5-hydroxy-1-methylhydantoin and Kidney-Failure--Chronic

In mammals, creatinine (Cr) is catabolized by a dual oxidative pathway via 5-hydroxy-1-methylhydantoin or 5-hydroxycreatinine. The former, an intrinsic antioxidant, termed NZ-419, has been reported to prevent the progression of chronic renal failure in animal models. However, its clinical intrinsic serum level has not yet been reported.. We analyzed serum NZ-419 levels in diabetic and nondiabetic patients with or without Stage 3 - 5 chronic kidney disease (CKD).. The levels of NZ-419 in diabetic patients with (88.1 ± 17.2 µg/dl, p < 0.001) or without (31.5 ± 2.4 µg/dl, p < 0.05) Stage 3 - 5 CKD were significantly higher than in nondiabetic normal controls (9.0 ± 5.6 µg/dl). The molar ratio data showed NZ-419/Cr was significantly higher in both diabetic patients with (p < 0.01) or without Stage 3 - 5 CKD (p < 0.001) compared to nondiabetic normal controls. No further increase occurred with increasing severity of renal failure. Furthermore, nondiabetic patients with or without Stage 3 - 5 CKD did not show significantly different molar ratio values than controls but had significantly higher values of NZ-419 levels (p < 0.001).. Overproduction and decreased clearance played a major role in the increased NZ-419 levels we observed in the patients with diabetes and Stage 3 - 5 CKD, respectively. The existence of chronic renal failure did not further enhance this overproduction.

Topics: Adult; Antioxidants; Creatinine; Diabetic Nephropathies; Female; Humans; Hydantoins; Kidney Failure, Chronic; Male; Middle Aged

For rats, glomerular filtration rate (GFR) and its relative GFR (ratio to normal GFR(0)) were estimated in order to classify their chronic kidney disease (CKD) into 5 stages like those in humans. The adenine-loaded rats, which were used to show the intrinsic antioxidant and creatinine (Cr) metabolite, NZ-419 (5-hydroxy-1- methylimidazolidine-2,4-dione), when taken orally, prevented the progression of chronic renal failure (CRF), were used as a model to reach the severest stage 5. In this report, we show that, by using both a tubular lesion and a glomerular lesion models (adenine-loaded and 5/6 nephrectomized rats, respectively), peroral NZ-419 might be a common tool to prevent the progression of CRF at CKD stages 3 and 4 under the condition that most rats in the control group still remained at stage 4 (0.15

Topics: Adenine; Administration, Oral; Animals; Antioxidants; Creatinine; Disease Models, Animal; Disease Progression; Glomerular Filtration Rate; Hydantoins; Kidney Failure, Chronic; Kidney Glomerulus; Kidney Tubules; Male; Nephrectomy; Rats; Rats, Wistar

The concentration of NZ-419 (5-hydroxy-1-methylimidazolidine-2,4-dione), an intrinsic antioxidant, has been shown to increase in the sera of animals and patients with chronic renal failure (CRF). This is the first report that orally administered exogenous NZ-419 prevents the initiation and/or progression of CRF in rats using an adenine-loaded model. After 24 d of adenine loading, there was a ca. 90% decrease in creatinine clearance (C(Cr)) in the control rats. Treatment with NZ-419 from the beginning significantly inhibited the decrease in C(Cr) and also the increase in serum creatinine (sCr). Bio-markers for in vivo hydroxyl radicals, the serum methylguanidine (sMG) level, and sMG/sCr molar ratio, not only in serum but also in the urine, kidney, liver, and muscle indicated that NZ-419 inhibited the increase in oxidative stress induced by CRF in rats. An increase of guanidinosuccinic acid, an another bio-marker of oxidative stress, was also inhibited with NZ-419.

Topics: Animals; Antioxidants; Biomarkers; Creatinine; Disease Models, Animal; Disease Progression; Dose-Response Relationship, Drug; Guanidines; Hydantoins; Kidney Failure, Chronic; Kidney Function Tests; Male; Methylguanidine; Oxidative Stress; Rats; Rats, Wistar; Succinates