Serum Indoxyl Sulfate Is Associated with Vascular Disease and Mortality in Chronic Kidney Disease Patients

Background and objectives: As a major component of uremic syndrome, cardiovascular disease is largely responsible for the high mortality observed in chronic kidney disease (CKD). Preclinical studies have evidenced an association between serum levels of indoxyl sulfate (IS, a protein-bound uremic toxin) and vascular alterations. The aim of this study is to investigate the association between serum IS, vascular calcification, vascular stiffness, and mortality in a cohort of CKD patients.Design, setting, participants, & measurements: One-hundred and thirty-nine patients (mean ± SD age: 67 ± 12; 60% male) at different stages of CKD (8% at stage 2, 26.5% at stage 3, 26.5% at stage 4, 7% at stage 5, and 32% at stage 5D) were enrolled.Results: Baseline IS levels presented an inverse relationship with renal function and a direct relationship with aortic calcification and pulse wave velocity. During the follow-up period (605 ± 217 d), 25 patients died, mostly because of cardiovascular events (n = 18). In crude survival analyses, the highest IS tertile was a powerful predictor of overall and cardiovascular mortality (P = 0.001 and 0.012, respectively). The predictive power of IS for death was maintained after adjustment for age, gender, diabetes, albumin, hemoglobin, phosphate, and aortic calcification.Conclusions: The study presented here indicates that IS may have a significant role in the vascular disease and higher mortality observed in CKD patients.Cardiovascular disease (CVD) mortality is significantly higher in patients with chronic kidney disease (CKD) than in the general population (1,2). Vascular calcification and arterial stiffness are considered to be major contributors to this elevated mortality (3). The pathophysiology of CVD in a CKD setting is not completely understood; in addition to the traditional CVD risk factors, uremia-related elements play an important role. Although these elements may differ from one individual to another, the accumulation of toxic compounds is a common scenario in CKD. These compounds are classified according to their molecular weight and protein binding ability and several have been shown to exert adverse biologic effects and thus enhance the potential for cardiovascular damage (4). Interestingly, we recently observed that cardiac and aortic abnormalities were independently associated with the extent of endothelial dysfunction and renal failure in a mouse model of CKD (5), corroborating the hypothesis whereby the accumulation of uremic toxins is involved in the development of CKD-related cardiovascular abnormalities.Indoxyl sulfate (IS) is a protein-bound uremic toxin that results from the metabolism of dietary tryptophan. Briefly, tryptophan is metabolized into indole by intestinal bacteria and after intestinal absorption is further converted to IS in the liver. The kidneys excrete the toxin via proximal tubular secretion. Consequently, IS accumulates in the blood of patients with impaired renal function. Moreover, IS cannot be efficiently removed by conventional hemodialysis because of its high binding affinity for albumin (6). The role of IS as a uremic toxin was first revealed by its accelerating effects on the progression of CKD (7). Recently, it has been reported that IS may also act as a vascular toxin. In endothelial cells, IS has been shown to (1) induce oxidative stress by modifying the balance between pro- and antioxidant mechanisms (8), (2) stimulate the release of endothelial microparticles (9), and (3) blunt endothelial healing ability (10). Furthermore, IS directly stimulates rat vascular smooth muscular cell proliferation in a concentration-dependent manner (11). Accordingly, increased aortic wall thickness and severe aortic calcification with colocalization of osteoblast-specific proteins (e.g., Cbfa-1, osteopontin, and alkaline phosphatase) were observed in Dahl salt-sensitive, hypertensive rats to which IS was administered (12). These findings suggest that IS may play a role in vascular dysfunction in CKD patients.To investigate this hypothesis, we assessed serum IS levels, aortic calcification, and vascular stiffness (as measured by pulse wave velocity, PWV) in a cohort of CKD patients. We further examined whether IS levels might predict mortality in this population.