Metabolic alterations by indoxyl sulfate in skeletal muscle induce uremic sarcopenia in chronic kidney disease.

Sarcopenia is associated with increased morbidity and mortality in chronic kidney disease (CKD). Pathogenic mechanism of skeletal muscle loss in CKD, which is defined as uremic sarcopenia, remains unclear. We found that causative pathological mechanism of uremic sarcopenia is metabolic alterations by uremic toxin indoxyl sulfate. Imaging mass spectrometry revealed indoxyl sulfate accumulated in muscle tissue of a mouse model of CKD. Comprehensive metabolomics revealed that indoxyl sulfate induces metabolic alterations such as upregulation of glycolysis, including pentose phosphate pathway acceleration as antioxidative stress response, via nuclear factor (erythroid-2-related factor)-2. The altered metabolic flow to excess antioxidative response resulted in downregulation of TCA cycle and its effected mitochondrial dysfunction and ATP shortage in muscle cells. In clinical research, a significant inverse association between plasma indoxyl sulfate and skeletal muscle mass in CKD patients was observed. Our results indicate that indoxyl sulfate is a pathogenic factor for sarcopenia in CKD.

Efficacy and Biocompatibility of Neutral Icodextrin Peritoneal Dialysis Fluid.

Neutral icodextrin peritoneal dialysis (PD) fluid (n-ICO) has become available for use in Japan. However, removal of water and solutes remains to be elucidated in detail. The present study was designed to determine removal of water, electrolytes, and small, middle, and large molecules in a period of 16 hours. In addition, biocompatibility with respect to peritoneal mesothelial cells was determined.Three stable patients undergoing PD at Tohoku University Hospital were administered n-ICO. Water removal was monitored every 2 hours. Sodium, urea nitrogen [molecular weight (MW): 28 Da], uric acid (MW: 168 Da), ß2-microglobulin [ß2M (MW: 11,800 Da)], α1-microglobulin [α1M (MW: 33,000 Da)], albumin (MW: 66,000 Da), and immunoglobulin G (MW: 160,000 Da) were measured in plasma and dialysate.Primary human peritoneal mesothelial cells were collected from 6 patients. Equal numbers of cells were seeded into 96-well culture plates and cultured for 12 hours. Culture medium was then replaced with dialysate, and 24-hour cell proliferation was determined by WST-1 assay.Water removal was sustained for 16 hours with n-ICO. The Na concentration in effluent did not change over that time. Small molecules such as urea nitrogen and uric acid were rapidly removed. Thus, their dialysate-to-plasma concentration ratio (D/P) approached 1.0 (equilibrium) in 2 - 4 hours. The D/P values for the larger molecules ß2M and α1M were 0.4 and less than 0.1 respectively at 16 hours. However, larger molecules were removed in a time-dependent manner.Cell proliferation with n-ICO PD fluid was not different from that with lactate-buffered glucose PD fluid, but was increased from that with acidic icodextrin PD fluid (a-ICO).Water and solute removal with the new n-ICO is not much different from that with a-ICO. However, biocompatibility as reflected by cell proliferation was superior under n-ICO than under a-ICO and equal to proliferation under glucose PD fluid.

Role of Chronic Use of Tolvaptan in Patients with Heart Failure Undergoing Peritoneal Dialysis.

In the present study, we assessed the effect of chronic tolvaptan treatment and compared it with the effect of conventional treatment without tolvaptan. In addition, changes in cardiac load and body fluid composition were compared.The study enrolled 22 patients undergoing peritoneal dialysis who had been receiving tolvaptan for more than 1 year and 10 patients undergoing peritoneal dialysis who had been treated with conventional diuretics. Left ventricular mass index (LVMI), left ventricular ejection fraction (LVEF), and E/e' index were measured by echocardiography at baseline and after 12 months of tolvaptan treatment (or an equivalent period). Body composition was analyzed by bioimpedance monitoring (BIM).In the tolvaptan group, LVMI was significantly reduced after 12 months of treatment; in the conventional-treatment group, it was significantly increased. The measured LVEF did not change in the tolvaptan group, but it increased significantly in the conventional-treatment group. The E/e' index was not altered in either group; however, it was reduced in patients receiving tolvaptan whose initial E/e' was greater than 15. Although urine volume was not significantly increased in either group, renal creatinine clearance increased significantly in tolvaptan group; no change was observed in the conventional-treatment group. Renal and peritoneal Kt/V did not significantly change during the study. In both groups, ß2-microglobulin was significantly and similarly increased. Extracellular water (ECW) and intracellular water (ICW) as determined by BIM were both reduced after 12 months of tolvaptan treatment. We observed a significant correlation between the ratio of ECW to total body water at the initiation of tolvaptan and the reduction in ECW after 12 months.Our results indicate that chronic tolvaptan treatment has a beneficial role in body fluid control without a reduction in cardiac and renal function. Volume control depends on an equal reduction in ECW and ICW, which can also have a benefit in avoiding hyponatremia.

Glucose and Insulin Response to Peritoneal Dialysis Fluid in Diabetic and Nondiabetic Peritoneal Dialysis Patients.

A postprandial increase in blood glucose in peritoneal dialysis (PD) patients with diabetes was observed in our previous study using continuous blood glucose monitoring. The response was observed in diabetic but not in nondiabetic PD patients. In addition, the response was reduced when patients used icodextrin; glucose absorbed from the peritoneum was responsible for the postprandial increase in blood glucose. Because our PD patients often change their PD fluid before meals, the present study aimed to determine the blood glucose and insulin responses to PD fluid. The 26 patients who agreed to participate in the study protocol [16 with diabetes (12 men, 4 women; 11 receiving insulin; 5 being controlled with oral antidiabetic drugs; average duration from diagnosis with diabetes: 16.4 ± 11 years); 10 without diabetes (4 men, 6 women)] had an average age of 60.5 ± 13.0 years. Average PD vintage was 578.7 ± 352.9 days. Blood samples were taken during a peritoneal equilibration test (PET) with 2.5% glucose solution at baseline and at 0.5, 2, and 4 hours. Levels of blood glucose and insulin were analyzed. A rapid increase in blood glucose (peak at 0.5 hours, 23.5 ± 22.2 mg/dL increase from baseline) was observed in nondiabetic patients. A delayed but higher peak response was observed in diabetic patients (peak at 1 hour, 54.9 ± 38.3 mg/dL increase from baseline). Peak response of insulin occurred at 0.5 hours in nondiabetic patients; in diabetic patients it occurred at 2 hours. No differences in the average insulin level during the PET were observed in the two groups (nondiabetic: 35.3 ± 15.6 µU/mL; diabetic: 38.9 ± 7.6 µU/mL). The study results suggest that a delayed insulin response after a PD fluid exchange could participate in the exaggerated postprandial increase in blood glucose in diabetic PD patients, particularly when the PD fluid exchange is performed before food intake.

Association Between Home Blood Pressure and Body Composition by Bioimpedance Monitoring in Patients Undergoing Peritoneal Dialysis.

Home blood pressure (HBP) is an independent predictor of cardiovascular and renal function. However, no particular guidelines have been established for optimal HBP in peritoneal dialysis (PD) patients. Bioelectrical impedance analysis (BIA) is a beneficial tool for determining body composition. In the present study, we used BIA to determine body composition parameters that might play a role in the regulation of HBP in PD patients, and we compared HBP with office blood pressure (BP). Our study enrolled 15 patients (11 men, 4 women) receiving PD at Tohoku University Hospital, who, for 1 year, agreed to monitor HBP and to undergo body composition analysis. Patients were requested to measure HBP twice daily (morning, night) using a home BP device. A bioimpedance monitor was used to monitor body composition each month. Blood and urine samples were also analyzed each month. The relationships of average morning systolic HBP (sMHBP) with parameters of body composition and of blood and urine analyses were evaluated. The enrolledpatients were 66.3 ± 7.7 years of age and had a PD vintage of 28.3 ± 6.4 months. Overall, their sMHBP was 128 ± 13 mmHg and their office systolic BP was 126 ± 15 mmHg. Although office systolic BP and sMHBP both correlated with body fluid parameters [total body water (TBW)/height2], renal function (renal Kt/V serum creatinine), and heart function (left ventricular mass index), the correlation coefficient for sMHBP and TBW/height2 was highest, with sMHBP being the only independent predictor. Sodium intake was associated only with sMHBP. Our results suggest that body fluid status determined by BIA, heart and renal function, and sodium intake show better associations with sMHBP than with office systolic BP. Monitoring HBP and body composition by BIA are beneficial for the maintenance of volume status in PD patients.