IMPACT OF RENAL DISEASE ON NITROGEN HOMEOSTASIS

点击翻译按钮获取中文摘要

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.