guanidinosuccinic-acid and Kidney-Failure--Chronic

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.

Topics: Animals; Arginine; Free Radicals; Guanidines; Homocysteine; Humans; Kidney; Kidney Failure, Chronic; Liver; Methionine; Mitochondria; Models, Biological; Models, Chemical; Oxygen; Succinates; Time Factors; Transaminases; Uremia

Topics: Anemia; Animals; Arginine; Bleeding Time; Blood Platelets; Endothelium, Vascular; Enzyme Inhibitors; Erythropoietin; Guanidines; Hemorrhage; History, 18th Century; History, 20th Century; Humans; Isoenzymes; Kidney Failure, Chronic; Nitric Oxide; Nitric Oxide Synthase; Nitroarginine; omega-N-Methylarginine; Rats; Succinates; Uremia

Guanidino compounds are known as uremic toxins which increase in the blood of patients with renal failure. Guanidino succinic acid (GSA) and methyl guanidine (MG) have been intensively studied since they are toxic and are candidate markers which reflect the pathological stage of nephritis. GSA correlates well with blood urea nitrogen and therefore indicates the reduction of renal function. MG does not appear in the early stage of renal failure and abruptly increases at the stage of serious uremia. MG is produced by the oxidation of creatinine (CTN) with active oxygen. The MG/CTN ratio in the serum therefore reflects the degree of the generation of active oxygen. Accordingly, active oxygen scavengers may be useful for the treatment of uremia.

Topics: Animals; Biomarkers; Creatinine; Guanidines; Humans; Kidney Failure, Chronic; Methylguanidine; Reactive Oxygen Species; Renal Dialysis; Succinates; Uremia

Topics: Amines; Binding, Competitive; Child; Guanidines; Humans; Inositol; Insulin; Insulin Antagonists; Kidney Failure, Chronic; Molecular Weight; Neurotoxins; Phenols; Serum Albumin; Somatomedins; Spermine; Succinates; Toxins, Biological; Urea

Effect of lactulose therapy was examined in patients with chronic renal failure (CRF) prior to hemodialysis (HD). Twenty three patients were included in this study. Ten out of the 23 patients were continuously treated with lactulose at a dosage of 18 g/day for eight weeks. However, 12 out of the 23 patients dropped out because of nausea and/or watery diarrhea during the therapy. One patient was transfered to HD one month after the beginning of lactulose therapy. Ratios of guanidinosuccinic acid (GSA) in plasma after eight weeks were significantly lower than those before treatment. Cessation of treatment was significantly related to worsening of the GSA (p less than 0.01). It seems that lactulose therapy could be useful in the treatment of CRF if compliance of the therapy is maintained after reducing some adverse effects.

Topics: Clinical Trials as Topic; Diarrhea; Disaccharides; Drug Tolerance; Female; Guanidines; Humans; Kidney Failure, Chronic; Lactulose; Male; Middle Aged; Nausea; Succinates

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

Arginine (Arg) produced from citrulline originates mostly from kidneys. Arg is involved in guanidino compound biosynthesis, which requires interorgan co-operation. In renal insufficiency, citrulline accumulates in the plasma in proportion to renal damage. Thus, disturbances in Arg and guanidino compound metabolism are expected in several tissues. An original use of the model of nephrectomy based on ligating branches of the renal artery allowed us to investigate Arg and guanidino compound metabolism simultaneously in injured (left) and healthy (right) kidneys. The left kidney of adult rats was subjected to 72% nephrectomy. Non-operated, sham-operated and nephrectomized rats were studied for a period of 21 days. Constant renal growth was observed only in the healthy kidneys. Guanidino compound levels were modified transiently during the first 48 h. The metabolism and/or tissue content of several guanidino compounds were disturbed throughout the experimental period. Arg synthesis was greatly reduced in the injured kidney, while it increased in the healthy kidney. The renal production of guanidinoacetic acid decreased in the injured kidney and its urinary excretion was reduced. The experimentally proven toxins alpha-keto-delta-guanidinovaleric acid and guanidinosuccinic acid (GSA) accumulated only in the injured kidney. The urinary excretion of GSA and methylguanidine increased in nephrectomized rats. When the injured kidney grew again, the level of some guanidino compounds tended to normalize. Nephrectomy affected the guanidino compound levels and metabolism in muscles and liver. In conclusion, the specific accumulation of toxic guanidino compounds in the injured kidney reflects disturbances in renal metabolism and function. The healthy kidney compensates for the injured kidney's loss of metabolic functions (e.g. Arg: production). This model is excellent for investigating renal metabolism when a disease destroys a limited area in one kidney, as is observed in patients.

Topics: Acute Kidney Injury; Animals; Arginine; Creatine; Creatinine; Glycine; Guanidines; Homoarginine; Kidney; Kidney Failure, Chronic; Male; Methylguanidine; Muscle, Skeletal; Nephrectomy; Propionates; Rats; Rats, Sprague-Dawley; Succinates; Time Factors; Urea; Uremia

Uremic polyneuropathy is a common complication in dialyzed patients (pts). In 37 end stage renal disease (ESRD) pts the electroneurophysiological (ENF) parameters and serum creatinine (Pcr), guanidino compounds (GC) and guanidinosuccinic acid (GSA) levels were studied. There were 21 nondialyzed (ND), 10-hemodialyzed (HD) and 6-intermittently peritoneally dialyzed (IPD) pts. The following ENF parameters on both upper extremities, using method described by Buchtal and Rosenfalck, were performed: sensory nerves (nn.) conduction velocity, amplitude of evoked potential, subjective and objective impulse and motor nerve-conduction velocity. Cr level in serum was measured by enzymatic method, GC-by Rosenberg, Ennor, Morison method, modified by Szczepkowska. GSA isolation was performed by column chromatography. The results indicated disturbances in peripheral nn. function in all studied groups of pts and did not correlate with levels of uremic toxins in serum. However, it does not mean, that sum of the accumulated various toxic metabolites in ESRD pts, does not influence the development of polyneuropathy. The degree of impairment of peripheral nn. conduction in ESRD did not differ significantly between ND and HD or IPD pts. We did not notice, any significant differences in the degree of polyneuropathy in HD or IPD pts.

Topics: Adult; Creatinine; Electrophysiology; Female; Guanidines; Humans; Kidney Failure, Chronic; Male; Middle Aged; Nervous System Diseases; Neural Conduction; Peritoneal Dialysis; Renal Dialysis; Succinates

Small molecular weight uremic toxins, guanidino compounds and aliphatic monoamines, were measured in the serum of chronic and acute renal failure (CRF and ARF) patients. A close correlation was noticed between guanidinosuccinic acid (GSA) and serum urea nitrogen (BUN) and also between methylguanidine and serum creatinine (Cr) in nondialyzed and dialyzed CRF patients. The same relation was seen in ARF patients showing rapid change of metabolic conditions, which suggested the tight linkage between guanidino compounds and protein metabolites. On the other hand, dimethylamine (DMA) was related with Cr in CRF patients, however, not in ARF patients. Since the production of DMA from Cr is carried out mainly, but relatively slowly, by bacterias in the intestine, the rapid metabolic change of ARF may not affect DMA synthesis. Furthermore, the DMA synthesis from trimethylamine-N-oxide (TMA-N-O) was studied using liver homogenate. The liver homogenate produced DMA by adding TMA-N-O as substrate. However, the kidney homogenate could synthesize it even without substrate. Therefore, the kidney seems to be a major site of DMA production as well as the intestine.

Topics: Acute Kidney Injury; Animals; Blood Urea Nitrogen; Creatinine; Dimethylamines; Guanidines; In Vitro Techniques; Kidney; Kidney Failure, Chronic; Liver; Methylguanidine; Rats; Rats, Wistar; Succinates

The effect of methylguanidine (MG) and guanidinosuccinic++ acid (GSA) on the anaerobic glycolysis of normal human red blood cells was studied in vitro after three-hours incubation at temperature 37 degrees C. The changes of glucose and lactic acid levels as well as intermediate metabolites and adenine nucleotides of carbohydrate metabolism were determined. Glucose and lactic acid were measured with enzymatic methods, however main phosphate compounds and nucleotide coenzymes were determined by a method of column chromatography. The studies have shown, that GSA in concentrations approximate to those appearing in the plasma patients with chronic renal failure, insignificant enhanced glucose utilization in normal erythrocytes with simultaneous significant decrease produce of lactic acid. Methylguanidine have weakly effected on this process. Subsequent studies have demonstrated that mixture MG (5.4 x 10(-5) mol/dm3) and GSA (2.8 x 10(-5) mol/dm3) induced characteristic changes in composition of main phosphate compounds of carbohydrate metabolism in human red blood cells. The statistically significant decrease of ATP in blood cells with simultaneous increase ADP and AMP were observed. The concentrations of hexose monophosphate, fructose-1,6-diphosphate, triosephosphate, and 2,3-diphosphoglycerinic acid were also higher. The inorganic phosphate concentration was over 80% higher than in control cells. The results of our studies have revealed that energetic metabolism was inhibited in red blood cells which were incubated with MG and GSA.

Topics: Adult; Anaerobiosis; Blood Glucose; Erythrocytes; Glycolysis; Guanidines; Humans; In Vitro Techniques; Kidney Failure, Chronic; Lactates; Lactic Acid; Methylguanidine; Middle Aged; Models, Biological; Molecular Weight; Succinates; Time Factors; Toxins, Biological

Studies were performed on the platelet aggregation (PA) in patients with chronic renal failure (CRF) and normal subjects (NS). The PA was investigated in the whole blood by the electrical impedance method. The concentrations of plasma (P-) and erythrocyte (E-) guanidinosuccinic acid (GSA) and methylguanidine (MG) in uremic patients with CRF were determined by high performance liquid chromatography. GSA and MG are guanidino compounds (GC) and have been widely shown to act as uremic toxins. The effects of GSA and/or MG on the PA of NS were also investigated. The results showed that the PA of conservative therapy patients with CRF was significantly lower than that of NS, while the PA of hemodialysis (HD) patients was improved. The PA of continuous ambulatory peritoneal dialysis (CAPD) patients was rather high and the possibility of sugar and lipid metabolic disorders was suggested as the cause. The concentrations of P- and E-GSA and MG in uremic patients with CRF were increased. But there were no significant correlations between the PA and the concentrations of GSA and MG. In vitro, GSA and/or MG at a high concentration exerted a significant inhibitory effect, while at a low concentration they showed a lesser inhibitory effect on the PA. In conclusion, based on their inhibition of the PA in patients with CRF, the dialyzable materials, GSA and MG, are considered to represent active uremic toxins.

Topics: Adult; Female; Guanidines; Humans; Kidney Failure, Chronic; Male; Methylguanidine; Middle Aged; Peritoneal Dialysis, Continuous Ambulatory; Platelet Aggregation; Platelet Aggregation Inhibitors; Renal Dialysis; Succinates; Uremia

Methylguanidine (MG), guanidinosuccinic acid (GSA) and creatinine (Cr), which accumulate in the body in parallel with the progress of renal failure after adenine administration, were given separately to rats in order to compare their toxicities. Food containing adenine was given to rats for 24 days to induce renal failure, and then each of the test substances was administered intraperitoneally from the following day, the survival rates of the rats being subsequently determined. Administration of MG at varying doses produced a dose-dependent decrease in the survival rate, whereas the survival curves obtained for rats given GSA or Cr indicated weak toxicity. The levels of MG, GSA or Cr accumulated in the body were extraordinarily high in surviving rats after 14 days of administration of each respective compound. The toxic effects are discussed on the basis of these results.

Topics: Adenine; Animals; Creatinine; Guanidines; Kidney Failure, Chronic; Male; Methylguanidine; Rats; Rats, Inbred Strains; Succinates

Topics: Adolescent; Adult; Aged; Blood Urea Nitrogen; Child; Creatinine; Female; Guanidines; Humans; Kidney Failure, Chronic; Male; Middle Aged; Succinates

Topics: Adult; Aged; Female; Guanidines; Humans; Kidney Failure, Chronic; Male; Methylguanidine; Middle Aged; Prolactin; Renal Dialysis; Succinates

Topics: Animals; Arginine; Blood Urea Nitrogen; Creatinine; Glycine; Guanidines; Kidney Failure, Chronic; Male; Methylguanidine; Rats; Rats, Inbred Strains; Succinates; Urea

Topics: Acute Kidney Injury; Blood Urea Nitrogen; Creatinine; Glycine; Guanidines; Hepatic Encephalopathy; Humans; Kidney Failure, Chronic; Methylguanidine; Renal Dialysis; Succinates

Topics: Adolescent; Adult; Aged; Child; Female; Guanidines; Humans; Kidney Failure, Chronic; Male; Methylguanidine; Middle Aged; Renal Dialysis; Succinates; Uremia

Urinary guanidinosuccinic acid (GSA) was measured in pediatric age: six normal subjects, six chronically uremic patients and five with acute renal failure. Urinary GSA was increased in uremic patients as compared to that in normal subjects: our levels was less than in the growth-up people. These differences might be correlated with different protein metabolism in children.

Topics: Acute Kidney Injury; Child; Child, Preschool; Guanidines; Humans; Kidney Failure, Chronic; Succinates; Uremia