Abstract
Guanidinosuccinic acid (GSA) is one of the earliest uremic toxins isolated and its toxicity identified. Its metabolic origins have remained obscure until recently when a series of studies showed that it arose from the oxidation of argininosuccinic acid (ASA) by free radicals. The stimulus for this oxidation, occurring optimally in the presence of the failed kidney, is the rising level of urea which, through enzyme inhibition, results in a decline in hepatic levels of the semi-essential amino acid, arginine. It is further noted that concentrations of GSA in both serum and urine decline sharply in animals and humans exposed to the essential amino acid, methionine. In this review the argument is advanced that uremics suffer from a defective ability to generate methyl groups due to anorexia, dietary restrictions and renal protein leakage. This leads to the accumulation of homocysteine, a substance known to produce vascular damage. Even in healthy subjects intake of choline together with methionine is insufficient to satisfy total metabolic requirements for methyl groups. In end-stage renal disease, therefore, protein restriction contributes to the build-up of toxins in uremia. Replacement using specific amino acid mixtures should be directed toward identified deficiencies and adequacy monitored by following serum levels of the related toxins, in this case GSA and homocysteine.
Similar content being viewed by others
References
Bonas JE, Cohen BD, Natelson S: Separation and estimation of certain guanidino compounds. Application to human urine. Microchem J 7: 63-77, 1963
Cohen BD, Stein IM, Bonas JE: Guanidinosuccinic aciduria in uremia. Am J Med 45: 63-68, 1968
Aoyagi K, Ohba S, Narita M, Tojo S: Regulation of the biosynthesis of guanidinosuccinic acid in isolated rat hepatocytes and in vivo. Kidney Int 24: S224-S228, 1983
Kopple JD, Gordon SI, Wang M, Swendseid ME: Factors affecting serum and urinary guanidinosuccinic acid levels in normal and uremic subjects. J Lab Clin Med 90: 303-311, 1977
Stein IM, Cohen BD, Kornhauser RS: Guanidinosuccinic acid in renal failure, experimental azotemia and inborn errors of the urea cycle. N Engl J Med 280: 926-930, 1969
Perez G, Abraira C, Rey A, Horn M: Removal of guanidinosuccinic acid by hemodialysis. Nephron 19: 214-219, 1977
Cohen BD: Guanidinosuccinic acid in uremia. Arch Intern Med 126: 846-850, 1970
Dobelstein H, Edel HH, Schmidt M, Schubart G, Wenzierl M: Guanidinosuccinic acid and uremia: A clinical study. Klin Wochenschr 49: 348-357, 1971
Horowitz HI, Cohen BD, Martinez P, Papayyoanou MF: Defective ADP-induced platelet factor 3 activation in uremia. Blood 30: 331-340, 1967
Horowitz HI, Stein IM, Cohen BD, White JG: Further studies on the platelet inhibitory effect of guanidinosuccinic acid and its role in uremic bleeding. Am J Med 49: 336-345, 1970
Lonergan ET, Semar M, Sterzel RB, Tresor G, Needle MA, Voyles L, Lange K: Erythrocyte transketolase activity in dialyzed patients: A reversible metabolic lesion of uremia. N Engl J Med 284: 1399-1403, 1971
Slavin RD, Fitch CD: Inhibition of lymphocyte transformation by guanidinosuccinic acid, a surplus metabolite. Experientia 27: 1340-1341, 1971
Shainkin-Kestenbaum R, Winikoff Y, Dvilansky A, Chaimowitz C, Nathan I: Effect of guanidinopropionic acid on lymphocyte proliferation. Nephron 44: 295-298, 1987
Acquatella H, Perez-Rojas M, Burger B, Lozano JR: Experimental modification of myocardial contractility produced by a toxin retained in uremia: Guanidinosuccinic acid. Arch Inst Cardiol Mex 44: 624-639, 1974
Acquatella H, Perez-Rojas M, Burger B, Quinan-Baldo A: Left ventricular function in terminal uremia: A hemodynamic and echocardiographic study. Nephron 22: 160-174, 1978
Scheuer J, Stezoski SW: The effect of uremic compounds on cardiac function and metabolism. J Mol Cell Cardiol 5: 287-300, 1973
Cohen BD, Handelsman DG, Pai BN: Toxicity arising from the urea cycle. Kidney Int 7: S285-S287, 1975
Patel H, Cohen BD: The effect of inhibitors of cytochrome P-450 microsomal enzymes on the biosynthesis of potential uremic toxins. Ann NY Acad Sci 434: 468-470, 1984
Aoyagi K, Nagase S, Tomida C, Takemura K, Akiyama K, Koyama A: Synthesis of guanidinosuccinate from argininosuccinate and reactive oxygen in vitro. Enzyme Prot 49: 199-204, 1996
Aoyagi K, Nagase S, Gotoh M, Akiyama K, Safoh M, Hirayama A, Koyama A: Role of reactive oxygen and argininosuccinate in guanidinosuccinate synthesis in isolated rat hepatocytes. Enzyme Prot 49: 205-211, 1996
Aoyagi K, Shahrzad S, Iida S, Tomida C, Hirayama A, Nagase S, Cohen BD: Role of nitric oxide in the synthesis of guanidinosuccinic acid, an activator of the N-methyl-D-aspartate receptor. Kidney Int 59: S93-S96, 2001
Menyhart Y, Grof J, Somogyi J: Abstracts of the 9th Annu Meet Eur Soc Clin Invest 9: 37-38, 1975
Aoyagi K: Significance of reactive oxygen in kidney disease elucidated by uremic toxins: From uremia to nephrosis. In: T. Yoshikawa, S. Toyokuni, Y. Yamamoto, Y. Naito (eds). Free Radicals in Chemistry, Biology and Medicine, ch. 42. OICA International, London, 2000, pp 1-7
Bohles H, Cohen BD, Michalk D: Guanidinosuccinic acid excretion in argininosuccinic aciduria. Adv Exp Med Biol 153: 443-448, 1982
Cohen BD: Guanidinosuccinic acid in uremia. Arch Int Med 162: 846-850, 1970
Aoyagi K, Teraoka S: The artificial kidney for the treatment of redox state abnormalities in renal failure. J Artif Organs 4: 1-2, 2001
Palmer RMJ: The L-arginine nitric oxide pathway. Curr Opin Nephrol Hypertens 2: 122-128, 1993
Cohen BD, Patel H: Glycine in acute renal tubular necrosis. In: P.P. DeDeyn, B. Marescau, I.A. Qureshi, A. Mori (eds). Guanidino Compounds in Biology and Medicine 2. John Libbey, London, 1997, pp 273-277
Aoyagi K, Akiyama K, Shahrzad S, Tomida C, Hirayama A, Nagase S, Takemura K, Koyama A, Ohba S, Narita M: Formation of guanidinosuccinic acid, a stable nitric oxide mimic, from argininosuccinic acid and nitric oxide-derived free radicals. Free Radic Res 31: 59-65, 1999
Aoyagi K: Inhibition of arginine synthesis by urea: a new mechanism of arginine deficiency in renal failure which leads to increased hydroxyl radical generation. Mol Cell Biochem 39: (abstr), 2, 2001
Mudd SH, Levy, HI: Disorders of transulfuration. In: J. Stanbury (ed). The Metabolic Basis of Inherited Disease. McGraw-Hill, New York, 1978, 460 pp
Cohen BD, Patel H, Kornhauser RS: Alternate reasons for atherogenesis in uremia. Proc Dialysis Transplant Forum 7: 178-180, 1977
Cohen BD: Guanidino compounds: Implications in uremia. In: A. Mori, B.D. Cohen, A. Lowenthal (eds). Guanidines. Plenum Press, New York, 1985, pp 265-275
Cohen BD: Homocysteine and the guanidines: An alternate source of atherogenesis in uremia. In: J.F. Clark, A. Mori, I. Masashi (eds). Guanidino Compounds in Biology and Medicine. Blackwell Science, Japan, 1999, pp 259-262
McCully KS: Vascular pathology of homocysteinemia: Implications for the pathogenesis of arteriosclerosis. Am J Pathol 56: 111-123, 1969
Lindner A, Charra B, Sherrard DJ, Scribner BH: Accelerated atherosclerosisin prolonged maintenance hemodialysis. N Engl J Med 290: 697-701, 1974
Cohen BD, Patel H: Methionine and the control of creatine synthesis. Ann NY Acad Sci 494: 329-331, 1987
Mudd SH: Homocystinuria and homocysteine metabolism. In: W.L. Nyhan (ed). Heritable Disorders of Amino Acid Metabolism. Wiley, New York, 1974, 372 pp
Mudd SH: Methyl group transfer. In: W.H. Fishman (ed). Metabolic Conjugation and Metabolic Hydrolysis. Lippincott, Philadelphia, 1971, pp 297-343
Avram MM, Sreedhara R, Fein P, Oo KK, Chattopadhyay J, Mittman N: Survival on hemodialysis and peritoneal dialysis over 12 years with emphasis on nutritional parameters. Am J Kidney Dis 37: S77-S80, 2001
Van Guldener C, Janssen MJFM, DeMeer K, Donker AJM, Stehouwer CDA: Effect of folic acid and betaine on fasting and post methionine-loading plasma homocysteine and methionine levels in chronic hemodialysis patients. J Int Med 245: 175-183, 1999
Manns B, Hyndman E, Burgess E, Parsons H, Schaefer J, Snyder F, Scott-Douglas N: Oral vitamin B12 and high dose folic acid in hemodialysis patients with hyper-homocysteinemia. Kidney Int 59: 1103-1109, 2001
Author information
Authors and Affiliations
Rights and permissions
About this article
Cite this article
Cohen, B.D. Methyl group deficiency and guanidine production in uremia. Mol Cell Biochem 244, 31–36 (2003). https://doi.org/10.1023/A:1022483117996
Issue Date:
DOI: https://doi.org/10.1023/A:1022483117996