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Background Pre–diabetes mellitus (DM) is associated with proteinuria, a risk factor for chronic kidney disease. While people with human immunodeficiency virus (HIV; PWH) have a higher risk of proteinuria than people without HIV (PWOH), it is unknown whether incident proteinuria differs by HIV serostatus among prediabetic persons. Methods The urine protein-to-creatinine ratio was measured at semiannual visits among men in the Multicenter AIDS Cohort Study since April 2006. Men with pre-DM on or after April 2006 and no prevalent proteinuria or use of antidiabetic medications were included. Pre-DM was defined as a fasting glucose level of 100–125 mg/dL confirmed within a year by a repeated fasting glucose or hemoglobin A1c measurement of 5.7%–6.4%. Incident proteinuria was defined as a urine protein-to-creatinine ratio (UPCR) >200 mg/g, confirmed within a year. We used Poisson regression models to determine whether incident proteinuria in participants with pre-DM differed by HIV serostatus and, among PWH, whether HIV-specific factors were related to incident proteinuria. Results Between 2006 and 2019, among 1276 men with pre-DM, proteinuria developed in 128 of 613 PWH (21%) and 50 of 663 PWOH (8%) over a median 10-year follow-up. After multivariable adjustment, the incidence of proteinuria in PWH with pre-DM was 3.3 times (95% confidence interval, 2.3–4.8 times) greater than in PWOH (P <.01). Among PWH, current CD4 cell count <50/µL (P <.01) and current use of protease inhibitors (P =.03) were associated with incident proteinuria, while lamivudine and integrase inhibitor use were associated with a lower risk. Conclusions Among men with pre-DM, the risk of incident proteinuria was 3 times higher in PWH. Strategies to preserve renal function are needed in this population. [ABSTRACT FROM AUTHOR]

Introduction The DAPA-CKD study showed a protective effect of dapagliflozin on kidney function in chronic kidney disease (CKD) patients with and without diabetes mellitus. Although dapagliflozin is expected to be effective also in CKD patients with autosomal dominant polycystic kidney disease (ADPKD), its efficacy and safety in this population remain unknown because ADPKD was an exclusion criterion in the DAPA-CKD study. Therefore, we evaluated the effects of dapagliflozin in CKD patients with ADPKD. Methods We performed a retrospective observational study of seven patients with ADPKD treated with dapagliflozin at Toranomon Hospital, Tokyo, Japan. We analyzed changes in estimated glomerular filtration rate (eGFR) slope and annual height-corrected total kidney volume before and after starting dapagliflozin treatment. Results The median observation period after starting dapagliflozin was 20 months. Four patients received concomitant tolvaptan. The eGFR slope before and after initiation of dapagliflozin could be calculated in six patients and improved in all of them except the one who did not receive a renin-angiotensin system (RAS) inhibitor. Annual height-corrected total kidney volume increased in all patients. Concurrent tolvaptan treatment had no effect. Conclusion In CKD patients with ADPKD, dapagliflozin may increase kidney volume but may have a protective effect on kidney function when used concomitantly with RAS inhibitors. [ABSTRACT FROM AUTHOR]

Background Hyperkalaemia is a barrier to achieving optimal, guideline-directed treatment with renin–angiotensin–aldosterone system inhibitors (RAASis) in patients with chronic kidney disease (CKD) and/or heart failure (HF). This study describes the association between hyperkalaemia-related RAASi treatment reduction and the number of hospitalized days in patients with CKD and/or HF in Sweden and Japan. Methods Using data from health registers and hospital medical records, patients with CKD and/or HF currently receiving RAASis who experienced an index hyperkalaemia episode were identified and categorized as having maintained or reduced RAASi treatment post-index; propensity score matching (1:1) was applied to balance the groups in terms of baseline characteristics. Changes in the number of all-cause, CKD- and HF-related hospitalized days per patient-year during 6 months pre- versus post-index and the number of days alive and out of hospital (DAOH) during 6 months post-index were described. Results Overall, 20 824 and 7789 patients were included from Sweden and Japan, respectively, 42% and 38% of whom reduced their RAASi treatment after the index hyperkalaemia episode. During the 6 months post-index, all-cause hospitalization increased by 18.2 days [95% confidence interval (CI) 17.0–19.2] per person-year in Sweden and 17.9 days (95% CI 17.4–18.5) per person-year in Japan among patients with reduced RAASi treatment compared with increases of 9.4 days (95% CI 8.6–10.4) and 8.5 days (95% CI 8.0–9.0) per person-year, respectively, among patients with maintained RAASi treatment. The mean DAOH was 121.5 [standard deviation (SD) 75.0] in Sweden and 141.7 (SD 54.5) in Japan among patients with reduced RAASi treatment compared with 154.0 (SD 51.3) and 157.5 (SD 31.6), respectively, among patients with maintained RAASi treatment. Conclusion Patients whose RAASi treatment was reduced after a hyperkalaemia episode had more hospitalized days and fewer DAOH compared with patients whose RAASi treatment was maintained. [ABSTRACT FROM AUTHOR]

Objectives: Intestinal ischemia reperfusion (IIR) is a critical emergency situation that needs immediate intervention. Small intestine is one of the most sensitive tissues to IR injury and it remains a highly morbid condition, with reported mortality rates ranging from 30% to 90%. Thus, we aimed to evaluate the suspected protective role of sacubitril/valsartan (SAC/VAL) on IIR injury. Methods: Thirty-two adult male Wistar rats were used in our model and divided into four groups: sham group, SAC/VAL treated group without IIR, IIR group, and SAC/VAL treated group with IIR. SAC/VAL in a dose of 30 mg/kg was administered orally just before induction of IIR. Key findings: SAC/VAL significantly ameliorated IIR-induced changes as it decreased malondialdehyde (MDA), tumor necrosis factor alpha (TNFα), angiotensin II (ANG II), interleukin 6 (IL 6), active caspase 3, and signal transducer- and activator-of transcription (STAT1). However, SAC/VAL administration significantly increased antioxidant parameters such as total antioxidant capacity (TAC), superoxide dismutase (SOD), and reduced glutathione (GSH). Moreover, alteration of the histological structure was observed in IIR group that was improved by SAC/VAL. Conclusions: SAC/VAL prevents IIR-induced damage via modulation of renin angiotensin aldosterone system, antioxidant, anti-apoptotic, anti-inflammatory properties, and regulation of IL6/STAT1 pathway. Graphical Abstract [ABSTRACT FROM AUTHOR]

BACKGROUND While renin–angiotensin system (RAS) inhibitors have a longstanding history in blood pressure control, their suitability as first-line in-patient treatment may be limited due to prolonged half-life and kidney failure concerns. METHODS Using a cohort design, we assessed the impact of RAS inhibitors, either alone or in combination with beta-blockers, on mortality, while exploring interactions, including those related to end-stage renal disease and serum creatinine levels. Eligible subjects were Acute Ischemic Stroke (AIS) patients aged 18 or older with specific subtypes who received in-patient antihypertensive treatment. The primary outcome was mortality rates. Statistical analyses included cross-sectional and longitudinal approaches, employing generalized linear models, G-computation, and discrete-time survival analysis over a 20-day follow-up period. RESULTS In our study of 3,058 AIS patients, those using RAS inhibitors had significantly lower in-hospital mortality (2.2%) compared to non-users (12.1%), resulting in a relative risk (RR) of 0.18 (95% CI: 0.12–0.26). Further analysis using G-computation revealed a marked reduction in mortality risk associated with RAS inhibitors (0.0281 vs. 0.0913, risk difference [RD] of 6.31% or 0.0631, 95% CI: 0.046–0.079). Subgroup analysis demonstrated notable benefits, with individuals having creatinine levels below and above 1.3 mg/dl exhibiting statistically significant RD (RD −0.0510 vs. −0.0895), and a significant difference in paired comparison (−0.0385 or 3.85%, CI 0.023–0.054). Additionally, longitudinal analysis confirmed a consistent daily reduction of 0.93% in mortality risk associated with the intake of RAS inhibitors. CONCLUSIONS RAS inhibitors are associated with a significant reduction in in-hospital mortality in AIS patients, suggesting potential clinical benefits in improving patient outcomes. [ABSTRACT FROM AUTHOR]

BACKGROUND The effectiveness of renal denervation (RDN) in reducing blood pressure and systemic sympathetic activity in hypertensive patients has been established. However, the underlying central mechanism remains unknown. This study aimed to investigate the role of RDN in regulating cardiovascular function via the central renin–angiotensin system (RAS) pathway. METHODS Ten-week-old spontaneously hypertensive rats (SHR) were subjected to selective afferent renal denervation (ADN) using capsaicin solution. We hypothesized that ADN would effectively reduce blood pressure and rebalance the RAS component of the paraventricular nucleus (PVN) in SHR. RESULTS The experimental results show that the ADN group exhibited significantly lower blood pressure, reduced systemic sympathetic activity, decreased chronic neuronal activation marker C-FOS expression in the PVN, and improved arterial baroreflex function, compared with the Sham group. Furthermore, ACE and AT1 protein expression was reduced while ACE2 and MAS protein expression was increased in the PVN of SHR after ADN. CONCLUSIONS These findings suggest that RDN may exert these beneficial effects through modulating the central RAS pathway. [ABSTRACT FROM AUTHOR]

Aims Prevention of human hypertension is an important challenge and has been achieved in experimental models. Brief treatment with renin–angiotensin system (RAS) inhibitors permanently reduces the genetic hypertension of the spontaneously hypertensive rat (SHR). The kidney is involved in this fascinating phenomenon, but relevant changes in gene expression are unknown. Methods and results In SHR, we studied the effect of treatment between 10 and 14 weeks of age with the angiotensin receptor blocker, losartan, or the angiotensin-converting enzyme inhibitor, perindopril [with controls for non-specific effects of lowering blood pressure (BP)], on differential RNA expression, DNA methylation, and renin immunolabelling in the kidney at 20 weeks of age. RNA sequencing revealed a six-fold increase in renin gene (Ren) expression during losartan treatment (P < 0.0001). Six weeks after losartan, arterial pressure remained lower (P = 0.006), yet kidney Ren showed reduced expression by 23% after losartan (P = 0.03) and by 43% after perindopril (P = 1.4 × 10−6) associated with increased DNA methylation (P = 0.04). Immunolabelling confirmed reduced cortical renin after earlier RAS blockade (P = 0.002). RNA sequencing identified differential expression of mRNAs, miRNAs, and lncRNAs with evidence of networking and co-regulation. These included 13 candidate genes (Grhl1 , Ammecr1l , Hs6st1 , Nfil3 , Fam221a , Lmo4 , Adamts1 , Cish , Hif3a , Bcl6 , Rad54l2 , Adap1 , Dok4), the miRNA miR-145-3p, and the lncRNA AC115371. Gene ontogeny analyses revealed that these networks were enriched with genes relevant to BP, RAS, and the kidneys. Conclusion Early RAS inhibition in SHR resets genetic pathways and networks resulting in a legacy of reduced Ren expression and BP persisting for a minimum of 6 weeks. [ABSTRACT FROM AUTHOR]

Background This observational cohort study compared the likelihood of maintained (stabilized/up-titrated) renin–angiotensin–aldosterone system inhibitor (RAASi) therapy at 6 months following hyperkalaemia in patients with chronic kidney disease (CKD) and/or heart failure (HF) from the USA, Japan and Spain who received sodium zirconium cyclosilicate (SZC) for at least 120 days, relative to those with no prescription for a potassium (K+) binder. Methods Using health registers and hospital medical records, patients with CKD and/or HF receiving RAASi therapy who experienced a hyperkalaemia episode were identified. Propensity score (PS) matching (1:4) was applied to balance the SZC cohort to the no K+ binder cohort on baseline characteristics. Logistic regression analysis was performed to compare the odds of maintained RAASi therapy at 6 months in the SZC versus no K+ binder cohorts. Results The PS-matched SZC cohort included 565 (USA), 776 (Japan) and 56 (Spain) patients; the no K+ binder cohort included 2068, 2629 and 203 patients, respectively. At 6 months, 68.9% (USA), 79.9% (Japan) and 69.6% (Spain) in the SZC cohorts versus 53.1% (USA), 56.0% (Japan) and 48.3% (Spain) in the no K+ binder cohorts had maintained RAASi therapy. Meta-analysed across countries, the odds ratio of maintained RAASi therapy in the SZC cohort versus no K+ binder cohort was 2.56 (95% confidence interval 1.92–3.41; P  < .0001). Conclusions In routine clinical practice across three countries, patients treated with SZC were substantially more likely to maintain guideline-concordant RAASi therapy at 6 months following hyperkalaemia relative to patients with no K+ binder treatment. [ABSTRACT FROM AUTHOR]

Aims There is a lack of robust data on the optimal medical treatment of heart failure in patients with severe aortic stenosis, with no randomized controlled trials guiding treatment. The study aimed to study the association between exposure to renin–angiotensin–aldosterone system (RAS) inhibitors or beta-blockers and outcome after aortic valve replacement in patients with aortic stenosis and heart failure. Methods and results The study included all patients with heart failure undergoing aortic valve replacement for aortic stenosis in Sweden between 2008 and 2016 (n = 4668 patients). Exposure to treatment was assessed by a continuous tracking of drug dispensations, and outcome events were all-cause mortality and hospitalization for heart failure collected from national patient registries. After adjustment for age, sex, atrial fibrillation, hypertension, diabetes mellitus, and prior myocardial infarction, Cox regression analysis showed that RAS inhibition was associated with a lower risk of all-cause mortality in patients with reduced left ventricular ejection fraction (LV-EF) [hazard ratio (HR) 0.58, 95% confidence interval (CI) 0.51–0.65] and preserved LV-EF (HR 0.69, 95% CI 0.56–0.85). Beta-blockade was associated with a lower risk of all-cause mortality in patients with reduced LV-EF (HR 0.81, 95% CI 0.71–0.92), but not in preserved LV-EF (HR 0.87, 95% CI 0.69–1.10). There was no association between RAS inhibition or beta-blockade and the risk of hospitalization for heart failure. Conclusion The RAS inhibition was associated with a lower all-cause mortality after valve replacement in patients with both reduced and preserved LV-EF. Beta-blockade was associated with lower all-cause mortality only in patients with reduced LV-EF. [ABSTRACT FROM AUTHOR]

Background and Aims Haemodynamic instability is associated with peri-operative myocardial injury, particularly in patients receiving renin–angiotensin system (RAS) inhibitors (angiotensin-converting-enzyme inhibitors/angiotensin II receptor blockers). Whether stopping RAS inhibitors to minimise hypotension, or continuing RAS inhibitors to avoid hypertension, reduces peri-operative myocardial injury remains unclear. Methods From 31 July 2017 to 1 October 2021, patients aged ≥60 years undergoing elective non-cardiac surgery were randomly assigned to either discontinue or continue RAS inhibitors prescribed for existing medical conditions in six UK centres. Renin–angiotensin system inhibitors were withheld for different durations (2–3 days) before surgery, according to their pharmacokinetic profile. The primary outcome, masked to investigators, clinicians, and patients, was myocardial injury [plasma high-sensitivity troponin-T (hs-TnT) ≥ 15 ng/L within 48 h after surgery, or ≥5 ng/L increase when pre-operative hs-TnT ≥15 ng/L]. Pre-specified adverse haemodynamic events occurring within 48 h of surgery included acute hypertension (>180 mmHg) and hypotension requiring vasoactive therapy. Results Two hundred and sixty-two participants were randomized to continue (n = 132) or stop (n = 130) RAS inhibitors. Myocardial injury occurred in 58 (48.3%) patients randomized to discontinue, compared with 50 (41.3%) patients who continued, RAS inhibitors [odds ratio (for continuing): 0.77; 95% confidence interval (CI) 0.45–1.31]. Hypertensive adverse events were more frequent when RAS inhibitors were stopped [16 (12.4%)], compared with 7 (5.3%) who continued RAS inhibitors [odds ratio (for continuing): 0.4; 95% CI 0.16–1.00]. Hypotension rates were similar when RAS inhibitors were stopped [12 (9.3%)] or continued [11 (8.4%)]. Conclusions Discontinuing RAS inhibitors before non-cardiac surgery did not reduce myocardial injury, and could increase the risk of clinically significant acute hypertension. These findings require confirmation in future studies. [ABSTRACT FROM AUTHOR]

Preeclampsia (PE) is a disorder involving de novo development of hypertension plus end organ damage after 20 weeks of gestation. PE is considered to be a heterogeneous disease. There are 2 main types of PE: early-onset (<34 weeks of gestation), which is considered to be a placental disorder and is associated with vasoconstriction, low cardiac output, and placental hypoperfusion and organ damage due to decreased microcirculation to maternal organs; and late-onset PE, which is primarily a disorder of pregnant women with obesity, diabetes, and/or cardiovascular abnormalities. In late-onset PE, there is avid sodium reabsorption by the maternal kidneys, causing hypervolemia and increased cardiac output, along with vasodilatation causing venous congestion of organs. Although PE has been a well-known disease for a long time, it is interesting to note that there is no specific sodium (salt) intake recommendation for these patients. This may be due to the fact that studies since as far back as the 1900s have shown conflicting results, and the reasons for the inconsistent findings have not been fully explained; furthermore, the type of PE in these studies was not specifically defined. Some studies suggest that sodium restriction may be detrimental in early-onset PE, but may be feasible in late-onset PE. To explore this paradox, the current review explains the hemodynamic factors involved in these 2 types of PE, summarizes the findings of the current studies, and highlights the knowledge gaps and the research needed to determine whether increase or restriction of salt or sodium intake is beneficial in different types of PE. [ABSTRACT FROM AUTHOR]

Among the broad spectrum of membranoproliferative glomerulonephritis (MPGN), immunofluorescence distinguishes C3 glomerulopathy (C3G), with predominant C3 deposits, and immunoglobulin-associated MPGN (Ig-MPGN), with combined C3 and Ig. However, there are several intersections between C3G and Ig-MPGN. Primary C3G and Ig-MPGN share the same prevalence of low serum C3 levels and of abnormalities of the alternative pathway of complement, and patients who present a bioptic pattern of Ig-MPGN at onset may show a C3G pattern in a subsequent biopsy. There is no specific therapy for primary C3G and Ig-MPGN and prognosis is unfavourable. The only recommended indications are inhibitors of the renin–angiotensin system, lipid-lowering agents and other renoprotective agents. The other drugs used currently, such as corticosteroids and mycophenolate mofetil, are often ineffective. The anti-C5 monoclonal antibody eculizumab has been tested in several patients, with mixed results. One reason for the uncertainty is the extremely variable clinical course, most likely reflecting a heterogeneous pathogenesis. An unsupervised clustering analysis that included histologic, biochemical, genetic and clinical data available at onset in patients with primary C3G and Ig-MPGN identified four clusters characterized by specific pathogenic mechanisms. This approach may facilitate accurate diagnosis and development of targeted therapies. Several trials are ongoing with drugs targeting different molecules of the complement cascade, however it is important to consider which component of the cascade may be the most appropriate for each patient. We review the current standards of treatment and discuss novel developments in the pathophysiology, diagnosis, outcome prediction and management of C3G and Ig-MPGN. [ABSTRACT FROM AUTHOR]

Background Many non-modifiable factors are associated with poorer health-related quality of life (HRQoL) experienced by people with chronic kidney disease (CKD). We hypothesize that potentially modifiable factors for poor HRQoL can be identified among CKD patients, providing potential targets for intervention. Method The National Unified Renal Translational Research Enterprise Chronic Kidney Disease (NURTuRE-CKD) cohort study recruited 2996 participants from nephrology centres with all stages of non-dialysis-dependent CKD. Baseline data collection for sociodemographic, anthropometric, biochemical and clinical information, including Integrated Palliative care Outcome Scale renal, Hospital Anxiety and Depression score (HADS) and the 5-level EuroQol-5D (EQ-5D-5L) as HRQoL measure, took place between 2017 and 2019. EQ-5D-5L dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression) were mapped to an EQ-5D-3L value set to derive index value. Multivariable mixed effects regression models, adjusted for known factors affecting HRQoL with recruitment region as a random effect, were fit to assess potentially modifiable factors associated with index value (linear) and within each dimension (logistic). Results Among the 2958/2996 (98.7%) participants with complete EQ-5D data, 2201 (74.4%) reported problems in at least one EQ-5D-5L dimension. Multivariable linear regression identified independent associations between poorer HRQoL (EQ-5D-3L index value) and obesity (body mass index ≥30.0 kg/m2, β −0.037, 95% CI −0.058 to −0.016, P  = .001), HADS depression score ≥8 (β −0.159, −0.182 to −0.137, P  < .001), anxiety score ≥8 (β −0.090, −0.110 to −0.069, P  < .001), taking ≥10 medications (β −0.065, −0.085 to −0.046, P  < .001), sarcopenia (β −0.062, −0.080 to −0.043, P  < .001) haemoglobin <100 g/L (β −0.047, −0.085 to −0.010, P  = .012) and pain (β −0.134, −0.152 to −0.117, P  < .001). Smoking and prescription of prednisolone independently associated with problems in self-care and usual activities respectively. Renin–angiotensin system inhibitor (RASi) prescription associated with fewer problems with mobility and usual activities. Conclusion Potentially modifiable factors including obesity, pain, depression, anxiety, anaemia, polypharmacy, smoking, steroid use and sarcopenia associated with poorer HRQoL in this cohort, whilst RASi use was associated with better HRQoL in two dimensions. [ABSTRACT FROM AUTHOR]

A reninoma is a functional tumor of afferent arteriolar juxtaglomerular cells that secretes the enzyme renin, leading to hyperactivation of the renin-angiotensin-aldosterone system. Reninoma is a potentially curable cause of pathological secondary hyperaldosteronism that results in often severe hypertension and hypokalemia. The lack of suppression of plasma renin contrasts sharply with the much more common primary aldosteronism, but diagnosis is often prompted by screening for that condition. The major differential diagnosis of reninoma is renovascular hypertension. Fewer than 200 cases of reninoma have been described. Reninomas have been reported across a broad demographic but have a 2:1 predilection for women, often of childbearing age. Aldosterone receptor blockade, angiotensin-converting enzyme inhibitors, or angiotensin receptor blockers offer effective medical management but are contraindicated in pregnancy, so surgical curative resection is ideal. The current optimal imaging and biochemical workup of reninoma and management approach (ideally, tumor excision with subtotal renal resection) are described. [ABSTRACT FROM AUTHOR]

The renin–angiotensin system (RAS) is dysregulated in Alzheimer's disease (AD). In this study, we have explored the hypothesis that an -age--related imbalance in brain RAS is a trigger for RAS dysregulation in AD. We characterized RAS gene expression in the frontal cortex from (i) a cohort of normal aging (n = 99, age range = 19–96 years) and (ii) a case–control cohort (n = 209) including AD (n = 66), mixed dementia (VaD + AD; n = 50), pure vascular dementia (VaD; n = 42), and age-matched controls (n = 51). The AD, mixed dementia, and age-matched controls were further stratified by Braak tangle stage (BS): BS0–II (n = 48), BSIII–IV (n = 44), and BSV–VI (n = 85). Gene expression was calculated by quantitative PCR (qPCR) for ACE1 , AGTR1 , AGTR2 , ACE2 , LNPEP , and MAS1 using the 2−∆∆Cq method, after adjustment for reference genes (RPL13 and UBE2D2) and cell-specific calibrator genes (NEUN , GFAP , PECAM). ACE1 and AGTR1 , markers of classical RAS signaling, and AGTR2 gene expression were elevated in normal aging and gene expression in markers of protective downstream regulatory RAS signaling, including ACE2 , MAS1 , and LNPEP , were unchanged. In AD and mixed dementia, AGTR1 and AGTR2 gene expression were elevated in BSIII–IV and BSV–VI, respectively. MAS1 gene expression was reduced at BSV–VI and was inversely related to parenchymal Aβ and tau load. LNPEP gene expression was specifically elevated in VaD. These data provide novel insights into RAS signaling in normal aging and dementia. [ABSTRACT FROM AUTHOR]

Context Renal sinus fat (RSF) accumulation is associated with cardiometabolic diseases, such as obesity, diabetes, hypertension, and chronic kidney disease. However, clinical implications of RSF in primary aldosteronism (PA) remain unclear. Objective We aimed to investigate relationships between RSF volume and key cardiometabolic and renin-angiotensin system (RAS) parameters in PA patients and clarify the differences in these relationships between unilateral and bilateral subtypes. Methods We analyzed data obtained from well-characterized PA patients that involved 45 unilateral (median age: 52 years; 42.2% men) and 92 bilateral patients (51 years; 42.4% men). Results RSF volume normalized by renal volume (RSF%) was greater in the unilateral group than in the bilateral group (P <.05). RSF% was greater in men than in women (P <.05). RSF% positively correlated with parameters related to cardiometabolic risk, including age, body mass index, visceral fat volume, creatinine, triglycerides/high-density lipoprotein cholesterol ratio, uric acid, fasting glucose, and C-reactive protein regardless of PA subtypes (all P <.05). Intriguingly, RSF% positively correlated with plasma aldosterone concentration (PAC), aldosterone-to-renin ratio, and intact parathyroid hormone (iPTH) (all P <.05) in bilateral patients but did not correlate with RAS parameters and even showed an opposite trend in unilateral patients. In subgroup analyses by sex, these distinctions became more evident in women. After adjustment for potential confounders, RSF% remained positively correlated with PAC and iPTH in bilateral patients. Conclusion Our results indicate that RSF accumulation is involved in cardiometabolic dysfunction associated with PA. However, there were distinct correlations between RSF volume and RAS parameters according to sex and PA subtypes. [ABSTRACT FROM AUTHOR]

Context Patients with obesity have an overactivated renin-angiotensin-aldosterone system (RAAS) that is associated with essential hypertension. However, the influence of obesity in primary aldosteronism (PA) is unknown. Objective We analyzed the effect of obesity on the characteristics of PA, and the association between obesity and RAAS components. Methods A retrospective study was conducted of the Spanish PA Registry (SPAIN-ALDO Registry), which included patients with PA seen at 20 tertiary centers between 2018 and 2022. Differences between patients with and without obesity were analyzed. Results A total of 415 patients were included; 189 (45.5%) with obesity. Median age was 55 years (range, 47.3-65.2 years) and 240 (58.4%) were male. Compared to those without obesity, patients with obesity had higher rates of diabetes mellitus, chronic kidney disease, obstructive apnea syndrome, left ventricular hypertrophy, prior cardiovascular events, higher means of systolic blood pressure, and required more antihypertensive drugs. Patients with PA and obesity also had higher values of serum glucose, glycated hemoglobin A1c, creatinine, uric acid, and triglycerides, and lower levels of high-density lipoprotein cholesterol. Levels of blood aldosterone (PAC) and renin were similar between patients with and without obesity. Body mass index was not correlated with PAC nor renin. The rates of adrenal lesions on imaging studies, as well as the rates of unilateral disease assessed by adrenal vein sampling or I-6β-iodomethyl-19-norcholesterol scintigraphy, were similar between groups. Conclusion Obesity in PA patients involves a worse cardiometabolic profile, and need for more antihypertensive drugs but similar PAC and renin levels, and rates of adrenal lesions and lateral disease than patients without obesity. However, obesity implicates a lower rate of hypertension cure after adrenalectomy. [ABSTRACT FROM AUTHOR]

This article discusses the potential benefits of inhibiting the renin-angiotensin system (RAS) in preventing hypertension. Hypertension is a global health problem that increases the risk of cardiovascular diseases. The RAS plays a crucial role in the development of hypertension, and pharmacological inhibition of the RAS can lower blood pressure. However, long-term treatment with RAS inhibitors can lead to side effects and poor compliance. The article explores the epigenetic mechanisms behind the long-term effects of RAS inhibition and identifies potential gene targets for future treatments. While animal studies have shown promising results, clinical trials have not yet confirmed the same effects in humans. Further research is needed to fully understand and utilize the potential of RAS inhibition in preventing hypertension. [Extracted from the article]

Cardiovascular disease is the leading cause of death worldwide. Its prevalence is rising due to ageing populations and the increasing incidence of diseases such as chronic kidney disease, obesity, and diabetes that are associated with elevated cardiovascular risk. Despite currently available treatments, there remains a huge burden of cardiovascular disease-associated morbidity for patients and healthcare systems, and newer treatments are needed. The apelin system, comprising the apelin receptor and its two endogenous ligands apelin and elabela, is a broad regulator of physiology that opposes the actions of the renin-angiotensin and vasopressin systems. Activation of the apelin receptor promotes endothelium-dependent vasodilatation and inotropy, lowers blood pressure, and promotes angiogenesis. The apelin system appears to protect against arrhythmias, inhibits thrombosis, and has broad anti-inflammatory and anti-fibrotic actions. It also promotes aqueous diuresis through direct and indirect (central) effects in the kidney. Thus, the apelin system offers therapeutic promise for a range of cardiovascular, kidney, and metabolic diseases. This review will discuss current cardiovascular disease targets of the apelin system and future clinical utility of apelin receptor agonism. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) is the most common primary glomerulonephritis worldwide, with a potentially serious prognosis. At present, management of IgAN is primarily based on therapeutic lifestyle changes, and excellent blood pressure control and maximized supportive treatment with the combination of inhibition of the renin–angiotensin–aldosterone system with either inhibitors of angiotensin-converting enzyme or angiotensin II receptor blockers and inhibitors of sodium-glucose cotransporter-2, and possibly in the future also with endothelin antagonists. Supportive care currently represents the cornerstone of treatment of IgAN. Targeted-release formulation of budesonide should replace systemic corticosteroids in patients with higher proteinuria and active histological lesions. New treatment options are aimed at immunopathogenesis of IgAN including depletion or modulation of Galactose-deficient-Immunoglobulin A1–producing B cells, plasma cells, and the alternate and/or lectin pathway of complement. The exact place of monoclonal antibodies and complement inhibitors will need to be determined. This article reviews potential supportive therapies currently available for patients with IgAN. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy (IgAN) is a common glomerulonephritis partially correlated with mucosal immune system dysfunction. Progressive renal failure occurs in many patients, with about 30–50% of the patients with IgAN developing end-stage kidney disease (ESKD). Many treatments have been used for decades, despite uncertainty about their effectiveness and the ideal dose. Randomised controlled trials reported that systemic glucocorticoids can be an effective treatment for patients with persistent and significant proteinuria despite renin-angiotensin system inhibitors use possibly causing systemic side effects. The primary focus of IgAN management should be based on optimised supportive care, including renin-angiotensin system (RAS) blockade and now SGLT2 inhibitors. The novel targeted-release formulation (TRF) of budesonide has been tested to reduce the adverse events of systemic steroids by delivering the drug to the distal ileum. The local efficacy of TRF-budesonide may represent a novel and promising approach to treating IgAN. Two clinical trials showed that TRF-budesonide could significantly reduce proteinuria and haematuria and possibly preserve renal function while significantly reducing the side effects. However, the limited number of treated patients and the relatively short follow-up suggest caution before considering budesonide superior to the current six-months steroid pulses scheme. Long-term data on the efficacy and safety of TRF budesonide are awaited, together with the design of trials with a head-to-head comparison with systemic steroids before considering TRF-budesonide as the standard of care treatment for IgAN nephropathy. [ABSTRACT FROM AUTHOR]

The management of immunoglobulin A nephropathy, membranous nephropathy, lupus nephritis, anti-neutrophil cytoplasmic antibody–associated vasculitis, C3 glomerulonephritis, autoimmune podocytopathies and other immune-mediated glomerular disorders is focused on two major treatment goals, preventing overall mortality and the loss of kidney function. Since minimizing irreversible kidney damage best serves both goals, the management of immune-mediated kidney disorders must focus on the two central pathomechanisms of kidney function decline, i.e. controlling the underlying immune disease process (e.g. with immunotherapies) and controlling the non-immune mechanisms of chronic kidney disease (CKD) progression. Here we review the pathophysiology of these non-immune mechanisms of CKD progression and discuss non-drug and drug interventions to attenuate CKD progression in immune-mediated kidney disorders. Non-pharmacological interventions include reducing salt intake, normalizing body weight, avoiding superimposed kidney injuries, smoking cessation and regular physical activity. Approved drug interventions include inhibitors of the renin–angiotensin–aldosterone system and sodium–glucose cotransporter-2. Numerous additional drugs to improve CKD care are currently being tested in clinical trials. Here we discuss how and when to use these drugs in the different clinical scenarios of immune-mediated kidney diseases. [ABSTRACT FROM AUTHOR]

Background Although renin–angiotensin–aldosterone system (RAAS) blockers have been considered the primary treatment for patients with Alport syndrome (AS) for a decade, there is no comprehensive review with evidence-based analysis evaluating the effectiveness of RAAS blockers in AS. Methods A systematic review and meta-analysis was performed of published studies that compared outcomes related to disease progression between patients with AS receiving RAAS blockers with those taking non-RAAS treatment. Outcomes were meta-analyzed using the random effects models. Cochrane risk-of-bias, Newcastle-Ottawa Scale and Grading of Recommendations Assessment, Development and Evaluation methodology (GRADE) assessment determined the certainty of evidence. Results A total of eight studies (1182 patients) were included in the analysis. Overall, the risk of bias was low to moderate. Compared with non-RAAS treatment, RAAS blockers could reduce the rate of progression to end-stage kidney disease (ESKD) [four studies; hazard ratio (HR) 0.33, 95% confidence interval (CI) 0.24–0.45; moderate certainty evidence]. After stratified by genetic types, a similar benefit was detected: male X-linked AS (XLAS) (HR 0.32, 95% CI 0.22–0.48), autosomal recessive AS (HR 0.25, 95% CI 0.10–0.62), female XLAS and autosomal dominant AS (HR 0.40, 95% CI 0.21–0.75). In addition, RAAS blockers showed a clear gradient of benefit depending on the stage of disease at the initiation of treatment. Conclusion This meta-analysis suggested that RAAS blockers could be considered as a specific therapy to delay of ESKD for AS with any genetic type, especially at the early stage of the disease, and every further more-effective therapy would be advised to be applied on top of this standard of care. [ABSTRACT FROM AUTHOR]

Background Increased renin angiotensin aldosterone system (RAAS) activity may contribute to excess cardiovascular disease in people with HIV (PWH). We investigated how RAAS blockade may improve myocardial perfusion, injury, and function among well-treated PWH. Methods Forty PWH, on stable ART, without known heart disease were randomized to eplerenone 50 mg PO BID (n = 20) or identical placebo (n = 20) for 12 months. The primary endpoints were (1) myocardial perfusion assessed by coronary flow reserve (CFR) on cardiac PET or stress myocardial blood flow (sMBF) on cardiac MRI or (2) myocardial inflammation by extracellular mass index (ECM i) on cardiac MRI. Results Beneficial effects on myocardial perfusion were seen for sMBF by cardiac MRI (mean [SD]: 0.09 [0.56] vs −0.53 [0.68] mL/min/g; P =.03) but not CFR by cardiac PET (0.01 [0.64] vs −0.07 [0.48]; P =.72, eplerenone vs placebo). Eplerenone improved parameters of myocardial function on cardiac MRI including left ventricular end diastolic volume (−13 [28] vs 10 [26] mL; P =.03) and global circumferential strain (GCS; median [interquartile range 25th–75th]: −1.3% [−2.9%–1.0%] vs 2.3% [−0.4%–4.1%]; P =.03), eplerenone versus placebo respectively. On cardiac MRI, improvement in sMBF related to improvement in global circumferential strain (ρ = −0.65, P =.057) among those treated with eplerenone. Selecting for those with impaired myocardial perfusion (CFR <2.5 and/or sMBF <1.8), there was a treatment effect of eplerenone versus placebo to improve CFR (0.28 [0.27] vs −0.05 [0.36]; P =.04). Eplerenone prevented a small increase in troponin (0.00 [−0.13–0.00] vs 0.00 [0.00–0.74] ng/L; P =.03) without effects on ECM i (0.9 [−2.3–4.3] vs −0.7 [−2.2–−0.1] g/m2; P =.38). CD4+ T-cell count (127 [−38–286] vs −6 [−168–53] cells/μL; P =.02) increased in the eplerenone- versus placebo-treated groups. Conclusions RAAS blockade with eplerenone benefitted key indices and prevented worsening of myocardial perfusion, injury, and function among PWH with subclinical cardiac disease when compared with placebo. Clinical Trials Registration NCT02740179 (https://clinicaltrials.gov/ct2/show/NCT02740179?term=NCT02740179&draw=2&rank=1). [ABSTRACT FROM AUTHOR]

Purpose To evaluate the impact of UI TEAM RX, a pharmacy-based enhanced services and care model, on adherence in patients with hypertension and prescribed a renin-angiotensin system antagonist (RASA). Methods A single-center, retrospective, observational cohort study was conducted in an academic health system, University of Illinois Hospital & Health Sciences System (UI Health). The cohort consisted of patients who utilized UI Health's outpatient pharmacies between May 2016 and December 2018 to fill RASA prescriptions. Patients who were not part of the UI TEAM RX care model served as the control group, while patients enrolled in UI TEAM RX formed the intervention group. The control and intervention groups were matched based on index date, age, gender, and race. The primary outcome was mean change in a rolling 6-month calculation of proportion of days covered (PDC). The secondary outcome was the percentage of patients who had reached their blood pressure goal at follow-up at 12 months. Results Patients receiving UI TEAM RX intervention showed significant improvement in mean PDC at 6-month follow-up compared to control patients (P < 0.01). The proportion of patients with a PDC above 0.8 was higher in the intervention group, but this difference was not statistically significant. There was also a 16.4% increase in the proportion of patients who reached their blood pressure goal in the intervention group, although this increase was not statistically significant. Conclusion The UI TEAM RX program had a statistically significant impact on patients' mean PDCs. An increase in the number of patients reaching their blood pressure goal was also seen. [ABSTRACT FROM AUTHOR]

Non-enzymatic activation of renin via its interaction with prorenin receptor (PRR) has been proposed as a key mechanism of local renin–angiotensin system (RAS) activation. The presence of renin and angiotensinogen has been reported in the rostral ventrolateral medulla (RVLM). Overactivation of bulbospinal neurons in the RVLM is linked to hypertension (HTN). Previous studies have shown that the brain RAS plays a role in the pathogenesis of the deoxycorticosterone (DOCA)-salt HTN model. Thus, we hypothesized that PRR in the RVLM is involved in the local activation of the RAS, facilitating the development of DOCA-salt HTN. Selective PRR ablation targeting the RVLM (PRRRVLM-Null mice) resulted in an unexpected sex-dependent and biphasic phenotype in DOCA-salt HTN. That is, PRRRVLM-Null females (but not males) exhibited a significant delay in achieving maximal pressor responses during the initial stage of DOCA-salt HTN. Female PRRRVLM-Null subsequently showed exacerbated DOCA-salt-induced pressor responses during the "maintenance" phase with a maximal peak at 13 d on DOCA-salt. This exacerbated response was associated with an increased sympathetic drive to the resistance arterioles and the kidney, exacerbated fluid and sodium intake and output in response to DOCA-salt, and induced mobilization of fluids from the intracellular to extracellular space concomitant with elevated vasopressin. Ablation of PRR suppressed genes involved in RAS activation and catecholamine synthesis in the RVLM but also induced expression of genes involved in inflammatory responses. This study illustrates complex and sex-dependent roles of PRR in the neural control of BP and hydromineral balance through autonomic and neuroendocrine systems. Graphical abstract Graphical Abstract [ABSTRACT FROM AUTHOR]

Background The effects of the renin–angiotensin–aldosterone system in cardiovascular system have been described based on small studies. The aim of this study was to evaluate the relationship between aldosterone and plasma renin activity (PRA) and cardiovascular structure and function. Methods We studied a random sample of Multi-Ethnic Study of Atherosclerosis participants who had aldosterone and PRA blood assays at 2003–2005 and underwent cardiac magnetic resonance at 2010. Participants taking angiotensin-converting enzyme inhibitors or angiotensin receptor blockers were excluded. Results The aldosterone group was composed by 615 participants, mean age 61.6 ± 8.9 years, while the renin group was 580 participants, mean age 61.5 ± 8.8 years and both groups had roughly 50% females. In multivariable analysis, 1 SD increment of log-transformed aldosterone level was associated with 0.07 g/m2 higher left ventricle (LV) mass index (P = 0.04) and 0.11 ml/m2 higher left atrium (LA) minimal volume index (P < 0.01). Additionally, higher log-transformed aldosterone was associated with lower LA maximum strain and LA emptying fraction (P < 0.01). Aldosterone levels were not significantly associated with aortic measures. Log-transformed PRA was associated with lower LV end diastolic volume index (β standardized = 0.08, P = 0.05). PRA levels were not significantly associated with LA and aortic structural or functional differences. Conclusions Higher levels of aldosterone and PRA are associated with concentric LV remodeling changes. Moreover, aldosterone was related to deleterious LA remodeling changes. [ABSTRACT FROM AUTHOR]

Since the 1950s, sodium polystyrene sulphonate (SPS) has been the dominant cation exchange agent prescribed for hyperkalaemia. Clinicians have had plenty of time to learn of SPS's advantages and limitations. The demands of drug regulatory agencies regarding the incorporation of medications into the market were not so stringent then as they are today, and the efficacy and safety of SPS have been questioned. In recent years, two novel cation exchangers, patiromer and sodium zirconium cyclosilicate, have received (or are in the process of receiving) regulatory approval in multiple jurisdictions globally, after scrutiny of carefully conducted trials regarding their short-term and mid-term efficacy. In this debate, we defend the view that all three agents are likely to have similar efficacy. Harms are much better understood for SPS than for newer agents, but currently there are no data to suggest that novel agents are safer than SPS. Drug choices need to consider costs, access and numbers-needed-to-treat to prevent clinically important events; for potassium exchangers, we need trials directly examining clinically important events. [ABSTRACT FROM AUTHOR]

'Old-generation' potassium (K) binders [i.e. sodium (SPS) and calcium polystyrene sulfonate] are widely used, but with substantial heterogeneity across countries to treat hyperkalaemia (HK). However, there are no randomized data to support their chronic use to manage HK, nor have they been shown to have a renin–angiotensin–aldosterone system inhibitor (RAASi)-enabling effect. These compounds have poor tolerability and an unpredictable onset of action and magnitude of K lowering. Furthermore, SPS may induce fluid overload, owing to the fact that it exchanges K for sodium. Its use has also been associated with colonic necrosis, as emphasized by a black box warning from the US Food and Drug Administration. In contrast, two new K binders, patiromer and sodium zirconium cyclosilicate, have been shown to be safe and well tolerated for chronic management of HK, thereby enabling RAASi optimization, as acknowledged by the latest international cardiorenal guidelines. In view of the lack of reliable evidence regarding the efficacy and safety of the old-generation K binders compared with the placebo-controlled randomized and real-word evidence demonstrating the safety, efficacy and RAASi-enabling effect of the new K binders, clinicians should now use these new K binders to treat HK (primum non nocere !). [ABSTRACT FROM AUTHOR]

Background Individuals with chronic kidney disease (CKD) hospitalized with hyperkalemia are at risk of hyperkalemia recurrence and re-hospitalization. We present the rationale and design of CONTINUITY, a study to examine the efficacy of continuing sodium zirconium cyclosilicate (SZC)—an oral, highly selective potassium (K+) binder—compared with standard of care (SoC) on maintaining normokalemia and reducing re-hospitalization and resource utilization among participants with CKD hospitalized with hyperkalemia. Methods This Phase 4, randomized, open-label, multicenter study will enroll adults with Stage 3b–5 CKD and/or estimated glomerular filtration rate <45 mL/min/1.73 m2, within 3 months of eligibility screening, hospitalized with a serum potassium (sK+) level of >5.0–≤6.5 mmol/L, without ongoing K+ binder treatment. The study will include an in-hospital phase, where participants receive SZC for 2–21 days, and an outpatient (post-discharge) phase. At discharge, participants with sK+ 3.5–5.0 mmol/L will be randomized (1:1) to SZC or SoC and monitored for 180 days. The primary endpoint is the occurrence of normokalemia at 180 days. Secondary outcomes include incidence and number of hospital admissions or emergency department visits both with hyperkalemia as a contributing factor, and renin–angiotensin–aldosterone system inhibitor down-titration. The safety and tolerability of SZC will be evaluated. Ethics approval has been received from all relevant ethics committees. Enrollment started March 2022 and the estimated study end date is December 2023. Conclusions This study will assess the potential of SZC versus SoC in managing people with CKD and hyperkalemia post-discharge. Trial registration ClinicalTrials.gov identifier: NCT05347693; EudraCT: 2021-003527-14, registered on 19 October 2021. [ABSTRACT FROM AUTHOR]

Background In March and April 2020, medical societies published statements recommending continued use of renin–angiotensin system (RAS) inhibitors despite theoretical concerns that these medications could increase COVID-19 severity. Determining if patients discontinued RAS inhibitors during the COVID-19 pandemic could inform responses to future public health emergencies. Methods We analyzed claims data from US adults with health insurance in the Marketscan database. We identified patients who filled a RAS inhibitor and were persistent, defined by not having a ≥30-day gap without medication available, and high adherence, defined by having medication available on ≥80% of days, from March 2019 to February 2020. Among these patients, we estimated the proportion who discontinued their RAS inhibitor (i.e. had ≥30 consecutive days without a RAS inhibitor available to take) between March and August 2020. For comparison, we estimated the proportion of patients that discontinued a RAS inhibitor between March and August 2019 after being persistent with high adherence from March 2018 to February 2019. Results Among 816,380 adults who were persistent and adherent to a RAS inhibitor from March 2019 to February 2020, 10.8% discontinued this medication between March and August 2020. Among 822,873 adults who were persistent and adherent to a RAS inhibitor from March 2018 to February 2019, 11.7% discontinued this medication between March and August 2019. The multivariable-adjusted relative risk for RAS inhibitor discontinuation in 2020 vs. 2019 was 0.94 (95% CI 0.93–0.95). Conclusions There was no evidence of an increase in RAS inhibitor discontinuation during the early stage of the COVID-19 pandemic. [ABSTRACT FROM AUTHOR]

Background: Most antihypertensives can induce dermal photosensitivity, which may increase melanoma risk. However, corroborating evidence is limited. We examined the associations between use of antihypertensives and melanoma risk.Methods: A nationwide nested case-control study was conducted using data from the Cancer Registry of Norway, the National Registry and the Norwegian Prescription Database in 2004-15. Ten controls were randomly selected for each melanoma case, matched on sex and birth year. The study included 12 048 cases and 117 895 controls. We estimated rate ratios (RRs) with 95% confidence intervals (CIs). All analyses were adjusted for ambient ultraviolet radiation (UVR). We additionally performed active comparator analyses, and sensitivity analyses by only including new users, distinguishing between exclusive and mixed users, allowing for different latency periods, and subgroup analyses by melanoma subtype and clinical stage.Results: Compared with non-use, we observed a slightly increased melanoma risk in users of diuretics (RR 1.08, CI 1.01-1.15), calcium-channel blockers (RR 1.10, CI 1.04-1.18) and drugs affecting the renin-angiotensin system (RR 1.10, CI 1.04-1.16), but not for beta blockers (RR 0.97, CI 0.92-1.03). We found no heterogeneity of associations by melanoma subtype or clinical stage and no dose-response relationship between the cumulative defined daily doses (DDDs) and melanoma. No interaction was found between cumulative DDDs and ambient UVR.Conclusions: Weak associations, with lack of a dose-response relationship and lack of interactions with ambient UVR, in the DDD analysis in this nationwide study do not support a causal relationship between antihypertensives and melanoma risk. [ABSTRACT FROM AUTHOR]

Renin–angiotensin–aldosterone system inhibitors (RAASi) and mineralocorticoid receptor antagonists (MRAs) are important interventions to improve outcomes in patients with chronic kidney disease and heart failure, but their use is limited in some patients by the development of hyperkalemia. The risk of hyperkalemia may differ between agents, with one trial showing lower risk of hyperkalemia with the novel non-steroidal MRA finerenone compared with steroidal MRA spironolactone. Novel potassium binders, including patiromer and sodium zirconium cyclosilicate, are available interventions to manage hyperkalemia and enable continuation of RAASi and MRAs in patients who could benefit from these treatments. These agents bind free potassium ions in the lumen of the gastrointestinal tract to prevent the absorption of dietary potassium and increase potassium secretion. Several studies showed that potassium binders are effective compared with placebo for preventing hyperkalemia or steroidal MRA discontinuation, but none has evaluated whether this strategy impacts clinically important endpoints such as cardiovascular events. Due to this and other limitations related to cost, clinical availability, pill burden and patient selection, alternative potential strategies to mitigate hyperkalemia may be more practical. Conservative strategies include increased monitoring and use of loop or thiazide diuretics to increase urinary potassium excretion. Non-steroidal MRAs may have a lower risk of hyperkalemia than steroidal MRAs and have stronger anti-inflammatory and anti-fibrotic effects with resultant reduced risk of kidney disease progression. Sodium-glucose cotransporter-2 inhibitors also decrease hyperkalemia risk in patients on MRAs and decrease cardiovascular events and kidney disease progression. These may be better first-line interventions to obviate the need for potassium binders and offer additional benefits. [ABSTRACT FROM AUTHOR]

Hypertension is one of the major health problems leading to the development of cardiovascular diseases. Despite a rapid expansion in global hypertension prevalence, molecular mechanisms leading to hypertension are not fully understood largely due to the complexity of pathogenesis involving several factors. Salt intake is recognized as a leading determinant of blood pressure, since reduced dietary salt intake is related to lower morbidity and mortality, and hypertension in relation to cardiovascular events. Compared with salt-resistant populations, salt-sensitive individuals exhibit high sensitivity in blood pressure responses according to changes in salt intake. In this setting, the kidney plays a major role in the maintenance of blood pressure under the hormonal control of the renin–angiotensin–aldosterone system. In the present review, we summarize the current overview on the molecular mechanisms for modulation of blood pressure associated with renal ion channels/transporters including sodium–hydrogen exchanger isoform 3 (NHE3), Na+-K+-2Cl– cotransporter (NKCC2), sodium–chloride cotransporter (NCC), epithelial sodium channel (ENaC) and pendrin expressed in different nephron segments. In particular, recent studies on experimental animal models with deletion of renal ion channels led to the identification of several crucial physiological mechanisms and molecules involved in hypertension. These findings could further provide a potential for novel therapeutic approaches applicable on human patients with hypertension. [ABSTRACT FROM AUTHOR]

Open in new tab Download slide OBJECTIVES Current clinical guidelines have no specific recommendations regarding medical therapy after surgical aortic valve replacement in patients with aortic regurgitation (AR). We studied the association between medical therapy with renin–angiotensin system (RAS) inhibitors, statins and β-blockers and long-term major adverse cardiovascular events. METHODS All patients undergoing valve replacement due to AR between 2006 and 2017 in Sweden and alive 6 months after discharge were included. Time-dependent multivariable Cox regression models adjusted for age, sex, patient characteristics, comorbidities, other medications and year of surgical aortic valve replacement were used. Primary outcome was a composite of all-cause mortality, myocardial infarction and stroke. Subgroup analyses based on age, sex, heart failure, low ejection fraction, hyperlipidaemia and hypertension were performed. RESULTS A total of 2204 patients were included [median follow-up 5.0 years (range 0.0–11.5)]. At baseline, 68% of the patients were dispensed RAS inhibitors, 80% β-blockers and 35% statins. Dispense of RAS inhibitors and β-blockers declined over time, especially during the first year after baseline, while dispense of statins remained stable. Treatment with RAS inhibitors or statins was associated with a reduced risk of the primary outcome [adjusted hazard ratio (aHR) 0.71, 95% confidence interval (CI) 0.57–0.87 and aHR 0.78, 95% CI 0.62–0.99, respectively]. The results were consistent in subgroups based on age, sex and comorbidities. β-Blocker treatment was associated with an increased risk for the primary outcome (aHR 1.35, 95% CI 1.07–1.70). CONCLUSIONS The results indicate a potential beneficial association of RAS inhibitors and statins as part of a secondary preventive treatment regime after aortic valve replacement in patients with AR. The role of β-blockers needs to be further investigated. [ABSTRACT FROM AUTHOR]

Klotho is a transmembrane anti-ageing protein that exists in three forms, i.e. α-Klotho, β-Klotho and γ-Klotho, with distinct organ-specific expression and functions in the body. Here we focus on α-Klotho (hereafter Klotho), abundantly expressed by the distal and proximal convoluted tubules of the kidney. A significant decline in systemic and renal Klotho levels is a new hallmark for kidney disease progression. Emerging research portrays Klotho as a promising diagnostic and therapeutic target for diabetic and non-diabetic kidney disease. Even so, the underlying mechanisms of Klotho regulation and the strategies to restore its systemic and renal levels are still lacking. Angiotensin-converting enzyme inhibitors and/or angiotensin receptor blockers are the current standard of care for kidney diseases, but the molecular mechanisms for their nephroprotective action are still ambiguous. Moreover, endoplasmic reticulum (ER) stress also plays a crucial role in kidney disease progression. Few studies have claimed that the renin–angiotensin–aldosterone system (RAAS) has a direct relation with ER stress generation and vice versa in kidney disease. Interestingly, RAAS and ER stress modulation are associated with Klotho regulation in kidney disease. Here we focus on how the RAAS and ER stress connect with Klotho regulation in kidney disease. We also discuss Klotho and ER stress in an alliance with the concept of haemodynamic and metabolic overload in kidney disease. In addition, we highlight novel approaches to implement Klotho as a therapeutic target via RAAS and ER stress modulation for the treatment of diabetic and non-diabetic kidney diseases. [ABSTRACT FROM AUTHOR]

Background Hypertension (HT) is highly prevalent and a major risk factor for cardiovascular disease. Over 42% of Portuguese adults have HT. Even though the benefits of antihypertensive (AHT) drugs have been demonstrated, HT control remains inadequate. One major reason is that patients often fail to take their medications as prescribed. This paper aims to determine primary adherence to AHT therapy in newly diagnosed and treated hypertensive patients in Primary Health Care (PHC) units of Lisbon and Tagus Valley Health Region. Methods This study reports data from a population-based, retrospective, cohort study from patients diagnosed with HT in PHC units of Lisbon and Tagus Valley Region from 1 January to 31 March 2011, with no prior use of AHT drugs. Primary adherence rate was expressed as number of claims records/total number of prescriptions records. Data were collected from SIARS for each patient during a 2-year period. Results Overall primary adherence rate was 58.5%, increasing with age. Rates were higher for men, living in the Lisbon Metropolitan Area and diagnosed with uncomplicated HT. Drugs acting on the renin–angiotensin system had the highest rates, increasing for fixed-dose combinations and diminishing with the increase of cost for the patient. Conclusions Overall, almost 1 out of 2 prescribed AHT drugs were not dispensed. Until this study, little was known in Portugal about primary adherence. Our findings imply that the potential benefits of AHT therapy cannot be fully realized in this population. [ABSTRACT FROM AUTHOR]

Context The SARS-CoV-2 virus is dependent on components of the renin-angiotensin-aldosterone system for infectivity. Primary aldosteronism (PA) is a form of secondary hypertension mediated by autonomous aldosterone production. The intersection of COVID-19 and PA, both which may involve components of the renin-angiotensin-aldosterone system, remains unknown. Methods We assessed PA as a risk factor for COVID-19 infection and compared management, severity of disease, and outcomes during COVID-19 with a matched population of patients with essential hypertension (EH) by conducting a retrospective observational cohort study. Results Of the patients with PA, 81 had a negative PCR test for COVID-19, whereas 43 had a documented positive PCR test for COVID-19. Those patients with PA who tested positive for COVID-19 tended to be female (P =.08) and the majority of those with COVID-19 infection identified as non-White race (P =.02) and Hispanic ethnicity (P =.02). In a subanalysis, 24-hour urine aldosterone on initial PA diagnosis tended to be higher those in the PA group who developed COVID-19 compared with those in the PA group who did not develop COVID-19 [median (interquartile range): 36.5 (16.9, 54.3) vs 22.0 (15.8, 26.8) mcg, P =.049] and was an independent predictor of COVID-19 infection controlling for sex, race, and ethnicity. Angiotensin-converting enzyme inhibitor, angiotensin II receptor blocker, and mineralocorticoid receptor antagonist use did not differ between those patients with PA who did and did not have COVID-19 infection. Comparing those patients with PA and matched patients with EH (n = 286) who were COVID-19 PCR positive, there was a significantly higher incidence of cardiovascular complications (12 vs 2%, P =.004) in the PA vs EH group. Conclusion These data begin to inform us as to whether PA should be a newly identified subpopulation at risk for COVID-19-related cardiovascular disease sequelae. [ABSTRACT FROM AUTHOR]

The renin-angiotensin system (RAS) is an essential endocrine system with roles in electrolyte balance, blood volume, and blood pressure. While the canonical RAS exerts systemic vasoregulatory effects through steps involving hepatic, renal, and pulmonaryderived compounds, there is also evidence of localized, independently acting RAS in organs such as the liver and kidney. Further, modulations in RAS resulting from fetal hypothyroidism have previously been documented, although the temporal specificity of this endocrine interaction is not well-characterized. Thus, the objective of the current study was to examine the timedependency of modulations in local hepatic and renal RAS in a porcine model of fetal hypothyroidism. To achieve this, pregnant gilts (n = 24) were divided evenly into either a control (CON) or methimazole (MMI) treatment group, with the MMI group receiving 5 mg kg-1 d-1 of oral MMI treatment and the CON group receiving an equivalent sham carrier. Each group was further divided into four timepoints (n = 3/treatment at each timepoint), with treatment beginning on d 34, 45, 55, or 65 of gestation. After 21 d of treatment, and at d 55, 66, 76, and 86, respectively, the gilts were humanely euthanized, blood samples taken from all fetuses (n = 340), and thyroid, liver (LVR), and kidney (KID) collected from a subset of four fetuses per litter (n = 96). Confirmation of fetal hypothyroidism in the MMI group was accomplished via histological assessment of the thyroid and measurement of circulating thyroxine (T4) concentrations. Each MMI-treated fetus (n = 96) subset showed evidence of goitrous thyroid histology, with the absence of healthy eosinophilic colloid indicating successful disruption of the fetal hypothalamic-pituitary-thyroid axis. T4 assays performed on a similar subset of n = 96 fetuses showed that MMI treatment significantly reduced T4 concentrations within each timepoint relative to CON (P < 0.001 at all timepoints). Following confirmation of hypothyroidism, RNA was extracted from the fetal LVR and KID samples to allow for gene expression analysis by qPCR. Ct values were normalized, fold changes calculated using the 2-ΔΔCt method, and differences within timepoint determined using a Wilcoxon signed-rank test. AGT, the precursor to all bioactive RAS peptides, was significantly downregulated in LVR at d 66 (P = 0.014) and 76 (P < 0.001). ACE was significantly upregulated at d 76 in both LVR (P = 0.037) and KID (P = 0.005). No significant changes were observed for ACE2 in either tissue, or for renal REN. Finally, AGTR1, the receptor that mediates RAS effects, was significantly downregulated at d 55 in KID (P < 0.001) and d 76 in LVR (P = 0.023), while also being upregulated at d 86 in LVR (P = 0.033). Collectively, these results show that fetal hypothyroidism modulates RAS function in a gestational age-dependent manner, which may alter fetal development and subsequent postnatal physiology. [ABSTRACT FROM AUTHOR]

This document is a response to a letter from Tapia-Castillo et al regarding a previous commentary. The authors discuss the expression of 11β-hydroxysteroid dehydrogenase type 1 (11βHSD1) in liver and visceral adipose tissue in extremely obese subjects. They found that there was an overexpression of 11βHSD1 in the liver, but peripheral cortisol levels remained normal due to hepatic metabolism. The authors also discuss the inflammatory effect of high amounts of aldosterone in mononuclear leukocytes (MNLs) and the role of NAD and NADP in regulating 11βHSD1 function. They conclude that the regulation of cortisol and cortisone levels is complex and involves various factors. [Extracted from the article]

This article explores the relationship between vascular insulin resistance and free fatty acids (FFAs) in the context of conditions like obesity, hypertension, and type 2 diabetes mellitus. Vascular dysfunction, characterized by impaired endothelial function and changes in large arteries, is associated with cardiovascular disease. The study by Love et al. investigates the interconnectedness of vascular insulin resistance across vessel sizes and finds that elevated FFAs contribute to endothelial dysfunction and panarterial insulin resistance. The study's comprehensive assessment of vascular responses and its crossover design contribute to the precision of the findings. Further research is needed to explore the long-term effects of reducing FFAs on vascular insulin resistance and potential therapeutic interventions. [Extracted from the article]

A study funded by the United Kingdom National Institute for Health Research and Medical Research Council examined whether discontinuing renin-angiotensin system (RAS) inhibitors would affect the estimated glomerular filtration rate (eGFR) in patients with severe chronic kidney disease (CKD). The study found that discontinuing RAS inhibitors did not significantly impact eGFR or the development of end-stage kidney disease. The study had limitations, such as a short follow-up duration and a predominantly white male study population, but it suggests that stopping RAS inhibitors may not provide any benefits in severe CKD. Further research is needed to explore the effects of RAS inhibitors in patients with concomitant cardiovascular diseases. [Extracted from the article]

Background Chronic kidney disease (CKD) is a complication of type 2 diabetes (T2D) with high morbidity and mortality. The prevalence of CKD in T2D is increasing due to rising numbers of persons with T2D. Multiple clinical trials have been conducted testing novel therapies to reduce the progression of CKD, cardiovascular morbidity, in particular hospitalization for heart failure, and mortality. Results of these clinical trials have informed guidelines for the management of CKD in T2D. Methods The epidemiology of CKD in T2D and the process of guideline writing, including data gathering, grading and consensus development, were reviewed. Recent guidelines for the management of CKD in T2D that include recent renal outcome clinical trials are reported, along with supporting evidence. Results All current guidelines recommend annual screening for CKD, control of blood pressure and glucose, although the target levels and background therapy recommendations vary. Renin–angiotensin system (RAS) inhibition is uniformly recommended. Sodium-glucose cotransporter-2 (SGLT2) inhibition with proven agents is recommended by all guidelines, with minor variations in suggested estimated glomerular filtration rate and albuminuria levels. Finerenone, the first nonsteroidal mineralocorticoid receptor antagonist with renal outcome data, is recommended by the most recent guideline available. Conclusions Current guidelines continue to recommend screening for CKD, blood pressure control using RAS inhibition as first-line therapy, and glucose control. SGLT2 inhibition and finerenone are recent additions to current guidelines to improve CKD outcomes in T2D, based on robust clinical trial data. [ABSTRACT FROM AUTHOR]

Similarly, higher body mass index was found to associate independently with increased susceptibility to SARS-CoV-2 infection and COVID-19, and higher titres of anti-S antibodies following COVID-19 and vaccination against SARS-CoV-2.[7],[9],[10] The mechanisms underlying these associations are also worthy of investigation. Follow-up online questionnaires capturing incident symptoms of COVID-19 and other acute respiratory infections, incident swab test-confirmed COVID-19, doses of SARS-CoV-2 vaccine received and quality of life are completed at monthly intervals. A major strength is that COVIDENCE UK was established specifically in response to the SARS-CoV-2 outbreak; thus, in contrast to previously established cohort studies, our questionnaires were tailored to capture potential risk factors and incident symptoms of COVID-19. Key Features The COVIDENCE UK cohort was established to investigate risk factors for, and impacts of, COVID-19 in UK residents aged >=16 years. [Extracted from the article]

Background Angiotensin-converting enzyme 2 (ACE2), the receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), is highly expressed in the kidneys. Beyond serving as a crucial endogenous regulator of the renin–angiotensin system, ACE2 also possess a unique function to facilitate amino acid absorption. Our observational study sought to explore the relationship between urine ACE2 (uACE2) and renal outcomes in coronavirus disease 2019 (COVID-19). Methods In a cohort of 104 patients with COVID-19 without acute kidney injury (AKI), 43 patients with COVID-19-mediated AKI and 36 non-COVID-19 controls, we measured uACE2, urine tumour necrosis factor receptors I and II (uTNF-RI and uTNF-RII) and neutrophil gelatinase-associated lipocalin (uNGAL). We also assessed ACE2 staining in autopsy kidney samples and generated a propensity score–matched subgroup of patients to perform a targeted urine metabolomic study to describe the characteristic signature of COVID-19. Results uACE2 is increased in patients with COVID-19 and further increased in those that developed AKI. After adjusting uACE2 levels for age, sex and previous comorbidities, increased uACE2 was independently associated with a >3-fold higher risk of developing AKI [odds ratio 3.05 (95% confidence interval 1.23‒7.58), P  = .017]. Increased uACE2 corresponded to a tubular loss of ACE2 in kidney sections and strongly correlated with uTNF-RI and uTNF-RII. Urine quantitative metabolome analysis revealed an increased excretion of essential amino acids in patients with COVID-19, including leucine, isoleucine, tryptophan and phenylalanine. Additionally, a strong correlation was observed between urine amino acids and uACE2. Conclusions Elevated uACE2 is related to AKI in patients with COVID-19. The loss of tubular ACE2 during SARS-CoV-2 infection demonstrates a potential link between aminoaciduria and proximal tubular injury. [ABSTRACT FROM AUTHOR]

Age-related declines in physical and cognitive function can have tremendous, negative impacts on health span and quality of life. Therefore, we investigated the potential of utilizing a probiotic treatment to target the renin–angiotensin system (RAS) in conjunction with moderate exercise to ameliorate age-related declines in cognitive and physical function in aged rats. Herein we utilized a genetically modified angiotensin (1–7), which activates a "complementary" arm of the RAS through binding Mas (AT7) receptors. This process induces several beneficial physiologic effects, including decreased inflammation and enhanced physical/cognitive function. Thus, in this short research report, we suggest the efficacy of this Ang(1-7) releasing Lactobacillus paracasei (LPA) as either an alternative strategy to exercise, or more likely as an adjuvant to moderate exercise, for the prevention of both physical and cognitive decline especially in female rats. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) develops in ∼40% of patients with diabetes and is the most common cause of chronic kidney disease (CKD) worldwide. Patients with CKD, especially those with diabetes mellitus, are at high risk of both developing kidney failure and cardiovascular (CV) death. The use of renin–angiotensin system (RAS) blockers to reduce the incidence of kidney failure in patients with DKD dates back to studies that are now ≥20 years old. During the last few years, sodium–glucose co-transporter-2 inhibitors (SGLT2is) have shown beneficial renal effects in randomized trials. However, even in response to combined treatment with RAS blockers and SGLT2is, the renal residual risk remains high with kidney failure only deferred, but not avoided. The risk of CV death also remains high even with optimal current treatment. Steroidal mineralocorticoid receptor antagonists (MRAs) reduce albuminuria and surrogate markers of CV disease in patients already on optimal therapy. However, their use has been curtailed by the significant risk of hyperkalaemia. In the FInerenone in reducing kiDnEy faiLure and dIsease prOgression in DKD (FIDELIO-DKD) study comparing the actions of the non-steroidal MRA finerenone with placebo, finerenone reduced the progression of DKD and the incidence of CV events, with a relatively safe adverse event profile. This document presents in detail the available evidence on the cardioprotective and nephroprotective effects of MRAs, analyses the potential mechanisms involved and discusses their potential future place in the treatment of patients with diabetic CKD. [ABSTRACT FROM AUTHOR]

Background Hyperkalemia (HK) is a frequent condition in patients with chronic kidney disease (CKD) that is associated with high morbidity and mortality. Patiromer has recently been introduced as a potassium binder. Data on patiromer use in patients with CKD in the real-world setting in Europe are lacking. We describe time to discontinuation and changes in serum potassium levels among German CKD stage 3–5 patients starting patiromer. Methods Duration of patiromer use was estimated by Kaplan–Meier curve, starting at patiromer initiation and censoring for death, dialysis, transplant or loss to follow-up. Serum potassium levels and renin–angiotensin–aldosterone system inhibitor (RAASi) use are described at baseline and during follow-up, restricted to patients remaining on patiromer. Results We identified 140 patiromer users within our analysis sample [81% CKD stage 4/5, 83% receiving RAASi, and median K+ 5.7 (5.4, 6.3) mmol/L]. Thirty percent of patiromer users had prior history of polystyrene sulfonate use. Overall, 95% of patiromer users stayed on treatment past 1 month, with 53% continuing for over a year. Mean serum potassium levels decreased after patiromer initiation and remained stable under treatment during follow-up (up to 180 days). Among these patients, 73%–82% used RAASis during the time periods before and after patiromer initiation, with no obvious trend indicating discontinuation. Conclusion Real-world evidence of patiromer use in Germany shows that, in line with what has been observed in clinical trials, patients on patiromer have a reduction in serum potassium when used long-term. Moreover, most patients on patiromer do not discontinue treatment prior to 1 year after initiation. [ABSTRACT FROM AUTHOR]

Muntner I et al. i in a large cohort study evaluated indirectly, the RAS Inhibitor medication controversy, whether it led to a significant number of patients discontinuing RAS inhibitor treatment.[22] The findings are important to inform responses to future public health emergencies. Despite the controversy at the beginning of the COVID-19 pandemic, overwhelming scientific evidence has shown RAS inhibitors to be safe and beneficial in COVID-19. [Extracted from the article]