Association of Increased Indoleamine 2, 3‐Dioxygenase With Impaired Natural Killer Cell Activity in Hemodialysis Patients

Indoleamine 2, 3‐dioxygenase (IDO) suppresses adaptive immune response. However, there was no study to examine whether IDO activity is associated with immune parameters in dialysis patients. In this study, we estimated serum IDO activity by the kynurenine/tryptophan ratio (KTR), and compared KTR with natural killer (NK) cell activity, soluble interleukin‐2 receptor (sIL‐2R) and serum levels of trace elements such as selenium (Se) and zinc (Zn) that affect T‐cell function in 28 hemodialysis (HD) patients (age: 72 ± 13 years old, time on HD: 79 ± 89 months). NK cell activity was decreased in 35.7% of the patients. KTR values were almost 10‐times higher in HD patients (380.81 ± 385.46 mM/M) than those in the referred controls (32.9 ± 9.10 mM/M). KTR was lower in patients with impaired NK cell activity than those without (279 ± 111 vs. 565 ± 603 mM/M, P = 0.07). There was no relationship between KTR and sIL‐2R and Zn, while KTR was significantly and negatively correlated with serum Se levels that can impair cellular immunity (r = ?0.41, P < 0.05). Our findings suggest that increased IDO activity with Se deficiency may be associated with impaired NK cell function in HD patients.     

Practical Approach to Evaluate Asymptomatic Coronary Artery Disease in End‐Stage Renal Disease Patients at the Initiation of Dialysis

The high prevalence of significant asymptomatic coronary artery disease (CAD) has been reported in patients with end‐stage renal disease (ESRD) at the initiation of dialysis. However, the approach to evaluate asymptomatic CAD for these patients has not been established. The aim of this study is to assess the applicability of our practical approach at the initiation of dialysis. We prospectively enrolled 182 consecutive ESRD patients who initiated dialysis. After echocardiography as primary screening, pharmacologic stress thallium‐201 scintigraphy and/or coronary angiography (CAG) were performed to diagnose CAD. The patients were classified into two groups: those with coronary artery stenosis by CAG (CAD+ group), those without coronary artery stenosis by CAG or with negative scintigraphy examination (CAD? group). Of the eligible 93 patients without the history of CAD, 22 patients were allocated to the CAD+ group (18 of 26 patients with abnormal echocardiography and 4 of 13 patients with positive scintigraphy examination) and 71 patients to the CAD? group. Patients were followed up for an average of 520 ± 304 days. The event‐free survival rate of major adverse cardiac events was significantly lower in the CAD+ group than in the CAD? group (P < 0.001). There was no cardiovascular event including major adverse cardiac events, unstable angina, coronary revascularization or stroke in the CAD? group during the first year of dialysis. Patients without CAD diagnosed by our approach had favorable clinical outcomes. Our approach may be useful for screening of occult CAD in ESRD patients at the initiation of dialysis.     

Skin Autofluorescence Predicts Cardiovascular Mortality in Patients on Chronic Hemodialysis

Tissue accumulation of advanced glycation end products (AGE) is thought to contribute to the progression of cardiovascular disease (CVD). Skin autofluorescence, a non‐invasive measure of AGE accumulation using autofluorescence of the skin under ultraviolet light, has been reported to be an independent predictor of mortality associated with CVD in Caucasian patients on chronic hemodialysis. The aim of this study was to assess the predictive value of skin autofluorescence on all‐cause and cardiovascular mortality in non‐Caucasian (Japanese) patients on chronic hemodialysis. Baseline skin autofluorescence was measured with an autofluorescence reader in 128 non‐Caucasian (Japanese) patients on chronic hemodialysis. All‐cause and cardiovascular mortality was monitored prospectively during a period of 6 years. During the follow‐up period, 42 of the 128 patients died; 19 of those patients died of CVD. Skin autofluorescence did not have a significant effect on all‐cause mortality. However, age, carotid artery intima‐media thickness (IMT), serum albumin, high‐sensitivity C‐reactive protein (hsCRP), skin autofluorescence and pre‐existing CVD were significantly correlated with cardiovascular mortality. Multivariate Cox regression analysis showed skin autofluorescence (adjusted hazard ratio [HR] 3.97; 95% confidence interval [CI]1.67–9.43), serum albumin (adjusted HR 0.05; 95% CI 0.01–0.32), and hsCRP (adjusted HR 1.55; 95% CI 1.18–2.05) to be independent predictors of cardiovascular mortality. The present study suggests that skin autofluorescence is an independent predictor of cardiovascular mortality in non‐Caucasian (Japanese) patients on chronic hemodialysis.     

Dihydrotestosterone inhibits lectin-like oxidized-LDL receptor-1 expression in aortic endothelial cells via a NF-κB/AP-1-mediated mechanism

The mechanisms involved in the antiatherosclerotic effects of androgens are unclear. Although lectin-like oxidized low-density lipoprotein receptor-1 (LOX-1) in endothelial cells plays critical roles in atherosclerosis, the effects of androgens on endothelial LOX-1 expression has not been examined. Therefore, to investigate the effects of dihydrotestosterone (DHT) on LOX-1 expression in rabbit aortic endothelial cells and cultured human aortic endothelial cells (HAEC), pellets containing DHT or placebo were s.c. implanted into 26 male New Zealand white rabbits at the time of castration or sham operation. The rabbits were then fed a high-cholesterol diet (HCD) for 2 wk. Microscopic examination of the aortic arch revealed that DHT significantly reduced HCD-induced LOX-1 expression in endothelial cells compared with placebo. In cultured HAEC, DHT at concentrations above 10(-9) to 10(-7) mol/liter inhibited TNFα-induced LOX-1 mRNA and protein expression. Deletion and mutation analysis of human LOX-1 promoter-luciferase constructs transfected into HAEC with an androgen receptor (AR) expression plasmid revealed that the 12-O-tetradecanoylphorbol-13-acetate (TPA) response element (TRE; nucleotides -60/-53) contributed to the inhibitory effects of DHT on TNFα-induced LOX-1 expression. Chromatin immunoprecipitation (ChIP) and re-ChIP assays revealed that TNFα- and TPA-dependent enrichment of p65 and phosphorylated c-Jun in the TRE chromatin region was inhibited by DHT-AR. Consistent with these results, DHT also suppressed TPA-induced expression of LOX-1. In conclusion, DHT exerts antiatherosclerotic effects by suppressing endothelial LOX-1 expression. This effect is partly mediated by the suppression of nuclear factor-κB- and activator protein 1-dependent activation of the LOX-1 promoter.