Rationale for the Inclusion of ß-Blockers Among Major Antihypertensive Drugs in the 2023 European Society of Hypertension Guidelines.

We address the reasons why, unlike other guidelines, in the 2023 guidelines of the European Society of Hypertension ß-blockers (BBs) have been regarded as major drugs for the treatment of hypertension, at the same level as diuretics, calcium channel blockers, and blockers of the renin-angiotensin system. We argue that BBs, (1) reduce blood pressure (the main factor responsible for treatment-related protection) not less than other drugs, (2) reduce pooled cardiovascular outcomes and mortality in placebo-controlled trials, in which there has also been a sizeable reduction of all major cause-specific cardiovascular outcomes, (3) have been associated with a lower global cardiovascular protection in 2 but not in several other comparison trials, in which the protective effect of BBs versus the other major drugs has been similar or even greater, with a slightly smaller or no difference of global benefit in large trial meta-analyses and a similar protective effect when comparisons extend to BBs in combination versus other drug combinations. We mention the large number of cardiac and other comorbidities for which BBs are elective drugs, and we express criticism against the exclusion of BBs because of their lower protective effect against stroke in comparison trials, because, for still uncertain reasons, differences in protection against cause-specific events (stroke, heart failure, and coronary disease) have been reported for other major drugs. These partial data cannot replace global benefits as the main deciding factor for drug choice, also because in the general hypertensive population whether and which type of event might occur is unknown.

Optimizing drug adherence in hypertension: More than a mind game.

Poor drug adherence to prescribed drug treatments and lifestyle recommendations is a major determinant of poor blood pressure control reported around the World. Prevalence rates of antihypertensive medication nonadherence are highly variable depending on the studied population and may reach up to 40%. Remarkably, the phenomenon stays often undiagnosed and unaddressed mainly because physicians have limited tools to perform a reliable diagnosis. In this review oriented toward practicality, 5 principal aspects of nonadherence will be addressed with a special emphasis on psychological factors influencing adherence patterns, both from a patient's and physician's perspectives.

A European Renal Association (ERA) synopsis for nephrology practice of the 2023 European Society of Hypertension (ESH) Guidelines for the Management of Arterial Hypertension.

In June 2023, the European Society of Hypertension (ESH) presented and published the new 2023 ESH Guidelines for the Management of Arterial Hypertension, a document that was endorsed by the European Renal Association (ERA). Following the evolution of evidence in recent years, several novel recommendations relevant to the management of hypertension in patients with chronic kidney disease (CKD) appeared in these Guidelines. These include recommendations for target office BP < 130/80 mmHg in most and against target office BP < 120/70 mmHg in all patients with CKD; recommendations for use of spironolactone or chlortalidone for patients with resistant hypertension with eGFR higher or lower than 30 ml/min/1.73 m2, respectively; use of an SGLT2-inhibitor for patients with CKD and eGFR ≥20 ml/min/1.73 m2; use of finerenone for patients with CKD, type 2 DM, albuminuria, eGFR ≥25 ml/min/1.73 m2 and serum potassium < 5.0 mmol/L; and revascularization in patients with atherosclerotic renovascular disease and secondary hypertension or high-risk phenotypes if stenosis ≥ 70% is present. The present report is a synopsis of sections of the ESH Guidelines that are relevant to the daily clinical practice of nephrologists, prepared by experts of ESH and ERA. The sections summarized are those referring to the role of CKD in hypertension staging and cardiovascular risk stratification, the evaluation of hypertension-mediated kidney damage and the overall management of hypertension in patients with CKD.

The differential impact of a 6-versus 12-month pharmacist-led interprofessional medication adherence program on medication adherence in patients with diabetic kidney disease: the randomized PANDIA-IRIS study.

Background: For every 100 patients with diabetes, 40 will develop diabetic kidney disease (DKD) over time. This diabetes complication may be partly due to poor adherence to their prescribed medications. In this study, we aimed to evaluate the differential impact of a 6- versus 12-month pharmacist-led interprofessional medication adherence program (IMAP) on the components of adherence (i.e., implementation and discontinuation) in patients with DKD, during and after the intervention. Methods: All included patients benefited from the IMAP, which consists in face-to-face regular motivational interviews between the patient and the pharmacist based on the adherence feedback from electronic monitors (EMs), in which the prescribed treatments were delivered. Adherence reports were available to prescribers during the intervention period. Patients were randomized 1:1 into two parallel arms: a 12-month IMAP intervention in group A versus a 6-month intervention in group B. Adherence was monitored continuously for 24 months post-inclusion during the consecutive intervention and follow-up phases. In the follow-up phase post-intervention, EM data were blinded. Blood pressure was measured by the pharmacist at each visit. The repeated measures of daily patient medication intake outcomes (1/0) to antidiabetics, antihypertensive drugs, and statins were modeled longitudinally using the generalized estimated equation in both groups and in both the intervention and the follow-up phases. Results: EM data of 72 patients were analyzed (34 in group A and 38 in group B). Patient implementation to antidiabetics and antihypertensive drugs increased during the IMAP intervention phase and decreased progressively during the follow-up period. At 12 months, implementation to antidiabetics was statistically higher in group A versus group B (93.8% versus 86.8%; Δ 7.0%, 95% CI: 5.7%; 8.3%); implementation to antihypertensive drugs was also higher in group A versus B (97.9% versus 92.1%; Δ 5.8%, 95% CI: 4.8%; 6.7%). At 24 months, implementation to antidiabetics and antihypertensive drugs remained higher in group A versus B (for antidiabetics: 88.6% versus 85.6%; Δ 3.0%, 95% CI: 1.7%; 4.4% and for antihypertensive drugs: 94.4% versus 85.9%; Δ 8.5%, 95% CI: 6.6%; 10.7%). No difference in pharmacy-based blood pressure was observed between groups. Implementation to statins was comparable at each time point between groups. Three patients discontinued at least one treatment; they were all in group B. In total, 46% (16/35) of patients in the 12-month intervention versus 37% (14/38) of patients in the 6-month intervention left the study during the intervention phase, mainly due to personal reasons. Conclusion: The IMAP improves adherence to chronic medications in patients with DKD. The longer the patients benefit from the intervention, the more the implementation increases over time, and the more the effect lasts after the end of the intervention. These data suggest that a 12-month rather than a 6-month program should be provided as a standard of care to support medication adherence in this population. The impact on clinical outcomes needs to be demonstrated. Clinical Trial Registration: Clinicaltrials.gov, identifier NCT04190251_PANDIA IRIS.

Rationale of treatment recommendations in the 2023 ESH hypertension guidelines.

No abstract available.

A new, deep learning-based method for the analysis of autopsy kidney samples used to study sex differences in glomerular density and size in a forensic population.

Artificial intelligence (AI) is increasingly used in forensic anthropology and genetics to identify the victim and the cause of death. The large autopsy samples from persons with traumatic causes of death but without comorbidities also offer possibilities to analyze normal histology with AI. We propose a new deep learning-based method to rapidly count glomerular number and measure glomerular density (GD) and volume in post-mortem kidney samples obtained in a forensic population. We assessed whether this new method detects glomerular differences between men and women without known kidney disease. Autopsies performed between 2009 and 2015 were analyzed if subjects were aged ≥ 18 years and had no known kidney disease, diabetes mellitus, or hypertension. A large biopsy was taken from each kidney, stained with hematoxylin and eosin, and scanned. An in-house developed deep learning-based algorithm counted the glomerular density (GD), number, and size. Out of 1165 forensic autopsies, 86 met all inclusion criteria (54 men). Mean (± SD) age was 43.5 ± 14.6; 786 ± 277 glomeruli were analyzed per individual. There was no significant difference in GD between men and women (2.18 ± 0.49 vs. 2.30 ± 0.57 glomeruli/mm2, p = 0.71); glomerular diameter, area, and volume also did not differ. GD correlated inversely with age, kidney weight, and glomerular area. Glomerular area and volume increased significantly with age. In this study, there were no sex differences in glomerular density or size. Considering the size of the kidney samples, the use of the presented deep learning method can help to analyze large renal autopsy biopsies and opens perspectives for the histological study of other organs.

Use of individual antihypertensive drug classes and combination therapies during the COVID-19 pandemic in Poland: a cross-sectional, nationwide study in the years 2019-2021.

INTRODUCTION: The 2018 European Society of Cardiology / European Society of Hypertension guidelines recommended the use of combination therapy, especially in the form of single­pill combinations (SPCs), for treatment of hypertension. OBJECTIVES: We assessed adherence to these recommendations after their publication and during the COVID­19 pandemic in Poland. PATIENTS AND METHODS: The frequencies of using individual antihypertensive drug classes and their combinations were analyzed for the years 2019, 2020, and 2021 in all patients who filled at least 1 prescription for an antihypertensive drug, using information from a database covering all prescriptions filled in Poland. RESULTS: In the years 2019, 2020, and 2021, a total of 10 328 341, 9 478 949, and 9 637 595 patients, respectively, fulfilled the inclusion criteria. There was a continuous decrease in the rate of patients meeting the criteria for coprescribing 2 or more antihypertensive drugs in the consecutive years (59.3%, 49%, 45.6%, respectively, in 2019, 2020, and 2021; P <0.001). In 2019, 2020, and 2021, a combination of renin­angiotensin system blockers, calcium channel blockers and / or diuretics was respectively used by 41.7%, 40.9%, and 42% of the patients taking 2 antihypertensive drugs (P <0.001), and by 15.2%, 17.2%, and 18.5% of the patients taking 3 antihypertensive drugs (P <0.001). There was an increase in the use of ß­blockers over the study period (62%, 62.8%, and 63.7%, respectively, in 2019, 2020, and 2021; P <0.001). Double SPCs were used by 28%, 28.7%, and 29.8% of the patients (P <0.001), and triple SPCs by 2.6%, 2.9%, and 3.4% of the patients (P <0.001), respectively, in 2019, 2020, and 2021. CONCLUSIONS: During the COVID­19 pandemic, a decrease in the frequency of combination treatments and an increase in the frequency of dual and triple SPC use were observed. Despite the slow increase in the frequency of prescribing the guideline­recommended drug combinations, their use remains suboptimal.

The role of adherence in patients with chronic diseases.

In the long-term management of chronic diseases, adherence and persistence to prescribed medications are continuous challenges in order to obtain all the potential benefits of drug therapies. Suboptimal drug adherence and discontinuations of therapies remain the most frequent reasons why several diseases are poorly controlled in the population. One the main issue is that physicians are relatively limited in time and tools to detect patients with a poor adherence. The present review discusses present and future strategies that are now available or are being developed to detect and to support adherence in patients with chronic diseases and provides some simple clues to identify patients at high risk of discontinuation in the clinic.

What Is the Current Best Drug Treatment for Hypertensive Heart Failure With Preserved Ejection Fraction? Review of the Totality of Evidence.

BACKGROUND: More than 90% of patients developing heart failure (HF) have an epidemiological background of hypertension. The most frequent concomitant conditions are type 2 diabetes mellitus, obesity, atrial fibrillation, and coronary disease, all disorders/diseases closely related to hypertension. METHODS: HF outcome research focuses on decreasing mortality and preventing hospitalization for worsening HF syndrome. All drugs that decrease these HF endpoints lower blood pressure. Current drug treatments for HF are (i) angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, or angiotensin receptor neprilysin inhibitors, (ii) selected beta-blockers, (iii) steroidal and nonsteroidal mineralocorticoid receptor antagonists, and (iv) sodium-glucose cotransporter 2 inhibitors. RESULTS: For various reasons, these drug treatments were first studied in HF patients with a reduced ejection fraction (HFrEF). However, subsequently, they have been investigated and, as we see it, documented as beneficial in HF patients with a preserved left ventricular ejection fraction (LVEF, HFpEF) and mostly hypertensive etiology, with effect estimates assessed partly on top of background treatment with the drugs already proven effective in HFrEF. Additionally, diuretics are given on symptomatic indications. CONCLUSIONS: Considering the totality of evidence and the overall need for antihypertensive treatment and/or treatment of hypertensive complications in almost all HF patients, the principal drug treatment of HF appears to be the same regardless of LVEF. Rather than LVEF-guided treatment of HF, treatment of HF should be directed by symptoms (related to the level of fluid retention), signs (tachycardia), severity (NYHA functional class), and concomitant diseases and conditions. All HF patients should be given all the drug classes mentioned above if well tolerated.

The current best drug treatment for hypertensive heart failure with preserved ejection fraction.

More than 90 % of patients developing heart failure (HF) have hypertension. The most frequent concomitant conditions are type-2 diabetes mellitus, obesity, atrial fibrillation, and coronary disease. HF outcome research focuses on decreasing mortality and preventing hospitalization for worsening HF syndrome. All drugs that decrease these HF endpoints lower blood pressure. Current drug treatments for HF are (i) angiotensin-converting enzyme inhibitors, angiotensin receptor blockers or angiotensin receptor neprilysin inhibitors, (ii) selected beta-blockers, (iii) steroidal and non-steroidal mineralocorticoid receptor antagonists, and (iv) sodium-glucose cotransporter 2 inhibitors. For various reasons, these drug treatments were first studied in HF patients with a reduced ejection fraction (HFrEF). Subsequently, they have been investigated in HF patients with a preserved left ventricular ejection fraction (LVEF, HFpEF) of mostly hypertensive etiology, and with modest benefits largely assessed on top of background treatment with the drugs already proven effective in HFrEF. Additionally, diuretics are given on symptomatic indications. Patients with HFpEF may have diastolic dysfunction but also systolic dysfunction visualized by lack of longitudinal shortening. Considering the totality of evidence and the overall need for antihypertensive treatment and/or treatment of hypertensive complications in almost all HF patients, the principal drug treatment of HF appears to be the same regardless of LVEF. Rather than LVEF-guided treatment of HF, treatment of HF should be directed by symptoms (related to the level of fluid retention), signs (tachycardia), severity (NYHA functional class), and concomitant diseases and conditions. All HF patients should be given all the drug classes mentioned above if well tolerated.

Medical Measures in Hypertensives Considered Resistant.

BACKGROUND: Patients with resistant hypertension are the group of hypertensive patients with the highest cardiovascular risk. METHODS: All rules and guidelines for treatment of hypertension should be followed strictly to obtain blood pressure (BP) control in resistant hypertension. The mainstay of treatment of hypertension, also for resistant hypertension, is pharmacological treatment, which should be tailored to each patient's specific phenotype. Therefore, it is pivotal to assess nonadherence to pharmacological treatment as this remains the most challenging problem to investigate and manage in the setting of resistant hypertension. RESULTS: Once adherence has been confirmed, patients must be thoroughly worked-up for secondary causes of hypertension. Until such possible specific causes have been clarified, the diagnosis is apparent treatment-resistant hypertension (TRH). Surprisingly few patients remain with true TRH when the various secondary causes and adherence problems have been detected and resolved. Refractory hypertension is a term used to characterize the treatment resistance in hypertensive patients using ≥5 antihypertensive drugs. All pressor mechanisms may then need blockage before their BPs are reasonably controlled. CONCLUSIONS: Patients with resistant hypertension need careful and sustained follow-up and review of their medications and dosages at each term since medication adherence is a very dynamic process.

How to optimize the use of diuretics in patients with heart failure?

Considering the pathophysiology and clinical presentation of heart failure, using diuretics or drugs with diuretic properties is indispensable for adequate management of heart failure patients. However, in clinical practice, fluid expansion is often undiagnosed, and diuretic therapy is not always adequately titrated. Today, several drug classes with diuretic properties are available in addition to classical thiazides, thiazide-like, and loop diuretics. The purpose of this short review is to discuss different ways to optimize diuretic therapy using currently available drugs. Several approaches are considered, including a combination of diuretics to obtain a sequential nephron blockade, use of a drug combining a blocker of the renin-angiotensin system (RAS) and an inhibitor of the metabolism of natriuretic peptides (ARNI), prescription of potassium binders to maintain and up-titrate RAS blockers and mineralocorticoid antagonists, and finally use of inhibitors of renal reabsorption of glucose through the sodium-glucose cotransporter 2 system. Optimal use of these various drug classes should improve the quality of life and reduce the need for hospital admissions and mortality in heart failure patients.

Diagnosis of cardiovascular disease in patients with chronic kidney disease.

Patients with chronic kidney disease (CKD) are at high risk of cardiovascular disease (CVD) and cardiovascular death. Identifying and monitoring cardiovascular complications and hypertension is important for managing patients with CKD or kidney failure and transplant recipients. Biomarkers of myocardial ischaemia, such as troponins and electrocardiography (ECG), have limited utility for diagnosing cardiac ischaemia in patients with advanced CKD. Dobutamine stress echocardiography, myocardial perfusion scintigraphy and dipyridamole stress testing can be used to detect coronary disease in these patients. Left ventricular hypertrophy and left ventricular dysfunction can be detected and monitored using various techniques with differing complexity and cost, including ECG, echocardiography, nuclear magnetic resonance, CT and myocardial scintigraphy. Atrial fibrillation and other major arrhythmias are common in all stages of CKD, and ambulatory heart rhythm monitoring enables precise time profiling of these disorders. Screening for cerebrovascular disease is only indicated in asymptomatic patients with autosomal dominant polycystic kidney disease. Standardized blood pressure is recommended for hypertension diagnosis and treatment monitoring and can be complemented by ambulatory blood pressure monitoring. Judicious use of these diagnostic techniques may assist clinicians in detecting the whole range of cardiovascular alterations in patients with CKD and enable timely treatment of CVD in this high-risk population.

Renal Denervation: A Practical Guide for Health Professionals Managing Hypertension.

Growing evidence demonstrates the suitability of renal denervation in a broad population of patients; however, questions remain over its suitability and practical implementation. Given the rapidity of emerging data, this has been a challenging field for potential adopters to navigate. The purpose of this article is twofold: to provide navigation through emerging clinical data and evolving guidance; and to provide physicians with practical, evidence-based advice for identifying eligible patients and providing appropriate management in the pre- and postintervention settings. Although many of these recommendations are based on existing published guidance documents, we reflect equally on our own experiences of using this technology.

Blood pressure and vascular determinants of glomerular filtration rate decline in diabetic kidney disease.

Objective: In patients with type 2 diabetes and diabetic kidney disease (DKD), explore the relationship between estimated glomerular filtration rate decline (eGFR-d) and simultaneously assessed vascular risk markers including office, ambulatory or central blood pressure, pulse pressure, carotid-femoral pulse wave velocity (PWV), carotid intima-media thickness (IMT) and renal resistive indexes (RRI). Research design and methods: At baseline, vascular risk markers were measured in addition to the routine clinical workup. The eGFR-d was based on 2000-2019 creatinine values. Parameters were compared by eGFR-d quartiles. Regression models of eGFR-d and vascular markers were assessed. Results: In total, 135 patients were included. Mean age was 63.8 ± 10.8y, baseline eGFR 60.2 ± 26.4 ml/min/1.73 m2 and urine albumin-creatinine ratio (ACR) 49 ± 108 mg/mmol. Mean eGFR-d was based on 43 ± 39 creatinine values within a time span of 7.0 ± 1.9y. The average yearly eGFR decline was -1.8 ± 3.0 ml/min/1.73 m2 ranging from -5.8 ± 2.3 in the first quartile to +1.4 ± 1.7 in the fourth quartile. Mean 24 h systolic (SBP) and diastolic (DBP) blood pressure were 126 ± 17 and 74 ± 9 mmHg. Mean PWV was 11.8 ± 2.8 m/s, RRI 0.76 ± 0.07 and IMT 0.77 ± 0.21 mm. SBP and pulse pressure correlated with eGFR-d but not DBP. 24 h SBP stood out as a stronger predictor of eGFR-d than office or central SBP. PWV and RRI correlated with eGFR decline in univariate, but not multivariate regression models including 24 SBP and ACR. Conclusions: In this study, eGFR decline was highly variable in patients with type 2 diabetes and DKD. Twenty-four hour SBP provided an added value to the routine measurement of ACR in predicting eGFR decline, whereas PWV and RRI did not.

Gout and hyperuricaemia: modifiable cardiovascular risk factors?

Gout and hyperuricaemia are two clinical situations associated with an elevated risk of developing cardiovascular (heart failure, myocardial infarction, stroke) and metabolic and renal complications. One reason is probably related to the fact that the prevalence of hyperuricaemia and gout is high in clinical situations, which themselves involve a high cardiovascular risk, such as hypertension, diabetes, chronic kidney disease or obesity. However, recent studies suggest that hyperuricaemia may promote cardiovascular complications independently of other cardiovascular risk factors, by inducing chronic inflammation, oxidative stress, and endothelial dysfunction. The questions that arise today concern primarily the treatment of asymptomatic hyperuricaemia. Should it be treated to decrease the patients' cardiovascular risk and if so, starting from which level and towards which target? There are now several pieces of evidence indicating that this might be useful, but data from large studies are not unanimous. This review will discuss this issue as well as new well-tolerated treatments, such as febuxostat or SGLT2 inhibitors, which lower uric acid levels, prevent gout and lower the risk of cardio-renal events.

2023 ESH Guidelines for the management of arterial hypertension The Task Force for the management of arterial hypertension of the European Society of Hypertension: Endorsed by the International Society of Hypertension (ISH) and the European Renal Association (ERA).

DOCUMENT REVIEWERS: Luis Alcocer (Mexico), Christina Antza (Greece), Mustafa Arici (Turkey), Eduardo Barbosa (Brazil), Adel Berbari (Lebanon), Luís Bronze (Portugal), John Chalmers (Australia), Tine De Backer (Belgium), Alejandro de la Sierra (Spain), Kyriakos Dimitriadis (Greece), Dorota Drozdz (Poland), Béatrice Duly-Bouhanick (France), Brent M. Egan (USA), Serap Erdine (Turkey), Claudio Ferri (Italy), Slavomira Filipova (Slovak Republic), Anthony Heagerty (UK), Michael Hecht Olsen (Denmark), Dagmara Hering (Poland), Sang Hyun Ihm (South Korea), Uday Jadhav (India), Manolis Kallistratos (Greece), Kazuomi Kario (Japan), Vasilios Kotsis (Greece), Adi Leiba (Israel), Patricio López-Jaramillo (Colombia), Hans-Peter Marti (Norway), Terry McCormack (UK), Paolo Mulatero (Italy), Dike B. Ojji (Nigeria), Sungha Park (South Korea), Priit Pauklin (Estonia), Sabine Perl (Austria), Arman Postadzhian (Bulgaria), Aleksander Prejbisz (Poland), Venkata Ram (India), Ramiro Sanchez (Argentina), Markus Schlaich (Australia), Alta Schutte (Australia), Cristina Sierra (Spain), Sekib Sokolovic (Bosnia and Herzegovina), Jonas Spaak (Sweden), Dimitrios Terentes-Printzios (Greece), Bruno Trimarco (Italy), Thomas Unger (The Netherlands), Bert-Jan van den Born (The Netherlands), Anna Vachulova (Slovak Republic), Agostino Virdis (Italy), Jiguang Wang (China), Ulrich Wenzel (Germany), Paul Whelton (USA), Jiri Widimsky (Czech Republic), Jacek Wolf (Poland), Grégoire Wuerzner (Switzerland), Eugene Yang (USA), Yuqing Zhang (China).

Determinants of Renal Micro-Perfusion as Assessed with Contrast-Enhanced Ultrasound in Healthy Males and Females.

(1) Background: The renal microcirculation is essential to maintain the renal function, but its determinants in humans have been poorly studied. Contrast-enhanced ultrasound (CEUS) allows the non-invasive quantification of the cortical micro-perfusion at the bedside using the perfusion index (PI). The aims of this study were to assess whether differences exist in PI between healthy males and females and to identify clinical determinants associated with cortical micro-perfusion. (2) Methods: Healthy, normotensive volunteers (eGFR > 60 mL/min/1.73 m2, no albuminuria) underwent CEUS under standardized conditions with the destruction-reperfusion (DR) technique. The mean PI of four DR sequences was reported as the primary outcome measure (3) Results: A total of 115 subjects (77 females and 38 males) completed the study; the mean ± SD age was, respectively, 37.1 ± 12.2 and 37.1 ± 12.7 years in females and males, and the mean eGFR was 105.9 ± 15.1 and 91.0 ± 17.4 mL/min/1.73 m2. The PI (median) was higher in females than in males, i.e., 2705 (IQR 1641-3777) vs. 1965 (IQR 1294-3346) arbitrary units (a.u), p = 0.02). A correlation analysis showed positive associations between PI and eGFR, female sex, heart rate, plasma renin activity (PRA) and plasma aldosterone concentrations (PAC), negative associations with potassium, bicarbonate and systolic blood pressure, and no associations with age, body mass index and renal resistive index (RRI). In a multivariate linear regression analysis, only PRA remained significantly associated with PI. (4) Conclusions: Although the PI was higher among females, this association was no longer significant after adjustment for covariates. There was no difference in females tested during the follicular or the luteal phases. In conclusion, the PI was only weakly influenced by classic clinical variables, but was positively associated with PRA, suggesting that the renin-angiotensin system plays a role in the regulation of the cortical micro-perfusion in humans. Identifying which other factors contribute to the large variations in micro-perfusion across individuals needs further study.