The first purpose of this project is to design an optimal dietary supplement for patients with chronic renal failure in the pre-dialysis stage. Criteria to be optimized (in descending order of importance) are progression of renal insufficiency, protein nutrition, PTH levels, and plasma levels of amino acids and electrolytes. A 20-25 gm mixed quality protein diet low in phosphorus will be used, and the composition of a supplement containing amino acids and N-free analogues will be varied. Short-term N balance plus long-term (three months) out-patient studies will be used. We will first compare the """"""""best"""""""" supplement identified to date, """"""""EE"""""""", with another containing different proportions and including serine (""""""""FF""""""""). Second, we will determine whether ornithine is more or less effective on short-term N balance than in equinitrogenous glycine and if so, whether this is because it inhibits oxidation of ketoleucine as suggested by in vitro data. Third, we will determine the effects of keto-leucine alone (added to a diet containing 35 gm of mostly high biological value protein), or keto-leucine plus smaller amounts of ketovaline and ketoisoleucine, first on N balance and if effective, long-term. At or about this point, we expect to have designed a nearly optimal supplement. We will then document its advantages by comparison in a cross-over desing with whatever amino acid formulation is then available. In study 2 we will continue to pursue continuous nasogastric alimentation with a mixture containing these same constituents plus oligosaccharides, in patients with end-stage renal failure. We have shown that highly efficient N conservation and improved protein nutrition results from this regimen. To explore why, we will (1) change the infusion schedule from essentially continuous to nocturnal only (12-16 hours) (2) replace ornithine with isonitrogenous alanine (3) later, vary other constituents. In each case, the comparison between two regimens will be made by treating individual patients first with one (for one week or more) followed by the other (for the same interval). N balance, plasma amino acid levels and serum chemistries will be the methods for evaluating the results.

National Institute of Health (NIH)
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
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General Medicine B Study Section (GMB)
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Johns Hopkins University
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Walser, M; Hill, S B; Ward, L et al. (1993) A crossover comparison of progression of chronic renal failure: ketoacids versus amino acids. Kidney Int 43:933-9
Walser, M (1993) Does prolonged protein restriction preceding dialysis lead to protein malnutrition at the onset of dialysis? Kidney Int 44:1139-44
Walser, M; Drew, H H; Guldan, J L (1993) Prediction of glomerular filtration rate from serum creatinine concentration in advanced chronic renal failure. Kidney Int 44:1145-8
Quan, Z Y; Walser, M (1992) Effects of corticosterone administration on nitrogen excretion and nitrogen balance in adrenalectomized rats. Am J Clin Nutr 55:695-700
Matsusue, S; Walser, M (1992) Healing of intestinal anastomoses in adrenalectomized rats given corticosterone. Am J Physiol 263:R164-8
Walser, M; Hill, S; Ward, L (1992) Progression of chronic renal failure on substituting a ketoacid supplement for an amino acid supplement. J Am Soc Nephrol 2:1178-85
Quan, Z Y; Walser, M; Hill, G S (1992) Adrenalectomy ameliorates ablative nephropathy in the rat independently of corticosterone maintenance level. Kidney Int 41:326-33
Quan, Z Y; Walser, M (1991) Effect of corticosterone administration at varying levels on leucine oxidation and whole body protein synthesis and breakdown in adrenalectomized rats. Metabolism 40:1263-7
Walser, M (1990) Role of branched-chain ketoacids in protein metabolism. Kidney Int 38:595-604
Watson, A J; Gimenez, L F; Cotton, S et al. (1990) Treatment of the anemia of chronic renal failure with subcutaneous recombinant human erythropoietin. Am J Med 89:432-5

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