Tomoya Hirayama

An Oral Adsorbent, AST-120, Suppresses Oxidative Stress in Uremic Rats

Background: The production of reactive oxygen species (ROS) has been suggested to play an important role in the progression of chronic kidney disease (CKD). An oral adsorbent, AST-120, removes uremic toxins such as indoxyl sulfate (IS) and delays the progression of CKD, but the effect on ROS production is unknown. The present study aimed to determine whether AST-120 reduces oxidative stress in uremic rat kidneys using markers of ROS production such as acrolein and 8-hydroxy-2′-deoxyguanosine (8-OHdG). Methods: Daily administration of AST-120 was started 6 weeks after 5/6 nephrectomy and continued for 18 weeks. The changes in metabolic data, serum and urine IS levels, urinary excretion of markers of oxidative stress, and renal histological findings were investigated in uremic rats with or without AST-120 treatment. Results: In parallel with the increase in serum and urine IS, the serum creatinine, urinary protein and acrolein levels started to increase at 6 weeks, but urinary 8-OHdG remained unchanged and significantly increased at 18 weeks in uremic rats. AST-120 markedly and significantly attenuated increases in uremic toxins and oxidative stress levels as well as the histological changes in glomerular sclerosis, interstitial fibrosis, and the tubular staining of 8-OHdG. Conclusion: AST-120 suppressed the progression of CKD, at least in part, via attenuation of oxidative stress induced by uremic toxin.

Potential impact of renin-angiotensin system inhibitors and calcium channel blockers on plasma high-molecular-weight adiponectin levels in hemodialysis patients.

Although metabolic syndrome confers an increased risk of cardiovascular disease in the general population, little is known about the alteration of abdominal adiposity and its association with adipocytokines in hemodialysis patients. We investigated the plasma high-molecular-weight (HMW) adiponectin level and its relationship to visceral fat area (VFA) and various markers of atherosclerosis in hemodialysis patients. In a cross-sectional study, conventional cardiovascular risk factors, plasma total and HMW adiponectin, the number of components of the metabolic syndrome and, using computed tomography, the distribution of abdominal adiposity were assessed in 144 hemodialysis patients (90 men and 54 women; mean age, 60.7 years) and 30 age- and sex-matched patients with chronic kidney disease (CKD). Plasma HMW adiponectin levels in hemodialysis patients were significantly higher than those in patients with CKD, negatively associated with VFA and serum triglycerides and positively associated with plasma total adiponectin, as well as the HMW-to-total adiponectin ratio in men and women (all P<0.05) in a simple regression analysis. In a multiple regression analysis, VFA was a significant determinant of HMW adiponectin in hemodialysis patients. Furthermore, after adjustment for classical risk factors, HMW adiponectin levels were significantly higher in patients undergoing treatment with renin–angiotensin system inhibitors or calcium channel blockers compared with patients not undergoing such treatment. This study shows that plasma HMW adiponectin levels were negatively associated with VFA and positively associated with treatment with blockade of the renin–angiotensin system and of the calcium channel. Therefore, these drugs might be effective for improving adipocytokine-related metabolic abnormalities in hemodialysis patients.

Impact of metabolic disturbances and malnutrition-inflammation on 6-year mortality in Japanese patients undergoing hemodialysis.

Metabolic syndrome confers an increased risk of cardiovascular disease (CVD) in the general population. The relationship between adiponectins, and clinical outcomes in patients undergoing hemodialysis remains controversial. We investigated whether adiponectins, biomarkers of inflammation, nutrition status and clinical features predict the mortality of patients undergoing hemodialysis for 6 years. We measured baseline plasma total and high‐molecular‐weight (HMW) adiponectins, tumor necrosis factor (TNF)‐α, serum high sensitivity C‐reactive protein (hsCRP), and clinical characteristics including visceral fat area (VFA) and the Geriatric Nutritional Risk Index (GNRI) in 133 patients undergoing chronic hemodialysis. Forty‐one of the 133 patients died during follow‐up. The deceased patients were significantly older, had more prior CVD and diabetes, higher TNF‐α and hsCRP levels but lower GNRI. VFA, and total and HMW adiponectin did not significantly differ between the two groups. TNF‐α and hsCRP levels and GNRI score were significant for predicting all‐cause and cardiovascular mortality in receiver operating curve analyses. When stratified by a GNRI score of 96, Cox proportional hazards analyses identified TNF‐α as a significant predictor of all‐cause mortality (hazard ratio [HR] 1.23; P = 0.038) and hsCRP as a significant predictor of all‐cause and cardiovascular mortality (HR, 2.32, P = 0.003; HR 2.30, P = 0.012, respectively) after adjusting for age, sex, diabetes mellitus, and prior CVD, only in malnourished patients. These results demonstrate that malnutrition and the inflammatory markers TNF‐α and hsCRP, but not metabolic markers, including VFA and adiponectins have a significant impact on 6‐year all‐cause and cardiovascular mortality in Japanese patients undergoing hemodialysis.

The balance of fetuin-A and osteoprotegerin is independently associated with diastolic dysfunction in hemodialysis patients

Fetuin-A and osteoprotegerin (OPG) are arterial calcification regulators, which are related to cardiovascular survival in hemodialysis patients. We hypothesized that a balance of these calcification regulators might mediate the progression of left ventricular (LV) diastolic dysfunction in hemodialysis patients. We recruited 63 hemodialysis patients and measured their serum fetuin-A, OPG, arterial stiffness, aortic calcification and echocardiographic parameters, including the transmitral early diastolic velocity/tissue Doppler mitral annular early diastolic velocity ratio (E/E′), and analyzed the relationships between these variables. Fetuin-A levels were significantly and negatively correlated with the ankle–brachial pulse wave velocity (baPWV), aortic calcification score (AOCS), left atrial volume index (LAVI), LV mass index (LVMI) and E/E′. OPG levels and the ratio of OPG to fetuin-A levels were significantly and positively correlated with the baPWV, AOCS, LAVI and E/E′. A stepwise multiple regression analysis revealed that E/E′ was independently correlated with fetuin-A levels (β=−0.334, P=0.02), OPG levels (β=0.367, P=0.01) and the ratio of OPG to fetuin-A (β=0.295, P=0.04). Categorizing the patients according to their serum fetuin-A and OPG levels revealed that patients with low fetuin-A and high OPG levels had the highest LAVI, LVMI and E/E′ values after adjusting for potential confounders. Serum fetuin-A levels negatively reflected, whereas OPG levels and the ratio of OPG to fetuin-A positively reflected an increase in vascular and ventricular stiffness, leading to the aggravation of diastolic dysfunction. Therefore, based on our results, the balance of the tissue calcification regulators fetuin-A and OPG could mediate the progression of LV diastolic dysfunction in hemodialysis patients.