Effect of increased potassium intake on the renin-angiotensin-aldosterone system and subcutaneous resistance arteries: a randomized crossover study.

BACKGROUND: Increased potassium intake lowers blood pressure (BP) in hypertensive patients. The underlying mechanism is not fully understood but must be complex because increased potassium intake elevates circulating concentrations of the BP-raising hormone aldosterone. METHODS: In a randomized placebo-controlled crossover study in 25 normotensive men, we investigated the effect of 4 weeks of potassium supplement (90 mmol/day) compared with 4 weeks of placebo on the renin-angiotensin-aldosterone system (RAAS), urine composition and 24-h ambulatory BP. Vascular function was also assessed through wire myograph experiments on subcutaneous resistance arteries from gluteal fat biopsies. RESULTS: Higher potassium intake increased urinary potassium excretion (144.7 ± 28.7 versus 67.5 ± 25.5 mmol/24-h; P < 0.0001) and plasma concentrations of potassium (4.3 ± 0.2 versus 4.0 ± 0.2 mmol/L; P = 0.0002), renin {mean 16 [95% confidence interval (CI) 12-23] versus 11 [5-16] mIU/L; P = 0.0047}, angiotensin II [mean 10.0 (95% CI 6.2-13.0) versus 6.1 (4.0-10.0) pmol/L; P = 0.0025] and aldosterone [mean 440 (95% CI 336-521) versus 237 (173-386) pmol/L; P < 0.0001]. Despite RAAS activation, systolic BP (117.6 ± 5.8 versus 118.2 ± 5.2 mmHg; P = 0.48) and diastolic BP (70.8 ± 6.2 versus 70.8 ± 6.3 mmHg; P = 0.97) were unchanged. In the wire myograph experiments, higher potassium intake did not affect endothelial function as assessed by acetylcholine [logarithmically transformed half maximal effective concentration (pEC50): 7.66 ± 0.95 versus 7.59 ± 0.85; P = 0.86] and substance P (pEC50: 8.42 ± 0.77 versus 8.41 ± 0.89; P = 0.97) or vascular smooth muscle cell reactivity as assessed by angiotensin II (pEC50: 9.01 ± 0.86 versus 9.02 ± 0.59; P = 0.93) and sodium nitroprusside (pEC50: 7.85 ± 1.07 versus 8.25 ± 1.32; P = 0.25) but attenuated the vasodilatory response of retigabine (pEC50: 7.47 ± 1.16 versus 8.14 ± 0.90; P = 0.0084), an activator of Kv7 channels. CONCLUSIONS: Four weeks of increased potassium intake activates the RAAS in normotensive men without changing BP and this is not explained by improved vasodilatory responses ex vivo.

Bacteriology of the Buttonhole Cannulation Tract in Hemodialysis Patients: A Prospective Cohort Study.

BACKGROUND: The buttonhole cannulation technique for arteriovenous fistulas is widely used, but has been associated with an increased rate of vascular access-related infections. We describe the frequency and type of bacterial colonization of the buttonhole tract over time and associated clinical infections. STUDY DESIGN: A prospective observational cohort study with 9 months of follow-up. SETTING & PARTICIPANTS: 84 in-center hemodialysis patients using the buttonhole cannulation technique at 2 Danish dialysis centers. OUTCOMES: Bacterial growth from the buttonhole tract and dialysis cannula tip and clinically important infections during follow-up. MEASUREMENTS: On 3 occasions 1 month apart, cultures before dialysis (from the skin surrounding the buttonhole before disinfection and from the cannulation tract after disinfection and scab removal) and the cannula tip after dialysis. Patients with positive cultures from the buttonhole tract or cannula tip had repeat cultures within 1 week, along with blood cultures. RESULTS: Growth from the cannulation tract and/or cannula tip at each of the 3 monthly sets of cultures was found in 18%, 20%, and 17% of patients, respectively. 38% of patients had at least 1 positive culture from the buttonhole tract. Sustained growth was detected in 11% of patients, whereas asymptomatic bacteremia was seen in 30% of those with positive buttonhole cultures. Staphylococci species were the most common pathogens (Staphylococcus aureus, 25%; and Staphylococcus epidermidis, 41%). Colonization-positive buttonholes had more localized redness and slightly more tenderness. During follow-up, significantly more access-related infections were diagnosed among those with positive buttonhole cultures (P<0.001). LIMITATIONS: No comparison to area puncture cannulation technique. Blood cultures were obtained only from patients with positive buttonhole bacteriology. CONCLUSIONS: Transient or sustained colonization of the buttonhole tract by staphylococci and asymptomatic bacteremia is common in hemodialysis patients, implying a substantial risk for access-related infections among patients using a buttonhole cannulation technique. These findings suggest the possible value of surveillance of buttonhole colonization.

Urine liver fatty acid binding protein and chronic kidney disease progression.

Excretion of the tubular protein liver fatty acid binding protein (L-FABP) is a potential novel biomarker of renal dysfunction. We examined whether urine L-FABP excretion adds prognostic information to the well-established risk markers, blood pressure (BP), albumin excretion and baseline GFR, regarding progression of chronic kidney disease (CKD). In a prospective study design a cohort of 74 stage 3-4 CKD patients (age 61 ± 13 years) were included. Glomerular filtration ratio (GFR, 51Cr-EDTA-clearance), 24-hour ambulatory BP, 24-hour urinary albumin/creatinine ratio (UAC) and urinary L-FABP/creatinine ratio (U-L-FABP/C) were determined at baseline and after 18 months of follow-up. For comparison 25 age-matched healthy controls were included. The U-L-FABP/C was elevated in CKD patients when compared to controls (mean U-L-FABP/C 2.3 [95% CI 1.7-2.9] µg/mmol vs 0.6 [0.5-0.7] µg/mmol, p < .001). In CKD patients, log U-L-FABP/C at baseline and at follow-up were positively associated (Pearson correlation coefficient r = 0.74, p < .001). Baseline log U-L-FABP/C was negatively correlated with baseline GFR (r = -0.32, p < .001) and directly correlated with UAC (r = 0.67, p < .001). The relative change in GFR from baseline to follow-up correlated with baseline UAC (p < .001), 24-hour systolic BP (p = 0.05) and log U-L-FABP/C (p < .001). Using multiple regression analysis adjusting for baseline GFR, UAC, BP, age and gender, baseline log U-L-FABP/C was associated with a decline in GFR only in patients with UAC <3 mg/mmol (n = 29, p = 0.001) and not in patients with UAC ≥3 mg/mmol (n = 44, p = 0.21). In conclusion urine L-FABP/C is permanently elevated in CKD patients, but only associated with GFR decline in those without albuminuria.

Estimated aortic blood pressure based on radial artery tonometry underestimates directly measured aortic blood pressure in patients with advancing chronic kidney disease staging and increasing arterial stiffness.

Central blood pressure (BP) can be assessed noninvasively based on radial tonometry and may potentially be a better predictor of clinical outcome than brachial BP. However, the validity of noninvasively obtained estimates has never been examined in patients with chronic kidney disease (CKD). Here we compared invasive aortic systolic BP (SBP) with estimated central SBP obtained by radial artery tonometry and examined the influence of renal function and arterial stiffness on this relationship. We evaluated 83 patients with stage 3 to 5 CKD (mean estimated glomerular filtration rate [eGFR] 30 ml/min/1.73 m(2)) and 41 controls without renal disease undergoing scheduled coronary angiography. BP in the ascending aorta was measured through the angiography catheter and simultaneously estimated using radial tonometry. The mean difference between estimated central and aortic SBP was -13.2 (95% confidence interval -14.9 to -11.4) mm Hg. Arterial stiffness was evaluated by carotid-femoral pulse wave velocity (cf-PWV) and was significantly increased in CKD patients compared with (versus) control patients (mean 10.7 vs. 9.3 m/s). The difference in BP significantly increased 1.0 mm Hg for every 10 ml/min decrease in eGFR and by 1.6 mm Hg per 1 m/s increase in cfPWV. Using multivariate regression analysis including both eGFR and cfPWV, the difference between estimated central and invasive aortic SBP was significantly increased by 0.7 mm Hg. For the entire cohort brachial SBP significantly better reflected invasive SBP than estimated SBP. Thus, tonometry-based estimates of central BP progressively underestimate invasive central SBP with decreasing renal function and increasing arterial stiffness in CKD patients.

Evaluation of Renal Blood Flow and Oxygenation in CKD Using Magnetic Resonance Imaging.

BACKGROUND: Animal studies suggest that progression of chronic kidney disease (CKD) is related to renal hypoxia. With renal blood supply determining oxygen delivery and sodium absorption being the main contributor to oxygen consumption, we describe the relationship between renal oxygenation, renal artery blood flow, and sodium absorption in patients with CKD and healthy controls. STUDY DESIGN: Cross-sectional study. SETTING & PARTICIPANTS: 62 stable patients with CKD stages 3 to 4 (mean age, 61±13 [SD] years) and 24 age- and sex-matched controls. PREDICTORS: CKD versus control status. OUTCOMES: Renal artery blood flow, tissue oxygenation (relative changes in deoxyhemoglobin concentration of the renal medulla [MR2*] and cortex [CR2*]), and sodium absorption. MEASUREMENTS: Renal artery blood flow was determined by phase-contrast magnetic resonance imaging (MRI); MR2* and CR2* were determined by blood oxygen level-dependent MRI. Ultrafiltered and reabsorbed sodium were determined from measured glomerular filtration rate (mGFR) and 24-hour urine collections. RESULTS: mGFR in patients was 37% that of controls (36±15 vs 97±23 mL/min/1.73 m(2); P < 0.001), and reabsorbed sodium was 37% that of controls (6.9 vs 19.1 mol/24 h; P < 0.001). Single-kidney patient renal artery blood flow was 72% that of controls (319 vs 443 mL/min; P < 0.001). Glomerular filtration fraction was 9% in patients and 18% in controls (P < 0.001). Patients and controls had similar CR2* (13.4 vs 13.3 s(-1)) and medullary MR2* (26.4 vs 26.5 s(-1)) values. Linear regression analysis demonstrated no associations between R2* and renal artery blood flow or sodium absorption. Increasing arterial blood oxygen tension by breathing 100% oxygen had very small effects on CR2*, but reduced MR2* in both groups. LIMITATIONS: Only renal artery blood flow was determined and thus regional perfusion could not be related to CR2* or MR2*. CONCLUSIONS: In CKD, reductions of mGFR and reabsorbed sodium are more than double that of renal artery blood flow, whereas cortical and medullary oxygenation are within the range of healthy persons. Reduction in glomerular filtration fraction may prevent renal hypoxia in CKD.

Reproducibility of MRI renal artery blood flow and BOLD measurements in patients with chronic kidney disease and healthy controls.

PURPOSE: Determine the reproducibility of renal artery blood flow (RABF) and blood-oxygenation level dependent (R2 *) in patients with chronic kidney disease (CKD) and healthy controls. MATERIALS AND METHODS: RABF and R2 * were measured in 11 CKD patients and 9 controls twice with 1- to 2-week interval. R2 * in the cortex and medulla were determined after breathing atmospheric air and 100% oxygen. Reproducibility was evaluated by coefficients of variation (CV), limits of agreements and intra-class coefficient calculated by variance components by maximum likelihood modeling. RESULTS: Single-kidney RABF (mL/min) for patients was: 170 ± 130 and 186 ± 137, and for controls: 365 ± 119 and 361 ± 107 (P < 0.05 versus patients), for first and second scans, respectively. RABF measurements were reproducible with a CV of 12.9% and 8.3% for patients and controls, respectively. Renal cortical R2 * was: 13.6 ± 0.9 and 13.5 ± 1.2 in patients (CV = 8.0%), and 13.8 ± 1.6 and 14.0 ± 1.5 in controls (CV = 5.6%), while medullary R2 *(s(-1) ) was: 26.9 ± 2.0 and 27.0 ± 4.0 (CV = 8.0%) in patients, and 26.0 ± 2.4 and 26.1 ± 2.1 (CV = 3.6%) in controls, for first and second scans, respectively. In both groups R2 * in medulla decreased after breathing 100% oxygen. CONCLUSION: The reproducibility was high for both RABF and R2 * in patients and controls, particularly in the cortex. Inhalation of 100% oxygen reduced medullary R2 *.

Influence of Renal Transplantation and Living Kidney Donation on Large Artery Stiffness and Peripheral Vascular Resistance.

BACKGROUND: Vascular status following renal transplantation (RT) may improve while living kidney donation (LKD) is possibly associated with an increased cardiovascular risk. METHODS: We prospectively assessed glomerular filtration rate (mGFR, 51Chrome EDTA clearance) and intermediate vascular risk factors in terms of blood pressure (BP), pulse wave velocity (PWV), central augmentation index (AIx), excess pressure (Pexcess), and forearm vascular resistance in donors (n = 58, 45 ± 13 years) and recipients (n = 51, 50 ± 12 years) before and one year following LKD or RT. RESULTS: After kidney donation, mGFR decreased by 33% to 65 ± 11 ml/min/1.73m2, while recipients obtained a mGFR of 55 ± 9 ml/min/1.73m.2 Ambulatory 24-hour mean arterial BP (MAP) remained unchanged in donors but decreased by 5 mm Hg in recipients (P < 0.05). Carotid-femoral PWV increased by 0.3 m/s in donors (P < 0.05) but remained unchanged in recipients. AIx was unaltered after LKD but decreased following RT (P < 0.01), and Pexcess did not change in either group. Resting forearm resistance (Rrest), measured by venous occlusion plethysmography, increased after LKD (P < 0.05) but was unaffected by RT, while no changes were seen in minimum resistance (Rmin). ΔPWV showed a positive linear association to Δ24-hour MAP in both groups. Multiple linear regression analysis (adjusting for age, gender, and the baseline value of the studied parameter) did not detect independent effects of graft function on 24-hour MAP, PWV, AIx, vascular resistance, or Pexcess, whereas low post-donation GFR was related to higher AIx and Rrest. CONCLUSIONS: RT reduced BP and AIx without affecting PWV, whereas LKD resulted in increased PWV and Rrest, despite unchanged BP.

Kidney structural characteristics based on a kidney biopsy and contrast-enhanced computed tomography in healthy living kidney donors.

The demands for kidney transplantations are increasing, and so is the number of live kidney donors (LKDs). Recent studies show that LKDs have an increased risk of developing end-stage renal disease compared with healthy non-donors. However, the knowledge about factors predicting renal disease in kidney donors is sparse. Some evidence points to increased glomerular sclerosis and kidney fibrosis, as well as a low number of glomeruli as associated with a worse renal outcome. This methodological study investigated that which estimates are obtainable with a standard kidney biopsy taken from the donated kidney during the transplantation, and a standard contrast-enhanced computed tomography (CT) in kidney donors. CT-scans were used to obtain total volume of the kidney and kidney cortex using the Cavalieri estimator and 2D-nucleator. Glomerular number density in the biopsies was estimated by a model-based method, and was multiplied by total cortex volume in order to estimate the total number of glomeruli in the kidney. Glomerular volume was estimated by the 2D-nucleator and a model-based stereological technique. Kidney fibrosis (point-counting), glomerular sclerosis (evaluation of glomerular profiles), and arteriole dimensions (2D-nucleator) were also estimated in the biopsy sections from the donated kidney. Various studies have attempted to identify predictors of renal outcome in LKDs. There is no consensus yet, and further studies are needed to elucidate if and how the estimates described in this study are associated with renal outcome in LKDs.

Effects of additional vasodilatory or nonvasodilatory treatment on renal function, vascular resistance and oxygenation in chronic kidney disease: a randomized clinical trial.

AIM: Progression of chronic kidney disease (CKD) may be accelerated by tissue hypoxia due to impaired blood supply. This could be induced by small artery narrowing resulting in abnormally high intrarenal vascular resistance (RVR). We investigated whether a reduction in RVR achieved by adding vasodilating medical therapy (AVT) is superior to adding nonvasodilating medical therapy (AnonVT) regarding tissue oxygenation and preservation of kidney function. METHODS: Eighty-three grade 3 and 4 CKD patients [estimated glomerular filtration rate (GFR) 34.6 ml/min per 1.73 m] were randomized to either AVT with amlodipine and/or renin angiotensin blockade or AnonVT with the nonvasodilating beta-blocker metoprolol. Investigations were performed at baseline and after 18 months of therapy. Systemic vasodilation was documented in the forearm vasculature using resting venous occlusion plethysmography. GFR was measured as Chrome-EDTA plasma clearance. Using MRI, renal artery blood flow was measured for calculation of RVR and for estimating renal oxygenation (R2*). RESULTS: AVT and AnonVT achieved as planned similar blood pressure levels throughout the study. At follow-up, resistance had decreased by 7% (P < 0.05) and RVR by 12% (P < 0.05) in the AVT group, whereas in the AnonVT group, resistance increased by 39% (P < 0.01), whereas RVR remained unchanged. At follow-up, no significant differences in cortical or medullary R2* values between AVT and AnonVT were observed, and the GFR decline was similar in the two groups (3.0 vs. 3.3 ml/min per 1.73 m). CONCLUSION: Long-term intensified vasodilation treatment reduced peripheral and RVR, but this was not associated with improvement of R2* or protection against loss of kidney function in CKD patients.

Impact of type 2 diabetes on nitric oxide and adrenergic modulation of myocardial perfusion.

Type 2 diabetic patients are characterized by a reduced adenosine-induced hyperemic myocardial perfusion, which may contribute to their increased cardiovascular morbidity. We hypothesized that the reduced hyperemia can be explained by functional changes in endothelial or autonomic nervous regulation. In 12 type 2 diabetic patients without signs of ischemic heart disease and 14 age-matched control subjects, myocardial perfusion was measured at rest, during adenosine, and during adenosine and alpha-receptor blockade (phentolamine) using positron emission tomography on two separate days: 1) with, and 2) without nitric oxide (NO) inhibition with N(G)-nitro-L-arginine methyl ester. Myocardial perfusion during adenosine was lower in type 2 diabetic patients compared with control subjects (P = 0.05). No significant effect of NO inhibition on myocardial perfusion during adenosine was found in any of the groups. In control subjects, alpha-receptor blockade increased hyperemic myocardial vascular resistance during NO inhibition, whereas no effect was observed in type 2 diabetic patients. At rest, a significant correlation was observed between rate-pressure product and myocardial perfusion in control subjects. NO inhibition and type 2 diabetes abolished this correlation. Endothelial and cardiac autonomic nerve function seems to play only a minimal role in the reduced hyperemic myocardial perfusion in type 2 diabetic patients. However, the linear correlation between resting perfusion and cardiac work appears to be abolished in type 2 diabetes and during NO synthase inhibition.

Severe Metformin Poisoning Successfully Treated with Simultaneous Venovenous Hemofiltration and Prolonged Intermittent Hemodialysis.

Metformin poisoning is a life-threatening condition with a high mortality rate. We present a patient case of metformin poisoning following intake of 80 g metformin resulting in severe lactate acidosis with a nadir pH of 6.73 and circulatory collapse, successfully treated with addition of prolonged intermittent hemodialysis (HD) to continuous venovenous hemofiltration (CVVH). The patient's pH became normal 48 hours after metformin ingestion during simultaneous CVVH and addition of 22 hours of intermittent HD in the ICU. The highest metformin level was found to be 991 µmol/L (therapeutic range 3.9-23.2 µmol/L). We conclude that in cases of severe metformin poisoning with circulatory shock and extreme lactic acidosis, the usual CVVH modality might not efficiently clear metformin. Therefore, additional prolonged HD should be considered even in the state of cardiovascular collapse with vasopressor requirement.

Effects of renal denervation on coronary flow reserve and forearm dilation capacity in patients with treatment-resistant hypertension. A randomized, double-blinded, sham-controlled clinical trial.

BACKGROUND: Microvascular impairment is well documented in hypertension. We investigated the effect of renal sympathetic denervation (RDN) on cardiac and peripheral microvasculature in patients with treatment-resistant essential hypertension (TRH). METHODS: A randomized, single centre, double-blinded, sham-controlled clinical trial. Fifty-eight patients with TRH (ambulatory systolic BP (ASBP) ≥ 145mmHg) despite stable treatment were randomized to RDN or SHAM. RDN was performed with the unipolar Medtronic Flex catheter. Coronary flow reserve (CFR) and coronary- and forearm minimum vascular resistance (C-Rmin and F-Rmin) were determined using transthoracic Doppler echocardiography and F-Rmin with venous occlusion plethysmography at baseline and at six-months follow-up. RESULTS: RDN was performed with 5.3±0.2 lesions in the right renal artery and 5.4±0.2 lesions in the left. Baseline ASBP was 152±2mmHg (RDN, n=29) and 154±2mmHg (SHAM, n=29). Similar reductions in MAP were seen at follow up (-3.5±2.0 vs. -3.2±1.8, P=0.92). Baseline CFR was 2.9±0.1 (RDN) and 2.4±0.1 (SHAM), with no significant change at follow-up (0.2±0.2 vs. -0.1±0.2, P=0.57). C-Rmin was 1.9±0.3 (RDN) and 2.7±0.6 (SHAM) (mmHgmin/ml pr. 100g) and did not change significantly (0.3±0.5 vs. -0.4±0.8, P=0.48). F-Rmin was 3.6±0.2 (RDN) and 3.6±0.3 (SHAM) (mmHgmin/ml pr. 100ml tissue) and unchanged at follow-up (4.2±0.4 vs. 3.8±0.2, P=0.17). Left ventricular mass index was unchanged following RDN (-4±7 (RDN) vs. 3±5 (SHAM) (g/m2) P=0.38). CONCLUSION: The current study does not support positive effects of RDN on microvascular impairment in TRH.

Small artery structure adapts to vasodilatation rather than to blood pressure during antihypertensive treatment.

OBJECTIVE: Correction of the abnormal structure of resistance arteries in essential hypertension may be an important treatment goal in addition to blood pressure (BP) reduction. We investigated how this may be achieved in a prospective clinical study. METHODS: Plethysmography was used to measure forearm resting vascular resistance (Rrest) and minimum vascular resistance (Rmin) as a measure of vascular structure. Two different groups of patients with essential hypertension were examined at baseline and after 6 months of antihypertensive treatment. In group A, 21 patients with never-treated essential hypertension were treated by their general practitioners using a variety of drugs to allow an assessment of the drug-independent effects. In group B, 28 beta-blocker-treated patients were shifted to angiotensin II receptor blocker treatment (eprosartan) to allow vasodilatation with no change in BP. RESULTS: In group A, mean ambulatory blood pressure (ABP) fell from 119 +/- 2 (SE) to 103 +/- 2 mmHg (P < 0.01), whereas mean ABP was unchanged in group B (100 +/- 1 to 99 +/- 1 mmHg, P = NS). Both groups showed similar reductions in Rrest (-33.4 and -28.5%, respectively) and in Rmin (-15.4 and -15.6%, respectively). There was a strong correlation between changes in Rrest and Rmin within both groups (r = 0.57, P < 0.01 and r = 0.68, P < 0.0001, respectively), whereas the change in BP in group A was not correlated to the change in Rmin (r = -0.03). CONCLUSION: The correction of forearm resistance artery structure during antihypertensive treatment depends on the vasodilatation achieved rather than BP reduction.

Small artery structure is an independent predictor of cardiovascular events in essential hypertension.

OBJECTIVE: Structural abnormality of resistance arteries is a characteristic pathophysiological phenomenon in essential hypertension and can be assessed in vitro as an increase in the media: lumen ratio (M: L) of isolated small arteries. We have investigated whether M: L is a risk predictor in uncomplicated essential hypertensive patients. Recently, high M: L was demonstrated as a prognostic marker in patients at high cardiovascular risk, including normotensive type 2 diabetic patients. Since diabetes is associated with pressure-independent changes in M: L, the relevance of this finding to essential hypertension has been uncertain. METHODS: We conducted a follow-up survey of 159 essential hypertensive patients, who had previously been submitted to a M: L evaluation while participating in a clinical trial. They composed a homogeneous moderate-risk group, with no concomitant diseases, and represented 1661 years of follow-up. RESULTS: Thirty patients suffered a documented predefined cardiovascular event during follow-up. Increased relative risk (RR) was associated with M: L >or= 0.083 (mean level of the hypertensive cohort), RR = 2.34 [95% confidence interval (CI) 1.11-4.95], and with M: L >or= 0.098 (mean level of a normotensive control group + 2SD), RR = 2.49 (95% CI 1.21-5.11). Both results remained significant (RR = 2.19, 95% CI 1.04-4.64, and RR = 2.20, 95% CI 1.06-4.56, respectively) when adjusted for Heart Score level (10-year mortality risk-estimate, integrating age, gender, systolic blood pressure, cholesterol and smoking). CONCLUSION: Abnormal resistance artery structure independently predicts cardiovascular events in essential hypertensive patients at moderate risk.

Effects of Renal Denervation on Insulin Sensitivity and Inflammatory Markers in Nondiabetic Patients with Treatment-Resistant Hypertension.

Increased sympathetic activity is important in the pathogenesis of hypertension and insulin resistance. Afferent signaling from the kidneys elevates the central sympathetic drive. We investigated the effect of catheter-based renal sympathetic denervation (RDN) on glucose metabolism, inflammatory markers, and blood pressure in nondiabetic patients with treatment-resistant hypertension. Eight subjects were included in an open-labelled study. Each patient was studied before and 6 months after RDN. Endogenous glucose production was assessed by a 3-3H glucose tracer, insulin sensitivity was examined by hyperinsulinemic euglycemic clamp, hormones and inflammatory markers were analyzed, and blood pressure was measured by office blood pressure readings and 24-hour ambulatory blood pressure monitoring. Insulin sensitivity (M-value) increased nonsignificantly from 2.68 ± 0.28 to 3.07 ± 0.41 (p = 0.12). A significant inverse correlation between the increase in M-value and BMI 6 months after RDN (p = 0.03) was found, suggesting beneficial effects on leaner subjects. Blood pressure decreased significantly, but there were no changes in hormones, inflammatory markers, or endogenous glucose production. Our results indicate that RDN may improve insulin sensitivity in some patients with treatment-resistant hypertension, albeit confirmation of these indications of beneficial effects on leaner subjects awaits the outcome of larger randomized controlled studies.

Intracellular smooth muscle [Ca2+] in acetylcholine and nitric oxide-mediated relaxation of human small arteries.

In human resistance arteries the role of intracellular calcium during receptor agonist and nitric oxide (NO)-mediated vasorelaxation is almost unknown. We examined changes in smooth muscle calcium concentration ([Ca2+]i) caused by acetylcholine and the NO donor S-nitroso-N-acetylpenicillamine (SNAP) in isolated human subcutaneous small arteries. In arteries constricted with 50 mM KCl, acetylcholine and SNAP induced relaxation without any change in [Ca2+]i, whereas in noradrenaline constricted vessels, both acetylcholine and to a lesser degree also SNAP-mediated relaxation were associated with a decrease in [Ca2+]i. Furthermore incubation with SNAP (1 microM) induced a rightward shift in the [Ca2+]i-force relationship. These results suggest that relaxation mediated by endothelium derived hyperpolarizing factors (EDHF) is associated with reduction in [Ca2+]i, whereas NO-mediated relaxation can take place without changes in [Ca2+]i. This finding seems to be, at least partly, due to NO-mediated desensitization of the contractile apparatus to calcium.

Renal resistance and long-term blood pressure in individuals genetically predisposed for essential hypertension: 10-year follow-up of the Danish Hypertension Prevention Project.

AIM: Young individuals genetically predisposed for essential hypertension have increased renal vascular resistance. We evaluated whether 1 year of angiotensin II receptor blockade decreases afferent arteriolar resistance (RA) and induces a sustained blood pressure (BP) reduction during a 10-year follow-up period in offspring of parents both diagnosed with essential hypertension. METHODS: Based on renal plasma flow (p-aminohippurate clearance) and glomerular filtration rate (Cr-EDTA clearance) RA was calculated according to the model originally established by Gomez. Following baseline measurements, the participants (n = 110, mean age 30 years) were randomly allocated to 12 months of treatment with either candesartan or placebo followed by repetition of measurements and withdrawal of medication. Four-hour ambulatory BP (ABP) was recorded at baseline, by end of active treatment and after 6 months, 1, 2, 3, 5, and 10 years. ABP was analyzed according to RA achieved at the end of active treatment. RESULTS: Candesartan reduced RA by 14% (P < 0.01). Ten years posttreatment systolic ABP increased by 2.1 mmHg (P = 0.04) and diastolic by 4.2 mmHg (P < 0.01) compared with baseline, without any difference between treatment arms. A high posttreatment RA was associated with higher BP levels during follow-up, but long-term alterations in 24-h BP were similar in participants with low and high RA and not different between treatment arms. CONCLUSION: RA is associated with 24-h BP levels, but temporary lowering of BP and RA by candesartan does not prevent BP from increasing further. Prevention of hypertension appears not feasible by short-term inhibition of the rennin-angiotensin system in young adults.

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.