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Abstract-Vitamin D regulates the renin-angiotensin system (RAS) in experimental animals, but corresponding human data are limited. We examined the relation between plasma 25-hydroxyvitamin D and elements of the RAS in 184 normotensive individuals in high sodium balance; these included circulating levels of plasma renin activity and angiotensin II (Ang II) and the renal plasma flow response to infused Ang II, which is an indirect measure of the intrinsic RAS activity in the kidney. Compared with individuals with sufficient 25-hydroxyvitamin D levels (Ն30.0 ng/mL), those with insufficiency (15.0 to 29.9 ng/mL) and deficiency (Ͻ15.0 ng/mL) had higher circulating Ang II levels (P for trendϭ0.03). Moreover, those with vitamin D deficiency had significantly blunted renal plasma flow responses to infused Ang II (mean decrease of 115 mL/min per 1.73 m 2 in renal plasma flow versus 145 mL/min per 1.73 m 2 among those with sufficient vitamin D levels; P for trendϭ0.009). Although plasma renin activity was higher among individuals with insufficient levels of vitamin D, the result was not statistically significant. These data suggest that low plasma 25-hydroxyvitamin D levels may result in upregulation of the RAS in otherwise healthy humans. A major proposed mechanism linking vitamin D with hypertension involves vitamin D-mediated suppression of the renin-angiotensin (Ang) system (RAS), yet data derive mostly from in vitro and animal studies. [15][16][17][18][19] Human investigation of the association between vitamin D and the RAS has been scant. Resnick et al 20 originally reported that plasma renin activity (PRA) and 1,25-dihydroxyvitamin D (1,25[OH] 2 D) were inversely correlated (rϭϪ0.65) among 61 individuals on an ambient diet. Several years later, Burgess et al 21 reported a similar association in 10 hypertensives (rϭϪ0.76). Interestingly, in a randomized trial that documented a 14-mm Hg decrease in SBP with vitamin D supplementation compared with placebo, the authors also noted a trend toward a decrease in circulating angiotensin II (Ang II) levels (Ϫ13.1 pg/mL; Pϭ0.14) relative to placebo. 22 To test the hypothesis that there is a mechanistic role for vitamin D in the regulation of the RAS in humans, we examined the relation between plasma 25(OH)D concentration with both circulating renin and Ang II levels, as well as the renal plasma flow (RPF) response to infused Ang II, which correlates inversely with endogenous intrarenal RAS activity, 23-27 among 184 normotensive individuals. Methods Study PopulationParticipants in this study included 184 normotensive white and black men and women, recruited as healthy volunteers from the general population, who completed RPF studies in high sodium balance at 1 of 4 General Clinical Research Centers, including Brigham and Women's Hospital in Boston; the University of Utah Medical Center in Salt Lake City, Utah; Vanderbilt University Hospital in Nashville, Tennessee; and the Hô pital Européen Georges Pompidou in Paris, France. We examined normotensive participants because of our...

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Background VEGF signaling pathway inhibitor (anti-VEGF) therapy is associated with hypertension, but little is known about predisposing clinical characteristics. This study describes the real-world association between baseline clinical characteristics, blood pressure (BP) response, and survival in patients prescribed anti-VEGF therapies. Methods Clinical data from Partners HealthCare in Massachusetts was obtained from adults treated with anti-VEGF therapies (2002–2013). Treatment-induced hypertensive response was defined as worsening of pre-existing hypertension or new diagnosis of hypertension (if no prior hypertension history). Results Data from 1120 patients with renal cell carcinoma (32.2%), hepatocellular carcinoma (11.6%), gastrointestinal stromal tumors (12.5%) and other sarcomas (15.3%) were analyzed. Most patients received sunitinib (52%), sorafenib (25.9%) or pazopanib (18%). A treatment-induced hypertensive response was identified in 49.7% of treated patients. Pre-existing hypertension, present in 65.4%, was an independent risk factor for BP elevation (odds ratio (OR) 1.56, 95% confidence interval (CI) 1.27–1.92); other risk factors included age ≥60 years (OR 1.26, 95%CI 1.06–1.52), and body mass index (BMI) ≥25 kg/m2 (OR 1.26, 95%CI 1.04–1.53). Race, gender, anti-VEGF therapy prescribed, and baseline antihypertensive class were not significant risk factors. The absolute observed mean increase in BP was 21 mmHg (systolic) / 15 mmHg (diastolic), both in patients with and without pre-existing hypertension. The development of hypertension predicted improved survival (hazard ratio 0.76, 95%CI 0.65–0.89). Conclusions Pre-existing hypertension, age, and BMI identify patients at risk for significant anti-VEGF therapy-induced BP elevation. Hypertension appears to be a clinical biomarker of efficacy to anti-VEGF therapies in a broad range of malignancies.