Presented in part at the International Symposium “Uremic Toxins and Oxidative Stress in Dialysis Patients” from the 55th Annual Meeting of the Japanese Society for Dialysis Therapy held 18–20 June 2010 in Kobe, Japan.
Role of Oxidative Stress and Indoxyl Sulfate in Progression of Cardiovascular Disease in Chronic Kidney Disease
Article first published online: 25 JAN 2011
© 2011 The Authors. Therapeutic Apheresis and Dialysis © 2011 International Society for Apheresis
Therapeutic Apheresis and Dialysis
Volume 15, Issue 2, pages 125–128, April 2011
How to Cite
Fujii, H., Nakai, K. and Fukagawa, M. (2011), Role of Oxidative Stress and Indoxyl Sulfate in Progression of Cardiovascular Disease in Chronic Kidney Disease. Therapeutic Apheresis and Dialysis, 15: 125–128. doi: 10.1111/j.1744-9987.2010.00883.x
- Issue published online: 22 MAR 2011
- Article first published online: 25 JAN 2011
- Received July 2010; revised August 2010.
- Cardiovascular disease;
- Chronic kidney disease;
- Oxidative stress;
- Uremic toxin
Several abnormalities of the cardiovascular system are observed in most cases of chronic kidney disease (CKD). Mechanisms underlying these abnormalities are complicated, and several factors contribute to their pathogenesis. Of these factors, oxidative stress and uremic toxins are considered to play key roles in the progression of cardiovascular disease (CVD) in CKD. Oxidative stress increases significantly in CKD and accelerates proteinuria and renal dysfunction. In addition, oxidative stress has been reported to induce cardiac hypertrophy and fibrosis. Indoxyl sulfate, a uremic toxin, has recently been suggested to play a crucial role in the development of CVD. Recent in vitro data suggest that indoxyl sulfate increases oxidative stress. Some reports have shown that AST-120, which is an oral charcoal adsorbent, can reduce oxidative stress by lowering serum indoxyl sulfate levels. Recently, we have also demonstrated that indoxyl sulfate is associated with the production of oxidative stress, and that increased oxidative stress is significantly correlated with cardiac hypertrophy and fibrosis. Furthermore, results of our basic and clinical studies suggested that AST-120 can prevent progression of cardiac hypertrophy by reducing oxidative stress in CKD. Thus, one of the main targets of the management of CKD and CVD is the control of oxidative stress and uremic toxins, such as indoxyl sulfate.
Several reports have demonstrated that chronic kidney disease (CKD) is an important risk factor for cardiovascular disease (CVD). In fact, the adjusted hazard ratio for CVD events increases with a decrease in the glomerular filtration rate (GFR) (1). In addition, both decreased renal function and the presence of albuminuria have been proven as powerful cardiovascular risk factors (2–5). Although the importance of the association between CKD and CVD has recently been emphasized, the detailed interaction between the kidneys and the cardiovascular system remains unclear. Several factors, such as anemia, inflammation, lipid and metabolic disorders, smoking, hypertension, oxidative stress, the renin-angiotensin system and uremic toxins including homocysteine, asymmetric dimethylarginine and indoxyl sulfate, are believed to contribute to this pathophysiology. These factors are closely associated with progression of CKD and CVD. Although multiple mechanisms are undoubtedly involved in this progression, we focused here on the role of oxidative stress and the uremic toxin indoxyl sulfate in the pathogenesis of this progression.
Oxidative stress can be considered an imbalance between the production and degradation of reactive oxygen species (ROS). This is considered the consequence of high ROS production, and the imbalance can lead to the oxidation of biological molecules, resulting in tissue damage. Oxidative stress increases with the increase in several other risk factors for CVD, including obesity, hypertension, diabetes, hyperlipidemia, and smoking. Furthermore, oxidative stress has been reported to increase in CKD (6,7). This increase seems to occur in a graded manner with a decline in renal function, because several studies have reported that GFR is inversely correlated with different markers of oxidative stress.
Increased oxidative stress is closely associated with kidney and cardiac damage. Especially in diabetic nephropathy, oxidative stress increases and is involved in the progression of renal damage (8). We have demonstrated that oxidative stress is significantly correlated with glomerular abnormalities, such as glomerular hypertrophy and mesangial proliferation, observed in the pathophysiology of diabetic nephropathy (9). Furthermore, diabetes mellitus is a major cause of CKD worldwide. Taken together, it is apparent that remarkably increased oxidative stress plays a very important role in CKD. In addition, increased oxidative stress is well known as a crucial cause of cardiac damage (10). Oxidative stress has been implicated in the development of cardiac damage, such as hypertrophy, fibrosis, apoptosis, and remodeling. Several experimental studies have indicated that various antioxidant approaches can attenuate these conditions (11–13). Amann et al. have demonstrated that antioxidant therapy with DL-α-tocopherol improves left ventricular hypertrophy (LVH) and reduces typical unfavorable changes of the myocardium in experimental CKD model rats (14).
Recently, several studies have reported that NADPH oxidases, which are major sources of ROS, play an important role in the pathogenesis of several aspects of cardiac remodeling and its antecedent conditions, largely through its actions on redox-sensitive signal transduction. Expression and activity of NADPH oxidase have been confirmed to be increased in the myocardium of patients with ischemic and non-ischemic heart failure (15–17). Increased NADPH oxidase activation has been implicated in cardiac hypertrophy and fibrosis (18,19); and we have also demonstrated that expression of NADPH oxidase is significantly increased even in diabetic rats (9). Several clinical studies have reported that diabetes is associated with LVH (20,21); thus, oxidative stress and NADPH oxidase seem to play a crucial role in the progression of both kidney and cardiac diseases.
Uremic toxins accumulate in the bodies of advanced-stage CKD patients. These cannot be easily removed from the body. Indoxyl sulfate has been implicated as one such uremic toxin and is a naturally occurring metabolite of tryptophan. Indoxyl sulfate is produced in the liver from indole, a tryptophan derivative that is generated by bacteria in the large intestine. Indoxyl sulfate levels seem to be elevated in CKD patients, mainly as a result of poor urinary clearance. In addition, indoxyl sulfate has been shown to bind efficiently to albumin, and therefore it is difficult to clear indoxyl sulfate by hemodialysis or other treatments (22). Recently, indoxyl sulfate has been reported to stimulate vascular smooth muscle cell proliferation and vascular calcification (23,24). Furthermore, the recent clinical study by Massy et al. showed that indoxyl sulfate may be associated with vascular disease and with higher mortality observed in CKD patients (25). Indoxyl sulfate also has been reported to relate with skeletal resistance to parathyroid hormone in hemodialysis patients (26). As one of the mechanisms leading to CVD, indoxyl sulfate is believed to induce ROS production through a pathway involving NADPH oxidase or NADPH-like oxidase. In fact, recent in vitro data suggest that indoxyl sulfate increases oxidative stress, and this increase is in the proportion with the increase in the concentration of added indoxyl sulfate (27). Increased ROS is considered to affect progression of CVD. In addition, indoxyl sulfate has been reported to strongly decrease the levels of total glutathione levels, which is the most active non-enzymatic antioxidant, in endothelial cells (27). Our recent study also demonstrated that positive linear relationships between urinary indoxyl sulfate excretion and oxidative stress markers, such as 8-hydroxydeoxyguanosine and acrolein, were observed in both urine and the cardiac tissue (28). Based on these findings, we believe that indoxyl sulfate might induce oxidative stress and accelerate the progression of CVD, and hence, lowering the indoxyl sulfate level is important for reducing oxidative stress in CKD.
AST-120 (Kremezin; Daiichi-Sankyo Industry, Tokyo, Japan) is an oral charcoal adsorbent that reduces the levels of circulating uremic toxins, such as indoxyl sulfate and indole acetic acid. Previous studies have shown that AST-120 has the potential to prevent histological and functional aggravation of CKD in both human patients and an animal model of CKD (29,30). In addition, recent reports have demonstrated that AST-120 can reduce oxidative stress produced by indoxyl sulfate in CKD (31,32). Based on these properties, we speculated that it may suppress oxidative stress and the progression of cardiac damage in CKD. In fact, our study has demonstrated that AST-120 administration reduces both serum and urinary indoxyl sulfate levels, heart and left ventricular volumes, cardiac fibrosis, and oxidative stress in both urine and cardiac tissue in a CKD rat model (28). Moreover, we have also demonstrated that treatment by AST-120 attenuates cardiac concentric change in pre-dialysis CKD patients (33). Taken together, these results suggest that AST-120 prevents progression of CVD, including LVH, vascular calcification, and atherosclerosis, possibly via the reduction of oxidative stress by removing uremic toxins, such as indoxyl sulfate (Figure 1). Therefore, treatment with AST-120 could be one of the useful options for improving cardiovascular health in CKD patients.
Cardiovascular consequences of CKD may be associated with oxidative stress and uremic toxins, including indoxyl sulfate. Because CVD is one of the main causes of death in CKD patients, controlling the levels of oxidative stress and uremic toxins is important for the prevention of cardiovascular complications associated with renal conditions.
This work was supported by a Grant-in-Aid for Young Scientists (B) (No. 21790810 to HF) from the Ministry of Education, Culture, Sports, Science, and Technology (MEXT) of Japan.
- 4Prevend Study Group. Microalbuminuria is common, also in a nondiabetic, nonhypertensive population, and an independent indicator of cardiovascular risk factors and cardiovascular morbidity. J Intern Med 2001;249:519–26., , et al.
- 33Effect of AST-120 on cardiac abnormalities in patients with chronic kidney disease (CKD) stage 4 and 5. The XLVII ERA-EDTA Congress—II DGfN Congress. 2010. [abstract]., , , .