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.

Methylguanidine concentration in blood cell of nondialysed patients with chronic renal failure was quantitatively determined by the method of the present authors. We also determined tissue methylguanidine concentrations in the liver, blood cell, kidney, colon, muscle and brain of uremic rat experimentally produced by Platt’s method. Methylguanidine concentrations in blood cell and tissues except the brain of the uremic rats and in blood cell of the uremic patients were 5–7 times higher than those in their serums. An increased methylguanidine concentration in the liver of the uremic rat receiving 40% protein diet was observed. These results imply that methylguanidine acts as one of the important uremic toxins in the intracellular space except for the brain, and suggest that the liver specifically affects the formation of methylguanidine.

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.

No abstract

Patients with mild to moderate IgA nephropathy (IgAN) who have diffuse mesangial proliferative changes, even if their proteinuria is less than 1 g/day, have a potential risk for end-stage renal disease. However, it has been assumed that these subgroups of IgAN do not need to be treated and the effect of corticosteroid treatment has not been assessed in a prospective randomized controlled trial.The inclusion criteria of the present study were as follows: (i) biopsy-proven IgAN; (ii) age between 15 and 55 years; (iii) proteinuria less than 1.5 g/day; (iv) serum creatinine less than 1.5 mg/dL; (v) mesangial cell prolife eration or matrix accumulation involving more than 50% of glomeruli; (vi) cellular crescent involving less than 20% of glomeruli; (vii) previously untreated; and (viii) known duration of history of abnormal urinalysis less than 36 months. Patients with hypertension were excluded. Eighteen patients were divided into two groups: (i) corticosteroid group: 9 patients receiving a tapering dose of oral prednisolone for 1 year beginning with 0.8 mg/kg body weight; and (ii) antiplatelet group: 9 patients receiving oral antiplatelet agent for 1 year and acting as controls. After 1 year of treatment, a repeat renal biopsy was performed in all patients. As an outcome measure, we evaluated clinical data such as proteinuria and glomerular filtration rate (GFR), histological parameters such as light microscopy findings, and the staining of a smooth muscle actin as a marker of myofibroblast and fibronectin-EDA (EDA-FN) as a marker of renal fibrosis using immunohistochemical techniques.Of the antiplatelet group, two patients later withdrew. After 1 year of treatment, the proteinuria significantly decreased in the corticosteroid group (799.9 (SD 277.8) M 328.9 (242.5)). Proteinuria in the antiplatelet group did not change. No significant changes in GFR were demonstrated in either group. We found that histological changes, such as mesangial cell proliferation, mesangial matrix accumulation and cellular crescent, improved in the corticosteroid group but not in the antiplatelet group.Expression of aSMA in the glomerulus significantly decreased in the corticosteroid group, but not in the antiplatelet group. Expression of EDA-FN did not change in either group.It is concluded that early treatment of mild to moderate IgAN with corticosteroid for 1 year retards its progression. Corticosteroid prevented phenotypic modulation of the mesangial cell in IgAN.