Does Heterogeneity Exist in Treatment Associations With Renin-Angiotensin-System Inhibitors or Beta-blockers According to Phenotype Clusters in Heart Failure with Preserved Ejection Fraction?

BACKGROUND: We explored the association between use of renin-angiotensin system inhibitors and beta-blockers, with mortality/morbidity in 5 previously identified clusters of patients with heart failure with preserved ejection fraction (HFpEF). METHODS AND RESULTS: We analyzed 20,980 patients with HFpEF from the Swedish HF registry, phenotyped into young-low comorbidity burden (12%), atrial fibrillation-hypertensive (32%), older-atrial fibrillation (24%), obese-diabetic (15%), and a cardiorenal cluster (17%). In Cox proportional hazard models with inverse probability weighting, there was no heterogeneity in the association between renin-angiotensin system inhibitor use and cluster membership for any of the outcomes: cardiovascular (CV) mortality, all-cause mortality, HF hospitalisation, CV hospitalisation, or non-CV hospitalisation. In contrast, we found a statistical interaction between beta-blocker use and cluster membership for all-cause mortality (P = .03) and non-CV hospitalisation (P = .001). In the young-low comorbidity burden and atrial fibrillation-hypertensive cluster, beta-blocker use was associated with statistically significant lower all-cause mortality and non-CV hospitalisation and in the obese-diabetic cluster beta-blocker use was only associated with a statistically significant lower non-CV hospitalisation. The interaction between beta-blocker use and cluster membership for all-cause mortality could potentially be driven by patients with improved EF. However, patient numbers were diminished when excluding those with improved EF and the direction of the associations remained similar. CONCLUSIONS: In patients with HFpEF, the association with all-cause mortality and non-CV hospitalisation was heterogeneous across clusters for beta-blockers. It remains to be elucidated how heterogeneity in HFpEF could influence personalized medicine and future clinical trial design.

Albuminuria-lowering effect of adding semaglutide on top of empagliflozin in individuals with type 2 diabetes: A randomized and placebo-controlled study.

AIM: To investigate whether combined treatment with empagliflozin (a sodium-glucose cotransporter-2 inhibitor) and semaglutide (a glucagon-like peptide-1 receptor agonist) can reduce urinary albumin-creatinine ratio (UACR) compared to treatment with empagliflozin alone in individuals with type 2 diabetes (T2D) and albuminuria. METHODS: We conducted a randomized, placebo-controlled, double-blind, parallel study including 60 individuals with T2D and albuminuria. All participants initiated open-label empagliflozin 25 mg once daily, on top of renin-angiotensin system inhibition, in a run-in period of 26 weeks. Subsequently, participants were randomized to semaglutide or placebo 1 mg once weekly for 26 weeks. The primary endpoint was change in UACR. Secondary endpoints were change in: (i) measured glomerular filtration rate (GFR); (ii) 24-hour systolic blood pressure; (iii) glycated haemoglobin (HbA1c) level; (iv) body weight; and (v) plasma renin and aldosterone levels. RESULTS: Addition of semaglutide to empagliflozin provided no additional change in UACR from randomization to end-of-treatment. The mean (95% confidence interval) difference in UACR was -22 (-44; 10)% (P = 0.15) between treatment groups. Neither GFR, 24-hour blood pressure, body weight, nor plasma renin activity was changed with semaglutide. HbA1c (-8 [-13; -3] mmol/mol; P = 0.003) and plasma aldosterone (-30 [-50; -3] pmol/L; P = 0.035) were reduced with semaglutide compared to placebo. CONCLUSIONS: Semaglutide added to empagliflozin did not change UACR, measured GFR, 24-hour systolic blood pressure, body weight or plasma renin levels in individuals with T2D and albuminuria. Semaglutide improved glycaemic control and plasma aldosterone levels compared to placebo.

Associations Between Aldosterone-Renin-Ratio and Bone Parameters Derived from Peripheral Quantitative Computed Tomography and Impact Microindentation in Men.

Components of the renin-angiotensin-aldosterone system (RAAS) are present on bone cells. One measure of RAAS activity, the aldosterone-renin-ratio (ARR), is used to screen for primary aldosteronism. Associations between ARR and bone mineral density are conflicting. This study investigated associations between ARR and peripheral quantitative computed tomography (pQCT) and impact microindentation (IMI). Male participants (n = 431) were from the Geelong Osteoporosis Study. "Likely" primary aldosteronism was defined as ARR ≥ 70 pmol/mIU. Another group, "possible" primary aldosteronism, was defined as either ARR ≥ 70 pmol/mIU or taking a medication that affects the RAAS, but not a beta blocker, and renin < 15 mU/L. Using pQCT, images at 4% and 66% of radial (n = 365) and tibial (n = 356) length were obtained. Using IMI measurements, bone material strength index (BMSi; n = 332) was determined. Associations between ARR or likely/possible primary aldosteronism and IMI or pQCT-derived bone parameters were tested using median regression. ARR and aldosterone values were not associated with any of the pQCT-derived bone variables in either unadjusted or adjusted analyses. Men with likely primary aldosteronism (n = 16), had lower adjusted total bone area (radial 66% site, - 12.5%). No associations were observed for men with possible primary aldosteronism (unadjusted or adjusted). No associations with BMSi were observed (p > 0.05). There were no associations between ARR or aldosterone and pQCT-derived bone parameters. Men with likely primary aldosteronism had lower bone area, suggesting clinically high levels of ARR may have a negative impact on bone health.

CYP11B2 inhibitor dexfadrostat phosphate suppresses the aldosterone-to-renin ratio, an indicator of sodium retention, in healthy volunteers.

AIMS: High aldosterone is a key driver of hypertension and long-term negative sequelae. We evaluated the safety and efficacy of dexfadrostat phosphate (DP13), a novel aldosterone synthase (CYP11B2) inhibitor, in healthy participants. METHODS: This randomized, double-blind, placebo-controlled study was conducted in two parts. In part A, a single-ascending dose escalation, 16 participants received oral DP13 1-16 mg. Part B was a multiple-ascending dose, sequential group study in which 32 participants received oral DP13 4, 8 or 16 mg once daily for 8 days. Safety and tolerability were monitored throughout. An adrenocorticotropic hormone (ACTH) stimulation test at maximal blood drug concentrations defined the dose range for multiple dosing. RESULTS: DP13 was well tolerated at all doses, with no serious adverse events. In part B, all DP13 doses (4, 8 and 16 mg) over 8 days effectively suppressed aldosterone production, increased the urinary sodium/potassium ratio, decreased plasma sodium and increased plasma potassium and renin levels compared with placebo, resulting in potent suppression of the aldosterone-to-renin ratio (ARR). Endocrine counter-regulation resulted in the 4 mg dose no longer sustaining 24-h aldosterone suppression after 8 days of treatment, unlike the 8- and 16 mg doses. There was no evidence of drug-induced adrenal insufficiency (ACTH stress challenge). CONCLUSIONS: In patients with excess aldosterone and ensuing sodium retention driving hypertension, managing sodium balance is critical. A CYP11B2 inhibitor like DP13, whose effectiveness can be monitored by a reduction in ARR, may prove valuable in managing aldosterone-dependent hypertension and primary aldosteronism.

The role of renin-angiotensin system in sepsis-associated acute kidney injury: mechanisms and therapeutic implications.

PURPOSE OF REVIEW: This review aims to explore the relationship between the renin angiotensin system (RAS) and sepsis-associated acute kidney injury (SA-AKI), a common complication in critically ill patients associated with mortality, morbidity, and long-term cardiovascular complications. Additionally, this review aims to identify potential therapeutic approaches to intervene with the RAS and prevent the development of AKI. RECENT FINDINGS: Recent studies have provided increasing evidence of RAS alteration during sepsis, with systemic and local RAS disturbance, which can contribute to SA-AKI. Angiotensin II was recently approved for catecholamine resistant vasodilatory shock and has been associated with improved outcomes in selected patients. SUMMARY: SA-AKI is a common condition that can involve disturbances in the RAS, particularly the canonical angiotensin-converting enzyme (ACE) angiotensin-II (Ang II)/angiotensin II receptor 1 (AT-1R) axis. Increased renin levels, a key enzyme in the RAS, have been shown to be associated with AKI and may also guide vasopressor therapy in shock. In patients with high renin levels, angiotensin II administration may reduce renin concentration, improve intra-renal hemodynamics, and enhance signaling through the angiotensin II receptor 1. Further studies are needed to explore the role of the RAS in SA-AKI and the potential for targeted therapies.

The Effects of Verapamil, Hydralazine, and Doxazosin on Renin, Aldosterone, and the Ratio Thereof.

PURPOSE: Hydralazine, doxazosin, and verapamil are currently recommended by the Endocrine Society as acceptable bridging treatment in those in whom full cessation of antihypertensive medication is infeasible during screening for primary aldosteronism (PA). This is under the assumption that they cause minimal to no effect on the aldosterone-to-renin ratio, the most widely used screening test for PA. However, limited evidence is available regarding the effects of these particular drugs on said ratio. METHODS: In the present study, we retrospectively assessed the changes in aldosterone, renin, and aldosterone-to-renin values in essential hypertensive participants before and after treatment with either hydralazine (n = 26) or doxazosin (n = 20) or verapamil (n = 15). All samples were taken under highly standardized conditions. RESULTS: Hydralazine resulted in a borderline significant rise in active plasma renin concentration (19 vs 25 mIU/L, p = 0.067) and a significant fall in the aldosterone-to-renin ratio (38 vs 24, p = 0.017). Doxazosin caused declines in both plasma aldosterone concentration (470 vs 330 pmol/L, p = 0.028) and the aldosterone-to-renin ratio (30 vs 20, p = 0.020). With respect to verapamil, we found no statistically significant effect on any of these outcome variables. CONCLUSION: We conclude that the assumption that these drugs can be used with little consequence to the aldosterone-to-renin cannot be substantiated. While it is possible that they are indeed the best option when full antihypertensive drug cessation is infeasible, the potential effects of these drugs must still be taken into account when interpreting the aldosterone-to-renin ratio.

Evaluating renin and aldosterone levels in children with organic acidemia-therapeutic experience with fludrocortisone.

Hyporeninemic hypoaldosteronism has been reported in only a few cases with methylmalonic acidemia (MMA) and has been attributed to the renal involvement. This study aims to investigate renin-aldosterone levels along with the renal functions of the patients with organic acidemia. This is a cross-sectional study conducted in patients with MMA, propionic acidemia (PA), and isovaleric acidemia (IVA). Serum renin, aldosterone, sodium, and potassium levels were measured, and glomerular filtration rates (GFR) were calculated. Comparisons were made between the MMA and non-MMA (PA+IVA) groups. Thirty-two patients (MMA:PA:IVA = 14:13:5) were included. The median GFR was significantly lower in the MMA group than in the non-MMA group (p < 0.001). MMA patients had the highest incidence of kidney damage (71.4%), followed by PA patients (23%), while none of the IVA patients had reduced GFR. GFR positively correlated with renin levels (p = 0.015, r = 0.433). Although renin levels were significantly lower in the MMA group than the non-MMA group (p = 0.026), no significant difference in aldosterone levels was found between the two groups. Hyporeninemic hypoaldosteronism was found in 3 patients with MMA who had different stages of kidney damage, and fludrocortisone was initiated, which normalized serum sodium and potassium levels.  Conclusions: This study, which has the largest number of patients among the studies investigating the renin-angiotensin system in organic acidemias to date, has demonstrated that hyporeninemic hypoaldosteronism is not a rare entity in the etiology of hyperkalemia in patients with MMA, and the use of fludrocortisone is an effective treatment of choice in selected cases. What is Known: • Hyperkalemia may be observed in cases of methylmalonic acidemia due to renal involvement and can be particularly prominent during metabolic decompensation. • Hyporeninemic hypoaldosteronism has been reported to be associated with hyperkalemia in only a few cases of methylmalonic acidemia. What is New: • Hyporeninemic hypoaldosteronism was found in one-fifth of cases with methylmalonic acidemia. • Fludrocortisone therapy leads to the normalization of serum sodium and potassium levels.

Screening for primary aldosteronism in the diabetic population: a cohort study.

BACKGROUND: Primary aldosteronism (PA) is the most common endocrine cause of hypertension. It is associated with higher cardio-metabolic risk than essential hypertension. Hypertension is common in patients with type 2 diabetes who carry increased cardiovascular risk; however, it is unknown how frequently they are tested for PA. AIM: To assess the extent to which the Endocrine Society's 2016 PA screening guidelines have been applied in a tertiary diabetes care setting and evaluate the demographic, clinical and biochemical characteristics of patients who met screening criteria compared with those who did not. METHODS: This is a retrospective cohort study. Data were collected from 272 patients who attended tertiary diabetes clinics and had two or more blood pressure measurements from January to December 2018. RESULTS: Of 272 patients, 60 (22.1%) had indication(s) for PA screening, but only 14 (23.3%) of 60 were screened using the aldosterone-to-renin ratio (ARR). Five patients who did not meet screening criteria were screened. Only one of 19 patients screened had an abnormal ARR; however, 16 were taking medications known to affect aldosterone and/or renin production. CONCLUSIONS: In a tertiary diabetes outpatient setting, only a minority of patients who fulfilled the Endocrine Society criteria for PA screening were actually screened. Appropriate screening for PA in the diabetic hypertensive population is necessary for the diagnosis and targeted treatment of a highly modifiable cardiovascular risk factor. Further studies are needed to develop feasible strategies to identify patients with PA in this population.

Plasma Renin Activity Increases With Cardiopulmonary Bypass and is Associated With Vasoplegia After Cardiac Surgery.

OBJECTIVES: To describe the trend in plasma renin activity over time in patients undergoing cardiac surgery on cardiopulmonary bypass, and to investigate if increased plasma renin activity is associated with postcardiopulmonary bypass vasoplegia. DESIGN: A prospective cohort study. SETTING: Patients were enrolled from June 2020 to May 2021 at a tertiary cardiac surgical institution. PATIENTS: A cohort of 100 adult patients undergoing cardiac surgery on cardiopulmonary bypass. INTERVENTIONS: None. MEASUREMENTS AND MAIN RESULTS: Plasma renin activity was measured at 5 time points: baseline, postoperatively, and at midnight on postoperative days 1, 2, and 3. Plasma renin activity and delta plasma renin activity were correlated with the incidence of vasoplegia and clinical outcomes. The median plasma renin activity increased approximately 3 times from baseline immediately after cardiac surgery, remained elevated on postoperative days 0, 1, and 2, and began to downtrend on postoperative day 3. Plasma renin activity was approximately 3 times higher at all measured time points in patients who developed vasoplegia versus those who did not. CONCLUSIONS: In patients undergoing cardiac surgery on cardiopulmonary bypass, plasma renin activity increased postoperatively and remained elevated through postoperative day 2. Additionally, patients with vasoplegic syndrome after cardiac surgery on cardiopulmonary bypass had more robust elevations in plasma renin activity than nonvasoplegic patients. These findings support the need for randomized controlled trials to determine if patients undergoing cardiac surgery with high plasma renin activity may benefit from targeted treatment with therapies such as synthetic angiotensin II.

Effects of Long-Term Intervention with Losartan, Aspirin and Atorvastatin on Vascular Remodeling in Juvenile Spontaneously Hypertensive Rats.

Hypertension in adolescents is associated with adverse cardiac and vascular events. In addition to lowering blood pressure, it is not clear whether pharmacological therapy in early life can improve vascular remodeling. This study aimed to evaluate the effects of long-term administration of losartan, aspirin, and atorvastatin on vascular remodeling in juvenile spontaneously hypertensive rats (SHRs). Losartan, aspirin, and atorvastatin were administered via gavage at doses of 20, 10, and 10 mg/kg/day, respectively, on SHRs aged 6-22 weeks. Paraffin sections of the blood vessels were stained with hematoxylin-eosin (H&E) and Sirius Red to evaluate the changes in the vascular structure and the accumulation of different types of collagen. The plasma levels of renin, angiotensin II (Ang II), aldosterone (ALD), endothelin-1 (ET-1), interleukin-6 (IL-6), and neutrophil elastase (NE) were determined using ELISA kits. After the 16-week treatment with losartan, aspirin, and atorvastatin, the wall thickness of the thoracic aorta and carotid artery decreased. The integrity of the elastic fibers in the tunica media was maintained in an orderly manner, and collagen deposition in the adventitia was retarded. The plasma levels of renin, ALD, ET-1, IL-6, and NE in the SHRs also decreased. These findings suggest that losartan, aspirin, and atorvastatin could improve vascular remodeling beyond their antihypertensive, anti-inflammatory, and lipid-lowering effects. Many aspects of the protection provided by pharmacological therapy are important for the prevention of cardiovascular diseases in adults and older adults.

Renal Hemodynamics and Renin-Angiotensin-Aldosterone System Profiles in Patients With Heart Failure.

OBJECTIVE: Understanding cardiorenal pathophysiology in heart failure (HF) is of clinical importance. We sought to characterize the renal hemodynamic function and the transrenal gradient of the renin-angiotensin-aldosterone system (RAAS) markers in patients with HF and in controls without HF. METHODS: In this post hoc analysis, the glomerular filtration rate (GFRinulin), effective renal plasma flow (ERPFPAH) and transrenal gradients (arterial-renal vein) of angiotensin converting enzyme (ACE), aldosterone, and plasma renin activity (PRA) were measured in 47 patients with HF and in 24 controls. Gomez equations were used to derive afferent (RA) and efferent (RE) arteriolar resistances. Transrenal RAAS gradients were also collected in patients treated with intravenous dobutamine (HF, n = 11; non-HF, n = 11) or nitroprusside (HF, n = 18; non-HF, n = 5). RESULTS: The concentrations of PRA, aldosterone and ACE were higher in the renal vein vs the artery in patients with HF vs patients without HF (P < 0.01). In patients with HF, a greater ACE gradient was associated with greater renal vascular resistance (r = 0.42; P 0.007) and greater arteriolar resistances (RA: r = 0.39; P = 0.012; RE: r = 0.48; P = 0.002). Similarly, a greater aldosterone gradient was associated with lower GFR (r = -0.51; P = 0.0007) and renal blood flow (RBF), r = -0.32; P = 0.042) whereas greater PRA gradient with lower ERPF (r = -0.33; P = 0.040), GFR (r = -0.36; P = 0.024), and RBF (r = -0.33; P = 0.036). Dobutamine and nitroprusside treatment decreased the transrenal gradient of ACE (P = 0.012, P < 0.0001, respectively), aldosterone (P = 0.005, P = 0.030) and PRA (P = 0.014, P = 0.002) in patients with HF only. CONCLUSIONS: A larger transrenal RAAS marker gradient in patients with HF suggests a renal origin for neurohormonal activation associated with a vasoconstrictive renal profile.

Treatment Persistence of Renin-Angiotensin-Aldosterone-System Inhibitors Over Time in Heart Failure with Reduced Ejection Fraction.

BACKGROUND: Clinical practice guidelines support sustained use of renin-angiotensin-aldosterone-system (RAAS) inhibitors over time in heart failure with reduced ejection fraction, yet few data are available regarding the frequency, timing or predictors of early treatment discontinuation in clinical practice. METHODS: Among prevalent or new users of angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs), angiotensin receptor-neprilysin inhibitors (ARNIs), and mineralocorticoid receptor antagonists (MRAs) in the CHAMP-HF (Change the Management of Patients with Heart Failure) registry, we estimated the frequency and independent predictors of treatment discontinuation during follow-up. Among sites with > 5 users of a given RAAS inhibitor, we evaluated practice variation in the proportion of patients with treatment discontinuation. RESULTS: Over median follow-up of 18 months, frequency of drug discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.7% (444 of 3509 users), 10.4% (140 of 1352 users), and 20.4% (435 of 2129 users), respectively. An additional, 149 (11.0%) of ARNI users were switched to ACEis/ARBs, and 447 (12.7%) of ACEi/ARB users were switched to ARNIs during follow-up. Across sites, the median proportion of discontinuation of ACEis/ARBs, ARNIs and MRAs was 12.5% (25th-75th percentiles 6.9%-18.9%), 18.8% (25th-75th percentiles 12.5%-28.6%), and 19.6% (25th-75th percentiles 10.7%-27.0%), respectively. Chronic kidney disease was the only independent predictor of increased risk of discontinuation of each of the RAAS inhibitor classes (P < 0.02 for all). Higher Kansas City Cardiomyopathy Questionnaire overall summary scores independently predicted lower risk of discontinuation of ACEis/ARBs and ARNIs (both P < 0.001) but not of MRAs. Investigator clinical experience was predictive of lower risks of discontinuation of ACEis/ARBs and MRAs (P < 0.02) but not of ARNIs. All other independent predictors of discontinuation were unique to individual therapeutic classes. CONCLUSIONS: One in 10 patients discontinue ACEis/ARBs or ARNIs, and 1 in 5 discontinue MRAs in routine clinical practice of heart failure with reduced ejection fraction. Unique patient-level and clinician/practice-level factors are associated with premature discontinuation of individual RAAS inhibitors, which may help to guide structured efforts to promote treatment persistence in clinical care.

Assessment of optimal renin-angiotensin-system inhibition strategy in Asian patients with STEMI after primary myocardial revascularization.

BACKGROUND: For the Asian patients with STEMI undergoing PCI, ACEIs are known to have a better outcome than ARBs. However, there is limited evidence to suggest so. METHODS: Among the STEMI registry consist of 1142 Korean patients, we compared the MACE, the composite of myocardial infarction, stoke, death, admission for heart failure, and target vessel revascularization, between the ACEI and ARB groups (Set 1). Further, we defined adequate medication as the administration of a dose equal to or higher than the initiation dose of ACEI according to the heart failure guideline recommendation with a mandatory addition of beta-blockers, and compared the outcomes between the inadequate and adequate medication groups (Set 2). Propensity score matching was used to eliminate difference. RESULTS: In the Set 1 comparison, patients in the ACEI group had a better outcome than those in the ARB group for both whole and matched populations (whole and matched population: Cox regression hazard ratio [HR], 0.645 and 0.535; 95% confidence interval [CI], 0.440-0.944 and 0.296-0.967; p = 0.024 and p = 0.039, respectively). In the Set 2 comparison for the whole population, patients in the inadequate medication group had more MACE than those in the adequate medication group (HR, 0.673; 95% CI, 0.459-0.985; p = 0.042). However, no difference was observed after propensity score matching (HR, 1.023; 95% CI, 0.654-1.602; p = 0.919). CONCLUSION: ACEIs might be a better choice than ARBs after primary revascularization. However, this study's findings suggest that early ACEI dose escalation combined with beta-blocker use may not improve prognosis.

Plasma renin, aldosterone, and urinary prostaglandin E2 levels in children with hypocalcemia due to vitamin D deficiency rickets.

We investigated the effect of hypocalcemia on plasma renin, aldosterone, and urine PGE2 levels in children with vitamin D deficiency rickets (VDDR). In the study group, 25 patients with VDDR-induced hypocalcemia were treated with a single dose of 150,000-300,000 IU cholecalciferol and 50 mg/kg/day elemental Ca for 10 days. On any day between 21th and 30th days after the treatment, the patients' clinical, biochemical and radiologic findings were re-evaluated. The healthy children with the same sex and similar age as the study group comprised the control group. Plasma sodium (Na), potassium (K), calcium (Ca), phosphorus (P), alkaline phosphatase (ALP), parathyroid hormone (PTH), 25- hydroxy vitamin D (25OHD), renin, aldosterone; and urinary Ca, creatinine (Cr) and prostaglandin E2 (PGE2) levels were measured in both the study (pre-treatment and post-treatment) and the control group. Plasma Ca, P, 25OHD and renin levels and urinary PGE2/Cr ratio in the post-treatment group were significantly higher than those in the pre-treatment group while K, ALP, and PTH concentrations were significantly lower. Plasma ALP and PTH levels in pre-treatment group were significantly higher than in the control group while Ca, P, 25OHD, aldosterone and renin concentrations and urinary PGE2/Cr ratio were significantly lower. Post-treatment plasma Ca level was significantly decreased in normal limits compared to the control group while other biochemical parameters were not different from the control group. Plasma Ca concentration was positively correlated with renin level and urinary PGE2/Cr ratio. The findings suggest that hypocalcemia may inhibit the production of renin, aldosterone and PGE2 and a blunt aldosterone secretion may develop even after recovery from hypocalcemia.

Promise of Physiological Profiling to Prevent Stroke in People of African Ancestry: Prototyping Ghana.

PURPOSE OF REVIEW: Worldwide, compared to other racial/ethnic groups, individuals of African ancestry have an excessively higher burden of hypertension-related morbidities, especially stroke. Identifying modifiable biological targets that contribute to these disparities could improve global stroke outcomes. In this scoping review, we discuss how pathological perturbations in the renin-angiotensin-aldosterone pathways could be harnessed via physiological profiling for the purposes of improving blood pressure control for stroke prevention among people of African ancestry. RECENT FINDINGS: Transcontinental comparative data from the USA and Ghana show that the prevalence of treatment-resistant hypertension among stroke survivors is 42.7% among indigenous Africans, 16.1% among African Americans, and 6.9% among non-Hispanic Whites, p < 0.0001. A multicenter clinical trial of patients without stroke in 3 African countries (Nigeria, Kenya, and South Africa) demonstrated that physiological profiling using plasma renin activity and aldosterone to individualize selection of antihypertensive medications compared with usual care resulted in better blood pressure control with fewer medications over 12 months. Among Ghanaian ischemic stroke survivors treated without renin-aldosterone profiling data, an analysis revealed that those with low renin phenotypes did not achieve any meaningful reduction in blood pressure over 12 months on 3-4 antihypertensive medications despite excellent adherence. For a polygenic condition such as hypertension, individualized therapy based on plasma renin-aldosterone-guided selection of therapy for uncontrolled BP following precision medicine principles may be a viable strategy for primary and secondary stroke prevention with the potential to reduce disparities in the poor outcomes of stroke disproportionately shared by individuals of African ancestry. A dedicated clinical trial to test this hypothesis is warranted.

Plasma Renin-guided Therapy in Patients of Primary Hypertension on Antihypertensives: A Prospective Cohort Study.

BACKGROUND: Most guidelines for hypertension overlook the underlying pathophysiologic basis in deciding antihypertensives. Based on renin levels, hypertension may be classified as high-renin hypertension (HRH), low-renin hypertension (LRH), and normal-renin hypertension (NRH). The study examined the renin levels in a hypertensive population and assessed the effect of renin-guided antihypertensive management on blood pressure (BP) control. MATERIALS AND METHODS: This study was a single-center prospective cohort study. Subjects with primary hypertension (aged 20-60 years) on antihypertensives were included in the study. Initial BP was recorded and subsequently, all antihypertensives were discontinued. After 2 weeks, second BP was recorded and plasma renin assay (PRA) sample was collected. All patients were restarted on the previous antihypertensives and further modification of medication was performed based on their PRA. Anti V drugs, such as diuretics and calcium channel blockers (CCBs) were used in LRH while beta-blockers and antirenin drugs (Anti R drugs) were used in HRH. RESULTS: The study included 918 patients with hypertension and 896 cases were finally analyzed. Of these patients, 287 (32.03%) had LRH (<0.51 ng/mL/hr), 412 (45.98%) had HRH (>2.64 ng/mL/hr), while 197 (21.99%) had NRH (0.51-2.64 ng/mL/hr). Renin-guided management caused significant BP reduction. In controlled BP group, the systolic BP (SBP)/diastolic BP (DBP) before and after modification were 133.83 ± 3.36/84.77 ± 3.12 and 123.87 ± 10.59/84.05 ± 1.84, respectively (p-value < 0.05). In uncontrolled BP group, the corresponding SBP/DBP were 152.17 ± 2.95/90.36 ± 5.02 and 138 ± 1.23/87.78 ± 0.84, respectively (p-value < 0.05). The number of hypertensives used in patients also reduced with reduction in patients on two, three, or four drugs. CONCLUSIONS: Renin-guided therapy is useful for improving BP control in both controlled and uncontrolled hypertensive patients and in reducing the number of antihypertensive drugs.

[A novel approach to rapid induction of remission in primary membranous nephropathy].

AIM: То evaluate the effectiveness of a novel multi-targeted treatment approach including rituximab (RTX), cyclophosphamide (CPH) and steroids (S) to the induction of remission in patients with primary membranous nephropathy (PMN) compared to standard immunosuppression (IST). MATERIALS AND METHODS: An open-label prospective comparative study included 56 PMN patients (pts) with nephrotic syndrome (NS) and high serum level of antibodies to the phospholipase A2 receptor anti-PLA2R (mean age 5112 years, men 70%). We recorded demographic and clinical parameters at the time of kidney biopsy, data from light-optical and immunomorphological studies. All pts were on stable doses of the renin-angiotensin systems blockers. We compared the effectiveness of different treatments in the inductions of clinical and immunological remissions in pts who received experimental treatment with RTX, CPH and S (RTX+CPH+S group, n=14) and two control groups: high-dose RTX therapy (group RTX, n=12), cyclosporine and steroids (group CsA+S, n=30). RESULTS: In the RTX+CPH+S group, remission was achieved in 100% of cases (of which complete remissions CR in 21.4%). The median time-to-remission (2.5 [1.0; 3.5] months) was significantly lower compared to both control groups: RTX (8.7 [6.6; 14.0] months, p=0.005) and CsA+S (12.4 [6.5; 19.9] months, p0.001). The cumulative incidence of clinical and immunological remissions was also significantly higher in the RTX+CPH+S group than in the control groups. These results were confirmed in comparative analyzes in the same treatment groups after propensity score matching. The cumulative incidence of clinical and immunological remissions in the RTX+CPH+S group was higher than in the combined group of patients who received other therapies (p0.001). The incidence of serious adverse events was low and did not differ between groups. CONCLUSION: The use of multi-targeted therapy with rituximab, cyclophosphamide, and steroids seems to be an effective approach for the rapid induction of PMN remission and prevention of NS complications.

The Effect of Combined Treatment with the (Pro)Renin Receptor Blocker HRP and Quinapril in Type 1 Diabetic Rats.

BACKGROUND/AIMS: Diabetic nephropathy remains a major clinical problem. The effects of prorenin might be adverse, but the literature data are controversial. We compared the renal effects of the (pro)renin receptor ((P)RR) blockade and angiotensin converting enzyme (ACE) inhibition on the progression of diabetic nephropathy in rats. METHODS: Diabetes (DM) was induced by ip. streptozotocin administration in adult male Sprague-Dawley rats, followed by eight weeks of treatment with the (P)RR blocker "handle region" decoy peptide (HRP, 0,1 mg/kg/day) or with the ACE inhibitor Quinapril (Q, 50 mg/kg/day) and grouped as follows: 1. Control (n=10); 2. DM (n=8); 3. DM+HRP (n=6); 4. DM+Q (n=10); 5. DM+Q+HRP (n=10). Renal functional parameters, histology and gene expressions were evaluated. RESULTS: HRP reduced glomerulosclerosis and podocyte desmin expression, but did not affect proteinuria and tubular ERK(1/2) phosphorylation. Both Q and Q+HRP treatment reduced proteinuria, glomerular and tubular damage, tubular TGF-ß1 expression and ERK(1/2) phosphorylation to the same extent. CONCLUSION: The effects of HRP were partially beneficial on diabetic kidney lesions as HRP reduced damage but did not improve tubular damage and failed to reduce ERK(1/2) phosphorylation in rats. The combination of HRP with Quinapril had no additive effects over Quinapril monotherapy on the progression of diabetic nephropathy.

Hypertension and Lorundrostat: Key Discoveries From the TARGET-HTN Trial.

Hypertension, characterized by persistent high blood pressure levels, is a major global health concern, contributing significantly to the risk of cardiovascular diseases (CVD) and overall mortality. It is classified into primary and secondary hypertension, with its prevalence steadily increasing due to ageing populations and unhealthy lifestyle factors. The World Health Organization (WHO) reports a staggering rise in hypertension cases, affecting one in 3 adults worldwide, doubling from 1990 to 2019. A significant development in the field of hypertension treatment is the Target-HTN trial, which investigated the efficacy of lorundrostat, an aldosterone synthase inhibitor, in reducing systolic blood pressure. This trial involved 2 cohorts. Cohort 1, comprising patients with suppressed plasma renin activity and elevated serum aldosterone levels, showed promising results. Lorundrostat doses of 100 mg and 50 mg administered once daily led to substantial reductions in systolic blood pressure compared to a placebo group. Cohort 2, although considered exploratory, also exhibited a notable reduction in systolic blood pressure with a 100 mg once-daily dose of lorundrostat. In conclusion, the Target-HTN trial has demonstrated that lorundrostat, an aldosterone synthase inhibitor, holds promise as an innovative therapeutic approach for reducing systolic blood pressure, especially in hypertensive patients with suppressed plasma renin activity and elevated serum aldosterone levels. These findings advocate for the initiation of Phase 3 trials to further validate the safety and efficacy of lorundrostat in a larger and more diverse patient population.

The scientific rationale and study protocol for the DPP3, Angiotensin II, and Renin Kinetics in Sepsis (DARK-Sepsis) randomized controlled trial: serum biomarkers to predict response to angiotensin II versus standard-of-care vasopressor therapy in the treatment of septic shock.

BACKGROUND: Data to support the use of specific vasopressors in septic shock are limited. Since angiotensin II (AT2) was approved by the Food and Drug Administration in 2017, multiple mechanistically distinct vasopressors are available to treat septic shock, but minimal data exist regarding which patients are most likely to benefit from each agent. Renin and dipeptidyl peptidase 3 (DPP3) are components of the renin-angiotensin-aldosterone system which have been shown to outperform lactate in predicting sepsis prognosis, and preliminary data suggest they could prove useful as biomarkers to guide AT2 use in septic shock. METHODS: The DARK-Sepsis trial is an investigator-initiated industry-funded, open-label, single-center randomized controlled trial of the use of AT2 versus standard of care (SOC) vasopressor therapy in patients admitted to the intensive care unit (ICU) with vasodilatory shock requiring norepinephrine ≥ 0.1 mcg/kg/min. In both groups, a series of renin and DPP3 levels will be obtained over the first 24 h of treatment with AT2 or SOC. The primary study outcome will be the ability of these biomarkers to predict response to vasopressor therapy, as measured by change in total norepinephrine equivalent dose of vasopressors at 3 h post-drug initiation or the equivalent timepoint in the SOC arm. To determine if the ability to predict vasopressor response is specific to AT2 therapy, the primary analysis will be the ability of baseline renin and DPP3 levels to predict vasopressor response adjusted for treatment arm (AT2 versus control) and Sequential Organ Failure Assessment (SOFA) scores. Secondary outcomes will include rates of acute kidney injury, need for mechanical ventilation and kidney replacement therapy, lengths of stay in the ICU and hospital, ICU and hospital mortality, and rates of prespecified adverse events. DISCUSSION: With an armamentarium of mechanistically distinct vasopressor agents now available, sub-phenotyping patients using biomarkers has the potential to improve septic shock outcomes by enabling treatment of the correct patient with the correct vasopressor at the correct time. However, this approach requires validation in a large definitive multicenter trial. The data generated through the DARK-Sepsis study will prove crucial to the optimal design and patient enrichment of such a pivotal trial. TRIAL REGISTRATION: ClinicalTrials.gov NCT05824767. Registered on April 24, 2023.