In patients with ESRD, the effects of online hemodiafiltration on all-cause mortality and cardiovascular events are unclear. In this prospective study, we randomly assigned 714 chronic hemodialysis patients to online postdilution hemodiafiltration (n=358) or to continue low-flux hemodialysis (n=356). The primary outcome measure was all-cause mortality. The main secondary endpoint was a composite of major cardiovascular events, including death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, therapeutic coronary intervention, therapeutic carotid intervention, vascular intervention, or amputation. After a mean 3.0 years of follow-up (range, 0.4-6.6 years), we did not detect a significant difference between treatment groups with regard to all-cause mortality (121 versus 127 deaths per 1000 person-years in the online hemodiafiltration and low-flux hemodialysis groups, respectively; hazard ratio, 0.95; 95% confidence interval, 0.75-1.20). The incidences of cardiovascular events were 127 and 116 per 1000 person-years, respectively (hazard ratio, 1.07; 95% confidence interval, 0.83-1.39). Receiving highvolume hemodiafiltration during the trial associated with lower all-cause mortality, a finding that persisted after adjusting for potential confounders and dialysis facility. In conclusion, this trial did not detect a beneficial effect of hemodiafiltration on all-cause mortality and cardiovascular events compared with low-flux hemodialysis. On-treatment analysis suggests the possibility of a survival benefit among patients who receive high-volume hemodiafiltration, although this subgroup finding requires confirmation.

Insulin sensitivity and blood pressure are associated well within the physiological range. Microvascular function strongly relates to both, consistent with a central role in linking these variables.

The renin-angiotensin-aldosterone system (RAAS) plays a pivotal role in renal progression and its complications. Accordingly, RAAS blockade has been the cornerstone of renoprotective interventions. Vitamin D deficiency is traditionally recognized as a key factor in the bone and mineral disturbances of chronic kidney disease (CKD), and vitamin D supplementation is standard treatment for many renal patients. As reviewed elsewhere, 1 vitamin D interacts with the more recently identified moieties, fibroblast growth factor 23 (FGF-23) and klotho. As such, vitamin D, FGF-23, and klotho represent an endocrine axis involved in the regulation of calcium and phosphate metabolism.Besides having effects on mineral metabolism, vitamin D deficiency is also associated with progressive renal disease and with mortality in chronic kidney disease (CKD). 2,3 In line with these observations, the use of vitamin D analogues may provide with a survival advantage in dialysis patients, 4 Recent studies show that angiotensin II reduces renal expression of klotho, which, in turn, modulates FGF-23-signaling and 1-alpha hydroxylase, the enzyme converting calcidiol to calcitriol. As derangement of the vitamin D-FGF-23-klotho axis associates with cardiovascular complications in several studies, the interactions of this axis with the RAAS may have therapeutic implications in CKD patients, regarding both renal and cardiovascular outcomes. MODULATION OF THE RAAS BY VITAMIN DThe first clinical studies suggesting an inverse relationship between calcitriol and renin levels were published two decades ago 9,10 and were recently confirmed in a large cohort study. 11 Vitamin D deficiency, defined as calcidiol levels below 15 ng/ml, associates with reduced renal plasma flow responses to infused angiotensin II, suggesting endogenous intrarenal RAAS activation in vitamin D deficient subjects, 12 and intervention with calcitriol decreases plasma renin and angiotensin II levels in hemodialysis patients with secondary hyperparathyroidism. 13 Published online ahead of print. Publication date available at www.jasn.org. ABSTRACTThere is increasingly evidence that the interactions between vitamin D, fibroblast growth factor 23 (FGF-23), and klotho form an endocrine axis for calcium and phosphate metabolism, and derangement of this axis contributes to the progression of renal disease. Several recent studies also demonstrate negative regulation of the renin gene by vitamin D. In chronic kidney disease (CKD), low levels of calcitriol, due to the loss of 1-alpha hydroxylase, increase renal renin production. Activation of the renin-angiotensin-aldosterone system (RAAS), in turn, reduces renal expression of klotho, a crucial factor for proper FGF-23 signaling. The resulting high FGF-23 levels suppress 1-alpha hydroxylase, further lowering calcitriol. This feedback loop results in vitamin D deficiency, RAAS activation, high FGF-23 levels, and renal klotho deficiency, all of which associate with progression of renal damage. Here we examine current evidence for an...

SummaryBackground and objectives Little is known about the influence of dietary phosphate intake on fibroblast growth factor-23 (FGF23) and its subsequent effects on vitamin D levels. This study addresses changes in intact FGF23 (iFGF23) and C-terminal FGF23 (cFGF23), phosphaturia, and levels of vitamin D on high and low phosphate and calcium intake.Design, setting, participants, & measurements Ten healthy subjects adhered to a diet low or high in phosphate and calcium content for 36 hours each with a 1-week interval during which subjects adhered to their usual diet. Serum phosphate, calcium, vitamin D metabolites, parathyroid hormone (PTH), and FGF23 levels (cFGF23 and iFGF23) were measured several times a day. Phosphate, calcium, and creatinine excretion was measured in 24-hour urine on all study days.Results Serum phosphate levels and urinary phosphate increased during high dietary phosphate intake (from 1.11 to 1.32 mmol/L, P Ͻ 0.0001 and 21.6 to 28.8 mmol/d, P ϭ 0.0005, respectively). FGF23 serum levels increased during high dietary phosphate/calcium intake (cFGF23 from 60 to 72 RU/ml, P Ͻ 0.001; iFGF23 from 33 to 37 ng/L, P ϭ 0.003), whereas PTH declined. 1,25-Dihydroxyvitamin D (1,25D) showed an inverse relation with FGF23.Conclusions Variation in dietary phosphate and calcium intake induces changes in FGF23 (on top of a circadian rhythm) and 1,25D blood levels as well as in urinary phosphate excretion. These changes are detectable the day after the change in the phosphate content of meals. Higher FGF23 levels are associated with phosphaturia and a decline in 1,25D levels.

In HD patients, xerostomia (XI) and thirst (DTI) are associated with a higher IWG. Our data provide evidence that, in HD patients, xerostomia is related to both salivary flow rate and thirst (DTI).