Serum indoxyl sulfate is associated with vascular disease and mortality in chronic kidney disease patients

Abstract

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.

Figures

Figure 1.

Serum levels of IS as a function of CKD stages. *P < 0.05 versus CKD stages 2, 3 or 5D; †P < 0.05 versus CKD stages 2, 3, 4, or 5. The dotted line indicates the reference value for healthy controls.

Figure 2.

Linear regression curve. Relationship between serum levels of IS and the estimated GFR for patients at CKD stages 2 to 5 (n = 95).

Figure 3.

Linear regression curves. (A) The relationship between serum IS and the aortic calcification score as quantified by MSCT (n = 129). (B) The relationship between serum IS and the aortic calcification score as quantified on a plain, abdominal x-ray (n = 122). (C) The relationship between serum IS and PWV (n = 139).

Figure 4.

Kaplan–Meyer estimates of (A) overall mortality and (B) cardiovascular mortality for patients as a function of tertiles for serum IS levels.