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 lactat 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.
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