Abstract:
Chronic kidney disease (CKD) is associated with significant reductions in lean body mass and in the mass of various tissues, including skeletal muscle, which causes fatigue and contributes to high mortality rates. In CKD, the cellular protein turnover is imbalanced, with protein degradation outweighing protein synthesis, leading to a loss of protein and cell mass, which impairs tissue function. As CKD itself, skeletal muscle wasting, or sarcopenia, can have various origins and causes, and both CKD and sarcopenia share common risk factors, such as diabetes, obesity, and age. While these pathologies together with reduced physical performance and malnutrition contribute to muscle loss, they cannot explain all features of CKD-associated sarcopenia. Metabolic acidosis, systemic inflammation, insulin resistance and the accumulation of uremic toxins have been identified as additional factors that occur in CKD and that can contribute to sarcopenia. Here, we discuss the elevation of systemic phosphate levels, also called hyperphosphatemia, and the imbalance in the endocrine regulators of phosphate metabolism as another CKD-associated pathology that can directly and indirectly harm skeletal muscle tissue. To identify causes, affected cell types, and the mechanisms of sarcopenia and thereby novel targets for therapeutic interventions, it is important to first characterize the precise pathologic changes on molecular, cellular, and histologic levels, and to do so in CKD patients as well as in animal models of CKD, which we describe here in detail. We also discuss the currently known pathomechanisms and therapeutic approaches of CKD-associated sarcopenia, as well as the effects of hyperphosphatemia and the novel drug targets it could provide to protect skeletal muscle in CKD.
摘要:
慢性肾脏疾病(CKD)与瘦体重和各种组织质量的显着减少有关,包括骨骼肌,导致疲劳并导致高死亡率。在CKD,细胞蛋白质周转不平衡,蛋白质降解超过蛋白质合成,导致蛋白质和细胞质量的损失,损害组织功能。作为CKD本身,骨骼肌萎缩,或者肌肉减少症,可以有各种起源和原因,CKD和肌少症都有共同的危险因素,比如糖尿病,肥胖,和年龄。虽然这些疾病与身体机能下降和营养不良一起导致肌肉损失,他们不能解释CKD相关肌少症的所有特征.代谢性酸中毒,全身性炎症,胰岛素抵抗和尿毒症毒素的积累已被确定为CKD中发生的其他因素,并且可能导致肌肉减少症。这里,我们讨论全身磷酸盐水平的升高,也称为高磷酸盐血症,以及磷酸盐代谢的内分泌调节因子的不平衡是另一种CKD相关病理,可以直接和间接损害骨骼肌组织。为了找出原因,受影响的细胞类型,以及肌肉减少症的机制,从而成为治疗性干预的新靶点,重要的是首先表征分子的精确病理变化,细胞,和组织学水平,在CKD患者以及CKD动物模型中这样做,我们在这里详细描述。我们还讨论了目前已知的CKD相关肌少症的病理机制和治疗方法。以及高磷血症的作用和它可以提供的保护CKD骨骼肌的新药物靶点。