IMPACT OF RENAL DISEASE ON NITROGEN HOMEOSTASIS

营养不良在肾病患者中很常见，似乎是 其中一个潜在的可逆风险因素导致了 发病率和死亡率。代谢性酸中毒(MA)在透析中很常见 患者，研究表明MA增加了氮的需求和 通过诱导调节基因的表达而导致消耗 肌肉蛋白分解和氨基酸(AA)氧化。更重要的是， 碳酸氢钠纠正MA可降低蛋白质分解代谢和 AA氧化，改善氮素平衡(BN)。第二个原因是 消瘦是肾病患者的尿蛋白丢失。 综合症。不幸的是，对新陈代谢几乎一无所知。 对尿蛋白丢失或蛋白尿是否增加的反应 氮素需求量。因此，我们提出以下两个假设： 1)代谢性酸中毒导致血液透析患者营养不良 通过增加氮需要量和刺激氨基酸的分解代谢 酸和体内蛋白质储存；以及2)蛋白尿导致内源性 蛋白质分解代谢，除非膳食蛋白质摄入量充足且 适应性代谢反应被激活。要确定MA是否 通过刺激蛋白质分解和氨基酸来增加氮素需求 氧化，10名血液透析患者将摄入推荐摄入量 膳食蛋白质(1.1克蛋白质/公斤/天)，而它们是酸性和 使用高碳酸氢盐透析液纠正MA(特定 目标1)。在这两种情况下，我们将测量全身蛋白质的周转率 (WBPT)，并进行臀肌活组织检查以测量活动和 负责蛋白质和氨基酸降解的酶的mRNA水平 骨骼肌(特定目标2)。为了解决第二个假设，我们 将比较10名肾病患者和10名对照组的BE和WBPT 提供0.8或1.6克蛋白质/公斤/天的日粮(具体目标3)。最后，为了 确定对尿蛋白丢失的赔偿是否涉及 AA氧化和蛋白分解的减少，我们将测量其活性 调节蛋白质和氨基酸的酶的状态和基因表达 肌肉降解(具体目标4)。我们对我们有限的理解 可能导致这一人群消瘦的因素(S)强调 需要进行详细的人体研究，以确定这种机制(S) 负责任，在全身和细胞层面都是如此。如果我们的假设 都是正确的，拟议的研究将为 对这些患者的未来治疗建议。

Malnutrition is common in patients with renal disease and appears to be one of the potentially reversible risk factors contributing to their morbidity and mortality. Metabolic acidosis (MA) is common in dialysis patients, and studies suggest that MA increases nitrogen requirements and contributes to wasting by inducing the expression of genes regulating muscle proteolysis and amino acid (AA) oxidation. More importantly, correction of MA with sodium bicarbonate decreases protein catabolism and AA oxidation, and improves nitrogen balance (BN). A second cause of wasting is the urinary loss of protein in patients with the nephrotic syndrome. Unfortunately, almost nothing is known regarding the metabolic responses to urinary protein losses or whether proteinuria increases nitrogen requirements. We therefore propose the following two hypotheses: 1) Metabolic acidosis contributes to malnutrition in hemodialysis patients by increasing nitrogen requirements and stimulating catabolism of amino acids and body protein stores; and 2) Proteinuria causes endogenous protein catabolism unless dietary protein intake is sufficient and adaptive metabolic responses are activated. To determine whether MA increases nitrogen requirements by stimulating proteolysis and AA oxidation, 10 hemodialysis patients will consume the recommended intake of dietary protein (1.1g protein/kg/day) while they are acidotic and following correction of MA using a high bicarbonate dialysate (Specific Aim 1). Under both conditions, we will measure whole-body protein turnover (WBPT) and perform a gluteal muscle biopsy to measure the activity and mRNA levels for the enzymes-responsible for protein and AA degradation in skeletal muscle (Specific Aim 2). To address the second hypothesis, we will compare BE and WBPT in 10 nephrotic and 10 control subjects consuming diets providing 0.8 or 1.6g protein/kg/day (Specific Aim 3). Finally, to determine whether compensation for urinary protein losses involves a reduction in AA oxidation and proteolysis, we will measure the activity state and gene expression for enzymes regulating protein and AA degradation in muscle (specific Aim 4). Our limited understanding of factor(s) which may contribute to wasting in this population, underscores the need for detailed human studies aimed at identifying the mechanism(s) responsible, both at the whole-body and cellular level. If our hypotheses are correct, the proposed studies will provide the scientific basis for future treatment recommendations for these patients.