EFFECT OF ARTERIAL PH ON N-BALANCE OF PATIENTS UNDERGOING AUTOMATED PERITONEAL

这个子项目是许多研究子项目中利用 资源由NIH/NCRR资助的中心拨款提供。子项目和 调查员(PI)可能从NIH的另一个来源获得了主要资金， 并因此可以在其他清晰的条目中表示。列出的机构是 该中心不一定是调查人员的机构。 蛋白质能量营养不良(PEM)是慢性肾功能衰竭晚期患者和维持性透析(MD)患者的常见症状。在终末期肾病的发病和流行患者中，PEM的存在预示着短期和长期预后较差。许多因素似乎在MD患者的PEM的病理生理学中起作用，但有四个因素似乎特别重要：营养摄入量低、全身炎症、代谢性酸中毒和对合成激素影响的抵抗。越来越多的证据表明，动脉pH值从较低的正常值上升到较高的正常值可能会改善患者的营养状况，包括那些正在接受持续腹膜透析(CPD)的患者。事实上，最近的一份报告表明，动脉pH值和静脉碳酸氢盐水平从低到高的正常值与泛素的mRNA含量下降有关，泛素是一种在骨骼肌蛋白质分解代谢中发挥重要作用的蛋白质。尽管自动腹膜透析是发展最快的透析方式，但对接受自动腹膜透析的患者的氮或蛋白质代谢进行的系统分析很少。考虑到这些考虑，我们建议检验以下假设：在接受apd治疗的MD患者中，动脉pH值为7.43-7.45与动脉pH值为7.36-7.38相比，净蛋白平衡明显更正。 为了验证这一假设，我们设计了一项前瞻性的、随机的交叉代谢平衡研究。该提案有两个具体目标。首先，我们将比较在两种不同的动脉血pH水平下接受apd治疗的8名受试者的氮平衡情况。其次，我们将测试其他次级假设，以研究动脉酸碱度在正常范围内变化的营养后果。具体地说，我们将比较(13)C-亮氨酸周转率并检查骨骼肌活检，以评估选定的合成代谢蛋白(胰岛素样生长因子I、IGF-I、IGF-II、IGF-I受体)的基因和蛋白表达以及抗合成代谢蛋白(肌肉生长抑素)的基因表达。我们将在动脉酸碱度的每个水平进行额外的营养状况评估；然而，由于研究持续时间较短，我们预计不会观察到受试者的营养状况或身体成分有任何重大变化。 在最初的筛查和磨合阶段之后，受试者将在GCRC住院，总共为期41天。动脉酸碱度的每个阶段将持续20天，第一个酸碱值阶段(低或高)将使用随机数字表进行选择。在整个研究期间，饮食、体力活动和透析处方将保持不变并严格控制。用含有35-mmoL/L乳酸的腹膜透析液透析受试者，并加或不加NH(4)Cl，可获得较低的动脉pH。用含40-mmoL/L乳酸的腹膜透析液透析受试者，加或不加NaHCO(3)，可获得较高的动脉pH。亮氨酸周转研究、肌肉活检和营养评估将在每个动脉酸碱期结束时进行。

This subproject is one of many research subprojects utilizing the resources provided by a Center grant funded by NIH/NCRR. The subproject and investigator (PI) may have received primary funding from another NIH source, and thus could be represented in other CRISP entries. The institution listed is for the Center, which is not necessarily the institution for the investigator. Protein-energy malnutrition (PEM) is a common finding in patients with advanced chronic renal failure and those undergoing maintenance dialysis (MD). The presence of PEM in both incident and prevalent patients with end-stage renal disease portends a poor short- and long-term prognosis. Numerous factors have been identified that appear to play a role in the pathophysiology of PEM in MD patients but four appear to be particularly important: low nutrient intake, systemic inflammation, metabolic acidosis and resistance to the effects of anabolic hormones. There is accumulating evidence that suggests an increase in arterial pH from lower normal to higher normal values may result in improvement in the nutritional status of patients, including those undergoing continuous peritoneal dialysis (CPD). Indeed, a recent report demonstrated that an increase in arterial pH and venous bicarbonate levels from low to high normal values was associated with a decrease in mRNA content of ubiquitin, a protein that plays an important role in the catabolism of skeletal muscle proteins. Even though automated peritoneal dialysis (APD) is the most rapidly growing dialysis modality, very few systematic analyses of nitrogen or protein metabolism of patients undergoing APD have been performed. Given these consideration, we propose to test the following hypothesis: In MD patients undergoing treatment with APD, an arterial pH of 7.43-7.45 is associated with a significantly more positive net protein balance than an arterial pH of 7.36-7.38. To test this hypothesis, we have designed a prospective, randomized crossover metabolic balance study. The proposal has two specific aims. First, we will compare the N-balances in 8 subjects treated with APD at two different levels of arterial blood pH. Second, we will test other secondary hypotheses to study the nutritional consequences of a change in arterial pH within the normal range. Specifically, we will compare (13)C-leucine turnover and examine skeletal muscle biopsies to evaluate the gene and protein expression of selected anabolic proteins (insulin like growth factor I, IGF-I, IGF-II, IGF-I receptor) and gene expression of an anti-anabolic (myostatin) protein. We will make additional assessment of nutritional status at each level of arterial pH; however, we do not anticipate observing any significant changes in the nutritional status or body composition of the subjects because of the short duration of the study. After an initial period of screen and run-in phase, subjects will be hospitalized in the GCRC for a total duration of 41 days. Each phase of arterial pH will last 20 days, and the first pH phase (low or high) will be chosen using a table of random numbers. The diet, physical activity and dialysis prescription will be constant and tightly controlled during the entire study period. The lower arterial pH will be obtained by dialyzing subjects with peritoneal dialysis solution containing 35-mmol/L of lactate with/without supplementation with NH(4)Cl. The higher arterial pH will be obtained by dialyzing subjects with peritoneal dialysis solution containing 40-mmol/L of lactate with/without supplementation with NaHCO(3). Leucine turnover studies, muscle biopsy and nutritional assessment will be performed at the end of each arterial pH phase.