Free P-Cresyl Sulfate Shows The Highest Association With Cardiovascular Outcome In Chronic Kidney Disease.

Abstract

BACKGROUND\nSeveral protein-bound uremic toxins (PBUT) have been associated with cardiovascular (CV) and all-cause mortality in chronic kidney disease (CKD) but the degree to which this is the case per individual PBUT and the pathophysiological mechanism had only partially been unraveled.\n\n\nMETHODS\nWe compared the prognostic value of both total and free concentrations of 5 PBUT [p-cresyl sulfate (pCS), p-cresyl glucuronide (pCG); indoxyl sulfate (IxS); indole acetic acid (IAA) and hippuric acid (HA)] in a cohort of 523 patients with non-dialysis CKD stage G1-G5. Patients were followed prospectively for the occurrence of a fatal or non-fatal CV event as the primary endpoint and a number of other major complications as secondary endpoints. In addition, association with and the prognostic value of 9 markers of endothelial activation/damage was compared.\n\n\nRESULTS\nAfter a median follow-up of 5.5\u2009years, 149 patients developed the primary endpoint. In multivariate Cox-regression models adjusted for age, sex, systolic blood pressure, diabetes mellitus, and eGFR, and corrected for multiple testing, only free p-cresyl sulfate (pCS) was associated with the primary endpoint (1.39[1.14-1.71]; p\u2009=\u20090.0014). Free pCS also correlated with ADAMST13 (r=-0.114; p\u2009<\u20090.05), ANGPT2 (r\u2009=\u20090.194; p\u2009<\u20090.001), MMP-7 (r\u2009=\u20090.238; p\u2009<\u20090.001) and syndecan 1 (r\u2009=\u20090.235; p\u2009<\u20090.001). Of these markers of endothelial activation/damage, ANGPT2 (1.46[1.25-1.70]; p\u2009<\u20090.0001) and MMP-7 (1.31[1.08-1.59]; p\u2009=\u20090.0056) were also predictive of the primary outcome.\n\n\nCONCLUSIONS\nAmong PBUTs, free pCS shows the highest association with cardiovascular outcome in non-dialysed patients with CKD. Two markers of endothelial activation/damage that were significantly correlated to free pCS, ANGPT2 and MMP-7, were also associated with CV outcome. The hypothesis that free pCS exerts its cardiovascular toxic effects by an adverse effect on endothelial function deserves further exploration.