High levels of tumor necrosis factor-α downregulate antimicrobial iron transport protein, Nramp1, in chronic hemodialysis patients: a key factor for infection risk.

BACKGROUND/AIMS: The susceptibility of patients on maintenance hemodialysis (MHD) to infections is a major cause of mortality and morbidity. Natural resistance-associated macrophage protein 1 (Nramp1) regulates intracellular pathogen proliferation, and its mRNA expression is highest in polymorphonuclear leukocytes (PMNLs). The purpose of this study was to determine the level of Nramp1 in PMNLs from MHD patients and the factors affecting its expression. METHODS: Twenty MHD patients and 24 healthy volunteers (controls) were recruited. Relative quantitative PCR was used to measure Nramp1 mRNA, and protein levels were semiquantified by means of real-time PCR and Western blot analysis or immunohistochemistry. The effect of tumor necrosis factor-α (TNF-α) or interleukin-6 (IL-6) on Nramp1 expression in PMNLs from controls was also examined. RESULTS: Nramp1 mRNA and protein levels were substantially lower in PMNLs from MHD than control subjects. Serum TNF-α levels were significantly higher in the MHD group and were inversely correlated with Nramp1 mRNA levels. The addition of TNF-α to PMNLs from control subjects decreased mRNA and protein levels of Nramp1. IL-6 did not alter Nramp1 mRNA or protein expression. CONCLUSION: We found that Nramp1 was downregulated in the PMNLs of MHD patients, which constitute the first defense barrier against bacterial challenges. High levels of TNF-α may be associated with the downregulation of Nramp1. Our findings indicate that the susceptibility to infection observed in MHD patients could be partly due to the impairment of the intracellular handling of iron and the donation of more iron to the bacteria.

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.