Renal denervation in treatment-resistant essential hypertension. A randomized, SHAM-controlled, double-blinded 24-h blood pressure-based trial.

BACKGROUND: Renal denervation (RDN), treating resistant hypertension, has, in open trial design, been shown to lower blood pressure (BP) dramatically, but this was primarily with respect to office BP. METHOD: We conducted a SHAM-controlled, double-blind, randomized, single-center trial to establish efficacy data based on 24-h ambulatory BP measurements (ABPM). Inclusion criteria were daytime systolic ABPM at least 145 mmHg following 1 month of stable medication and 2 weeks of compliance registration. All RDN procedures were carried out by an experienced operator using the unipolar Medtronic Flex catheter (Medtronic, Santa Rosa, California, USA). RESULTS: We randomized 69 patients with treatment-resistant hypertension to RDN (n = 36) or SHAM (n = 33). Groups were well balanced at baseline. Mean baseline daytime systolic ABPM was 159 ±â€Š12 mmHg (RDN) and 159 ±â€Š14 mmHg (SHAM). Groups had similar reductions in daytime systolic ABPM compared with baseline at 3 months [-6.2 ±â€Š18.8 mmHg (RDN) vs. -6.0 ±â€Š13.5 mmHg (SHAM)] and at 6 months [-6.1 ±â€Š18.9 mmHg (RDN) vs. -4.3 ±â€Š15.1 mmHg (SHAM)]. Mean usage of antihypertensive medication (daily defined doses) at 3 months was equal [6.8 ±â€Š2.7 (RDN) vs. 7.0 ±â€Š2.5 (SHAM)].RDN performed at a single center and by a high-volume operator reduced ABPM to the same level as SHAM treatment and thus confirms the result of the HTN3 trial. CONCLUSION: Further, clinical use of RDN for treatment of resistant hypertension should await positive results from double-blinded, SHAM-controlled trials with multipolar ablation catheters or novel denervation techniques.

Changes in urinary excretion of water and sodium transporters during amiloride and bendroflumethiazide treatment.

AIM: To quantify changes in urinary excretion of aquaporin2 water channels (u-AQP2), the sodium-potassium-chloride co-transporter (u-NKCC2) and the epithelial sodium channels (u-ENaC) during treatment with bendroflumethiazide (BFTZ), amiloride and placebo. METHODS: In a randomized, double-blinded, placebo-controlled, 3-way crossover study we examined 23 healthy subjects on a standardized diet and fluid intake. The subjects were treated with amiloride 5 mg, BFTZ 1.25 mg or placebo twice a day for 4.5 d before each examination day. On the examination day, glomerular filtration rate was measured by the constant infusion clearance technique with (51)Cr-EDTA as reference substance. To estimate the changes in water transport via AQP2 and sodium transport via NKCC2 and ENaC, u-NKCC2, the gamma fraction of ENaC (u-ENaCγ), and u-AQP2 were measured at baseline and after infusion with 3% hypertonic saline. U-NKCC2, u-ENaCγ, u-AQP2 and plasma concentrations of vasopressin (p-AVP), renin (PRC), angiotensin II (p-ANG II) and aldosterone (p-Aldo) were measured, by radioimmunoassay. Central blood pressure was estimated by applanation tonometry and body fluid volumes were estimated by bio-impedance spectroscopy. General linear model with repeated measures or related samples Friedman's two-way analysis was used to compare differences. Post hoc Bonferroni correction was used for multiple comparisons of post infusion periods to baseline within each treatment group. RESULTS: At baseline there were no differences in u-NKCC2, u-ENaCγ and u-AQP2. PRC, p-Ang II and p-Aldo were increased during active treatments (P < 0.001). After hypertonic saline, u-NKCC2 increased during amiloride (6% ± 34%; P = 0.081) and increased significantly during placebo (17% ± 24%; P = 0.010). U-AQP2 increased significantly during amiloride (31% ± 22%; P < 0.001) and placebo (34% ± 27%; P < 0.001), while u-NKCC2 and u-AQP2 did not change significantly during BFTZ (-7% ± 28%; P = 0.257 and 5% ± 16%; P = 0.261). U- ENaCγ increased in all three groups (P < 0.050). PRC, AngII and p-Aldo decreased to the same extent, while AVP increased, but to a smaller degree during BFTZ (P = 0.048). cDBP decreased significantly during BFTZ (P < 0.001), but not during amiloride or placebo. There were no significant differences in body fluid volumes. CONCLUSION: After hypertonic saline, u-NKCC2 and u-AQP2 increased during amiloride, but not during BFTZ. Lower p-AVP during BFTZ potentially caused less stimulation of NKCC2 and AQP2 and subsequent lower reabsorption of water and sodium.

Cardiovascular effects of cholecalciferol treatment in dialysis patients--a randomized controlled trial.

BACKGROUND: Patients on chronic dialysis are at increased risk of vitamin D deficiency. In observational studies plasma 25-hydroxyvitamin D (p-25(OH) D) levels are inversely correlated with plasma BNP and adverse cardiovascular outcomes. Whether a causal relation exists has yet to be established. The aim of this study was to test the hypothesis that cholecalciferol supplementation improves cardiac function and reduces blood pressure (BP) and pulse wave velocity (PWV) in patients on chronic dialysis. METHODS: In a randomized, placebo-controlled, double-blind study, we investigated the effect of 75 µg (3000 IU) cholecalciferol daily for 6 months, in patients on chronic dialysis. We performed two-dimensional echocardiography, with doppler and tissue-doppler imaging, 24-h ambulatory BP (24-h BP), PWV, augmentation index (AIx), central BP (cBP) and brain natriuretic peptide (BNP) measurements at baseline and after 6 months. RESULTS: Sixty-four patients were allocated to the study. Fifty dialysis patients with a mean age of 68 years (range: 46-88) and baseline p-25(OH) D of 28 (20;53) nmol/l completed the trial. Cholecalciferol increased left ventricular (LV) volume, but had no impact on other parameters regarding LV structure or left atrial structure. LV systolic function, LV diastolic function, PWV, cBP, AIx and BNP were not changed in placebo or cholecalciferol group at follow-up. 24-h BP decreased significantly in placebo group and tended to decrease in cholecalciferol group without any difference between treatments. CONCLUSION: Six months of cholecalciferol treatment in patients on chronic dialysis did not improve 24-h BP, arterial stiffness or cardiac function. TRIAL REGISTRATION: NCT01312714, Registration Date: March 9, 2011.

Effect of paricalcitol on renin and albuminuria in non-diabetic stage III-IV chronic kidney disease: a randomized placebo-controlled trial.

BACKGROUND: Vitamin D receptor activators reduce albuminuria, and may improve survival in chronic kidney disease (CKD). Animal studies suggest that these pleiotropic effects of vitamin D may be mediated by suppression of renin. However, randomized trials in humans have yet to establish this relationship. METHODS: In a randomized, placebo-controlled, double-blinded crossover study, the effect of oral paricalcitol (2 µg/day) was investigated in 26 patients with non-diabetic, albuminuric stage III-IV CKD. After treatment, plasma concentrations of renin (PRC), angiotensin II (AngII) and aldosterone (Aldo) were measured. GFR was determined by 51Cr-EDTA clearance. Assessment of renal NO dependency was performed by infusion of NG-monomethyl-L-arginine (L-NMMA). Albumin excretion rate (AER) was analyzed in 24-h urine and during 51Cr-EDTA clearance. RESULTS: Paricalcitol did not alter plasma levels of renin, AngII, Aldo, or urinary excretion of sodium and potassium. A modest reduction of borderline significance was observed in AER, and paricalcitol abrogated the albuminuric response to L-NMMA. CONCLUSIONS: In this randomized, placebo-controlled trial paricalcitol only marginally decreased AER and did not alter circulating levels of renin, AngII or Aldo. The abrogation of the rise in albumin excretion by paricalcitol during NOS blockade may indicate that favourable modulation of renal NO dependency could be involved in mediating reno-protection and survival benefits in CKD. TRIAL REGISTRATION: ClinicalTrials.gov identifier: NCT01136564.

Effect of cholecalciferol supplementation during winter months in patients with hypertension: a randomized, placebo-controlled trial.

BACKGROUND: Low 25-hydroxy-vitamin D (25(OH)D) levels are inversely related to blood pressure (BP) and have been associated with incident hypertension. In people living at northern latitudes diminished cholecalciferol synthesis in the winter increases the risk of vitamin D deficiency. We wanted to test the hypothesis that daily cholecalciferol supplementation in the winter lowers BP in patients with hypertension. METHODS: We investigated the effect of 75 µg (3,000 IU) cholecalciferol per day in a randomized, placebo-controlled, double-blind study in 130 hypertensive patients residing in Denmark (56º N). Ambulatory BP (24-h BP) and arterial stiffness were measured before and after 20 weeks of treatment, that took place between October and March. RESULTS: A total of 112 patients (mean age 61 ± 10) with a baseline p-25(OH)D of 23 ± 10 ng/ml completed the study. Compared with placebo, a nonsignificant 3/1 mm Hg (P = 0.26/0.18) reduction was found in 24-h BP. In patients with vitamin D insufficiency (<32 ng/ml) at baseline (n = 92), 24-h BP decreased by 4/3 mm Hg (P = 0.05/0.01). Central BP (CBP) estimated by applanation tonometry and calibrated with a standardized office BP was reduced by 7/2 mm Hg (P = 0.007/0.15) vs. placebo. No differences in carotid-femoral pulse wave velocity (PWV) or central augmentation index (AIx) were found between treatment arms. CONCLUSIONS: Cholecalciferol supplementation, by a dose that effectively increased vitamin D levels, did not reduce 24-h BP, although central systolic BP decreased significantly. In a post-hoc subgroup analysis of 92 subjects with baseline p-25(OH)D levels <32 ng/ml, significant decreases in 24-h systolic and diastolic BP occurred during cholecalciferol supplementation.

Effect of potassium supplementation on renal tubular function, ambulatory blood pressure and pulse wave velocity in healthy humans.

BACKGROUND: Potassium is the main intracellular cation, which contributes to keeping the intracellular membrane potential slightly negative and elicits contraction of smooth, skeletal and cardiac muscle. A change in potassium intake modifies both cardiovascular and renal tubular function. The purpose of the trial was to investigate the effect of dietary potassium supplementation, 100 mmol daily in a randomized, placebo-controlled, crossover trial of healthy participants during two periods of 28 days duration. The participants (N = 21) received a diet that was standardized regarding energy requirement, and sodium and water intake. METHODS: 24-hour ambulatory blood pressure (ABP) and applanation tonometry were used to assess blood pressure, pulse wave velocity (PWV), augmentation index (AIx) and central blood pressure (CBP). Immunoassays were used for measurements of plasma concentrations of vasoactive hormones: renin (PRC), angiotensin II (Ang II), aldosterone (Aldo), atrial natriuretic peptide (ANP), vasopressin (AVP), pro-brain natriuretic peptide (pro-BNP),endothelin (Endo), urinary excretions of aquaporin 2 (AQP2), cyclic AMP (cAMP), and the ß-fraction of the epithelial sodium channel (ENaC(ß)). RESULTS: AQP2 excretion increased during potassium supplementation, and free water clearance fell. The changes in urinary potassium excretion and urinary AQP2 excretion were significantly and positively correlated. Aldo increased. GFR, u-ENaC- ß, PRC, Ang II, ANP, BNP, Endo, blood pressure and AI were not significantly changed by potassium supplementation, whereas PWV increased slightly. CONCLUSIONS: Potassium supplementation changed renal tubular function and increased water absorption in the distal part of the nephron. In spite of an increase in aldosterone in plasma, blood pressure remained unchanged after potassium supplementation.

Heart rate variability in white-coat hypertension.

OBJECTIVES: The objective of this study was to compare heart rate variability (HRV) in patients with essential hypertension, in patients with white-coat hypertension and in normotensive control individuals, and to investigate a possible relation between HRV and vasoactive hormones. METHODS: Patients with essential hypertension (n=19, 61 years, median and interquartile range: 40-66 years), patients with white-coat hypertension (n=8, 52 years, median and interquartile range: 41-64 years) and normotensive participants (n=13, 50 years, median and interquartile range: 39-57 years) participated in the study. HRV was measured at rest in the supine position, during standing and during controlled forced breathing (respiration frequency >20/min). Power spectral density was calculated using Fourier transformation. RESULTS: Controlled breathing caused a decrease in low frequency (LF) variation and LF/high frequency variation (LF/HF) in all blood pressure groups. The decrease in LF was smaller in the hypertensive group (-60 ms2) than in the normotensive group (-139 ms2) (P=0.03; hypertensive group vs. normotensive group). The decrease in LF/HF induced by controlled breathing was -0.9 ms in the hypertensive group, -2.0 ms2 in the white-coat hypertensive group and -2.8 ms2 in the normotensive group, (P=0.037; hypertensive group vs. normotensive group). We found a positive correlation between baseline plasma renin concentration and LF (r=0.330, P=0.037) and LF/HF (r=0.378, P=0.016) at rest. CONCLUSION: The observed differences in HRV might reflect the impaired responsiveness to autonomic challenge in hypertensive patients. We did not find the HRV spectrum in white-coat hypertension different from the HRV spectrum in hypertension or normotension.