Adrenal fast-track and enhanced recovery in retroperitoneoscopic surgery for primary aldosteronism improving patient outcome and efficiency.

PURPOSE: No data exist on perioperative strategies for enhancing recovery after posterior retroperitoneoscopic adrenalectomy (PRA). Our objective was to determine whether a multimodality adrenal fast-track and enhanced recovery (AFTER) protocol for PRA can reduce recovery time, improve patient satisfaction and maintain safety. METHODS: Thirty primary aldosteronism patients were included. Fifteen patients were treated with 'standard-of-care' PRA and compared with 15 in the AFTER protocol. The AFTER protocol contains: a preoperative information video, postoperative oral analgesics, early postoperative mobilisation and enteral feeding, and blood pressure monitoring at home. The primary outcome was recovery time. Secondary outcomes were length of hospital stay, postoperative pain and analgesics requirements, patient satisfaction, perioperative complications and quality of life (QoL). RESULTS: Recovery time was much shorter in both groups than anticipated and was not significantly different (median 28 days). Postoperative length of hospital stay was significantly reduced in AFTER patients (mean 32 vs 42 h, CI 95%, p = 0.004). No significant differences were seen in pain, but less analgesics were used in the AFTER group. Satisfaction improved amongst AFTER patients for time of admission and postoperative visit to the outpatient clinic. There were no significant differences in complication rates or QoL. CONCLUSION: Despite no difference in recovery time between the two groups, probably due to small sample size, the AFTER protocol led to shorter hospital stays and less analgesic use after surgery, whilst maintaining and even enhancing patient satisfaction for several aspects of perioperative care. Complication rates and QoL are comparable to standard-of-care.

Management of patients with hypertension and chronic kidney disease referred to Hypertension Excellence Centres among 27 countries. On behalf of the European Society of Hypertension Working Group on Hypertension and the Kidney.

Objective Real-life management of patients with hypertension and chronic kidney disease (CKD) among European Society of Hypertension Excellence Centres (ESH-ECs) is unclear : we aimed to investigate it. Methods A survey was conducted in 2023. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed. Results Overall, 88 ESH-ECS representatives from 27 countries participated. According to the responders, renin-angiotensin system (RAS) blockers, calcium-channel blockers and thiazides were often added when these medications were lacking in CKD patients, but physicians were more prone to initiate RAS blockers (90% [interquartile range: 70-95%]) than MRA (20% [10-30%]), SGLT2i (30% [20-50%]) or (GLP1-RA (10% [5-15%]). Despite treatment optimisation, 30% of responders indicated that hypertension remained uncontrolled (30% (15-40%) vs 18% [10%-25%]) in CKD and CKD patients, respectively). Hyperkalemia was the most frequent barrier to initiate RAS blockers, and dosage reduction was considered in 45% of responders when kalaemia was 5.5-5.9 mmol/L. Conclusions RAS blockers are initiated in most ESH-ECS in CKD patients, but MRA and SGLT2i initiations are less frequent. Hyperkalemia was the main barrier for initiation or adequate dosing of RAS blockade, and RAS blockers' dosage reduction was the usual management.

What is the context? Hypertension is a strong independent risk factor for development of chronic kidney disease (CKD) and progression of CKD to ESKD. Improved adherence to the guidelines in the treatment of CKD is believed to provide further reduction of cardiorenal events. European Society of Hypertension Excellence Centres (ESH-ECs) have been developed in Europe to provide excellency regarding management of patients with hypertension and implement guidelines. Numerous deficits regarding general practitioner CKD screening, use of nephroprotective drugs and referral to nephrologists prior to referral to ESH-ECs have been reported. In contrast, real-life management of these patients among ESH-ECs is unknown. Before implementation of strategies to improve guideline adherence in Europe, we aimed to investigate how patients with CKD are managed among the ESH-ECs.What is the study about? In this study, a survey was conducted in 2023 by the ESH to assess management of CKD patients referred to ESH-ECs. The questionnaire contained 64 questions asking ESH-ECs representatives to estimate how patients with CKD are managed among their centres.What are the results? RAAS blockers are initiated in 90% of ESH-ECs in CKD patients, but the initiation of MRA and SGLT2i is less frequently done. Hyperkalemia is the main barrier for initiation or adequate dosing of RAAS blockade, and its most reported management was RAAS blockers dosage reduction. These findings will be crucial to implement strategies in order to improve management of patients with CKD and guideline adherence among ESH-ECs.

Electrolyte Disorders in Mitochondrial Cytopathies: A Systematic Review.

SIGNIFICANCE STATEMENT: Several recent studies identified mitochondrial mutations in patients with Gitelman or Fanconi syndrome. Mitochondrial cytopathies are generally not considered in the diagnostic workup of patients with electrolyte disorders. In this systematic review, we investigated the presence of electrolyte disorders in patients with mitochondrial cytopathies to determine the relevance of mitochondrial mutation screening in this population. Our analysis demonstrates that electrolyte disorders are commonly reported in mitochondrial cytopathies, often as presenting symptoms. Consequently, more clinical attention should be raised for mitochondrial disease as cause for disturbances in electrolyte homeostasis. Further prospective cohort studies are required to determine the exact prevalence of electrolyte disorders in mitochondrial cytopathies. BACKGROUND: Electrolyte reabsorption in the kidney has a high energy demand. Proximal and distal tubular epithelial cells have a high mitochondrial density for energy release. Recently, electrolyte disorders have been reported as the primary presentation of some mitochondrial cytopathies. However, the prevalence and the pathophysiology of electrolyte disturbances in mitochondrial disease are unknown. Therefore, we systematically investigated electrolyte disorders in patients with mitochondrial cytopathies. METHODS: We searched PubMed, Embase, and Google Scholar for articles on genetically confirmed mitochondrial disease in patients for whom at least one electrolyte is reported. Patients with a known second genetic anomaly were excluded. We evaluated 214 case series and reports (362 patients) as well as nine observational studies. Joanna Briggs Institute criteria were used to evaluate the quality of included studies. RESULTS: Of 362 reported patients, 289 had an electrolyte disorder, with it being the presenting or main symptom in 38 patients. The average number of different electrolyte abnormalities per patient ranged from 2.4 to 1.0, depending on genotype. Patients with mitochondrial DNA structural variants seemed most affected. Reported pathophysiologic mechanisms included renal tubulopathies and hormonal, gastrointestinal, and iatrogenic causes. CONCLUSIONS: Mitochondrial diseases should be considered in the evaluation of unexplained electrolyte disorders. Furthermore, clinicians should be aware of electrolyte abnormalities in patients with mitochondrial disease.

Monogenic forms of low-renin hypertension: clinical and molecular insights.

Monogenic disorders of hypertension are a distinct group of diseases causing dysregulation of the renin-angiotensin-aldosterone system and are characterized by low plasma renin activity. These can chiefly be classified as causing (i) excessive aldosterone synthesis (familial hyperaldosteronism), (ii) dysregulated adrenal steroid metabolism and action (apparent mineralocorticoid excess, congenital adrenal hyperplasia, activating mineralocorticoid receptor mutation, primary glucocorticoid resistance), and (iii) hyperactivity of sodium and chloride transporters in the distal tubule (Liddle syndrome and pseudohypoaldosteronism type 2). The final common pathway is plasma volume expansion and catecholamine/sympathetic excess that causes urinary potassium wasting; hypokalemia and early-onset refractory hypertension are characteristic. However, several single gene defects may show phenotypic heterogeneity, presenting with mild hypertension with normal electrolytes. Evaluation is based on careful attention to family history, physical examination, and measurement of blood levels of potassium, renin, and aldosterone. Genetic sequencing is essential for precise diagnosis and individualized therapy. Early recognition and specific management improves prognosis and prevents long-term sequelae of severe hypertension.

Predicting surgical outcome in posterior retroperitoneoscopic adrenalectomy with the aid of a preoperative nomogram.

BACKGROUND: Posterior retroperitoneoscopic adrenalectomy (PRA) has several advantages over transperitoneal laparoscopic adrenalectomy (TLA) regarding operative time, blood loss, postoperative pain, and recovery. However, it can be a technically challenging procedure. To improve patient selection for PRA, we developed a preoperative nomogram to predict operative time. METHODS: All consecutive patients with tumors of ≤ 7 cm and a body mass index (BMI) of < 35 kg/m2 undergoing unilateral PRA between February 2011 and March 2020 were included in the study. The primary outcome was operative time as surrogate endpoint for surgical complexity. Using ten patient variables, an optimal prediction model was created, with a best subsets regression analysis to find the best one-variable up to the best seven-variable model. RESULTS: In total 215 patients were included, with a mean age of 52 years and mean tumor size of 2.4 cm. After best subsets regression analysis, a four-variable nomogram was selected and calibrated. This model included sex, pheochromocytoma, BMI, and perinephric fat, which were all individually significant predictors. This model showed an ideal balance between predictive power and applicability, with an R2 of 38.6. CONCLUSIONS: A four-variable nomogram was developed to predict operative time in PRA, which can aid the surgeon to preoperatively identify suitable patients for PRA. If the nomogram predicts longer operative time and therefore a more complex operation, TLA should be considered as an alternative approach since it provides a larger working space. Also, the nomogram can be used for training purposes to select patients with favorable characteristics when learning this surgical approach.

Partial Adrenalectomy Carries a Considerable Risk of Incomplete Cure in Primary Aldosteronism.

PURPOSE: Laparoscopic adrenalectomy is standard treatment for patients with unilateral aldosterone-producing adenomas, but surgeons are increasingly tempted to perform partial adrenalectomy, disregarding potential multinodularity of the adrenal. We assess the diagnostic value of endoscopic ultrasound for differentiating solitary adenomas from multinodularity by examining in-depth adrenal pathology with ex vivo 11.7 T magnetic resonance imaging and immunohistochemistry. MATERIALS AND METHODS: In 15 primary aldosteronism patients, we performed intraoperative endoscopic ultrasound, ex vivo magnetic resonance imaging and histopathological examination. Every adrenal was intraoperatively and postoperatively assessed for solitary adenomas or multinodular hyperplasia. After unblinding for ex vivo magnetic resonance imaging results a second detailed histopathological examination, including immunohistochemistry analysis with CYP11B2 (aldosterone synthase) and chemokine receptor 4 (CXCR4), a new marker for aldosterone-producing adenomas, was performed. Finally, presence of somatic mutations linked to aldosterone-producing adenomas was assessed. RESULTS: The sensitivity and specificity of endoscopic ultrasound to identify multinodularity were 46% and 50%, respectively. We found multinodular hyperplasia in 87% of adrenals with ex vivo magnetic resonance imaging combined with detailed histopathology, and 6 adrenals contained multiple CYP11B2-producing nodules. Every CYP11B2 positive nodule and 61% of CYP11B2 negative nodules showed CXCR4 staining. Finally, in 4 adrenals (27%) we found somatic mutations. In multinodular glands, only 1 nodule harbored this mutation. CONCLUSIONS: Intraoperative endoscopic ultrasound in primary aldosteronism patients has low accuracy to identify multinodularity. Ex vivo magnetic resonance imaging can serve as a tool to direct detailed histopathological examination, which frequently shows CYP11B2 production in multiple nodules. Therefore, partial adrenalectomy is inappropriate in primary aldosteronism as multiple aldosterone-producing nodules easily stay behind.

Clinical presentation and long-term follow-up of dopamine beta hydroxylase deficiency.

Dopamine beta hydroxylase (DBH) deficiency is an extremely rare autosomal recessive disorder with severe orthostatic hypotension, that can be treated with L-threo-3,4-dihydroxyphenylserine (L-DOPS). We aimed to summarize clinical, biochemical, and genetic data of all world-wide reported patients with DBH-deficiency, and to present detailed new data on long-term follow-up of a relatively large Dutch cohort. We retrospectively describe 10 patients from a Dutch cohort and 15 additional patients from the literature. We identified 25 patients (15 females) from 20 families. Ten patients were diagnosed in the Netherlands. Duration of follow-up of Dutch patients ranged from 1 to 21 years (median 13 years). All patients had severe orthostatic hypotension. Severely decreased or absent (nor)epinephrine, and increased dopamine plasma concentrations were found in 24/25 patients. Impaired kidney function and anemia were present in all Dutch patients, hypomagnesaemia in 5 out of 10. Clinically, all patients responded very well to L-DOPS, with marked reduction of orthostatic complaints. However, orthostatic hypotension remained present, and kidney function, anemia, and hypomagnesaemia only partially improved. Plasma norepinephrine increased and became detectable, while epinephrine remained undetectable in most patients. We confirm the core clinical characteristics of DBH-deficiency and the pathognomonic profile of catecholamines in body fluids. Impaired renal function, anemia, and hypomagnesaemia can be part of the clinical presentation. The subjective response to L-DOPS treatment is excellent and sustained, although the neurotransmitter profile in plasma does not normalize completely. Furthermore, orthostatic hypotension as well as renal function, anemia, and hypomagnesaemia improve only partially.

Functional tests to guide management in an adult with loss of function of type-1 angiotensin II receptor.

BACKGROUND: Genetic loss of function of AGT (angiotensinogen), REN (renin), ACE (angiotensin-converting enzyme), or AGTR1 (type-1 angiotensin II receptor) leads to renal tubular dysgenesis (RTD). This syndrome is almost invariably lethal. Most surviving patients reach stage 5 chronic kidney disease at a young age. METHODS: Here, we report a 28-year-old male with a homozygous truncating mutation in AGTR1 (p.Arg216*), who survived the perinatal period with a mildly impaired kidney function. In contrast to classic RTD, kidney biopsy showed proximal tubules that were mostly normal. During the subsequent three decades, we observed evidence of both tubular dysfunction (hyperkalemia, metabolic acidosis, salt-wasting and a urinary concentrating defect) and glomerular dysfunction (reduced glomerular filtration rate, currently ~30 mL/min/1.73 m2, accompanied by proteinuria). To investigate the recurrent and severe hyperkalemia, we performed a patient-tailored functional test and showed that high doses of fludrocortisone induced renal potassium excretion by 155%. Furthermore, fludrocortisone lowered renal sodium excretion by 39%, which would have a mitigating effect on salt-wasting. In addition, urinary pH decreased in response to fludrocortisone. Opposite effects on urinary potassium and pH occurred with administration of amiloride, further supporting the notion that a collecting duct is present and able to react to fludrocortisone. CONCLUSIONS: This report provides living proof that even truncating loss-of-function mutations in AGTR1 are compatible with life and relatively good GFR and provides evidence for the prescription of fludrocortisone to treat hyperkalemia and salt-wasting in such patients.

A comparison of high-throughput plasma NMR protocols for comparative untargeted metabolomics.

INTRODUCTION: When analyzing the human plasma metabolome with Nuclear Magnetic Resonance (NMR) spectroscopy, the Carr-Purcell-Meiboom-Gill (CPMG) experiment is commonly employed for large studies. However, this process can lead to compromised statistical analyses due to residual macromolecule signals. In addition, the utilization of Trimethylsilylpropanoic acid (TSP) as an internal standard often leads to quantification issues, and binning, as a spectral summarization step, can result in features not clearly assignable to metabolites. OBJECTIVES: Our aim was to establish a new complete protocol for large plasma cohorts collected with the purpose of describing the comparative metabolic profile of groups of samples. METHODS: We compared the conventional CPMG approach to a novel procedure that involves diffusion NMR, using the Longitudinal Eddy-Current Delay (LED) experiment, maleic acid (MA) as the quantification reference and peak picking for spectral reduction. This comparison was carried out using the ultrafiltration method as a gold standard in a simple sample classification experiment, with Partial Least Squares-Discriminant Analysis (PLS-DA) and the resulting metabolic signatures for multivariate data analysis. In addition, the quantification capabilities of the method were evaluated. RESULTS: We found that the LED method applied was able to detect more metabolites than CPMG and suppress macromolecule signals more efficiently. The complete protocol was able to yield PLS-DA models with enhanced classification accuracy as well as a more reliable set of important features than the conventional CPMG approach. Assessment of the quantitative capabilities of the method resulted in good linearity, recovery and agreement with an established amino acid assay for the majority of the metabolites tested. Regarding repeatability, ~ 85% of all peaks had an adequately low coefficient of variation (< 30%) in replicate samples. CONCLUSION: Overall, our comparison yielded a high-throughput untargeted plasma NMR protocol for optimized data acquisition and processing that is expected to be a valuable contribution in the field of metabolic biomarker discovery.

Correction to: A comparison of high­throughput plasma NMR protocols for comparative untargeted metabolomics.

Following publication of the original article, the authors would like to correct a sentence in the paragraph "1H-NMR spectra were recorded at 298 K…" under the heading "NMR experiments".

Plasma levels of the cardiovascular protective endogenous nucleoside adenosine are reduced in patients with primary aldosteronism without affecting ischaemia-reperfusion injury: A prospective case-control study.

BACKGROUND: Patients with primary aldosteronism (PA) experience more cardiovascular events compared to patients with essential hypertension (EHT), independent from blood pressure levels. In animals, mineralocorticoid receptor antagonists limit ischaemia-reperfusion (IR) injury by increasing extracellular adenosine formation and adenosine receptor stimulation. Adenosine is an endogenous compound with profound cardiovascular protective effects. Firstly, we hypothesized that patients with PA have lower circulating adenosine levels which might contribute to the observed increased cardiovascular risk. Secondly, we hypothesized that by this mechanism, patients with PA are more susceptible to IR compared to patients with EHT. DESIGN: In our prospective study in 20 patients with PA and 20 patients with EHT, circulating adenosine was measured using a pharmacological blocker solution that halts adenosine metabolism after blood drawing. Brachial artery flow-mediated dilation (FMD) before and after forearm IR was used as a well-established method to study IR injury. RESULTS: Patients with PA had a 33% lower adenosine level compared to patients with EHT (15.3 [13.3-20.4] vs 22.7 [19.4-36.8] nmol/L, respectively, P < .01). The reduction in FMD after IR, however, did not differ between patients with PA and patients with EHT (-1.0 ± 2.9% vs -1.6 ± 1.6%, respectively, P = .52). CONCLUSIONS: As adenosine receptor stimulation induces various powerful protective cardiovascular effects, its lower concentration in patients with PA might be an important novel mechanism that contributes to their increased cardiovascular risk. We suggest that modulation of the adenosine metabolism is an exciting novel pharmacological opportunity to limit cardiovascular risk in patients with PA that needs further exploration.

Clinical biomarker innovation: when is it worthwhile?

Background Choosing which biomarker tests to select for further research and development is not only a matter of diagnostic accuracy, but also of the clinical and monetary benefits downstream. Early health economic modeling provides tools to assess the potential effects of biomarker innovation and support decision-making. Methods We applied early health economic modeling to the case of diagnosing primary aldosteronism in patients with resistant hypertension. We simulated a cohort of patients using a Markov cohort state-transition model. Using the headroom method, we compared the currently used aldosterone-to-renin ratio to a hypothetical new test with perfect diagnostic properties to determine the headroom based on quality-adjusted life-years (QALYs) and costs, followed by threshold analyses to determine the minimal diagnostic accuracy for a cost-effective product. Results Our model indicated that a perfect diagnostic test would yield 0.027 QALYs and increase costs by €43 per patient. At a cost-effectiveness threshold of €20,000 per QALY, the maximum price for this perfect test to be cost-effective is €498 (95% confidence interval [CI]: €275-€808). The value of the perfect test was most strongly influenced by the sensitivity of the current biomarker test. Threshold analysis showed the novel test needs a sensitivity of at least 0.9 and a specificity of at least 0.7 to be cost-effective. Conclusions Our model-based approach evaluated the added value of a clinical biomarker innovation, prior to extensive investment in development, clinical studies and implementation. We conclude that early health economic modeling can be a valuable tool when prioritizing biomarker innovations in the laboratory.

Is the plasma aldosterone-to-renin ratio associated with blood pressure response to treatment in general practice?

BACKGROUND: Individualized antihypertensive treatment based on specific biomarkers such as renin may lead to more effective blood pressure control in patients with newly diagnosed essential hypertension. Recent studies suggested that the plasma aldosterone-to-renin ratio (ARR) may also be a candidate predictor for this purpose. OBJECTIVE: To assess whether the ARR is associated with the blood pressure response to antihypertensive treatment in patients with newly diagnosed hypertension. METHODS: In this prospective cohort study in primary care, we determined the ARR in patients with newly diagnosed hypertension prior to starting treatment. Treatment was categorized in five groups: no medication, use of angiotensin-converting-enzyme inhibitor or angiotensin receptor blocker, use of calcium channel blocker, use of diuretic, or use of beta blocker. We examined the relation between the ARR and blood pressure response within 1 year of treatment, taking into account the type of antihypertensive treatment and adjusting for gender, age, baseline blood pressure, and comorbidity. RESULTS: Out of 304 patients, we used 947 measurements (727 no medication, 220 medication) for analysis. There was no association between the ARR and the response in blood pressure, and this applied to each treatment group. Target blood pressure, defined as systolic blood pressure <140 mmHg, was reached in 31% of patients. There was no association between the ARR and reaching target blood pressure (OR 1.002, 95% CI 0.983-1.022). CONCLUSION: The ARR is not associated with the response in blood pressure within 1 year of antihypertensive treatment in primary care.

Effect of Antihypertensive Medication on Cerebral Small Vessel Disease: A Systematic Review and Meta-Analysis.

BACKGROUND AND PURPOSE: Hypertension is an important risk factor for cerebral small vessel disease. We aimed to study the effect of antihypertensive medication (AHM) on the progression of cerebral small vessel disease. METHODS: We performed a systematic literature search of electronic databases up to January 30, 2017, for randomized controlled trials on the effect of AHM on ≥1 cerebral small vessel disease magnetic resonance imaging markers (ie, white matter hyperintensities, lacunes, microbleeds, enlarged perivascular spaces, acute small subcortical infarcts, and brain atrophy) after ≥1 year. We performed a random-effects meta-analysis using standardized mean difference. RESULTS: We included 4 trials, including patients with stroke, with diabetes mellitus, and people ≥70 years of age. Patients in the AHM group had less progression of white matter hyperintensity during 28 to 47 months (standardized mean difference, -0.19; 95% confidence interval, -0.32 to -0.06; I2=20%; n=1369). Two trials reported on progression of brain atrophy with conflicting results. None of the trials reported on other cerebral small vessel disease markers. CONCLUSIONS: AHM has a protective effect on the progression of white matter hyperintensities, but no effect on brain atrophy. There are no trials on the effect of AHM on lacunes, microbleeds, enlarged perivascular spaces, or acute small subcortical infarcts.

Psychological Symptoms and Well-Being After Treatment for Primary Aldosteronism.

Primary aldosteronism (PA) is an increasingly identified cause of secondary hypertension. PA can be caused by an aldosterone-producing adenoma or by bilateral adrenal hyperplasia, generally treated by adrenalectomy or mineralocorticoid receptor antagonists, respectively. Recent studies suggest that PA is associated with more psychological symptoms and lower levels of well-being. The purpose of this study was to investigate the associations between subtype of PA and psychological symptoms and well-being after specific treatment. We analyzed the outcomes of the Mental Health Continuum-Short Form and the Symptom Checklist in 160 patients (mean age 57 years; 74.3% males) with PA, comparing the scores for psychological symptoms and well-being between both subtypes of PA. Additionally, we performed subgroup analyses based on gender, age, time since initiation of treatment, and co-morbidity. Moreover, we compared the results with published norm scores. Mean follow-up after adrenalectomy or start of medication was four years and two months. Depressive symptoms, anxiety and obsessive-compulsive thoughts and well-being did not differ between subtypes of PA. Subgroup analysis did not reveal any differences, except for women with bilateral adrenal hyperplasia who scored higher on the anxiety subscale than women after adrenalectomy. Compared to the general population, patients with treated PA reported more psychological symptoms. In contrast, well-being did not differ significantly from norm scores. Subtype and treatment of PA were no important determinants of psychological symptoms and well-being on the long-term. We suggest that physicians should be alert for psychological symptoms, as these were more frequently present in patients with PA.

Patient characteristics do not predict the individual response to antihypertensive medication: a cross-over trial.

Background: International guidelines on hypertension management do not agree on whether patient characteristics can be used for the first choice of treatment of uncomplicated essential hypertension. Objective: We wanted to identify predictive patient characteristics to the response of two different classes of antihypertensive drugs in patients with newly diagnosed hypertension in primary care. Methods: We conducted a prospective, open label, blinded endpoint cross-over trial in 120 patients with a new diagnosis of hypertension from 10 family practices. Patients received 4 weeks of 12.5 mgr hydrochlorothiazide once daily and 4 weeks of 80 mgr valsartan once daily, each followed by a 4-week washout. The sequence of drugs was randomized. Age, sex and menopausal state were recorded at run in and 24 h ambulatory blood pressure, office blood pressure, plasma renin concentration, NT-proBNP, potassium, estimated glomerular filtration rate, urinary albumin, body mass index and waist circumference at each regimen change. The difference in systolic blood pressure response between both study drugs, calculated from mean daytime ambulatory blood pressures, was the main outcome measure. Results: Ninety-eight patients (52% female; median age 53 years) were eligible for per-protocol-analysis. None of the studied variables were predictive for the difference in systolic blood pressure response. Individual systolic blood pressure responses ranged from an increase by 18 mmHg to a decrease of 39 mmHg. Conclusion: In a relevant group of primary care patients with newly diagnosed hypertension, we were unable to detect predictors of treatment response. This study rather supports the United States and European guidelines than the United Kingdom and Dutch guidelines on hypertension.

Hydrochlorothiazide treatment increases the abundance of the NaCl cotransporter in urinary extracellular vesicles of essential hypertensive patients.

The thiazide-sensitive NaCl cotransporter (NCC), located apically in distal convoluted tubule epithelia, regulates the fine-tuning of renal sodium excretion. Three isoforms of NCC are generated through alternative splicing of the transcript, of which the third isoform has been the most extensively investigated in pathophysiological conditions. The aim of this study was to investigate the effect of different anti-hypertensive treatments on the abundance and phosphorylation of all three NCC isoforms in urinary extracellular vesicles (uEVs) of essential hypertensive patients. In uEVs isolated from patients (n = 23) before and after hydrochlorothiazide or valsartan treatment, the abundance and phosphorylation of the NCC isoforms was determined. Additionally, clinical biochemistry and blood pressure of the patients was assessed. Our results show that NCC detected in human uEVs has a glycosylated and oligomeric structure, comparable to NCC present in human kidney membrane fractions. Despite the inhibitory action of hydrochlorothiazide on NCC activity, immunoblot analysis of uEVs showed significantly increased abundance of NCC isoforms 1 and 2 (NCC1/2), total NCC (NCC1-3), and the phosphorylated form of total NCC (pNCC1-3-T55/T60) in essential hypertensive patients treated with hydrochlorothiazide but not with valsartan. This study highlights that NCC1/2, NCC1-3, and pNCC1-3-T55/T60 are upregulated by hydrochlorothiazide, and the increase in NCC abundance in uEVs of essential hypertensive patients correlates with the blood pressure response to hydrochlorothiazide.

A Network Meta-Analysis of Clinical Management Strategies for Treatment-Resistant Hypertension: Making Optimal Use of the Evidence.

BACKGROUND: With the addition of surgical interventions to current medicinal treatments, it is increasingly challenging for clinicians to rationally choose among the various options for treating patients with apparent treatment-resistant hypertension (ATRHTN). This study aims to establish the comparative effectiveness of mineralocorticoid receptor antagonists (MRA), renal denervation (RDN), darusentan and central arteriovenous anastomosis (CAA) for patients with ATRHTN by performing a network meta-analysis. METHODS: Data Sources: Studies from recent meta-analyses for RDN and placebo effect were supplemented with a systematic search for MRAs in ATRHTN in the Pubmed, EMBASE, CINAHL and Cochrane databases through November 2016. STUDY SELECTION: Randomized controlled trials comparing treatment options for patients with ATRHTN. DATA EXTRACTION AND SYNTHESIS: Data were extracted using predefined data extraction forms, including the Grading of Recommendations Assessment, Development and Evaluation (GRADE) criteria. A Bayesian random effects model was used to conduct a network meta-analysis. Spironolactone was used as the main comparator. Main Outcomes and Measures: Reduction in 24-h ambulatory blood pressure measurement (ABPM). RESULTS: Twenty articles met our inclusion criteria, and seven treatment alternatives were compared. Compared to MRA, CAA had the highest probability of being more effective, further reducing 24-h SBP (-4.8 mmHg [-13.0, 3.7]) and 24-h DBP (-9.7 mmHg [-18, -0.63]). This difference is likely to be clinically meaningful, with a probability of 78 and 96% at a threshold of a 2-mmHg reduction in blood pressure. CONCLUSIONS: When compared to MRA as anchor, darusentan, CAA and RDN are not more effective in achieving a clinically significant reduction in ambulatory blood pressure in individuals with apparent treatment-resistant hypertension.

Health-Related Quality of Life and Mental Health in Primary Aldosteronism: A Systematic Review.

The aim of this review was to determine the impact of primary aldosteronism on health-related quality of life (HRQoL) and mental health. We performed a systematic literature search up to July 2017 in six electronic databases. First, we screened the articles derived from this search based on title and abstract. Second, the selected studies were systematically reviewed and checked for our predefined inclusion criteria. The search yielded 753 articles, of which 15 studies met our inclusion criteria. Untreated patients with primary aldosteronism showed an impaired physical and mental HRQoL as compared to the general population. Multiple domains of HRQoL were affected. This applied to patients with both an aldosterone-producing adenoma and bilateral adrenal hyperplasia. Adrenalectomy improves HRQoL. Conflicting results have been reported on the extent of this improvement, the improvement after initiation of medical treatment, and whether there is a difference in HRQoL after both treatments. Similarly, psychopathological symptoms of anxiety, demoralization, stress, depression and nervousness were more frequently reported in untreated patients with primary aldosteronism than in the general population and patients with hypertension. Also an impaired sleep quality has been reported. Improvement of these symptoms was observed after treatment with both adrenalectomy and mineralocorticoid receptor antagonists. This review shows that HRQoL is impaired and psychopathology is more frequently reported in patients with primary aldosteronism. This seems to be at least partly reversible after treatment but the extent of improvement remains unknown. To assess HRQoL in these patients more precisely a primary aldosteronism-specific HRQoL questionnaire is required.

Adrenal Vein Catecholamine Levels and Ratios: Reference Intervals Derived from Patients with Primary Aldosteronism.

Phaeochromocytoma localisation is generally reliably achieved with modern imaging techniques, particularly in sporadic cases. On occasion, however, there can be diagnostic doubt due to the presence of bilateral adrenal abnormalities, particularly in patients with mutations in genes predisposing them to the development of multiple phaeochromocytomas. In such cases, surgical intervention is ideally limited to large or functional lesions due to the long-term consequences associated with hypoadrenalism. Adrenal venous sampling (AVS) for catecholamines has been used in this situation to guide surgery, although there are few data available to support diagnostic thresholds. Retrospective analyses of AVS results from 2 centres were carried out. A total of 172 patients (88 men, 84 women) underwent AVS under cosyntropin stimulation for the diagnosis of established primary aldosteronism (PA) with measurement of adrenal and peripheral venous cortisol, aldosterone and catecholamines. Six patients (3 men, 3 women) with phaeochromocytoma underwent AVS for diagnostic purposes with subsequent histological confirmation. Reference intervals for the adrenal venous norepinephrine to epinephrine ratio were created from the PA group. Using the 97.5th centile (1.21 on the left, 1.04 on the right), the false negative rate in the phaeochromocytoma group was 0%. In conclusion, this study describes the largest dataset of adrenal venous catecholamine measurements and provides reference intervals in patients without phaeochromocytoma. This strengthens the certainty with which conclusions related to adrenal venous sampling for catecholamines can be drawn, acknowledging the procedure is not part of the routine diagnostic workup and is an adjunct for use only in difficult clinical cases.