Persistent homocysteine metabolism abnormality accelerates cardiovascular disease in hemodialyzed patients--the Nishinomiya Study.

OBJECTIVE: Homocysteine (Hcy) is an intermediate in sulfur amino acid metabolism and may induce oxidative stress. Several studies have reported that elevated Hcy in end-stage renal failure may contribute to cardiovascular disease (CVD). The purpose of this study is to investigate whether the changes in Hcy levels correlate better with the CVD outcomes than baseline Hcy level. METHODS: A total of 187 patients on dialysis participated in the present prospective observational study and were followed up for 107 months. Baseline cross-sectional analysis of the relationship between Hcy and several factors related to its metabolism was performed, along with survival analysis for the occurrence of CVD. All subjects were divided into the Increase or Decrease of Hcy group on the basis of changes in Hcy from baseline to year 3. RESULTS: The occurrence of CVD was higher in the Increase (30.1%) than in the Decrease group (9.0%). Greater change of Hcy was associated with risk of CVD (hazard ratio: 3.658) after adjusting basic factors and nutritional status. In stepwise multiple analyses, serum folate, vitamin B(12), cysteine, creatinine, and body mass index were considered to be independent predictors of Hcy. CONCLUSIONS: These data show that increase in Hcy is a powerful predictor of the occurrence of CVD in patients on dialysis.

Defective regulation of iron transporters leading to iron excess in the polymorphonuclear leukocytes of patients on maintenance hemodialysis.

BACKGROUND: Although hemodialysis (HD) patients are suspected of having defectively regulated iron metabolism, intracellular iron status has never been investigated thoroughly. To clarify the iron metabolism of HD patients, proteins involved in iron import (transferrin receptor [TfR]), as well as export (ferroportin 1), were investigated in polymorphonuclear leukocytes (PMNLs). Relations between iron status and several PMNL functions also were tested. METHODS: Seventeen HD patients and 17 controls were recruited. Relative quantitative polymerase chain reaction was used to measure ferroportin 1 and TfR messenger RNA (mRNA), and ferroportin 1 and TfR expression were semiquantified by means of Western blot analysis or immunohistochemistry. PMNL functions also were examined. RESULTS: Serum iron levels were significantly lower in HD patients than controls, and serum ferritin levels, as well as PMNL ferritin and iron content, were elevated in HD patients. Ferroportin 1 mRNA levels were substantially lower in PMNLs from HD patients, whereas TfR mRNA levels were higher. Western blot analysis and immunohistochemistry confirmed that expression of the corresponding proteins paralleled those of the mRNAs. PMNL phagocytic and bactericidal activity did not differ between HD patients and controls. Chemotactic peptide f-Met-Leu-Phe-stimulated degranulation activity of lactoferrin (Lf) was decreased significantly in HD patients, whereas those of myeloperoxidase and elastase were accelerated. Lf release correlated negatively with intracellular ferritin level. CONCLUSION: We show for the first time that increased iron levels in PMNLs of HD patients were associated with downregulation of ferroportin 1 and upregulation of TfR, which might be linked to hypercytokinemia.

Accumulation of cyanide and thiocyanate in haemodialysis patients.

BACKGROUND: Cyanide is a toxic agent, and its detoxification product, thiocyanate, may be a major pathogenetic substance in uraemia. Recent studies examining the myeloperoxidase(MPO)/thiocyanate system have suggested a link between thiocyanate and atherosclerosis. However, inaccuracies in conventional assays for cyanide and thiocyanate have limited the understanding of their metabolism in haemodialysis (HD) patients. METHODS: We used high-performance liquid chromatography to measure cyanide in erythrocytes and thiocyanate in plasma in 43 HD patients and in a group of 46 healthy controls that included 15 current smokers. To clarify the metabolic conversion of cyanide to thiocyanate in uraemic patients, we also measured cysteine and sulfate. We then used stepwise regression analysis to analyse factors that determine erythrocyte cyanide and plasma thiocyanate. RESULTS: Mean cyanide and thiocyanate were significantly greater in HD patients than in non-smoking controls. However, cyanide was far below lethal concentrations in dialysis patients. Thiocyanate was six to seven times greater in HD patients than in non-smoking controls, and decreases in thiocyanate following dialysis were only 19.3+/-3.5%. Multiple regression analysis showed a positive correlation between cyanide and thiocyanate in controls, but a negative correlation in HD patients. In patients, an inverse relationship between thiocyanate and BUN was also observed. CONCLUSIONS: The elevation of thiocyanate in patients undergoing dialysis probably is secondary to both limited efficiency of HD and deranged metabolism of cyanide and thiocyanate. Because thiocyanate is a preferred substrate for MPO, it may play a role in uraemic complications including cardiovascular events.

Free cysteine is increased in plasma from hemodialysis patients.

BACKGROUND: Although only the total thiol concentration, which includes bound and free forms, has been determined in most previous clinical studies, the free form may be a better predictor of cardiovascular risk. METHODS: We measured the apparent concentration of free homocysteine (Hcy) and cysteine (Cys) in filtered and acid-soluble fractions of plasma in healthy control subjects and in patients with chronic renal failure just before and after a hemodialysis session. RESULTS: In control, filtered Hcy and acid-soluble Hcy were similar, while filtered Cys was much smaller than in acid-soluble Cys. In prehemodialysis samples, filtered Cys was more than 60 times as abundant (259.2 +/- 26.2 micromol/L) as in control samples (4.1 +/- 0.7 micromol/L ). Free-to-total ratios for filtered Cys were 1.6 +/- 0.3% in controls, but 40.9 +/- 2.7% in prehemodialysis patients. CONCLUSIONS: The filtered fraction of thiols can be used to estimate solute transport across the dialysis membrane. In addition, the possible involvement of cysteine in the pathogenesis of atherosclerosis in hemodialysis patients should be reexamined.