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The metabolic pathway of methylguanidine (MG) is mainly speculated from the change in urinary excretion of MG in the arginine (Arg)-injected normal rat, the creatinine (Cr)-injected normal rat, and the Arg-injected uremic rat. ¹⁵N-Arg was ingested to 2 uremic patients. Arg administration resulted in marked increase in urinary MG excretion both in the uremic rat and patient, but not in the normal rat. In the first phase of the ¹⁵N-Arg ingestion experiment, a rapid rise of ¹⁵N atom percent excess of urinary MG was observed in the uremic patient. In the second phase of this study, after 24 h of ¹⁵N-Arg ingestion, the ¹⁵N atom percent excess of urinary Cr and that of MG closely paralleled. These findings imply that there might be two metabolic origins of MG: one is a formation of MG from Arg itself or an Arg metabolite other than Cr, the other a pathway producing MG via Cr. The former is compatible with the hypothesis by Cohen.

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20 patients with moderate renal failure (serum creatinine 4.5–12.0 mg/dl) and some uremic symptoms on a diet ad libitum were treated with a high caloric diet containing 0.5–0.7 g/kg/day protein, supplemented with eight essential amino acids and histidine in the form of solution and/or granules. During the treatment uremic symptoms subsided or diminished without the signs of malnutrition, SUN and the ratio SUN/S-creatinine fell and the nitrogen balance and the ratio N-balance/intake N improved. The serum concentration and the urinary excretion of MG and GSA of the 12 patients were determined by Stein’s method using the modified Sakaguchi reaction. In all patients, the serum, concentration and the urinary excretion of MG and GSA diminished remarkably during the treatment with a low protein diet alone and furthermore with a low protein diet and essential amino acid supply. We concluded that conservative treatment – low nitrogen diet supplemented with sufficient calories and essential amino acids – improved the nutritional state of uremic subjects, and decreased the metabolic production of MG and GSA. The results show that the supplementation of essential amino acids to uremic patients may be a useful treatment.

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