Indoxyl Sulfate and Incident Peripheral Artery Disease in Hemodialysis Patients

Abstract

Peripheral artery disease (PAD) is highly prevalent among patients with chronic kidney disease (CKD) and portends a very poor prognosis. Indoxyl sulfate has been shown to induce atherothrombosis and impaired neovascularization in uremic mice. However, there is no clinical evidence regarding the role of indoxyl sulfate in PAD associated with CKD. We examined associations between indoxyl sulfate and incident symptomatic lower extremity PAD events as well as major adverse cardiovascular events (MACE) and all-cause mortality using Cox proportional hazards models in a prospective cohort of 200 hemodialysis patients free of PAD at baseline. Patients were considered as having PAD if they developed PAD symptoms confirmed by an ankle-brachial index with waveforms, duplex ultrasound or angiography, and/or major adverse limb events including revascularization and amputation. During a median follow-up of 6.5 years, 37 patients (18.5%) experienced incident symptomatic PAD. MACE occurred in 52 patients, and a total of 85 patients died. After adjusting for traditional risk factors for PAD, including age, current smoking, diabetes, and cardiovascular disease, indoxyl sulfate was significantly associated with the risk of PAD (hazard ratio (HR), 1.19 for every 10-µg/mL increase in indoxyl sulfate; 95% confidence interval (CI), 1.05–1.35). However, indoxyl sulfate was not associated with risk of MACE (HR, 1.00; 95% CI, 0.90–1.12) or death from any cause (HR, 0.98; 95% CI, 0.90–1.07). Indoxyl sulfate was associated with incident symptomatic PAD but not with MACE or all-cause mortality, suggesting that indoxyl sulfate toxicity may be unique to PAD among hemodialysis patients.