Subtype Identification of Surgically Curable Primary Aldosteronism During Treatment With Mineralocorticoid Receptor Blockade.

BACKGROUND: Current guidelines and consensus documents recommend withdrawal of mineralocorticoid receptor antagonists (MRAs) before primary aldosteronism (PA) subtyping by adrenal vein sampling (AVS), but this practice can cause severe hypokalemia and uncontrolled high blood pressure. Our aim was to investigate if unilateral PA can be identified by AVS during MRA treatment. METHODS: We compared the rate of unilateral PA identification between patients with and without MRA treatment in large data sets of patients submitted to AVS while off renin-angiotensin system blockers and ß-blockers. In sensitivity analyses, the between-group differences of lateralization index values after propensity score matching and the rate of unilateral PA identification in subgroups with undetectable (≤2 mUI/L), suppressed (<8.2 mUI/L), and unsuppressed (≥8.2 mUI/L) direct renin concentration levels were also evaluated. RESULTS: Plasma aldosterone concentration, direct renin concentration, and blood pressure values were similar in non-MRA-treated (n=779) and MRA-treated (n=61) patients with PA, but the latter required more antihypertensive agents (P=0.001) and showed a higher rate of adrenal nodules (82% versus 67%; P=0.022) and adrenalectomy (72% versus 54%; P=0.01). However, they exhibited no significant differences in commonly used AVS indices and the area under the receiving operating characteristic curve of lateralization index, both under unstimulated conditions and postcosyntropin. Several sensitivity analyses confirmed these results in propensity score matching adjusted models and in patients with undetectable, or suppressed or unsuppressed renin levels. CONCLUSIONS: At doses that controlled blood pressure and potassium levels, MRAs did not preclude the identification of unilateral PA at AVS. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

[The new recommendations for hypertension therapy]. / Die neuen Empfehlungen zur Hypertonietherapie.

The new guidelines of the European Society of Hypertension (ESH) are a milestone for the improved care of patients with hypertension. The aim was to provide a comprehensive guide and a detailed description of uncomplicated but also complicated hypertension with its comorbidities for everyday practice. Numerous new aspects were added, and clinical situations were also described and recommendations for action were given. The most important general aspects of practical high-pressure diagnostics, prognosis assessment, and basic treatment with the blood pressure goals, as well as follow-up care are presented in the overview.

Unilaterally Selective Adrenal Vein Sampling for Identification of Surgically Curable Primary Aldosteronism.

BACKGROUND: Adrenal venous sampling is recommended for the identification of unilateral surgically curable primary aldosteronism but is often clinically useless, owing to failed bilateral adrenal vein cannulation. OBJECTIVES: To investigate if only unilaterally selective adrenal vein sampling studies can allow the identification of the responsible adrenal. METHODS: Among 1625 patients consecutively submitted to adrenal vein sampling in tertiary referral centers, we selected those with selective adrenal vein sampling results in at least one side; we used surgically cured unilateral primary aldosteronism as gold reference. The accuracy of different values of the relative aldosterone secretion index (RASI), which estimates the amount of aldosterone produced in each adrenal gland corrected for catheterization selectivity, was examined. RESULTS: We found prominent differences in RASI values distribution between patients with and without unilateral primary aldosteronism. The diagnostic accuracy of RASI values estimated by the area under receiver operating characteristic curves was 0.714 and 0.855, respectively, in the responsible and the contralateral side; RASI values >2.55 and ≤0.96 on the former and the latter side furnished the highest accuracy for detection of surgically cured unilateral primary aldosteronism. Moreover, in the patients without unilateral primary aldosteronism, only 20% and 16% had RASI values ≤0.96 and >2.55. CONCLUSIONS: With the strength of a large real-life data set and use of the gold reference entailing an unambiguous diagnosis of unilateral primary aldosteronism, these results indicate the feasibility of identifying unilateral primary aldosteronism using unilaterally selective adrenal vein sampling results. REGISTRATION: URL: https://www. CLINICALTRIALS: gov; Unique identifier: NCT01234220.

The Effect of Renal Denervation on T Cells in Patients with Resistant Hypertension.

(1) Background: Sympathetic overactivity is a major contributor to resistant hypertension (RH). According to animal studies, sympathetic overactivity increases immune responses, thereby aggravating hypertension and cardiovascular outcomes. Renal denervation (RDN) reduces sympathetic nerve activity in RH. Here, we investigate the effect of RDN on T-cell signatures in RH. (2) Methods: Systemic inflammation and T-cell subsets were analyzed in 17 healthy individuals and 30 patients with RH at baseline and 6 months after RDN. (3) Results: The patients with RH demonstrated higher levels of pro-inflammatory cytokines and higher frequencies of CD4+ effector memory (TEM), CD4+ effector memory residential (TEMRA) and CD8+ central memory (TCM) cells than the controls. After RDN, systolic automated office blood pressure (BP) decreased by -17.6 ± 18.9 mmHg. Greater BP reductions were associated with higher CD4+ TEM (r -0.421, p = 0.02) and CD8+ TCM (r -0.424, p = 0.02) frequencies at baseline. The RDN responders, that is, the patients with ≥10mmHg systolic BP reduction, showed reduced pro-inflammatory cytokine levels, whereas the non-responders had unchanged inflammatory activity and higher CD8+ TEMRA frequencies with increased cellular cytokine production. (4) Conclusions: The pro-inflammatory state of patients with RH is characterized by altered T-cell signatures, especially in non-responders. A detailed analysis of T cells might be useful in selecting patients for RDN.

Drug-resistant hypertension in primary aldosteronism patients undergoing adrenal vein sampling: the AVIS-2-RH study.

AIMS: We aimed at determining the rate of drug-resistant arterial hypertension in patients with an unambiguous diagnosis of primary aldosteronism (PA). Moreover, we sought for investigating the diagnostic performance of adrenal vein sampling (AVS), and the effect of adrenalectomy on blood pressure (BP) and prior treatment resistance in PA patients subtyped by AVS in major referral centres. METHODS AND RESULTS: The Adrenal Vein Sampling International Study-2 (AVIS-2) was a multicentre international study that recruited consecutive PA patients submitted to AVS, according to current guidelines, during 15 years. The patients were over 18 years old with arterial hypertension and had an unambiguous diagnosis of PA. The rate of resistant hypertension was assessed at baseline and after adrenalectomy using the American Heart Association (AHA) 2018 definition. Information on presence or absence of resistant hypertension was available in 89% of the 1625 enrolled PA patients. Based on the AHA 2018 criteria, resistant hypertension was found in 20% of patients, of which about two-thirds (14%) were men and one-third (6%) women (χ2 = 17.1, P < 1*10-4) with a higher rate of RH in men than in women (23% vs. 15% P < 1*10-4). Of the 292 patients with resistant hypertension, 98 (34%) underwent unilateral AVS-guided adrenalectomy, which resolved BP resistance to antihypertensive treatment in all. CONCLUSIONS: (i) Resistant hypertension is a common presentation in patients seeking surgical cure of PA; (ii) AVS is key for the optimal management of patients with PA due to resistant hypertension; and (iii) AVS-guided adrenalectomy allowed resolution of treatment-resistant hypertension.

Feasibility of Imaging-Guided Adrenalectomy in Young Patients With Primary Aldosteronism.

Many of the patients with primary aldosteronism (PA) are denied curative adrenalectomy because of limited availability or failure of adrenal vein sampling. It has been suggested that adrenal vein sampling can be omitted in young patients with a unilateral adrenal nodule, who show a florid biochemical PA phenotype. As this suggestion was based on a very low quality of evidence, we tested the applicability and accuracy of imaging, performed by computed tomography and/or magnetic resonance, for identification of unilateral PA, as determined by biochemical and/or clinical cure after unilateral adrenalectomy. Among 1625 patients with PA submitted to adrenal vein sampling in a multicenter multiethnic international study, 473 were ≤45 years of age; 231 of them had exhaustive imaging and follow-up data. Fifty-three percentage had a unilateral adrenal nodule, 43% had no nodules, and 4% bilateral nodules. Fifty-six percentage (n=131) received adrenalectomy and 128 were unambiguously diagnosed as unilateral PA. A unilateral adrenal nodule on imaging and hypokalemia were the strongest predictors of unilateral PA at regression analysis. Accordingly, imaging allowed correct identification of the responsible adrenal in 95% of the adrenalectomized patients with a unilateral nodule. The rate raised to 100% in the patients with hypokalemia, who comprised 29% of the total, but fell to 88% in those without hypokalemia. Therefore, a unilateral nodule and hypokalemia could be used to identify unilateral PA in patients ≤45 years of age if adrenal vein sampling is not easily available. However, adrenal vein sampling remains indispensable in 71% of the young patients, who showed no nodules/bilateral nodules at imaging and/or no hypokalemia. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01234220.

Identification of Surgically Curable Primary Aldosteronism by Imaging in a Large, Multiethnic International Study.

CONTEXT: Adrenal gland imaging is recommended by the current guidelines for the workup of primary aldosteronism (PA). However, its diagnostic performance has not been established in large, multiethnic cohorts of patients who undergo adrenal vein sampling (AVS) and adrenalectomy. OBJECTIVE: This work aims to assess the diagnostic accuracy of cross-sectional adrenal imaging. METHODS: This international multicenter study took place in tertiary referral centers. A total of 1625 PA patients seeking surgical cure were enrolled in an international study involving 19 centers in North America, Europe, Asia, and Australia. Of these, 1311 (81%) had imaging data available and 369 (23%), who received a final diagnosis of surgically cured unilateral PA, were examined. Patients underwent AVS and imaging by computed tomography and/or magnetic resonance imaging. The accuracy of detection of unilateral PA at imaging was estimated by the area under the receiver operator characteristics curve using cure (biochemical and/or full clinical success) as the reference at follow-up after unilateral adrenalectomy. RESULTS: In the cohort of 1311 patients with imaging data available, 34% and 7% of cases showed no detectable or bilateral nodules, respectively. Imaging did not detect the culprit adrenal in 28% of the surgically cured unilateral PA patients. Moreover, the clinical outcome did not differ significantly between the imaging-positive and imaging-negative patients. CONCLUSION: Cross-sectional imaging did not identify a lateralized cause of disease in around 40% of PA patients and failed to identify the culprit adrenal in more than one-fourth of patients with unilateral PA.

Aldosterone-Mediated Sodium Retention Is Reflected by the Serum Sodium to Urinary Sodium to (Serum Potassium)2 to Urinary Potassium (SUSPPUP) Index.

The serum sodium to urinary sodium ratio divided by the (serum potassium)2 to urinary potassium ratio (SUSPPUP formula) reflects aldosterone action. We here prospectively investigated into the usefulness of the SUSPPUP ratio as a diagnostic tool in primary hyperaldosteronism. Parallel measurements of serum and urinary sodium and potassium concentrations (given in mmol/L) in the fasting state were done in 225 patients. Of them, 69 were diagnosed with primary aldosteronism (PA), 102 with essential hypertension (EH), 26 with adrenal insufficiency (AI) and 28 did not suffer from the above-mentioned disorders and were assigned to the reference group (REF). The result of the SUSPPUP formula was highest in the PA group (7.4, 4.2-12.3 L/mmol), followed by EH (3.2, 2.3-4.3 L/mmol), PA after surgery (3.9, 3.0-6.0 L/mmol), REF (3.4 ± 1.4 L/mmol) and AI (2.9 +/- 1.2 L/mmol). The best sensitivity in distinguishing PA from EH was reached by multiplication of the aldosterone to renin-ratio (ARR) with the SUSPPUP formula (92.7% at a cut off > 110 L/mmol), highest specificity was reached by the SUSPPUP determinations (87.2%). The integration of the SUSPPUP ratio into the ARR helps to improve the diagnosis of hyperaldosteronism substantially.

Percutaneous transluminal renal angioplasty of global kidney ischemia improves renal function and blood pressure.

BACKGROUND: Renal artery stenosis (RAS) can lead to hypertension and renal failure. Nevertheless, its treatment by percutaneous transluminal renal angioplasty (PTRA) remains controversial. It is unknown, whether patients with global kidney ischemia (GKI), that means patients with bilateral RAS or RAS with a single functioning kidney, may benefit from PTRA or not. METHODS: We retrospectively analyzed 93 patients with RAS (25 bilateral or single functioning kidney) undergoing PTRA. Patients had refractory hypertension (≥3 medications). Blood pressure, antihypertensive drugs and serum-creatinine were compared pre-/post-intervention and at 1 year's follow-up. RESULTS: At 1 year after PTRA of patients with GKI, systolic and diastolic blood pressure were significantly reduced compared to patients with unilateral PTRA (systolic: -19.1 ± 10.5 [bilateral] vs. -11.4 ± 12.1 mmHg [unilateral], P < 0.01; diastolic: -10.1 ± 6.8 mmHg vs. -6.3 ± 6.6 mmHg, P < 0.05). The number of antihypertensive drugs was reduced by -0.8 ± 3.0 at 1 year in patients with GKI, while it increased by +0.1 ± 3.5 in the unilateral RAS group (P < 0.001). Furthermore, post-interventional serum-creatinine decreased by -34.6 ± 31.4 µmol/I after of patients with GKI (P < 0.001 vs. baseline). In patients with unilateral PTRA, a non-significant increase in serum-creatinine was observed (+8.3 ± 2 µmol/l). CONCLUSION: PTRA in patients with GKI led to improved blood pressure and renal function. A large, well-designed, randomized clinical trial targeting this population is still needed. The benefit of PTRA should be measured with the risks in each patient individually.

α2A-Adrenoceptors Modulate Renal Sympathetic Neurotransmission and Protect against Hypertensive Kidney Disease.

BACKGROUND: Increased nerve activity causes hypertension and kidney disease. Recent studies suggest that renal denervation reduces BP in patients with hypertension. Renal NE release is regulated by prejunctional α2A-adrenoceptors on sympathetic nerves, and α2A-adrenoceptors act as autoreceptors by binding endogenous NE to inhibit its own release. However, the role of α2A-adrenoceptors in the pathogenesis of hypertensive kidney disease is unknown. METHODS: We investigated effects of α2A-adrenoceptor-regulated renal NE release on the development of angiotensin II-dependent hypertension and kidney disease. In uninephrectomized wild-type and α2A-adrenoceptor-knockout mice, we induced hypertensive kidney disease by infusing AngII for 28 days. RESULTS: Urinary NE excretion and BP did not differ between normotensive α2A-adrenoceptor-knockout mice and wild-type mice at baseline. However, NE excretion increased during AngII treatment, with the knockout mice displaying NE levels that were significantly higher than those of wild-type mice. Accordingly, the α2A-adrenoceptor-knockout mice exhibited a systolic BP increase, which was about 40 mm Hg higher than that found in wild-type mice, and more extensive kidney damage. In isolated kidneys, AngII-enhanced renal nerve stimulation induced NE release and pressor responses to a greater extent in kidneys from α2A-adrenoceptor-knockout mice. Activation of specific sodium transporters accompanied the exaggerated hypertensive BP response in α2A-adrenoceptor-deficient kidneys. These effects depend on renal nerves, as demonstrated by reduced severity of AngII-mediated hypertension and improved kidney function observed in α2A-adrenoceptor-knockout mice after renal denervation. CONCLUSIONS: Our findings reveal a protective role of prejunctional inhibitory α2A-adrenoceptors in pathophysiologic conditions with an activated renin-angiotensin system, such as hypertensive kidney disease, and support the concept of sympatholytic therapy as a treatment.

[Diagnostics in Secondary Hypertension: What is to Consider?] / Diagnostik der sekundären Hypertonie: An was ist bei wem zu denken?

The prevalence of arterial hypertension with its cardiovascular diseases like myocardial infarction, stroke, chronic kidney disease and peripheral artery disease is increasing in our aging population. Despite numerous efficient and well-tolerated antihypertensive drugs more than eight million people die worldwide from the consequences of insufficiently controlled hypertension every year. One third of the german adult population suffers from high blood pressure. The fact that in only 50 % of hypertonic patients the blood pressure is on a string is even more disturbing. Several factors can counteract sufficient blood pressure control. This article should help to identify patients with possible secondary hypertension. It is certainly not decisive to request a broad screening for all hypertensive patients. A certain pre-selection of potential patients is mandatory. The most common types of secondary hypertension are discussed and the diagnostic and therapeutic pathways are specified.

Subtyping of Primary Aldosteronism in the AVIS-2 Study: Assessment of Selectivity and Lateralization.

CONTEXT: Adrenal venous sampling (AVS) is the key test for subtyping primary aldosteronism (PA), but its interpretation varies widely across referral centers and this can adversely affect the management of PA patients. OBJECTIVES: To investigate in a real-life study the rate of bilateral success and identification of unilateral aldosteronism and their impact on blood pressure outcomes in PA subtyped by AVS. DESIGN AND SETTINGS: In a retrospective analysis of the largest international registry of individual AVS data (AVIS-2 study), we investigated how different cut-off values of the selectivity index (SI) and lateralization index (LI) affected rate of bilateral success, identification of unilateral aldosteronism, and blood pressure outcomes. RESULTS: AVIS-2 recruited 1625 individual AVS studies performed between 2000 and 2015 in 19 tertiary referral centers. Under unstimulated conditions, the rate of biochemically confirmed bilateral AVS success progressively decreased with increasing SI cut-offs; furthermore, with currently used LI cut-offs, the rate of identified unilateral PA leading to adrenalectomy was as low as <25%. A within-patient pairwise comparison of 402 AVS performed both under unstimulated and cosyntropin-stimulated conditions showed that cosyntropin increased the confirmed rate of bilateral selectivity for SI cut-offs ≥ 2.0, but reduced lateralization rates (P < 0.001). Post-adrenalectomy outcomes were not improved by use of cosyntropin or more restrictive diagnostic criteria. CONCLUSION: Commonly used SI and LI cut-offs are associated with disappointingly low rates of biochemically defined AVS success and identified unilateral PA. Evidence-based protocols entailing less restrictive interpretative cut-offs might optimize the clinical use of this costly and invasive test. (J Clin Endocrinol Metab XX: 0-0, 2020).

Everolimus in de novo kidney transplant recipients participating in the Eurotransplant senior program: Results of a prospective randomized multicenter study (SENATOR).

Early conversion to everolimus was assessed in kidney transplant recipients participating in the Eurotransplant Senior Program (ESP), a population in whom data are lacking. The SENATOR multicenter study enrolled 207 kidney transplant recipients undergoing steroid withdrawal at week 2 post-transplant (ClinicalTrials.gov [NCT00956293]). At week 7, patients were randomized (1:2 ratio) to continue the previous calcineurin inhibitor (CNI)-based regimen with mycophenolic acid (MPA) and cyclosporine or switch to a CNI-free regimen with MPA, everolimus (5-10 ng/mL) and basiliximab at weeks 7 and 12, then followed for 18 weeks to month 6 post-transplant. The primary endpoint was estimated GFR (eGFR). At week 7, 77/207 (37.2%) patients were randomized (53 everolimus, 24 control). At month 6, eGFR was comparable: 36.5±10.8ml/min with everolimus versus 42.0±13.0ml/min in the control group (p = 0.784). Discontinuation due to adverse events occurred in 27.8% of everolimus-treated patients and 0.0% of control patients (p = 0005). Efficacy profiles showed no difference. In conclusion, eGFR, safety and efficacy outcomes at month 6 post-transplant showed no difference between groups. The everolimus group experienced a higher rate of discontinuation due to adverse events. However, the high rate of non-randomization is highly relevant, indicating this to be a somewhat unstable patient population regardless of treatment.

Clinical Outcomes of 1625 Patients With Primary Aldosteronism Subtyped With Adrenal Vein Sampling.

We sought to measure the clinical benefits of adrenal venous sampling (AVS), a test recommended by guidelines for primary aldosteronism (PA) patients seeking surgical cure, in a large registry of PA patients submitted to AVS. Data of 1625 consecutive patients submitted to AVS in 19 tertiary referral centers located in Asia, Australia, Europe, and North America were collected in a large multicenter international registry. The primary end points were the rate of bilateral success, ascertained lateralization of PA, adrenalectomy, and of cured arterial hypertension among AVS-guided and non AVS-guided adrenalectomy patients. AVS was successful in 80.1% of all cases but allowed identification of unilateral PA in only 45.5% by the criteria in use at each center. Adrenalectomy was performed in 41.8% of all patients and cured arterial hypertension in 19.6% of the patients, 2-fold more frequently in women than men (P<0.001). When AVS-guided, surgery provided a higher rate of cure of hypertension than when non-AVS-guided (40.0% versus 30.5%; P=0.027). Compared with surgical cases, patients treated medically needed more antihypertensive medications (P<0.001) and exhibited a higher rate of persistent hypokalemia requiring potassium supplementation (4.9% versus 2.3%; P<0.01). The low rate of adrenalectomy and cure of hypertension in PA patients seeking surgical cure indicates suboptimal AVS use, possibly related to issues in patient selection, technical success, and AVS data interpretation. Given the better outcomes of AVS-guided adrenalectomy, these results call for actions to improve the diagnostic use of this test that is necessary for detection of surgical PA candidates. Clinical Trial Registration- URL: http://www.clinicaltrials.gov. Unique identifier: NCT01234220.

Erythrocyte Salt Sedimentation Assay Does Not Predict Response to Renal Denervation.

Renal denervation (RDN) has recently been shown to be effective in patients without antihypertensive medication. However, about 30% of patients do not respond to RDN, and therefore, there exists a need to find predictors of response. Individuals are either salt-sensitive (SS) or non-salt-sensitive (NSS) in terms of their blood pressure (BP) regulation. The sympathetic nervous system can influence water and salt handling. RDN reduces sympathetic drive and has an impact on salt excretion. The present study was conducted to test the influence of salt sensitivity in terms of the BP reducing effect after RDN procedure. Salt sensitivity was estimated using the in vitro Erythrocyte Salt Sedimentation Assay (ESS). In 88 patients with resistant hypertension, RDN was performed. Office BP and lab testing were performed at baseline and at month 1, 3, 6, 12, 18, and 24 after RDN. A responder rate of 64.7% has been observed. Salt sensitivity measurements (ESS-Test) were completed in a subgroup of 37 patients with resistant hypertension. In this group, 15 were SS and 17 were salt-resistant according to the in vitro assay, respectively. The responder rate was 60% in SS patients and 59.1% in NSS patients, respectively. Electrolytes as well as aldosterone and renin levels did not differ between the two groups at baseline and in the follow-up measurements. The present study showed that salt sensitivity, estimated using the ESS in vitro test, did not affect the outcome of RDN and, therefore, does not help to identify patients suitable for RDN.

[Renal denervation in refractory hypertension: joint statement of the German hypertension league DHL eV and the German societies of cardiology, angiology, nephrology and radiology]. / Renale Denervation bei nicht-kontrollierter arterieller Hypertonie.

Arterial hypertension is a major risk factor for cardiovascular mortality and remains insufficiently controlled in Germany. The sham controlled Symplicity HTN-3 trial did meet its primary safety endpoint but failed to meet its primary efficacy endpoint. Renal denervation can not replace established, well-proven therapies. It can only be used in selected truly resistant hypertensive patients as an additive approach and should be performed by specialized centers only. Randomized controlled trials are needed to further evaluate renal denervation.

Effects of renal sympathetic denervation on urinary sodium excretion in patients with resistant hypertension.

BACKGROUND: Sympathetic overactivity increases sodium retention and contributes to the pathophysiology of hypertension. Renal sympathetic denervation lowers blood pressure and reduces sympathetic activity in certain patients with resistant hypertension. METHODS AND RESULTS: This study aimed to assess the effect of renal denervation on urinary sodium excretion. 24-h urinary sodium excretion was estimated at baseline and after 6 months using the Kawasaki formula in 137 patients with resistant hypertension undergoing renal denervation. Sodium excretion was adjusted for cystatin C GFR and fractional sodium excretion was assessed. Mean office systolic blood pressure at baseline was 171 ± 2 mmHg despite an intake of 5.2 ± 0.1 antihypertensive drugs. Six months after renal denervation, systolic and diastolic BP decreased by 18 ± 2 mmHg (p < 0.0001) and 10 ± 1 mmHg (p < 0.001). 90 patients (65.7%) had SBP reductions ≥ 10 mmHg (responders). After 6 months, 24-h UNa increased by 13% compared to baseline (236 ± 9 vs. 268 ± 9 mmol/day, p < 0.003). This increase was most pronounced in patients with less response in BP. These findings were paralleled by a significant increase in fractional sodium excretion (1.19 ± 0.11 vs. 1.64 ± 0.14%, p < 0.0001) and were observed independently of the intake of antihypertensive drugs affecting sodium balance, such as mineralocorticoid receptor antagonists or diuretics. CONCLUSION: RDN lowered BP and increased estimated UNa and fractional sodium excretion in patients with resistant hypertension independently of renal function and antihypertensive therapy.