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. 1973 Mar;52(3):678–690. doi: 10.1172/JCI107229

The Effect of Keto-analogues of Essential Amino Acids in Severe Chronic Uremia

Mackenzie Walser 1,2, A Will Coulter 1,2, Shrikant Dighe 1,2, Frank R Crantz 1,2
PMCID: PMC302306  PMID: 4685089

Abstract

Alpha keto-analogues of valine, leucine, isoleucine, methionine, phenylalanine, and (in one instance) tryptophan and histidine, along with the remaining essential amino acids, were administered orally to 10 patients with severe chronic uremia fed a diet low in protein but adequate in calories. Ketoacid dosage varied from 6 to 14 g daily, as sodium or calcium salts. Net nitrogen intake, calculated as intake minus urinary protein nitrogen, averaged 1.8 g/day. The urea space was either estimated or measured with [14C]urea and daily changes in the body urea pool were calculated. Urea appearance was measured as the sum of urea excretion and the change in urea pool. If these ketoacids were converted to amino acids and utilized for protein synthesis, a fall in urea nitrogen appearance should occur. In five subjects, ketoacids were given for 15-18 days and then withdrawn. Urea nitrogen appearance increased 1.55 g/day on withdrawing ketoacids, and corrected nitrogen balance decreased by 1.73 g/day. In two other subjects ketoacid administration was followed, on two occasions each, by a period of administration of nine essential amino acids. In three of these four instances, urea appearance rose significantly with amino acids. In four patients studied at high blood urea levels, ketoacid treatment was relatively ineffective; two of these patients responded more favorably when studied again after peritoneal dialysis. One of these improved enough clinically to be managed as an out-patient for short intervals, despite virtual anuria. No accumulation of ketoacids in plasma or urine could be detected, and no toxicity was identified.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Adibi S. A. Alteration in the urinary excretion rate of amino acids and nitrogen by dietary means in obese and normal human subjects. J Lab Clin Med. 1971 Feb;77(2):278–289. [PubMed] [Google Scholar]
  2. Bergström J., Fürst P., Josephson B., Norée L. O. Improvement of nitrogen balance in a uremic patient by the addition of histidine to essential amino acid solutions given intravenously. Life Sci II. 1970 Jul 22;9(14):787–794. doi: 10.1016/0024-3205(70)90083-4. [DOI] [PubMed] [Google Scholar]
  3. Calloway D. H., Margen S. Variation in endogenous nitrogen excretion and dietary nitrogen utilization as determinants of human protein requirement. J Nutr. 1971 Feb;101(2):205–216. doi: 10.1093/jn/101.2.205. [DOI] [PubMed] [Google Scholar]
  4. Chang T. M., MacIntosh F. C., Mason S. G. Semipermeable aqueous microcapsules. I. Preparation and properties. Can J Physiol Pharmacol. 1966 Jan;44(1):115–128. doi: 10.1139/y66-013. [DOI] [PubMed] [Google Scholar]
  5. DEKKER E. E., ROSE W. C. Urea as a source of nitrogen for the biosynthesis of amino acids. J Biol Chem. 1956 Nov;223(1):107–121. [PubMed] [Google Scholar]
  6. Fürst P., Josephson B., Maschio G., Vinnars E. Nitrogen balance after intravenous and oral administration of ammonium salts to man. J Appl Physiol. 1969 Jan;26(1):13–22. doi: 10.1152/jappl.1969.26.1.13. [DOI] [PubMed] [Google Scholar]
  7. GIORDANO C. USE OF EXOGENOUS AND ENDOGENOUS UREA FOR PROTEIN SYNTHESIS IN NORMAL AND UREMIC SUBJECTS. J Lab Clin Med. 1963 Aug;62:231–246. [PubMed] [Google Scholar]
  8. GIOVANNETTI S., MAGGIORE Q. A LOW-NITROGEN DIET WITH PROTEINS OF HIGH BIOLOGICAL VALUE FOR SEVERE CHRONIC URAEMIA. Lancet. 1964 May 9;1(7341):1000–1003. doi: 10.1016/s0140-6736(64)91919-1. [DOI] [PubMed] [Google Scholar]
  9. Gallina D. L., Dominguez J. M. Human utilization of urea nitrogen in low calorie diets. J Nutr. 1971 Aug;101(8):1029–1035. doi: 10.1093/jn/101.8.1029. [DOI] [PubMed] [Google Scholar]
  10. Gallina D. L., Domínguez J. M., Hoschoian J. C., Barrio J. R. Maintenance of nitrogen balance in a young woman by substitution of -ketoisovaleric acid for valine. J Nutr. 1971 Sep;101(9):1165–1167. doi: 10.1093/jn/101.9.1165. [DOI] [PubMed] [Google Scholar]
  11. Giordano C., Phillips M. E., De Santo N. G., De Pascale C., Fürst P., Brown C. L., Houghton B. J., Richards P. Utilisation of ketoacid analogues of valine and phenylalanine in health and uraemia. Lancet. 1972 Jan 22;1(7743):178–182. doi: 10.1016/s0140-6736(72)90573-9. [DOI] [PubMed] [Google Scholar]
  12. Irwin M. I., Hegsted D. M. A conspectus of research on amino acid requirements of man. J Nutr. 1971 Apr;101(4):539–566. doi: 10.1093/jn/101.4.539. [DOI] [PubMed] [Google Scholar]
  13. Johnson W. J., Hagge W. W., Wagoner R. D., Dinapoli R. P., Rosevear J. W. Effects of urea loading in patients with far-advanced renal failure. Mayo Clin Proc. 1972 Jan;47(1):21–29. [PubMed] [Google Scholar]
  14. Jones E. A., Smallwood R. A., Craigie A., Rosenoer V. M. The enterohepatic circulation of urea nitrogen. Clin Sci. 1969 Dec;37(3):825–836. [PubMed] [Google Scholar]
  15. LOWRY O. H., ROSEBROUGH N. J., FARR A. L., RANDALL R. J. Protein measurement with the Folin phenol reagent. J Biol Chem. 1951 Nov;193(1):265–275. [PubMed] [Google Scholar]
  16. Lacy W. W. Effect of acute uremia on amino acid uptake and urea production by perfused rat liver. Am J Physiol. 1969 Jun;216(6):1300–1305. doi: 10.1152/ajplegacy.1969.216.6.1300. [DOI] [PubMed] [Google Scholar]
  17. MEISTER A. Studies on d- and tau-alpha-keto-beta-methylvaleric acids. J Biol Chem. 1951 May;190(1):269–276. [PubMed] [Google Scholar]
  18. Nicholson J. F. Metabolism of ingested ammonium-15N by premature infants. Pediatr Res. 1970 Sep;4(5):398–404. doi: 10.1203/00006450-197009000-00002. [DOI] [PubMed] [Google Scholar]
  19. Owen O. E., Felig P., Morgan A. P., Wahren J., Cahill G. F., Jr Liver and kidney metabolism during prolonged starvation. J Clin Invest. 1969 Mar;48(3):574–583. doi: 10.1172/JCI106016. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. ROSE W. C., WIXOM R. L., LOCKHART H. B., LAMBERT G. F. The amino acid requirements of man. XV. The valine requirement; summary and final observations. J Biol Chem. 1955 Dec;217(2):987–995. [PubMed] [Google Scholar]
  21. Read W. W., McLaren D. S., Tchalian M., Nassar S. Studies with 15N-labeled ammonia and urea in the malnourished child. J Clin Invest. 1969 Jun;48(6):1143–1149. doi: 10.1172/JCI106071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  22. Richards P., Houghton B. J., Brown C. L., Thompson E. Synthesis of phenylalanine and valine by healthy and uraemic men. Lancet. 1971 Jul 17;2(7716):128–134. doi: 10.1016/s0140-6736(71)92304-x. [DOI] [PubMed] [Google Scholar]
  23. Richards P., Metcalfe-Gibson A., Ward E. E., Wrong O., Houghton B. J. Utilisation of ammonia nitrogen for protein synthesis in man, and the effect of protein restriction and uraemia. Lancet. 1967 Oct 21;2(7521):845–849. doi: 10.1016/s0140-6736(67)92588-3. [DOI] [PubMed] [Google Scholar]
  24. Rudman D. Capacity of human subjects to utilize keto analogues of valine and phenylalanine. J Clin Invest. 1971 Jan;50(1):90–96. doi: 10.1172/JCI106488. [DOI] [PMC free article] [PubMed] [Google Scholar]
  25. Tripathy K., Klahr S., Lotero H. Utilization of exogenous urea nitrogen in malnourished adults. Metabolism. 1970 Mar;19(3):253–262. doi: 10.1016/0026-0495(70)90060-0. [DOI] [PubMed] [Google Scholar]
  26. WALSER M., BODENLOS L. J. Urea metabolism in man. J Clin Invest. 1959 Sep;38:1617–1626. doi: 10.1172/JCI103940. [DOI] [PMC free article] [PubMed] [Google Scholar]
  27. WOOD J. L., COOLEY S. L. Substitution of alpha-keto acids for five amino acids essential for growth of the rat. Proc Soc Exp Biol Med. 1954 Mar;85(3):409–411. doi: 10.3181/00379727-85-20898. [DOI] [PubMed] [Google Scholar]
  28. WRETLIND K. A. J. Replacement of valine in the diet by alpha-ketoisovaleric acid. Acta Physiol Scand. 1952;27(2-3):183–188. doi: 10.1111/j.1748-1716.1953.tb00933.x. [DOI] [PubMed] [Google Scholar]
  29. Wrong O. The metabolism of urea and ammonia in the healthy and uraemic colon. Med J Aust. 1967 Aug 12;2(7):281–283. doi: 10.5694/j.1326-5377.1967.tb97794.x. [DOI] [PubMed] [Google Scholar]
  30. Young V. R., Scrimshaw N. S. Endogenous nitrogen metabolism and plasma free amino acids in young adults given a 'protein-free' diet. Br J Nutr. 1968 Feb;22(1):9–20. doi: 10.1079/bjn19680004. [DOI] [PubMed] [Google Scholar]

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