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疾病(CKD)中很常见，对发病率和死亡率有不利影响。在患有晚期CKD的男性中，三分之二的人血清睾酮(TT)水平降低，可能是导致消瘦的原因之一。由于在相对安全的生理性替代剂量下，TT缺乏者的肌肉质量增加，我们推测生理性替代能有效地预防和治疗CKD患者肌肉质量和功能的丧失，提高生活质量，并可能减少一些心血管疾病(CVD)的危险因素。TT在尿毒症肌肉中影响其反应的机制尚不清楚；我们假设骨骼肌受益是通过雄激素受体上调、改变IGF-1和肌肉生长抑素之间的平衡、改变泛素-蛋白酶体和钙蛋白酶蛋白分解系统以及抑制炎症细胞因子来实现的。我们的具体目标是：1.确定生理性TT替代是否能有效地改善低血清TT水平和晚期CKD男性的肌肉质量、力量和生活质量。2.探讨TT刺激慢性肾脏病大鼠肌肉肥大的机制。3.确定TT是否能改善CKD的某些心血管危险因素。研究对象为55-75岁的男性，患有晚期、稳定或进展缓慢的CKD(GFR 15-29ml/min/1.73m2)和血清TT水平低(&lt；300 ng/ml)。受试者(18人/组)将接受生理替代剂量的安慰剂或TT治疗，并进行为期16周的研究，监测任何副作用。TT水平正常、久坐不动的健康男性将作为正常基线对照，不接受治疗。治疗前后分别测量以下指标：DEXA测定瘦体重和脂肪质量，MRI测定大腿肌肉体积和组成，肌肉力量和功能，生活质量，血脂，炎症标志物和胰岛素敏感性。在治疗前和治疗后将进行股外侧肌活组织检查，检查肌纤维类型、横截面积、肌核和卫星细胞数量、肌肉质量的关键正负调节因子(IGF-1、肌肉生长抑素及其受体、雄激素受体、选定的炎性细胞因子)以及泛素-蛋白酶体和钙蛋白酶蛋白分解系统的关键组成部分的mRNA和蛋白表达。本研究旨在探讨生理性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，以及是否还能改善生活质量，减少某些CVD危险因素。此外，这项研究应该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替代策略将为更广泛的TT治疗研究奠定基础。这可以与运动或另一种合成代谢药物相结合，并扩展到女性和患有CKD的年轻受试者。肌肉萎缩在晚期慢性肾脏疾病(CKD)中很常见，对发病率和死亡率有不利影响。对于肺病和心脏病等其他疾病也是如此。在患有晚期CKD的男性中，2/3的人血清睾酮水平降低，这可能是导致消瘦的原因之一。我们计划测试将低睾酮水平正常化是否将有效地预防和治疗CKD患者的肌肉质量和功能丧失，并提高生活质量。如果对这些患者有效，那么这就有可能改善对患者的管理，不仅是CKD患者，还有那些患有其他肌肉萎缩疾病的患者。

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.