IMPACT OF RENAL DISEASE ON NITROGEN HOMEOSTASIS

肾脏疾病对氮稳态的影响

• 批准号: 2141503
• 负责人: BRADLEY J MARONI
• 金额: $ 19.76万
• 依托单位: EMORY UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 1990
• 资助国家: 美国
• 起止时间: 1990-09-01 至 1998-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2141503
• 关键词: acidosis; aldehyde /ketone oxidoreductase; aminoacid metabolism; bicarbonates; biopsy; branched chain aminoacid; calorimetry; chronic renal failure; clinical chemistry; dietary proteins; gene expression; hemodialysis; human genetic material tag; human subject; malnutrition; muscle metabolism; nephrotic syndrome; nitrogen balance; northern blottings; nutrient requirement; nutrition related tag; oxygen consumption; protein degradation; proteinuria; proteolysis

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.

营养不良在肾病患者中很常见， 其中一个潜在的可逆的风险因素， 发病率和死亡率。代谢性酸中毒（MA）在透析中很常见 研究表明，MA增加了氮的需求， 通过诱导基因的表达， 肌肉蛋白水解和氨基酸（AA）氧化。 更重要的是， 用碳酸氢钠校正MA会降低蛋白质催化剂， AA氧化，并改善氮平衡（BN）。第二个原因 肾衰竭是肾病患者尿蛋白的损失 综合征不幸的是，几乎没有什么是已知的代谢 对尿蛋白丢失的反应或蛋白尿是否增加 氮的需求。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 通过增加氮的需要量和刺激氨基的催化作用， 酸和身体蛋白质储存;和2）蛋白尿引起内源性 除非膳食蛋白质摄入量足够， 适应性代谢反应被激活。为了确定MA是否 通过刺激蛋白水解和AA增加氮需求 氧化，10名血液透析患者将消耗推荐摄入量 饮食蛋白质（1.1g蛋白质/kg/天）， 使用高碳酸氢盐透析液（特定 目标1）。在这两种情况下，我们将测量全身蛋白质周转 （WBPT）并进行臀肌活检以测量活动， mRNA水平的酶负责蛋白质和AA降解， 骨骼肌（具体目标2）。为了解决第二个假设，我们 将比较10名肾病患者和10名对照受试者的BE和WBPT， 提供0.8或1.6g蛋白质/kg/天的饲料（具体目标3）。最后为 确定尿蛋白损失的补偿是否涉及 减少AA氧化和蛋白水解，我们将测量活性 调节蛋白质和AA的酶的状态和基因表达 肌肉降解（具体目标4）。 我们对的了解有限 可能导致该人群消瘦的因素，强调 需要进行详细的人体研究，以确定机制 负责，无论是在整个身体和细胞水平。如果我们的假设 正确的，拟议的研究将提供科学依据， 对这些患者的未来治疗建议。