Renin-angiotensin System Inhibitors Research Articles

COmbinatioN effect of FInerenone anD EmpaglifloziN in participants with chronic kidney disease and type 2 diabetes using a UACR Endpoint (CONFIDENCE) trial: Baseline clinical characteristics.

Finerenone, a selective nonsteroidal MRA, and SGLT2is both reduce CKD progression and improve kidney/CV outcomes. The CONFIDENCE study (NCT05254002; EudraCT 2021-003037-11) hypothesis is that early combination of finerenone and empagliflozin, a SGLT2i, is superior to either drug alone in reducing UACR over 6 months. CONFIDENCE is an ongoing, fully enrolled, randomized, controlled, double-blind, multicentre phase 2 clinical trial in adults (≥18 years of age) with CKD and T2D, eGFR of 30 to 90 ml/min/1.73 m2, and UACR of ≥100 to <5000 mg/g. Participants taking the clinically maximum tolerated dose of a renin-angiotensin system inhibitor for >1 month at screening were eligible. Participants were randomized 1:1:1 to once daily finerenone plus empagliflozin, finerenone plus placebo, or empagliflozin plus placebo; doses were 10 mg once daily for empagliflozin and 10 or 20 mg once daily for finerenone, depending on eGFR at baseline. Randomization was stratified by eGFR (< or ≥60 ml/min/1.73 m2) and UACR (≤ or >850 mg/g). The primary efficacy outcome is the relative change in UACR from baseline at Day 180. There were 818 participants randomized across 143 sites from 14 countries between July 2022 and August 2024. Mean eGFR (ml/min/1.73 m2 [SD]) was 54.2 (17.1). Median UACR (mg/g [IQR]) was 583 (292, 1140). Mean HbA1c (% [SD]) was 7.3 (1.2). Mean systolic/diastolic BP (mmHg) was 135.2/77.3. GLP-1 RAs and insulin were used by 182 (23%) and 313 (39%) participants, respectively. Atherosclerotic CV disease, diabetic retinopathy, and a history of heart failure were present in 223 (28%), 126 (16%), and 30 (4%) participants, respectively. The CONFIDENCE trial enrolled a diverse population with CKD and T2D and will determine the impact of simultaneous initiation of combination finerenone and a SGLT2i versus individual therapy on potentially mitigating the progression of CKD in people with T2D. Trial registration number: Clinicaltrials.gov NCT05254002; EudraCT 2021-003037-11.

Design considerations for future renoprotection trials in the era of multiple therapies for chronic kidney disease.

Nephrology has benefited from conducting increasingly large high-quality trials in the last 5-10 years. In addition to the long-standing known benefits of renin-angiotensin system inhibitors, we now have multiple pharmacotherapies that provide kidney and/or cardiovascular protection for certain types of patient with chronic kidney disease (CKD). These include sodium-glucose co-transporter 2 inhibitors (SGLT2i), a non-steroidal mineralocorticoid receptor antagonist and a glucagon-like peptide-1 receptor agonist. Trials of SGLT2i have had particularly important impact, as wide eligibility criteria in pivotal trials have enabled safety and efficacy across a wide range of causes of CKD to be demonstrated. These findings support the concept of final common pathways of CKD progression and should encourage similar trial designs recruiting broad ranges of patients at risk of CKD progression. This is important as these new drugs do not completely arrest CKD progression nor do they mitigate the full excess of cardiovascular disease. In the current era of multiple therapies to manage risk of CKD progression, trial design and conduct also need to consider new challenges. These include falling event rates, establishing standard of care for participants pre-randomization and improving the inclusion of trial participants understudied in previous trials. Streamlining trial design and conduct and reducing participation burden for patients and clinicians is increasingly important to facilitate larger sample sizes and to optimize adherence to study interventions and follow-up. Potential other solutions include maintaining a focus on wide generalizability (to include understudied patient groups) and empowering patients to volunteer for trials (through public and patient involvement and large-scale invitation methods), as well as innovations in trial design (including use of pre-randomization run-in periods to implement standard of care and factorial or platform trials to assess multiple treatments simultaneously).

Urinary Dickkopf-related protein 3 as a novel biomarker for kidney function decline in children with Alport syndrome.

Chronic kidney disease (CKD) seriously affects the well-being and shortens the life expectancy of children and adolescents, but its progression is challenging to predict. Therefore, there is an urgent need for biomarkers that can identify children at risk of faster CKD progression. Alport syndrome (AS) is the most common monogenetic glomerular kidney disease. Urinary Dickkopf-related protein 3 (DKK3) is associated with a decline in estimated glomerular filtration rate (eGFR) in adults and children with advanced CKD. However, its potential for early detection of CKD and its prognostic value in children with AS remain unknown. Urine samples from 49 children enrolled in the EARLY PRO-TECT Alport trial were analyzed to evaluate whether DKK3 could identify children with AS to be at risk for faster CKD progression. DKK3 levels in patients with AS were higher than those of healthy individuals reported in the literature. DKK3 levels were more elevated in patients with later stages of AS. Furthermore, children who were not treated with renin angiotensin system inhibitors (RASi) had higher DKK3 levels than treated children. Children with above-average DKK3 levels were more likely to have increased albuminuria after 2years of follow-up than children with below-average DKK3 levels. Urinary DKK3 is significantly elevated in children at early stages of AS. There was a potential association between higher DKK3 levels, worsening albuminuria, and a decline in kidney function. These findings suggest that DKK3 may be a prognostic marker for predicting the risk of kidney damage in children with AS.

Restoring lung renin-angiotensin system balance through blood pressure control.

Dysregulated renin-angiotensin system (RAS) signaling contributes to elevated blood pressure (BP), inflammation, and organ damage in systemic arterial hypertension (HTN). We have demonstrated that hypertensive humans and rats exhibit higher expression of classic RAS components and lower expression of counterregulatory RAS components in the lungs compared with normotensive counterparts. Here, we investigated whether BP control could restore the balance between classic [angiotensin I-converting enzyme 2 (ACE)/angiotensin II (Ang II)] and counterregulatory [angiotensin I-converting enzyme 2 (ACE2)/Ang (1-7)] RAS, thereby mitigating lung inflammation. Male spontaneously hypertensive rats (SHRs) were treated with either losartan or amlodipine, both of which effectively reduced BP. These interventions up-regulated lung Ace2 and down-regulated Ace gene expression. Pulmonary membrane ACE2 abundance and activity were higher in losartan- and amlodipine-treated SHRs than in vehicle-treated SHRs, whereas ACE protein and function remained unchanged. Drug-treated SHRs exhibited lower levels of lung Ang II and higher levels of Ang (1-7) than vehicle-treated SHRs. Rebalancing the pulmonary RAS remarkably reduced macrophage number and down-regulated pro-inflammatory genes in SHR lungs, with lower expression of lung pro-inflammatory genes correlating with lower circulating levels of ACE2. Serum analysis in healthy and hypertensive individuals supported these findings, showing higher ACE2 levels in uncontrolled compared with controlled hypertension and normotension. Collectively, these findings suggest that high blood pressure may induce lung inflammation via an ACE/ACE2 imbalance. BP control with either an RAS inhibitor or a calcium channel blocker rebalances RAS in SHR lungs and alleviates inflammation. Furthermore, this study provides a mechanistic link between inflammatory lung diseases (such as COVID-19) and hypertension as a major risk factor.

The road ahead: emerging therapies for primary IgA nephropathy

Primary IgA nephropathy (IgAN) is the most common form of primary glomerulopathy. A slowly progressive disease presenting in the young to middle-aged, most patients with reduced eGFR or proteinuria will progress to end-stage kidney disease (ESKD) in their lifetimes. The pathogenesis involves increased production of galactose-deficient IgA1 (Gd-IgA1) that forms immune complexes that deposit in the glomerulus, eliciting mesangial cell proliferation, inflammation, and complement activation. The backbone of therapy is supportive, including lifestyle modifications, strict blood pressure control, and renin-angiotensin system inhibition targeting proteinuria &amp;lt; 300 mg/day. Sodium-glucose transporter 2 inhibitors are indicated for persisting proteinuria or declining eGFR. Sparsentan is indicated for persisting proteinuria. Immunosuppression should be considered for all patients at risk for progression (persisting proteinuria and/or declining eGFR). To reduce Gd-IgA1 production, targeted-release budesonide is approved. Agents targeting B cell survival factors APRIL or BAFF/APRIL have significantly reduced Gd-IgA1 production and proteinuria in phase 2 trials but await phase 3 data for approval. To reduce inflammation, high-dose steroids are ineffective and toxic in Caucasian patients, although lower-dose regimens may be effective in Chinese patients. Complement inhibition is being actively studied. The factor B inhibitor iptacopan has conditional approval. The terminal pathway inhibitors cemdisiran and ravulizumab show promise in phase 2 studies. Our current approach for those requiring immunosuppression involves combining the reduction of Gd-IgA1 (nefecon) with suppressing the effects of inflammation (iptacopan). The optimal duration of such therapy is uncertain. Clearly, there is more to be learned with many trials underway.

Secondary Prevention Medications in17Countries Grouped by IncomeLevel(PURE): AProspective Cohort Study.

It is unclear whether global use of medications for secondary cardiovascular (CVD) prevention is improving over time. This study across 17 high-, middle- and low-income countries described variations in secondary CVD prevention medication use over a median follow-up of 12 years. In the multinational PURE (Prospective Urban Rural Epidemiology) cohort study, we conducted a repeated cross-sectional analysis to examine temporal variations in the use of secondary prevention medications in participants with CVD. In participants with coronary artery disease, we focused on antiplatelet agents, statins, renin-angiotensin system (RAS) inhibitors, and β-blockers. In participants with stroke, we focused on antiplatelet agents, statins, RAS inhibitors, and other blood pressure-lowering drugs. Medications were collected at baseline and on 4 subsequent follow-up visits. The analysis included 7,409 participants with a diagnosis of CVD at the baseline visit, 8,792 at the second visit, 9,236 at the third visit, 11,082 at the fourth visit, and 11,677 at the last visit. The median age at baseline was 58.0 years, and 52.9% of the participants were female. The median follow-up was 12 years, with the median year of the baseline visit in 2007 and the fifth visit in 2019. Over this period, use of 1 or more classes of medications for secondary CVD prevention was 41.3% (95%CI: 40.2%-42.4%) at baseline, peaked at 43.1% (95%CI: 42.0%-44.1%), and then decreased to 31.3% (95%CI: 30.4%-32.1%) by the last study visit. In high-income countries, this use decreased from 88.8% (95%CI: 86.6%-91.0%) to 77.3% (95%CI: 74.9%-79.6%). In upper-middle-income countries, this use increased from 55.0% (95%CI: 52.8%-57.3%) to 61.1% (95%CI: 59.1%-63.1%). In lower-middle-income countries, use of at least 1 class of medications was 29.5% (95%CI: 28.1%-30.9%) at baseline, peaked at 31.7% (95%CI: 30.4%-33.1%), and then decreased to 13.4% (95%CI: 12.5%-14.2%) by the last visit. In low-income countries, use of at least 1 class of medications was 20.8% (95%CI: 18.1%-23.5%) at baseline, peaked at 47.3% (95%CI: 44.8%-49.9%), and then decreased to 27.5% (95%CI: 25.2%-29.9%) by the last study visit. Globally and in most country income-level groups, the use of medications for secondary CVD prevention has been low, with little improvement over time.

The effect of renin-angiotensin system inhibitors on patients with pancreatic cancer receiving systemic treatment: A retrospective cohort study from TriNetX US collaborative networks.

734 Background: This study aimed to assess the impact of renin-angiotensin system inhibitors, including angiotensin receptor blockers (ARBs) and angiotensin-converting enzyme inhibitors (ACEIs), on patients with pancreatic cancer undergoing systemic chemotherapy. Methods: We conducted a global, retrospective collaborative network analysis using TriNetX data from January 1, 2014, to December 31, 2023, to explore this question. The study captured data on pancreatic cancer diagnoses, comorbidities, medications, and survival outcomes. Propensity score matching (PSM) was used to create 1:1 matched groups. Hazard ratios (HR) with 95% confidence intervals (95% CI) were calculated to assess survival outcomes, while the Kaplan–Meier method was employed to evaluate survival probabilities. Subgroup analyses were performed based on sex, age, surgery, race, and comorbidities. Results: The study included 1,861 patients who were on ARBs/ACEIs and 4,875 patients who were not on these medications at baseline. After 1:1 propensity score matching, both groups were well-balanced with 1,627 patients each. Compared to the non-ARBs/ACEIs group, patients receiving ARBs/ACEIs demonstrated significantly better overall survival (HR: 0.846, 95% CI: 0.753–0.949). Subgroup analyses revealed significantly improved survival outcomes in patients on ARBs/ACEIs, including those without surgery (HR: 0.846, 95% CI: 0.749–0.956), males (HR: 0.762, 95% CI: 0.640–0.908), patients aged 65 years and older (HR: 0.801, 95% CI: 0.709–0.906), and White patients (HR: 0.806, 95% CI: 0.704–0.924). Notably, similar survival benefits were observed in patients with comorbidities such as diabetes, ischemic heart disease, dyslipidemia, and hypertension. Conclusions: In the largest TriNetX matched cohort study on pancreatic cancer, the use of ARBs/ACEIs was associated with a reduced risk of overall mortality. However, prospective studies are needed to further evaluate the effects of concomitant ARB/ACEI use in patients with pancreatic cancer undergoing systemic treatment.

Impact of Renin-angiotensin system inhibitors on response to PD1/L1 inhibitors in patients with Metastatic Renal Cell Carcinoma

BackgroundThe renin-angiotensin-aldosterone system (RAAS), traditionally associated with blood pressure and fluid regulation, also plays a role in tumorigenesis. Renin-angiotensin-aldosterone system inhibitors (RAASI), including angiotensin converting enzyme inhibitors (ACEI) and angiotensin receptor blockers (ARBs), have been shown to improve outcomes in various malignant neoplasms. In metastatic urothelial cancer, the use of RAASI have been associated with higher rates of tumor regression in patients receiving immunotherapy (IO) with PD1/L1 inhibitors. This is thought to be due to RAASI-induced downregulation of TGF-beta, for which increased expression is a known mechanism of PD1/L1 inhibitor resistance. We hypothesized that concurrent RAASI in patients with mRCC receiving IO is associated with increased tumor regression. MethodsWe conducted a retrospective analysis of patients with mRCC receiving IO as a first- or second-line therapy from 2016-2023 at the University of Virginia. A logistic regression model was used to evaluate the impact of concurrent RAASI on tumor regression. The primary endpoint was any regression of tumor on imaging. ResultsData were available for 128 patients with mRCC who received IO as a first- (n=91, 71.0%) or second- (n=37, 28.9%) line treatment. Patients who received RAASI during IO were more likely to have tumor regression compared to patients who were not on concurrent RAASI (OR 3.84 [95% CI 1.81-8.47, p=<0.001). This held true regardless if patients received IO as a first-line (OR 2.83 [95% CI 1.2-6.94], p=0.0173) or second-line (OR 9.5 [95% CI 1.89-73.1], p=0.005) treatment. ConclusionsOur hypothesis generating study suggests that in our mRCC population, concurrent use of RAASI in patients receiving IO was associated with a significantly increased likelihood of tumor regression. These findings highlight the potential therapeutic advantage of RAASI in combination with IO for mRCC patients. Further exploration of this association is warranted in prospective studies to improve treatment outcomes for this patient population. MicroAbstractRenin-angiotensin-aldosterone system inhibitors (RAASI) have been shown to improve outcomes in various malignancies. In this retrospective, single-center study, we found that concurrent use of RAASI in patients with mRCC receiving IO is associated with a significantly increased likelihood of tumor regression. Our findings suggest the potential therapeutic advantage of RAASI in combination with IO for mRCC patients.

Enzyme replacement therapy with renin-angiotensin system inhibition prevents kidney function decrease in most Finnish Fabry disease patients treated for 5 or 10 years

Enzyme replacement therapy with renin-angiotensin system inhibition prevents kidney function decrease in most Finnish Fabry disease patients treated for 5 or 10 years

Therapeutic Potential of RAS Inhibitors in the Management of Diabetes

The global prevalence of diabetes is on the rise, with its pathogenesis closely related to the renin-angiotensin system (RAS) that includes the classical antagonistic pathway and the ACE2-Ang-(1-7)-Mas axis. Despite its well-documented role in cardiovascular health, the potential mechanisms by which RAS is associated with diabetes require further study. RAS interacts with metabolic regulatory factors such as obesity and autophagy. Excessive activation of the Ang II-AT1 receptor pathway can contribute to insulin resistance and diabetic complications. This review elucidates the mechanisms by which RAS contributes to diabetes development and discusses both clinical applications and future directions for RAS inhibitory drugs in managing diabetes. And it concludes that RAS inhibitors hold significant promise for treating diabetes and its associated complications, warranting deeper exploration into their future roles within this field. The results indicate the intricate relationship between RAS and diabetes, alongside the therapeutic potential offered by RAS inhibitors.

Implementation of guideline-recommended therapies in heart failure with reduced ejection fraction according to heart failure duration: An analysis of 55 581 patients from the Swedish Heart Failure (SwedeHF) Registry.

Guidelines recommend immediate initiation of all four class I guideline-directed medical therapies, renin-angiotensin system inhibitors (RASI) or angiotensin receptor-neprilysin inhibitors (ARNI), beta-blockers, mineralocorticoid receptor antagonists (MRA) and sodium-glucose cotransporter 2 inhibitors (SGLT2i) following the diagnosis of heart failure (HF) with reduced ejection fraction (HFrEF). The extent to which this occurs in new-onset HFrEF is unclear. We assessed guideline-recommended therapies during the first year following a HFrEF diagnosis. The Swedish HF Registry was linked to additional national registries. In patients with HFrEF (ejection fraction <40%), clinical characteristics and HF treatment from when they were available and recommended in guidelines were assessed according to time from HF diagnosis (<3, 3 to <6, 6-12 and >12 months). Of 55 581 patients with HFrEF enrolled between 2000 and 2021, 54%, 5.8%, 4.8% and 36% had an HF duration of <3, 3 to <6, 6-12 and >12 months, respectively. Patients with shorter HF duration were younger, had lower New York Heart Association class and had fewer cardiovascular comorbidities. Within 3 months, 3 to <6 months, 6-12 months and >12 months from HF diagnosis, 93%, 92%, 90% and 89% were on RASI or ARNI, 9.8%, 17%, 19% and 22% on ARNI alone, 35%, 43%, 44% and 46% on MRA, 92%, 92%, 92% and 91% on beta-blockers, and 26%, 30%, 19% and 28% on SGLT2i, respectively. Additionally, 18% received cardiac resynchronization therapy/implantable cardioverter-defibrillator >12 months after diagnosis. Most patients received RASI and beta-blockers in the first months following HFrEF diagnosis. Use of ARNI, MRA and SGLT2i was limited, both in the early and later time periods. Our findings suggest that strategies to improve guideline-directed use of HFrEF therapies remain urgently needed.

Use of a trigger tool to describe and screen drug-related hospital admissions in older adults: the TRIGGAge retrospective cohort study.

Drug-related hospital admissions (DRAs) can account for 5%-40% of total hospital admissions in older adults, with a significant proportion deemed preventable. To increase the detection of DRAs, in 2021, a revised trigger tool listing 21 frequent causes of admissions and medications at risk was proposed. This study aimed to describe DRAs using this trigger tool in a French acute geriatric ward and to assess the performance of the tool. This was a retrospective cohort study in a 20-bed geriatric unit including all patients hospitalised in 2023. During the first quarter of 2024, each patient's chart was adjudicated by using a two-step standardised review procedure to assess whether the admission was a DRA. The potentially at cause medications and reasons for admission were also assessed. During the study period, 483 patients were hospitalised in the acute-care geriatric ward (mean age 86.7 ± 6.15years). After adjudication, 207 admissions (43%) were identified as DRAs; 70% were considered preventable. The main causes of DRAs were falls/fractures (33%), bleeding (23%) and delirium (14%). The drugs most frequently responsible were diuretics (21%), renin-angiotensin system inhibitors (20%) and direct oral anticoagulants (15%). The overall sensitivity and specificity of the tool for detecting DRAs was 90% (95% CI 88-93) and 72% (68-76), respectively. After adjudication, the trigger tool helped detect 83% more DRAs as compared with the attending geriatrician. DRAs are frequent in a geriatric population and often preventable. Their detection may be improved by the use of a trigger tool.

Characteristics of patients with undiagnosed stage 3 chronic kidney disease: results from an observational study (REVEAL-CKD) in China.

Early diagnosis of chronic kidney disease (CKD) is crucial for timely intervention to delay disease progressionand improve patient outcomes. However, data for clinical characteristics of Chinese patients with undiagnosed, early-stage CKD are lacking. REVEAL-CKD is a multinational, observational study using real-world data in selected countries to describe factors associated with undiagnosed stage 3 CKD, time to diagnosis, and CKD management post diagnosis. We analysed patient data from 20 hospitals in the China Renal Data System. Adult patients with two consecutive estimated glomerular filtration rate (eGFR) measurements indicating stage 3 CKD (30-<60ml/min/1.73m2) recorded >90-730 days apart from 2015 to 2020 were eligible. Among 35,222 eligible patients, 25,214 (71.6%) were undiagnosed (lacked a CKD diagnostic code before and up to six months post-second-qualifying-eGFR). Only 2344 (9.3%) undiagnosed patients eventually received a delayed diagnosis, whose median time to diagnosis was 18.1 (95% CI: 17.6-18.8) months. Age ≥65 years, being female, stage 3A CKD, and the absence of nephrology visit and comorbidities (diabetes, established cardiovascular disease, heart failure, hypertension, or chronic nephritic syndrome) were associated with undiagnosed CKD (P<0.001). Among the diagnosed patients, the proportion receiving ≥1 prescription of guideline-recommended medications (e.g. renin-angiotensin system inhibitors) increased and their eGFR decline attenuated post-diagnosis. The high proportion of undiagnosed, early-stage CKD, and delayed diagnosis are concerning. The improved prescription patterns and the attenuation of eGFR decline post-diagnosis demonstrate the importance of early diagnosis and timely intervention in CKD patients. AstraZeneca China.

Review on The Potential of Herbal Medicine in the Treatment of Diabetic Kidney Disease

Diabetic Kidney Disease (DKD), a leading complication of diabetes mellitus, presents a significant global health challenge due to its progression to end-stage renal disease (ESRD). Conventional therapies for DKD focus on glycemic control, blood pressure regulation, and renin-angiotensin system inhibition but often fall short in halting disease progression. This review explores the potential of herbal medicine as a complementary approach to managing DKD. Herbal medicines, rich in bioactive phytochemicals, exhibit antioxidant, anti-inflammatory, and renoprotective properties that may mitigate key mechanisms driving DKD progression. Notable compounds include quercetin, curcumin, berberine, and ursolic acid, which target oxidative stress, inflammation, and fibrosis. Furthermore, herbs like Curcuma longa, Zingiber officinale, and Panax ginseng have shown promising results in preclinical and clinical studies, improving renal function and reducing proteinuria. Despite their potential, challenges remain in standardizing herbal formulations, understanding herb-drug interactions, and ensuring safety in patients with compromised renal function. Future research should prioritize large-scale clinical trials, mechanistic studies, and integrative treatment models combining herbal and conventional therapies. By leveraging the strengths of traditional and modern medicine, herbal interventions offer a promising pathway to improve outcomes for individuals with DKD

Prevalence of heart failure pharmacotherapy utilisation, frailty and adverse drug events among hospitalised adults older than 75 years: a multicentre cross-sectional study.

Optimal heart failure (HF) pharmacotherapy (guideline-directed medical therapy and diuretics) in older people with frailty is uncertain due to limited evidence. To evaluate utilisation of HF pharmacotherapy and prevalence of polypharmacy, adverse drug events (ADEs), falls, delirium, renal impairment and duration of hospitalisation in older inpatients, according to frailty. A retrospective cross-sectional study of the TO HOME cohort of 2000 inpatients ≥75 years admitted for ≥48 h to rehabilitation, geriatricor general medicine from 1 July 2016 to 30 June 2017 across six hospitals in Sydney, Australia. Data were collected from electronic medical records. International Statistical Classification of Diseases and Related Health Problems, Tenth Revision, Australian Modification identified HF diagnosis, ADEs and frailty using hospital frailty risk score. Outcomes included utilisation of HF pharmacotherapy; polypharmacy; ADEs, falls, delirium, renal and impairment; and duration of hospitalisation. Among 439 (22.0% of TO HOME cohort) patients with undifferentiated HF, 284 (69.5%) had intermediate or high risk of frailty, and 412 (94%) took ≥1 HF pharmacotherapy, with 357 (81.3%) patients on loop diuretics. Patients with high frailty risk frequently continued beta-blockers (70%) and discontinued renin-angiotensin system inhibitors (57%). Most patients experienced polypharmacy (n = 426, 97.0%). Renal impairment prevalence was 67%-76% across frailty groups. Increasing frailty risk (low, intermediate and high) was associated with increasing prevalence of ADEs (31%, 56% and 84%), falls (12%, 25% and 46%) and delirium (8%, 27% and 49%) and longer hospitalisation. Frailty, HF-pharmacotherapy changes in hospital and ADEs were common among older inpatients with HF. The association of adverse outcomes according to frailty needs further investigation. Poor documentation of HF phenotype may be a barrier to medication optimisation in older inpatients.

Azelnidipine and its role in decreasing urinary albumin creatinine ratio in people with type 2 diabetes and hypertension: a systematic review and meta-analysis.

Type 2 diabetes mellitus and hypertension frequently coexist, increasing the risk of cardiovascular and renal complications. Urinary Albumin Creatinine Ratio (UACR) serves as a crucial predictor of these outcomes. While renin-angiotensin system inhibitors are often initial therapy, evidence suggests a potential role for Azelnidipine, a non-dihydropyridine calcium channel blocker, in reducing UACR, especially in cases of persistent proteinuria despite optimal therapy. However, conflicting results from existing studies necessitate a comprehensive systematic review and meta-analysis to clarify Azelnidipine's (AZL) efficacy in reducing UACR in people with type 2 diabetes mellitus and hypertension. This meta-analysis, following Cochrane and Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines, included randomized controlled trials (RCTs) published until January 15, 2024. Studies involving individuals with type 2 diabetes mellitus and hypertension were included, comparing AZL or AZL-containing regimens with other antihypertensive agents. The primary outcome was changes in UACR, with secondary outcomes including alterations in Glycated Hemoglobin (HbA1c), systolic and diastolic blood pressure (SBP and DBP), heart rate (HR), and estimated glomerular filtration rate (eGFR). Six RCTs involving 731 participants were included. Meta-analysis revealed a significant reduction in UACR in the AZL group compared to controls (Mean Difference (MD) = -47.96; 95% Confidence Interval (CI): -79.56, -16.37; p = 0.003). AZL also significantly decreased HR (MD = -3.70; 95% CI: -6.66, -0.74; p = 0.01), while no significant changes were observed in HbA1c, SBP, DBP, or eGFR. Sensitivity analyses demonstrated the nuanced impacts of individual studies on results, highlighting the importance of careful interpretation. This meta-analysis confirms AZL's efficacy in reducing UACR and HR in people with type 2 diabetes mellitus and hypertension.

Long-term effects of esaxerenone in patients with type 2 diabetes, diabetic kidney disease, and hypertension (JDDM77).

This clinical study assessed the three-year, long-term effects of esaxerenone, a non-steroidal aldosterone receptor blocker, on Japanese patients with type 2 diabetes, diabetic kidney disease, and hypertension who were receiving renin-angiotensin system inhibitors. Data from a computerized diabetic care database were used to retrospectively compare esaxerenone users (Group A) with non-esaxerenone users (Group B). Propensity score weighting was applied to Group B. The study primarily focused on percent changes in the Urine Albumin-Creatinine Ratio (UACR) from baseline and also examined the estimated Glomerular Filtration Rate (eGFR), blood pressure, serum potassium levels, and HbA1c. There were 199 patients in Group A and 199 in Group B, matched 1:1 using propensity scores. UACR and blood pressure were significantly lower in Group A than in Group B. Geometric mean percent changes in UACR from baseline between the two groups were as follows: - 62.7% at 1year (95% Confidence Interval (CI): - 91.0 to - 34.1%), - 48.9% at 2years (95% CI: - 79.4 to - 19.3%), and - 63.8% at 3years (95% CI: - 107.4 to - 20.2%). Additionally, the present study examined the impact of combining esaxerenone with SGLT2 inhibitors and GLP-1 receptor agonists and showed consistent effects on UACR irrespective of these medications. Esaxerenone slightly lowered eGFR with a low risk of hyperkalemia but did not adversely impact glucose metabolism. Esaxerenone exerted antihypertensive and antialbuminuric effects in patients with type 2 diabetes, diabetic kidney disease, and hypertension.

Efficacy and Safety of Sacubitril/Valsartan Versus Amlodipine in Japanese Patients With Essential Hypertension: A Randomized, Multicenter, Open-Label, Noninferiority Study (PARASOL Study).

Sacubitril/valsartan, an angiotensin receptor-neprilysin inhibitor, has demonstrated a superior blood pressure-lowering effect compared with renin-angiotensin system inhibitors in several clinical trials. However, there has been no available evidence on the comparison between sacubitril/valsartan and calcium channel blockers (CCBs), a well-established class of antihypertensive drugs. In this open-label, multicenter study, we aimed to demonstrate the efficacy and safety of sacubitril/valsartan versus amlodipine, one of the most widely used CCBs, after 8 weeks of treatment. A total of 359 Japanese patients with essential hypertension (office systolic blood pressure [SBP] ≥150 to <180mmHg), aged 18-79, were randomly assigned to receive either once-daily sacubitril/valsartan 200mg or once-daily amlodipine 5mg in a 1:1 allocation ratio. The primary endpoint was the noninferiority of sacubitril/valsartan compared with amlodipine in mean change in 24-h SBP from baseline to Week 8, followed by a significance test as a secondary endpoint analysis. The mean change in 24-h SBP in sacubitril/valsartan was noninferior to that in amlodipine (between-treatment difference -0.62mmHg [95% confidential interval: -3.23 to 1.98; p = 0.003 for noninferiority; independent t-test with noninferiority margin 3.0mmHg]), with no significant difference observed (p=0.637). There was no significant difference in the incidence of adverse events (AEs). These results suggested that the blood pressure-lowering effect of sacubitril/valsartan is comparable to that of amlodipine, with no marked differences in tolerability between the two groups. Sacubitril/valsartan, a potent antihypertensive drug comparable to amlodipine, is expected to improve blood pressure control in clinical practice.

First real-world evidence of sparsentan efficacy in patients with IgA nephropathy treated with SGLT2 inhibitors.

Sparsentan, a dual-acting antagonist for both the angiotensin II receptor type 1 and the endothelin receptor type A, has emerged as a promising therapeutic agent for the treatment of IgA nephropathy (IgAN). Following the publication of the PROTECT trial, sparsentan recently received approval for the treatment of IgAN in Europe. However, it remains uncertain whether an additive effect can be observed in the context of existing treatment with sodium-glucose co-transporter 2 (SGLT2) inhibitors, given that the PROTECT study did not investigate this dual therapy approach. A total of 23 patients with IgAN were treated with sparsentan via the Managed Access Programme between December 2023 and August 2024. The patients were stable on maximum tolerated doses of renin-angiotensin system (RAS) and SGLT2 inhibitors, with an estimated glomerular filtration rate (eGFR) >30mL/min/1.73m² and a urine protein/creatinine ratio (UPCR) >0.75g/g. In the 23 patients, median (IQR) baseline eGFR (CKD-EPI) was 42mL/min/1.73m2 (32-63) and median baseline UPCR was 1.5g/g (0.9-1.8). After initiation of sparsentan, UPCR significantly decreased (P<0.0001) to a median of 0.85g/g (0.42-1.15) in the 2-week follow-up and further declined (P=0.001) to a median of 0.60g/g (0.32-0.82) after 14 weeks, equivalent to a relative reduction in proteinuria up to 62% (45-74). A similar significant reduction was observed for the urine albumin/creatinine ratio. No drug-related serious adverse events were reported. In this real-world setting, sparsentan shows a significant impact on proteinuria, leading to a relative reduction of 62% in UPCR after 14 weeks and beyond, even in patients already receiving SGLT2 inhibitors.

Genotype-First Analysis in an Unselected Health System-Based Population and Phenotypic Severity of COL4A5 Variants.

Our knowledge of X-linked Alport Syndrome comes mostly from selected cohorts with more severe disease. We examined the phenotypic spectrum of X-linked Alport Syndrome in males and females with a genotype-based approach using data from the Geisinger MyCode DiscovEHR study, an unselected health system-based cohort with exome sequencing and electronic health records. Patients with COL4A5 variants reported as pathogenic or likely pathogenic in ClinVar, or protein-truncating variants, were each matched with up to 5 controls without COL4A3/4/5 variants by sociodemographics, diabetes diagnosis, and year of first outpatient encounter. Phenotypes examined included dipstick hematuria, bilateral sensorineural hearing loss, proteinuria, decreased estimated glomerular filtration rate, and kidney failure. Out of 170,856 patients, there were 29 hemizygous males (mean age 52 y [SD 20]) and 55 heterozygous females (mean age 59 y [SD 19]) with a pathogenic/likely pathogenic COL4A5 variant, including 48 with the hypomorphic variant p.Gly624Asp. Overall, penetrance (having any Alport Syndrome phenotypic feature) was highest for non-p.Gly624Asp variants (males: 94%, females: 85%), intermediate for p.Gly624Asp (males: 77%, females: 69%), compared to controls (males: 32%; females: 50%). The proportion with kidney failure was highest for males with non-p.Gly624Asp variants (44%), intermediate for males with p.Gly624Asp (15%) and females with non-p.Gly624Asp variants (10%), compared to controls (males: 3%, females 2%). Only 47% of individuals with COL4A5 had completed albuminuria screening, and a minority were taking renin-angiotensin aldosterone system inhibitors. Only 38% of males and 16% of females had a known diagnosis of Alport Syndrome or thin basement membrane disease. Using a genotype-first approach, we show that men and women with X-linked Alport Syndrome are at higher risk of related phenotypic features with a wider spectrum of severity than has been described previously and variability by genotype.