Indoxyl Sulfate: A Novel Cardiovascular Risk Factor in Chronic Kidney Disease

C hronic kidney disease (CKD) is now clearly recognized as a public health problem worldwide. Patients with CKD display a substantial increase in end-stage renal disease (ESRD) and cardiovascular disease (CVD). Moreover, the prognosis of CVD in CKD is extremely poor. Understanding the pathophysiology of CVD in CKD might help to develop treatment strategies to reduce its morbidity and mortality. Traditional cardiovascular risk factors for the general population, such as diabetes mellitus, high blood pressure, and dyslipidemia, are more common in patients with CKD, but cannot entirely explain the increased cardiovascular risk. Compelling evidence suggests that the uremic milieu itself plays a critical role in the development and progression of CVD. Various solutes that would normally be excreted by the kidneys accumulate in patients with CKD. These solutes are called uremic toxins when they interact negatively with biological functions and contribute to the uremic syndrome. Of note, the gut microbiota is markedly altered in CKD. Fermentation of protein and amino acids by certain gut microbiota results in the generation of different toxic metabolites that are absorbed into the circulation and are retained in CKD. Indoxyl sulfate, indole-3 acetic acid, p-cresyl sulfate, trimethylamine N-oxide, and phenylacetylglutamine are uremic toxins derived from dietary protein metabolism by gut microbiota (Table 1) that have been associated with CVD in patients with CKD (Table 2). Indoxyl sulfate is among the most representative gut-derived uremic toxins and has emerged as an important therapeutic target. In this review, we will summarize recent advances in understanding the association between gut-derived uremic toxins and CVD in CKD, with special emphasis on the pathogenic role of indoxyl sulfate.