will serve as normal baseline controls and will not be treated. The following will be measured before and after treatment; Lean body and fat mass by DEXA, thigh muscle volume and composition by MRI, muscle strength and function quality of life, lipids, inflammatory markers and insulin sensitivity. Vastus lateralis muscle biopsies will be taken at baseline and post-treatment and examined for fiber type, cross-sectional area, myonuclei and satellite cell number, mRNA and protein expression of key positive and negative regulators of muscle mass (IGF-1, myostatin and their receptors, androgen receptors, selected inflammatory cytokines) and key components of the ubiquitin-proteasome and calpain proteolytic systems. This study tests whether physiologic TT replacement therapy is effective in preventing and treating loss of muscle mass and function in CKD and whether it also improves quality of life and reduces some CVD risk factors. Furthermore the study should provide new insight into the molecular mechanisms of muscle wasting in uremia. If effective as anticipated, this TT replacement strategy will form the basis for more extensive studies of TT therapy. This could be combined with exercise or another anabolic agent and extended to include females and younger subjects with CKD. Muscle wasting is common in advanced chronic kidney disease (CKD) and adversely affects morbidity and mortality. This is true also for other disease such as lung and heart disease. In 2/3 of males with advanced CKD serum testosterone levels are reduced, and likely contributes to the wasting. We plan to test whether normalizing the low testosterone levels will be effective in preventing and treating the loss of muscle mass and function in CKD patients and improving quality of life. If effective in these patients, then this holds the potential of improving management of patients, not only with CKD, but also those with other muscle wasting illnesses.