European society of hypertension position paper on ambulatory blood pressure monitoring.

Ambulatory blood pressure monitoring (ABPM) is being used increasingly in both clinical practice and hypertension research. Although there are many guidelines that emphasize the indications for ABPM, there is no comprehensive guideline dealing with all aspects of the technique. It was agreed at a consensus meeting on ABPM in Milan in 2011 that the 34 attendees should prepare a comprehensive position paper on the scientific evidence for ABPM.This position paper considers the historical background, the advantages and limitations of ABPM, the threshold levels for practice, and the cost-effectiveness of the technique. It examines the need for selecting an appropriate device, the accuracy of devices, the additional information and indices that ABPM devices may provide, and the software requirements.At a practical level, the paper details the requirements for using ABPM in clinical practice, editing considerations, the number of measurements required, and the circumstances, such as obesity and arrhythmias, when particular care needs to be taken when using ABPM.The clinical indications for ABPM, among which white-coat phenomena, masked hypertension, and nocturnal hypertension appear to be prominent, are outlined in detail along with special considerations that apply in certain clinical circumstances, such as childhood, the elderly and pregnancy, and in cardiovascular illness, examples being stroke and chronic renal disease, and the place of home measurement of blood pressure in relation to ABPM is appraised.The role of ABPM in research circumstances, such as pharmacological trials and in the prediction of outcome in epidemiological studies is examined and finally the implementation of ABPM in practice is considered in relation to the issue of reimbursement in different countries, the provision of the technique by primary care practices, hospital clinics and pharmacies, and the growing role of registries of ABPM in many countries.

Genome-wide association study of blood pressure extremes identifies variant near UMOD associated with hypertension.

Hypertension is a heritable and major contributor to the global burden of disease. The sum of rare and common genetic variants robustly identified so far explain only 1%-2% of the population variation in BP and hypertension. This suggests the existence of more undiscovered common variants. We conducted a genome-wide association study in 1,621 hypertensive cases and 1,699 controls and follow-up validation analyses in 19,845 cases and 16,541 controls using an extreme case-control design. We identified a locus on chromosome 16 in the 5' region of Uromodulin (UMOD; rs13333226, combined P value of 3.6×10(-11)). The minor G allele is associated with a lower risk of hypertension (OR [95%CI]: 0.87 [0.84-0.91]), reduced urinary uromodulin excretion, better renal function; and each copy of the G allele is associated with a 7.7% reduction in risk of CVD events after adjusting for age, sex, BMI, and smoking status (H.R. = 0.923, 95% CI 0.860-0.991; p = 0.027). In a subset of 13,446 individuals with estimated glomerular filtration rate (eGFR) measurements, we show that rs13333226 is independently associated with hypertension (unadjusted for eGFR: 0.89 [0.83-0.96], p = 0.004; after eGFR adjustment: 0.89 [0.83-0.96], p = 0.003). In clinical functional studies, we also consistently show the minor G allele is associated with lower urinary uromodulin excretion. The exclusive expression of uromodulin in the thick portion of the ascending limb of Henle suggests a putative role of this variant in hypertension through an effect on sodium homeostasis. The newly discovered UMOD locus for hypertension has the potential to give new insights into the role of uromodulin in BP regulation and to identify novel drugable targets for reducing cardiovascular risk.

Salt-sensitive hypertension and cardiac hypertrophy in mice deficient in the ubiquitin ligase Nedd4-2.

Nedd4-2 has been proposed to play a critical role in regulating epithelial Na+ channel (ENaC) activity. Biochemical and overexpression experiments suggest that Nedd4-2 binds to the PY motifs of ENaC subunits via its WW domains, ubiquitinates them, and decreases their expression on the apical membrane. Phosphorylation of Nedd4-2 (for example by Sgk1) may regulate its binding to ENaC, and thus ENaC ubiquitination. These results suggest that the interaction between Nedd4-2 and ENaC may play a crucial role in Na+ homeostasis and blood pressure (BP) regulation. To test these predictions in vivo, we generated Nedd4-2 null mice. The knockout mice had higher BP on a normal diet and a further increase in BP when on a high-salt diet. The hypertension was probably mediated by ENaC overactivity because 1) Nedd4-2 null mice had higher expression levels of all three ENaC subunits in kidney, but not of other Na+ transporters; 2) the downregulation of ENaC function in colon was impaired; and 3) NaCl-sensitive hypertension was substantially reduced in the presence of amiloride, a specific inhibitor of ENaC. Nedd4-2 null mice on a chronic high-salt diet showed cardiac hypertrophy and markedly depressed cardiac function. Overall, our results demonstrate that in vivo Nedd4-2 is a critical regulator of ENaC activity and BP. The absence of this gene is sufficient to produce salt-sensitive hypertension. This model provides an opportunity to further investigate mechanisms and consequences of this common disorder.

Short-term and sustained renal effects of angiotensin II receptor blockade in healthy subjects.

We investigated the short-term and sustained hormonal and renal effects of angiotensin II (Ang II) receptor blockade in normotensive healthy volunteers. Twenty-four subjects maintained on a fixed sodium diet were randomized to receive for 8 days a placebo or 10 or 50 mg doses of the Ang II antagonist irbesartan (SR 47436, BMS 186295) according to a double-blind, parallel group design. Plasma renin activity, plasma immunoreactive Ang II and aldosterone levels, blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 8 hours after the first and eighth administration of each dose of irbesartan or placebo. Ang II receptor blockade with irbesartan induced a dose-dependent compensatory increase in plasma renin activity and plasma angiotensin levels and a significant decrease in plasma aldosterone levels. The compensatory rise in plasma renin activity and Ang II levels was more pronounced on day 8, reflecting a long duration of the blocking effect of irbesartan. Irbesartan induced small changes in blood pressure and did not significantly modify renal blood flow and glomerular filtration rate. However, a significant decrease in filtration fraction was observed during receptor blockade on days 1 and 8. The tubular effects of irbesartan were characterized by a dose-dependent increase in sodium and chloride excretions. Interestingly, the cumulative natriuretic response to Ang II receptor blockade was similar on days 1 and 8, suggesting that in these subjects, renal Ang II receptors are not blocked over 24 hours during repeated administration even though this antagonist has a long duration of action (t1/2 of 15 to 17 hours).(ABSTRACT TRUNCATED AT 250 WORDS)

Evidence for a sodium-induced activation of central neurogenic mechanisms in one-kidney, one-clip renal hypertensive rats

The mechanisms sustaining high blood pressure in conscious one-kidney, one-clip Goldblatt rats were evaluated with the use of SK&F 64139, a phenylethanolamine N-methyltransferase inhibitor capable of crossing the blood-brain barrier and of captopril, an angiotensin converting enzyme inhibitor. The rats were studied 3 weeks after left renal artery clipping and contralateral nephrectomy. During the developmental phase of hypertension, two groups of rats were maintained on a regular salt (RNa) intake, whereas two other groups were given a low salt (LNa) diet. On the day of the experiment, the base-line mean blood pressure measured in the LNa rats (177.4 +/- 5.2 mm Hg, mean +/- S.E., n = 15) was similar to that measured in the RNa rats (178.7 +/- 5.4 mm Hg, n = 16). SK&F 64139 (12.5 mg p.o.) induced a significantly more pronounced (P less than .001) blood pressure decrease in the RNa rats (-25.6 +/- 3.6 mm Hg, n = 8) than in the LNa rats (-4.3 +/- 3.3 mm Hg, n = 7) during a 90-min observation period. On the other hand, captopril (10 mg p.o.) normalized blood pressure in LNa rats (n = 8), but produced only a 13.4 mm Hg blood pressure drop in RNa rats (n = 8). RNa rats treated with SK&F 64139 were found to have decreased phenylethanolamine N-methyltransferase activity by an average 80% in selected brain stem nuclei when compared with nontreated rats. No significant difference in plasma catecholamine levels was found between the RNa and LNa rats. These results suggest that, in this experimental model of hypertension, the sodium ion might increase the model of hypertension, the sodium ion might increase the vasoconstrictor contribution of the sympathetic system via a centrally mediated neurogenic mechanism while at the same time it decreases the renin-dependency of the high blood pressure.

Salt-dependent renal effects of an angiotensin II antagonist in healthy subjects.

This study was designed to evaluate in healthy volunteers the renal hemodynamic and tubular effects of the orally active angiotensin II receptor antagonist losartan (DuP 753 or MK 954). Losartan or a placebo was administered to 23 subjects maintained on a high-sodium (200 mmol/d) or a low-sodium (50 mmol/d) diet in a randomized, double-blind, crossover study. The two 6-day diet periods were separated by a 5-day washout period. On day 6, the subjects were water loaded, and blood pressure, renal hemodynamics, and urinary electrolyte excretion were measured for 6 hours after a single 100-mg oral dose of losartan (n = 16) or placebo (n = 7). Losartan induced no significant changes in blood pressure, glomerular filtration rate, or renal blood flow in these water-loaded subjects, whatever the sodium diet. In subjects on a low-salt diet, losartan markedly increased urinary sodium excretion from 115 +/- 9 to 207 +/- 21 mumol/min (P < .05). The fractional excretion of endogenous lithium was unchanged, suggesting no effect of losartan on the early proximal tubule in our experimental conditions. Losartan also increased urine flow rate (from 10.5 +/- 0.4 to 13.1 +/- 0.6 mL/min, P < .05); urinary potassium excretion (from 117 +/- 6.9 to 155 +/- 11 mumol/min); and the excretion of chloride, magnesium, calcium, and phosphate. In subjects on a high-salt diet, similar effects of losartan were observed, but the changes induced by the angiotensin II antagonist did not reach statistical significance. In addition, losartan demonstrated significant uricosuric properties with both sodium diets.(ABSTRACT TRUNCATED AT 250 WORDS)

A patient with Hypertension Uncontrolled by Previous treatment

Co-administration of antihypertensive agents with different modes of action is required in most hypertensive patients to control blood pressure. This led to the development of fixed-dose combinations of established efficacy and tolerability, with the convenience of a single tablet facilitating long-term adherence with therapy. Blockade of the renin-angiotensin system (RAS) is widely used in hypertensive patients, particularly in those at high risk of cardiovascular or renal diseases. There is therefore a strong rationale for including a blocker of the RAS in fixed combinations, together with either a diuretic or a calcium antagonist. Patient characteristics and cardiovascular risk profiles are useful in guiding the choice of combinations administered. Adding a diuretic or a calciumantagonist to aRAS blocker is a valuable option in practically all patients, whether or not they have comorbidities. Amajor task is to individualize the treatment, ie, to find a drug regimen that normalizes the patient's blood pressure while preserving his or her quality of life. This can be achieved in most patients using the fixeddose combination containing the angiotensin-converting enzyme inhibitor perindopril and the diuretic indapamide. A number of trials have established the antihypertensive efficacy and the protective effects of this combination in hypertensive patients, which justifies its broad use in patients with blood pressure uncontrolled by other blood pressure-lowering agents.

Increased Expression of Renal Cyclooxygenase-2 and Neuronal Nitric Oxide Synthase in Hypertensive Cx40-Deficient Mice.

Cx40-deficient mice (Cx40-/-) are hypertensive due to increased renin secretion. We evaluated the renal expression of neuronal nitric oxide synthase (nNOS) and cyclooxygenases COX-1 and COX-2, three macula densa enzymes. The levels of nNOS were increased in kidneys of Cx40-/- mice, as well as in those of wild-type (WT) mice subjected to the two-kidney one-clip model of hypertension. In contrast, the levels of COX-2 expression were only increased in the hypoperfused kidney of Cx40-/- mice. Treatment with indomethacin lowered blood pressure and renin mRNA in Cx40-/- mice without affecting renin levels, indicating that changes in COX-2 do not cause the altered secretion of renin. Suppression of NOS activity by N(G)-nitro-L-arginine methyl ester (L-NAME) decreased renin levels in Cx40-/- animals, indicating that NO regulates renin expression in the absence of Cx40. Treatment with candesartan normalized blood pressure in Cx40-/- mice, and decreased the levels of both COX-2 and nNOS. After a treatment combining candesartan and L-NAME, the blood pressure of Cx40-/- mice was higher than that of WT mice, showing that NO may counterbalance the vasoconstrictor effects of angiotensin II in Cx40-/- mice. These data document that renal COX-2 and nNOS are differentially regulated due to the elevation of renin-dependent blood pressure in mice lacking Cx40.

A guide for easy- and difficult-to-treat hypertension.

Although the blood pressure (BP) of many patients can be controlled using standard combinations, treatment of hypertension frequently represents a clinical challenge to the primary care physician. This article will review best practices for managing patients with easy- and difficult-to-treat hypertension, including preferred antihypertensive combinations, optimizing adherence and persistence, recognizing white-coat hypertension, and intensifying therapy for treatment-resistant patients. Each physician must decide based on his or her own level of experience at what point a patient becomes too challenging and would benefit from referral to a hypertension specialist for more intensive management and to complete the exclusion of secondary forms of arterial hypertension. With intensive pharmacotherapy, many patients with difficult-to-treat hypertension can achieve BP control. If it fails, interventional strategies (e.g., renal denervation) are a valid option to get BP controlled.

Hypercalcaemia and acute renal failure after major burns: An under-diagnosed condition.

BACKGROUND: Hypercalcaemia has been shown to occur in about 20% of patients with major burns requiring prolonged intensive care unit (ICU) treatment, and it may be associated with renal failure. Having observed the early onset of hypercalcaemia, the study aimed to determine the frequency and timing of this condition in a European patient cohort. METHODS: A retrospective cohort study on a prospectively collected, computerised database of the 225 burn-injury ICU admissions between 2001 and 2007 was undertaken. The inclusion criteria included: burns &gt;20% of the body surface area (BSA) or in-hospital stay &gt;20 days. Hypercalcaemia was defined as an ionised plasma calcium (Ca(2+)) concentration &gt;1.32 mmol l(-1) (or total corrected calcium=[Ca]c&gt;2.55 mmol l(-1)). Four emblematic cases are reported in this article. RESULTS: A total of 73 patients met the inclusion criteria (age: 13-88 years, burns: 12-85% BSA): of these, 22 (30%) developed hypercalcaemia. The median time to the first hypercalcaemia value was 21 days. Only 11 patients had both high Ca(2+) and elevated [Ca]c (which remained normal in others). The risk factors of the disorder were burned surface (p=0.017) and immobilisation (fluidised bed use: p&lt;0.05, duration: p=0.02) followed by burned BSA. Acute renal failure tended to be more frequent in hypercalcaemic patients (five (23%) vs. three (6%): p=0.11), while mortality was not increased. The disorder resolved with hydration and mobilisation in most cases: pamidronate was successful in three cases that were most severe. CONCLUSION: Hypercalcaemia and associated acute renal failure occur more frequently and earlier than previously reported. Determining the ionised Ca rather than the total Ca with albumin correction enables earlier detection of hypercalcaemia. Bisphosphonates are an effective treatment option in controlling severe hypercalcaemia and preventing bone loss.

Fixed-dose combinations as initial therapy for hypertension : a review of approved agents and a guide to patient selection.

Recent guidelines recommend initiation of antihypertensive therapy with fixed-dose combinations in high-risk patients because such patients usually need two or more blood pressure (BP)-lowering agents in order to normalize their BP. Agents that block the renin-angiotensin system (ACE inhibitors or angiotensin II receptor antagonists [angiotensin receptor blockers; ARBs]) are preferred for the management of hypertension in most patients exhibiting subclinical target organ damage, or established cardiovascular or renal diseases. Unless contraindicated they should be one of the components of fixed-dose combinations, whereas the other component may be either a calcium channel antagonist or a thiazide diuretic. Fixed-dose combinations containing an ACE inhibitor or ARB plus a calcium channel antagonist appear particularly effective in preventing complications of coronary heart disease.

Common noncoding UMOD gene variants induce salt-sensitive hypertension and kidney damage by increasing uromodulin expression.

Hypertension and chronic kidney disease (CKD) are complex traits representing major global health problems. Multiple genome-wide association studies have identified common variants in the promoter of the UMOD gene, which encodes uromodulin, the major protein secreted in normal urine, that cause independent susceptibility to CKD and hypertension. Despite compelling genetic evidence for the association between UMOD risk variants and disease susceptibility in the general population, the underlying biological mechanism is not understood. Here, we demonstrate that UMOD risk variants increased UMOD expression in vitro and in vivo. Uromodulin overexpression in transgenic mice led to salt-sensitive hypertension and to the presence of age-dependent renal lesions similar to those observed in elderly individuals homozygous for UMOD promoter risk variants. The link between uromodulin and hypertension is due to activation of the renal sodium cotransporter NKCC2. We demonstrated the relevance of this mechanism in humans by showing that pharmacological inhibition of NKCC2 was more effective in lowering blood pressure in hypertensive patients who are homozygous for UMOD promoter risk variants than in other hypertensive patients. Our findings link genetic susceptibility to hypertension and CKD to the level of uromodulin expression and uromodulin's effect on salt reabsorption in the kidney. These findings point to uromodulin as a therapeutic target for lowering blood pressure and preserving renal function.