Patients with chronic kidney disease have an increased prevalence of peripheral arterial disease. Endothelial progenitor cells (EPC) are pivotal in neovascularization, but their role in mediating peripheral arterial disease in chronic kidney disease is not fully known. Here we studied the impact of indoxyl sulfate, a protein-bound uremic toxin, on EPC function in response to tissue ischemia or cell hypoxia in mice that underwent subtotal nephrectomy or sham operation. At 16 weeks, unilateral hindlimb ischemia was induced in all. Four weeks later, subtotal nephrectomy mice had significantly increased plasma levels of indoxyl sulfate, reduced reperfusion, decreased EPC mobilization, and impaired neovascularization in ischemic hindlimbs compared with control mice. Treatment with AST-120, an oral adsorbent of uremic toxins, reversed these changes. Ischemia-induced protein expression including phospho-eNOS, phospho-STAT3, interleukin-10, and VEGF were significantly decreased in ischemic hindlimbs of subtotal nephrectomy mice versus control mice; all effects were reversed by AST-120. Subtotal nephrectomy mice fed a diet with indole for 12 weeks resulted in impaired neovascularization in ischemic hindlimbs; also reversed by AST-120. In cultured human EPCs, VEGF expression was increased in hypoxia through HIF-1α and interleukin-10/STAT3 signaling; effects suppressed by pretreatment with indoxyl sulfate. Moreover, indoxyl sulfate markedly attenuated hypoxia-induced EPC migration and tube formation. Thus, indoxyl sulfate may be a therapeutic target for EPC-rescue of impaired neovascularization in patients with chronic kidney disease and peripheral arterial disease.

BackgroundElevated aldosterone is associated with increased mortality in the general population. In patients on dialysis, however, the association is reversed. This paradox may be explained by volume overload, which is associated with lower aldosterone and higher mortality.MethodsWe evaluated the relationship between aldosterone and outcomes in a prospective cohort of 328 hemodialysis patients stratified by the presence or absence of volume overload (defined as extracellular water/total body water >48%, as measured with bioimpedance). Baseline plasma aldosterone was measured before dialysis and categorized as low (<140 pg/mL), middle (140 to 280 pg/mL) and high (>280 pg/mL).ResultsOverall, 36% (n = 119) of the hemodialysis patients had evidence of volume overload. Baseline aldosterone was significantly lower in the presence of volume overload than in its absence. During a median follow-up of 54 months, 83 deaths and 70 cardiovascular events occurred. Cox multivariate analysis showed that by using the low aldosterone as the reference, high aldosterone was inversely associated with decreased hazard ratios for mortality (0.49; 95% confidence interval, 0.25–0.76) and first cardiovascular event (0.70; 95% confidence interval, 0.33−0.78) in the presence of volume overload. In contrast, high aldosterone was associated with an increased risk for mortality (1.97; 95% confidence interval, 1.69–3.75) and first cardiovascular event (2.01; 95% confidence interval, 1.28−4.15) in the absence of volume overload.ConclusionsThe inverse association of aldosterone with adverse outcomes in hemodialysis patients is due to the confounding effect of volume overload. These findings support treatment of hyperaldosteronemia in hemodialysis patients who have achieved strict volume control.

Background Epicardial adipose tissue is associated with coronary artery disease (CAD). Circulating endothelial progenitor cell (EPC) level represents a marker of endothelial dysfunction and vascular health. However, the relationship between epicardial fat and circulating EPC remains unknown. This study aimed to investigate association between echocardiographic epicardial fat thickness (EFT) and circulating EPC level. Hypothesis Epicardial fat causes inflammation and contributes to progression of CAD. Methods We enrolled 213 consecutive patients with stable angina, and EFT was determined by echocardiography. Quantification of EPC markers (defined as CD34 +, CD34 + KDR +, CD34 + KDR + CD133 + cells) in peripheral blood samples was used to measure circulating EPCs. All patients were divided into 3 tertiles according to EFT levels: group 1, low tertile of EFT; group 2, middle tertile of EFT; and group 3, high tertile of EFT. Results Among the 3 groups, CAD disease severity determined by SXscore was negatively correlated with EFT, but the difference did not reach statistical significance (P = 0.066). Additionally, patients in the high and middle tertiles of EFT had higher circulating EPC levels than did those in the low tertile of EFT (P = 0.001 and P < 0.001, respectively). In multivariate analysis, EPC level was significantly associated with echocardiographic EFT (standardized β = −0.233, P = 0.001), independent of multiple covariates. Conclusions Epicardial adipose tissue is associated with circulating EPC levels. There was a trend between epicardial fat and severity of CAD, though analysis did not reach statistical significance, and this may be attributed to the interaction between several risk factors of CAD.