Serum Indoxyl Sulfate Associates with Postangioplasty Thrombosis of Dialysis Grafts

Abstract

Hemodialysis vascular accesses are prone to recurrent stenosis and thrombosis after endovascular interventions.In vitro data suggest that indoxyl sulfate, a protein-bound uremic toxin, may induce vascular dysfunction and thrombosis. However, there is no clinical evidence regarding the role of indoxyl sulfate in hemodialysis vascular access. From January 2010 to June 2013, we prospectively enrolled patients undergoing angioplasty for dialysis access dysfunction. Patients were stratified into tertiles by baseline serum indoxyl sulfate levels. Study participants received clinical follow-up at 6-month intervals until June 2014. Primary end points were restenosis, thrombosis, and failure of vascular access. Median follow-up duration was 32 months. Of the 306 patients enrolled, 262 (86%) had symptomatic restenosis, 153 (50%) had access thrombosis, and 25 (8%) had access failure. In patients with graft access, free indoxyl sulfate tertiles showed a negative association with thrombosis-free patency (thrombosis-free patency rates of 54%, 38%, and 26% for low, middle, and high tertiles, respectively;P=0.001). Patients with graft thrombosis had higher free and total indoxyl sulfate levels. Using multivariate Cox regression analysis, graft thrombosis was independently predicted by absolute levels of free indoxyl sulfate (hazard ratio=1.14;P=0.01) and free indoxyl sulfate tertiles (high versus low, hazard ratio=2.41;P=0.001). Results of this study provide translational evidence that serum indoxyl sulfate is a novel risk factor for dialysis graft thrombosis after endovascular interventions.

Keywords: arteriovenous shunt; hemodialysis access; thrombosis.

Figure 1.

Kaplan–Meier curves of access patency. (A) Restenosis-free patency and (B) thrombosis-free patency stratified by the tertiles of baseline free indoxyl sulfate levels. P values were tested by log-rank test. H, high; L, low; M, middle.

Figure 2.

Kaplan–Meier curves of thrombosis-free patency by groups. (A) Graft access, (B) native access, (C) nondiabetic patients, and (D) diabetic patients stratified by the tertiles of baseline free indoxyl sulfate levels. P values were tested by log-rank test. H, high; L, low; M, middle; PTA, percutaneous transluminal angioplasty.

Figure 3.

Comparisons of indoxyl sulfate levels between patients with and without access thrombosis. (A and B) All participants, (C and D) stratified by diabetes or nondiabetes, and (E and F) stratified by graft or native accesses. Upper row (A, C, and E): free form; and lower row (B, D, and F): total form. Whisker plots show the 10th, 25th, 50th, 75th, and 90th percentile distributions in each panel. P values were tested by Mann–Whitney U test. DM, diabetes; IS, indoxyl sulfate; T, thrombosis.