Toxic Effects of Indoxyl Sulfate on Osteoclastogenesis and Osteoblastogenesis.

Uremic toxins, such as indoxyl sulfate (IS) and kynurenine, accumulate in the blood in the event of kidney failure and contribute to further bone damage. To maintain the homeostasis of the skeletal system, bone remodeling is a persistent process of bone formation and bone resorption that depends on a dynamic balance of osteoblasts and osteoclasts. The aryl hydrocarbon receptor (AhR) is a ligand-activated transcription factor that regulates the toxic effects of uremic toxins. IS is an endogenous AhR ligand and is metabolized from tryptophan. In osteoclastogenesis, IS affects the expression of the osteoclast precursor nuclear factor of activated T cells, cytoplasmic 1 (NFATc1) through AhR signaling. It is possible to increase osteoclast differentiation with short-term and low-dose IS exposure and to decrease differentiation with long-term and/or high-dose IS exposure. Coincidentally, during osteoblastogenesis, through the AhR signaling pathway, IS inhibits the phosphorylation of ERK, and p38 reduces the expression of the transcription factor 2 (Runx2), disturbing osteoblastogenesis. The AhR antagonist resveratrol has a protective effect on the IS/AhR pathway. Therefore, it is necessary to understand the multifaceted role of AhR in CKD, as knowledge of these transcription signals could provide a safe and effective method to prevent and treat CKD mineral bone disease.

Association of polyunsaturated fatty acids with improved heart rate variability and cardiovascular events in patients with end-stage renal disease receiving maintenance dialysis: a systematic review and meta-analysis of randomized controlled trials.

OBJECTIVE: Apart from dietary restriction and medical therapy, the benefits of cardiovascular protection offered by polyunsaturated fatty acid (PUFA) supplements in patients with ESRD receiving maintenance dialysis remain unclear. This systematic review and meta-analysis examined the effects of PUFAs on blood pressure, heart rate (HR), HR variability (HRV), and cardiovascular disease (CVD) prognosis. METHODS: We identified randomized controlled trials (RCTs) from Embase, PubMed (including MEDLINE), and Web of Science. We included seven RCTs that involved 724 patients with ESRD receiving dialysis and PUFA supplements. RESULTS: The data indicated that compared with the control group, the PUFA group demonstrated decreased cardiovascular events (Peto odds ratio = 0.52, 95% confidence interval [CI] = 0.32 to 0.85, P = 0.009) and HRV (changes in the mean HR [mean difference = -2.59, 95% CI = -4.91 to -0.26, P = 0.03, I2 = 0%]; mean RR interval [MD = 29.03, 95% CI = 5.43 to 52.63, P = 0.02, I2 = 0%]; mean of the standard deviation of all normal RR intervals for all 5 min segments [MD = 2.73, 95% CI = 0.48 to 4.99, P = 0.02, I2 = 0%], and square root of the mean of the sum of the squares of differences between adjacent intervals [MD = 2.03, 95% CI = 0.04 to 4.03, P = 0.05, I2 = 0%]). CONCLUSION: PUFA supplements appeared to improve CVD prognosis in patients receiving dialysis. Additional RCTs with longer follow-up periods need to clarify the benefits of PUFA supplements in this patient population.

Systematic Review of Nutrition Supplements in Chronic Kidney Diseases: A GRADE Approach.

Chronic kidney disease (CKD) is cumulative worldwide and an increasing public health issue. Aside from the widely known protein restriction and medical therapy, less evident is the renal protection of nutrition supplements in CKD patients. This systematic review (SR), using a Grading of Recommendations Assessment, Development, and Evaluation (GRADE) approach, aims to summarize and quantify evidence about the prevention effects of vitamin D and analogues, omega-3 polyunsaturated fatty acid (omega-3 PUFA), dietary fiber, coenzyme Q10 (CoQ10), and biotics on CKD progression. This study was conducted following the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement to examine SRs and/or meta-analysis of clinical controlled trials identified from PubMed, Embase, and the Cochrane Library. Finally, seventeen SRs were included in the qualitative analysis. The beneficial effects of these nutrition supplements in CKD patients mostly seem to be at low to very low evidence on proteinuria, kidney function, and inflammations and did not appear to improve CKD prognosis. The recommendation of nutrition supplements in CKD patients needs to discuss with physicians and consider the benefits over the adverse effects. Longer follow-up of larger randomized trials is necessary to clarify the benefits of nutrition supplements in CKD patients.

Long-Term Effects of Ketoanalogues on Mortality and Renal Outcomes in Advanced Chronic Kidney Disease Patients Receiving a Low-Protein Diet.

The effects of ketoanalogues (KA) supplementation on mortality and progression to dialysis in patients with pre-dialysis stage 5 chronic kidney disease (CKD) receiving a low-protein diet (LPD) remain ambiguous. From Taiwan's National Health Insurance Research Database during 1996-2011, 165 patients with pre-dialysis CKD on an LPD (0.6 g/kg/day) with KA supplementation were matched with 165 patients with pre-dialysis CKD on an LPD without KA supplementation. Of the 165 patients with advanced CKD receiving KA supplementation, 34 (20.6%) died, and 124 (75.2%) underwent long-term dialysis during the study period. There was no significant difference in mortality between the KA-user group and the KA-nonuser group (adjusted hazard ratio [HR], 1.41; 95% confidence interval [CI], 0.68-2.93; p = 0.355). KA supplementation significantly increased long-term dialysis risk (adjusted HR, 1.41; 95% CI, 1.04-1.90; p = 0.025) and combined outcome risk (defined as long-term dialysis and death; adjusted HR, 1.37; 95% CI, 1.02-1.83; p = 0.034). KA supplementation also increased long-term dialysis risk (adjusted HR, 1.49; 95% CI, 1.00-2.20; p = 0.048) in the subgroup of pre-dialysis patients with diabetes mellitus (DM), but not in those patients without DM. In conclusion, KA supplementation might increase long-term dialysis risk in patients with advanced CKD receiving an LPD, but it did not increase mortality.

The Powdered Root of Eurycoma longifolia Jack Improves Beta-Cell Number and Pancreatic Islet Performance through PDX1 Induction and Shows Antihyperglycemic Activity in db/db Mice.

Non-insulin-dependent diabetes mellitus (NIDDM) is a common metabolic disorder worldwide. In addition to the chief feature of long-standing hyperglycemia, dyslipidemia, hyperinsulinemia, and a number of complications develop in parallel. It is believed that an adequate control of blood glucose levels can cause these complications to go into remission. This study was performed to evaluate the antidiabetic activity of Eurycoma longifolia Jack (EL) in vivo. The blood-glucose-lowering activity of EL was studied in db/db mice administered crude powdered EL root (25, 50, and 100 mg/kg) orally for eight weeks. At the end of the study, HbA1c, insulin, plasma lipid levels, and histopathology were performed. Powdered EL root showed significant antihyperglycemic activity along with the control of body weight. After eight weeks of treatment, both the blood cholesterol level and the glycogen deposit in hepatocytes were remarkably lower, whereas the secreting insulin level was elevated. An improvement in islet performance was manifested as an increase in beta-cell number and pancreatic and duodenal homeobox 1 (PDX1) expression. Neogenesis or formation of new islets from pancreatic duct epithelial cells seen in the EL-treated group was encouraging. This study confirms the antihyperglycemic activity of EL through PDX1-associated beta-cell expansion resulting in an enhancement of islet performance.

Risk of Mortality and of Atherosclerotic Events Among Patients Who Underwent Hemodialysis and Subsequently Developed Retinal Vascular Occlusion: A Taiwanese Retrospective Cohort Study.

IMPORTANCE: Retinal vascular occlusion is considered a risk factor for cardiovascular diseases in the general population. However, the long-term outcomes of patients who undergo incident hemodialysis and subsequently develop retinal vascular occlusion have not been examined. OBJECTIVE: To determine the mortality rate and subsequent prevalence of systemic vascular diseases associated with retinal vascular occlusion among patients undergoing hemodialysis in Taiwan. DESIGN, SETTING, AND PARTICIPANTS: Data from the Taiwan National Health Institutes research database were used, and we identified 105,956 patients undergoing hemodialysis during the period from January 1997 to December 2008. In total, 113 patients with retinal artery occlusion and 463 patients with retinal vein occlusion were enrolled and matched for age, sex, and the duration of hemodialysis (at a 1:5 ratio) with patients without ocular disorders. MAIN OUTCOMES AND MEASURES: Mortality and atherosclerotic events. A multivariate Cox regression model for mortality and a competing risk regression model for atherosclerotic events were used for this population-based retrospective cohort study. RESULTS: Of 113 patients with retinal artery occlusion and 463 patients with retinal vein occlusion, 66 (58.4%) and 245 (52.9%) were females, respectively (ranging in age from ≤40 to 80 years). Our study showed there was a significant risk of mortality among patients undergoing hemodialysis who subsequently developed retinal artery occlusion or retinal vein occlusion compared with patients undergoing hemodialysis without ocular disorders. Patients with retinal artery occlusion had higher risks of ischemic stroke (adjusted hazard ratio [HR], 3.35 [95% CI, 2.00-5.59]; P < .001), coronary artery disease (adjusted HR, 1.70 [95% CI, 1.23-2.36]; P = .001), acute coronary syndrome (adjusted HR, 2.03 [95% CI, 1.24-3.33]; P = .002), and peripheral arterial occlusive disease (adjusted HR, 2.15 [95% CI, 1.26-3.66]; P = .002) than did patients without ocular disorders. Patients with retinal vein occlusion had higher risks of hemorrhagic stroke (adjusted HR, 2.54 [95% CI, 1.50-4.30]; P = .001), coronary artery disease (adjusted HR, 1.55 [95% CI, 1.31-1.83]; P < .001), and acute coronary syndrome (adjusted HR, 1.53 [95% CI, 1.14-2.06]; P = .002) than did patients without ocular disorders. CONCLUSIONS AND RELEVANCE: Our data demonstrate that the risks of mortality and atherosclerotic events were increased among patients undergoing incident hemodialysis who subsequently developed retinal vascular occlusion.

Beneficial effects of calcitriol on hypertension, glucose intolerance, impairment of endothelium-dependent vascular relaxation, and visceral adiposity in fructose-fed hypertensive rats.

Besides regulating calcium homeostasis, the effects of vitamin D on vascular tone and metabolic disturbances remain scarce in the literature despite an increase intake with high-fructose corn syrup worldwide. We investigated the effects of calcitriol, an active form of vitamin D, on vascular relaxation, glucose tolerance, and visceral fat pads in fructose-fed rats. Male Wistar-Kyoto rats were divided into 4 groups (n = 6 per group). Group Con: standard chow diet for 8 weeks; Group Fru: high-fructose diet (60% fructose) for 8 weeks; Group Fru-HVD: high-fructose diet as Group Fru, high-dose calcitriol treatment (20 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding; and Group Fru-LVD: high-fructose diet as Group Fru, low-dose calcitriol treatment (10 ng / 100 g body weight per day) 4 weeks after the beginning of fructose feeding. Systolic blood pressure was measured twice a week by the tail-cuff method. Blood was examined for serum ionized calcium, phosphate, creatinine, glucose, triglycerides, and total cholesterol. Intra-peritoneal glucose intolerance test, aortic vascular reactivity, the weight of visceral fat pads, adipose size, and adipose angiotensin II levels were analyzed at the end of the study. The results showed that the fructose-fed rats significantly developed hypertension, impaired glucose tolerance, heavier weight and larger adipose size of visceral fat pads, and raised adipose angiotensin II expressions compared with the control rats. High- and low-dose calcitriol reduced modestly systolic blood pressure, increased endothelium-dependent aortic relaxation, ameliorated glucose intolerance, reduced the weight and adipose size of visceral fat pads, and lowered adipose angiotensin II expressions in the fructose-fed rats. However, high-dose calcitriol treatment mildly increased serum ionized calcium levels (1.44 ± 0.05 mmol/L). These results suggest a protective role of calcitriol treatment on endothelial function, glucose tolerance, and visceral adiposity in fructose-fed rats.