Sulfur amino acids and their metabolites in patients with renal failure : relation to nutritional status and cardiovascular disease

Abstract: Patients with chronic renal failure (CRF) have a high prevalence of cardiovascular disease (CVD), malnutrition and diabetes mellitus (DM) and exhibit several abnormalities in amino acid metabolism. The aims of this thesis were to assess alterations in sulfur amino acids and related sulfur compounds in relation to nutritional status, CVD and DM in CRF patients. In addition, the effects of methionine (Met) loading, B-vitamin supplementation and hemodialysis (HD) treatment on Met metabolites were evaluated in CR17. Reversed-phase HPLC was used to determine sulfur-containing compounds in plasma, erythrocytes (RBC) and whole blood. Subjective global nutritional assessment (SGNA) and anthropometric measurements were used to assess the overall protein-energy nutritional status. Patient records and medical examination were used to assess the presence of CVD. In this thesis, several abnormalities in sulfur-containing compounds were found in CR17 patients. Specifically, almost all (> 90%) patients bad hyperhomocysteineniia, which was associated with high levels of plasma cysteine (Cys), cysteinesulfinic acid (CSA), [gamma]-glutamylcysteine, glutathione (GSH), cysteinylglycine (Cys-Gly), inorganic sulfate, low levels of plasma taurine (Tau) and low or normal plasma Met level. In RBC the concentrations of Met, Cys, GSH and Cys-Gly did not differ from the levels in healthy subjects, but the levels of RBC homocysteine (Hcy) and Tau were significantly higher in the CR17 patients. The RBC and whole blood GSH concentrations were significantly lower in the CR17 patients with low hematocrit (<37%) than in patients with high hematocrit (>37%), and the concentrations were not different between the malnourished and well-nourished CR17 patients, suggesting that the low concentrations of GSH in whole blood, in presence of a normal RBC GSH level, in CR17 patients, are related to low hematocrit rather than nutritional status. The CR17 patients with malnutrition and low serum albumin bad lower plasma, but not RBC, Hcy, Cys, Met, GSH and Cys-Gly concentrations than the patients with normal nutritional status. Moreover, the plasma Hcy was inversely correlated with SGNA and was positively correlated with s-albumin, protein intake (nPNA) and objective nutritional parameters. The CR17 patients with DM bad lower plasma Hcy and s-albumin than the non-diabetic patients irrespectively whether they were malnourished or not. The CRF with CVD had higher prevalence of malnutrition, hypoalbuminemia and DM, which was associated with lower plasma Hcy level. This may explain why plasma Hcy was lower in CR17 patients with CVD. However, this does not contradict the assumption that hyperhomocysteinemia, which was present in almost all CR17 patients, is a risk factor for CVD in CR17. The CR17 patients with and without CVD had similar plasma Cys levels; whereas those with CVD had a significantly higher plasma Cys/Hcy ratio compared to the patients with no CVD. This ratio (but not Hcy or Cys per se) was related to several cardiovascular risk factors suggesting that the disturbed balance between plasma Cys and Hcy may be related to CVD. In HD patients, daily oral supplementation with 15 mg of folic acid and 200 mg of pyridoxine for one month reduced plasma Hcy by 28%, but failed to normalize it, and increased the erythrocyte and plasma GSH concentrations, but bad no effect on other Met metabolites. A single HD session decreased significantly the plasma concentrations of total Hcy (by 26%), total Cys (by 40%), Tau and CSA. Thus, HD can transiently normalize plasma total Cys, hut not plasma total Hcy, presumably because plasma Hcy is predominantly protein-bound. Oral methionine loading in HD patients caused accumulation of Hcy and other Met metabolites in plasma and to a lesser extent in RBC. Supplementation with pharmacological doses of pyridoxine and folic acid did not correct the impairments in the transsulfuration pathway. In summary, these studies have demonstrated. that in CRF 1) the metabolism of sulfur-containing compounds exhibit many abnormalities, 2) GSH concentrations in RBC and whole blood are related to hernatocrit and not to nutritional parameters, 3) plasma rather than RBC concentrations of sulfur containing compounds, especially plasma Hcy, are influenced by nutritional status and serum albumin and this relation is more obvious in the patients without DM, 4) the low plasma Hcy in patients with CVD is related to higher prevalence of malnutrition, hypoalbuminemia and DM, which should be considered when evaluating Hcy as a risk factor for CVD, 5) B- vitamin supplementation reduces plasma Hey, but does not normalize it, and increases RBC GSH and 6) accumulation of Met metabolites after Met loading indicates an impairment in the transsulf ration pathway, which is not corrected by vitamin supplementation.