Mineralocorticoid Receptor Antagonists Research Articles

Renal effects and safety between Asian and non-Asian chronic kidney disease and type 2 diabetes treated with nonsteroidal mineralocorticoid antagonists.

Asians bear a heavier burden of chronic kidney disease (CKD), a common comorbidity of type 2 diabetes mellitus (T2DM), than non-Asians. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) have garnered attention for their potential advantages in renal outcomes. Nevertheless, the impact on diverse ethnic groups remains unknown. The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database, and clinical trial registries were searched through August 2023 with the following keywords: nonsteroidal MRAs (finerenone, apararenone, esaxerenone, AZD9977, KBP-5074), CKD, T2DM, and randomized controlled trial (RCT). A random effects model was used to calculate overall effect sizes. Seven RCTs with 14 997 participants were enrolled. Nonsteroidal MRAs reduced urinary albumin to creatinine ratio (UACR) significantly more in Asians than non-Asians: (weighted mean difference [WMD], -0.59, 95% CI, -0.73 to -0.45, p < .01) vs (WMD, -0.29, 95% CI, -0.32 to -0.27, p < .01), respectively. The average decline of estimated glomerular filtration rate (eGFR) was similar in Asians and non-Asians (p > .05). Regarding systolic blood pressure (SBP), nonsteroidal MRAs had a better antihypertension performance in Asians (WMD, -5.12, 95% CI, -5.84 to -4.41, p < .01) compared to non-Asians (WMD, -3.64, 95% CI, -4.38 to -2.89, p < .01). A higher incidence of hyperkalemia and eGFR decrease ≥30% was found in Asians than non-Asians (p < .01). Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non-Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%.

Advancements in diabetic kidney disease management: integrating innovative therapies and targeted drug development.

Diabetic kidney disease (DKD) is a leading cause of chronic kidney disease and affects approximately 40% of individuals with diabetes . Cases of DKD continue to rise globally as the prevalence of diabetes mellitus increases, with an estimated 415 million people living with diabetes in 2015 and a projected 642 million by 2040. DKD is associated with significant morbidity and mortality, representing 34% and 36% of all chronic kidney disease deaths in men and women, respectively. Common comorbidities including hypertension and ageing-related nephron loss further complicate disease diagnosis and progression. The progression of DKD involves several mechanisms including glomerular endothelial cell dysfunction, inflammation, and fibrosis. Targeting these mechanisms has formed the basis of several therapeutic agents. Renin-angiotensin-aldosterone system (RAAS) blockers, specifically angiotensin receptor blockers (ARBs), demonstrate significant reductions in macroalbuminuria. Sodium-glucose transporter type 2 (SGLT-2) inhibitors demonstrate kidney protection independent of diabetes control while also decreasing the incidence of cardiovascular events. Emerging agents including glucagon-like peptide 1 (GLP-1) agonists, anti-inflammatory agents like bardoxolone, and mineralocorticoid receptor antagonists show promise in mitigating DKD progression. Many novel therapies including monoclonal antibodies CSL346, lixudebart, and tozorakimab; mesenchymal stem/stromal cell infusion; and cannabinoid-1 receptor inverse agonism via INV-202 are currently in clinical trials and present opportunities for further drug development.

Association between socioeconomic position and discontinuation of pharmacotherapy for heart failure after cardiac resynchronization therapy.

Pharmacological therapy remains a cornerstone in heart failure (HF) treatment despite implantation of a cardiac resynchronization therapy (CRT) device. The aim of this study was to investigate the association between 1) drug discontinuation, and 2) long-term adherence to HF pharmacotherapy after CRT implantation and socioeconomic position and multimorbidity. We conducted a registry-based cohort study including all patients who underwent a first-time CRT implantation at Aarhus University Hospital from 2000-2017. HF pharmacotherapy included beta blockers (BBs), renin angiotensin system inhibitors (ACEI/ARB), and mineralocorticoid receptor antagonists (MRAs). Patients were identified using the Danish Pacemaker and ICD Registry, and information about medication and comorbidities was obtained through linkage to the Danish health registries. We identified 2,007 patients of whom 1,880 (94%) were eligible for inclusion. The cumulative incidence of drug discontinuation at 10 years was 6% (95% confidence interval [CI] 5-8%) for BB, 10% (95% CI 9-12%) for ACEI/ARB, and 24% (95% CI 20-27%) for MRAs. Living alone was associated with higher BB discontinuation rates (hazard ratio [HR] 1.83, 95%CI 1.20-2.79), whereas patients with multimorbidity were more likely to discontinue ACEI/ARB- (HR 1.92, 95%CI 1.33-2.80) and MRA therapy (HR 1.51, 95% CI 1.10-2.09). Income- and educational level did not influence drug discontinuation rates, and similar adherence patterns were observed across all strata of socioeconomic position and multimorbidity. In patients with CRTs, drug discontinuation rates were low, and adherence to HF pharmacotherapy was comparable regardless of socioeconomic position. Living alone and multimorbidity were associated with discontinuation of specific HF drugs.

2024 update in heart failure.

In the last years, major progress has occurred in heart failure (HF) management. The 2023 ESC focused update of the 2021 HF guidelines introduced new key recommendations based on the results of the last years of science. First, two drugs, sodium-glucose co-transporter-2 (SGLT2) inhibitors and finerenone, a novel nonsteroidal, selective mineralocorticoid receptor antagonist (MRA), are recommended for the prevention of HF in patients with diabetic chronic kidney disease (CKD). Second, SGLT2 inhibitors are now recommended for the treatment of HF across the entire left ventricular ejection fraction spectrum. The benefits of quadruple therapy in patients with HF with reduced ejection fraction (HFrEF) are well established. Its rapid and early up-titration along with a close follow-up with frequent clinical and laboratory re-assessment after an episode of acute HF (the so-called 'high-intensity care' strategy) was associated with better outcomes in the STRONG-HF trial. Patients experiencing an episode of worsening HF might require a fifth drug, vericiguat. In the STEP-HFpEF-DM and STEP-HFpEF trials, semaglutide 2.4mg once weekly administered for 1year decreased body weight and significantly improved quality of life and the 6min walk distance in obese patients with HF with preserved ejection fraction (HFpEF) with or without a history of diabetes. Further data on safety and efficacy, including also hard endpoints, are needed to support the addition of acetazolamide or hydrochlorothiazide to a standard diuretic regimen in patients hospitalized due to acute HF. In the meantime, PUSH-AHF supported the use of natriuresis-guided diuretic therapy. Further options and most recent evidence for the treatment of HF, including specific drugs for cardiomyopathies (i.e., mavacamten in hypertrophic cardiomyopathy and tafamidis in transthyretin cardiac amyloidosis), device therapies, cardiac contractility modulation and percutaneous treatment of valvulopathies, with the recent finding from the TRILUMINATE Pivotal trial, are also reviewed in this article.

Resident-led improvement project to screen for primary hyperaldosteronism in patients with resistant hypertension in an outpatient clinic.

Clinical practice guidelines recommend screening for primary hyperaldosteronism (PH) in patients with resistant hypertension. However, screening rates are low in the outpatient setting. We sought to increase screening rates for PH in patients with resistant hypertension in our Veterans Affairs (VA) outpatient resident physician clinic, with the goal of improving blood pressure control. Patients with possible resistant hypertension were identified through a VA Primary Care Almanac Metric query, with subsequent chart review for resistant hypertension criteria. Three sequential patient-directed cycles were implemented using rapid cycle improvement methodology during a weekly dedicated resident quality improvement half-day. In the first cycle, patients with resistant hypertension had preclinic PH screening labs ordered and were scheduled in the clinic for hypertension follow-up. In the second cycle, patients without screening labs completed were called to confirm medication adherence and counselled to screen for PH. In the third cycle, patients with positive screening labs were called to discuss mineralocorticoid receptor antagonist (MRA) initiation and possible endocrinology referral. Of 97 patients initially identified, 58 (60%) were found to have resistant hypertension while 39 had pseudoresistant hypertension from medication non-adherence. Of the 58 with resistant hypertension, 44 had not previously been screened for PH while 14 (24%) had already been screened or were already taking an MRA. Our screening rate for PH in resistant hypertension patients increased from 24% at the start of the project to 84% (37/44) after two cycles. Of the 37 tested, 24% (9/37) screened positive for PH, and 5 patients were started on MRAs. This resident-led quality improvement project demonstrated that a focused intervention process can improve PH identification and treatment.

Esaxerenone: blood pressure reduction and cardiorenal protection without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats.

Mineralocorticoid receptor (MR) is involved in the mechanisms of blood pressure elevation, organ fibrosis, and inflammation. MR antagonists have been used in patients with hypertension, heart failure, or chronic kidney disease. Esaxerenone, a recently approved MR blocker with a nonsteroidal structure, has demonstrated a strong blood pressure-lowering effect. However, blood pressure reduction may lead to sympathetic activation through the baroreflex. The effect of esaxerenone on the sympathetic nervous system remains unclear. We investigated the effect of esaxerenone on organ damage and the sympathetic nervous system in salt-loaded stroke-prone spontaneously hypertensive rats (SHRSP), a well-established model of essential hypertension with sympathoexcitation and organ damage. Three-week administration of esaxerenone or hydralazine successfully attenuated the blood pressure elevation. Both esaxerenone and hydralazine comparably suppressed left ventricular hypertrophy and urinary albumin excretion. However, renal fibrosis and glomerular sclerosis were suppressed by esaxerenone but not hydralazine. Furthermore, plasma norepinephrine level, a parameter of systemic sympathetic activity, was significantly increased by hydralazine but not by esaxerenone. Consistent with these findings, the activity of the control centers of sympathetic nervous system, the parvocellular region of the paraventricular nucleus in the hypothalamus and the rostral ventrolateral medulla, was enhanced by hydralazine but remained unaffected by esaxerenone. These results suggest that esaxerenone effectively lowers blood pressure without inducing reflex sympathetic nervous system activation. Moreover, the organ-protective effects of esaxerenone appear to be partially independent of its blood pressure-lowering effect. In conclusion, esaxerenone demonstrates a blood pressure-lowering effect without concurrent sympathetic activation and exerts organ-protective effects in salt-loaded SHRSP. Esaxerenone has antihypertensive and cardiorenal protective effects without reflex sympathetic activation in salt-loaded stroke-prone spontaneously hypertensive rats.

Progress of patients hospitalized with acute heart failure treated with empagliflozin.

Aim: To describe the epidemiological, clinical and laboratory characteristics and clinical progress of patients hospitalized with heart failure (HF) who started treatment with empagliflozin before discharge. Methods: We performed a retrospective observational study of patients aged ≥18years admitted to the Internal Medicine Department of University Hospital Jaen, Jaen, Spain with acute HF between 1 May 2022 and 31 May 2023. Patients had to have a life expectancy of ≥1year and have started treatment with empagliflozin during admission. Results: We included 112 patients (mean age, 85.2±6.5years; 67.9% women; 35.7 and 31.3% in NYHA functional classes III and IV; 73.2% with HF and preserved ejection fraction). Before admission, 80.4% were taking loop diuretics, 70.6% renin-angiotensin-aldosterone system inhibitors, 49.1% betablockers and 25% mineralocorticoid receptor antagonists. At admission, 94.6% were taking furosemide (15.2% at high doses, 36.6% at intermediate doses). The dose of furosemide was reduced at initiation of empagliflozin. At the end of follow-up, 13.4% of patients had died, 93.8% of the survivors continued treatment with empagliflozin and 26.8% had attended the emergency department with signs and symptoms of HF. Conclusion: Introduction of empagliflozin before discharge from hospital in patients admitted with HF made it possible to reduce the dose of diuretics during admission. The frequency of complications was as expected, and treatment was largely maintained.

Comparison of eplerenone and spironolactone treatment in patients with ischemic heart disease hospitalized due to ventricular tachycardia

Abstract Background The beneficial effects of mineralocorticoid receptor antagonists (MRAs) regarding sudden cardiac death (SCD) risk and cardiac remodeling are well known, moreover, they also reduce episodes of ventricular tachycardia (VT). However, superiority in effectiveness between receptor selective eplerenone and conventional spironolactone is unknown. Purpose Our aim was to assess the effect of eplerenone and spironolactone on ventricular tachycardia (VT) recurrence in patients with ischemic heart disease (IHD). Methods We collected data of 563 patients with IHD following hospitalization due to a sustained VT episode in a structured registry. Propensity score matching was performed based on age, hypertension, diabetes, history of acute myocardial infarction, left ventricular ejection fraction (LVEF) and presentation with incessant VT. The matched population consisted of 188 patients and was further analyzed. Predictors were assessed using univariate and multivariate Cox regression models. Kaplan-Meier curves were used for time-to-event analyses. Results The median age was 70 years with 81% being male. One third of the patients had an ICD implanted, while 43 (23%) had CRT. The median LVEF was 30%. Twenty-five (13%) patients presented with an electrical storm and 19 (10%) had incessant VT. In 86 cases (46%), the VT caused hemodynamic instability. Ablation was performed in 66 patients (35%), while 4 required mechanical circulatory support. During the median follow-up of 856 [399-1624] days, 69 patients had VT recurrence and 118 patients died. Eplerenone use significantly reduced the risk of VT recurrence compared to spironolactone (HR: 0.48 [0.29-0.78], log-rank p=0.003). This effect was consistent in the multivariate model as well (p=0.006). Conclusions Eplerenone use may be more beneficial in terms of VT recurrence in patients with IHD who present with a sustained VT. Further analysis is required to confirm these findings.

Ventricular arrhythmia events in patients with implantable cardioverter-defibrillator before and after the treatment with sodium-glucose co-transporter 2 inhibitors

Abstract Background The role of sodium-glucose co-transporter 2 inhibitors (SGLT2i) in the treatment of chronic heart failure is expanding. However, the timing of implantable cardioverter-defibrillator (ICD) implantation for primary prevention in relation to the use of SGLT2i remains unclear. A small case series has described appropriate shocks from ICD in two patients following the initiation of SGLT2i, but a comprehensive analysis is lacking in the literature. Methods This study aimed to investigate the rate of ventricular arrhythmic burden and appropriate anti-tachycardia therapy from ICD before and after the initiation of SGLT2i therapy. We conducted a retrospective single-center analysis, comparing ventricular events from home monitoring reports three months before and three months after SGLT2i therapy initiation. Results Seventeen patients were enrolled in the study. At baseline, clinical characteristics were as follows: 13 (76%) were male, 9 (53%) had ischemic, 2 (12%) had valvular, and 6 (35%) had idiopathic cardiomyopathy. The mean end-diastolic volume (EDV) was 203 ± 90 ml, and the mean left ventricular ejection fraction was 0.36 ± 0.09. All patients were treated with beta-blockers, 14 (82%) with sacubitril-valsartan, 13 (76%) with aldosterone antagonists, 16 (94%) with furosemide, and 5 (29%) with amiodarone. SGLT2i started with dapagliflozin for 13 patients (76%), empagliflozin for 3 patients (18%), and canagliflozin for 1 patient (6%). Ten patients (59%) had single-chamber or dual-chamber ICDs, and 7 had implantable cardiac resynchronization therapy (CRT) defibrillators. In the three months before SGLT2i treatment, 4/17 patients had non-sustained ventricular tachycardia (NSVT), compared to 8/17 (23% vs. 47%, p-value 0.23) patients with NSVT after treatment. Seven patients (41%) experienced an increase in the rate of NSVT events, with one patient having 28 NSVT events after treatment versus none before treatment. No patients had anti-tachycardia therapy in the three months before treatment, while in the three months after SGLT2i treatment, 1 patient had ventricular tachycardia treated with anti-tachycardia pacing (110 days after the beginning of the treatment), and 2 patients had ventricular tachycardia treated with appropriate shocks (2 and 25 days after the initiation of SGLT2i treatment). Conclusion This small retrospective analysis revealed an increase in ventricular arrhythmic events in the three months following the initiation of SGLT2i. These findings highlight the need for a more extensive analysis to establish a stronger statistical correlation.

Factors influencing inappropriate device therapy in implantable cardioverter defibrillators: a predictive analysis

Abstract Background Implantable cardioverter defibrillator (ICD) implantation and subsequent ICD therapy have shown to be efficacious in the prevention of sudden cardiac death. However, patients with an ICD are at risk of inappropriate device therapy (IDT), which is associated with worse outcomes, reduced quality of life (QoL), and may influence psychosocial and mental wellbeing. Purpose This study aimed to predict which patients are at risk of IDT by investigating the influence of pre-implant clinical parameters on occurrence of IDT. Methods From January 2010 to December 2019, patients who received an ICD in our medical center, were included in a prospective registry. Only patients with ICD (including ICDs used for cardiac resynchronization therapy, i.e. CRT-D) with an atrial lead were included in the current analysis, to better distinguish between appropriate and inappropriate device therapy. After implant, the device was interrogated at least every 6 months and clinical symptoms related to the device, recorded events, and relevant technical setting changes were recorded. IDT was defined as antitachycardia pacing (ATP) or shock delivered for any reason other than ventricular arrhythmia. Follow-up ended after IDT, death, or loss-to-follow-up. Results 428 patients underwent an implantation of a dual chamber ICD or CRT-D of various manufacturers. 14 patients were lost to follow-up within the first year and one patient was excluded because of a dislocated atrial lead, leaving 413 patients (76% male, mean age 67±9.7 years, 39% CRT-D) with a minimum of 1-year follow-up. During a mean of 5.3 (±3.0) years, 136 (32.9%) patients received appropriate therapy and 36 (8.7%) patients received IDT. Of those 36 patients, 18 patients received only ATP, 12 received ATP followed by a shock, and 6 patients received a shock without prior ATP. The median time from implantation to IDT was 2.8 [0.3-5.8] years. Univariate logistic regression on 40 clinical parameters followed by a forward multivariate logistic regression was performed. The area under the ROC curve of the resulting multivariate model was 0.724 (95%CI 0.622-0.826). Cox regression analysis resulted in device type (CRT-D) (HR=0.533, 95%CI 0.234-1.211, p=0.133), use of mineralocorticoid receptor-antagonists (MRA) (HR=0.280, 95%CI 0.104-0.754, p=0.012), use of diuretics (HR=3.378, 95%CI 1.479-7.714, p=0.004), and eGFR (HR=1.217, 95%CI 0.972-1.523, p=0.087) as predictors of IDT. A history of atrial fibrillation was not a significant predictor of IDT. Conclusion This study identified CRT-D and use of MRAs to be protective against IDT, and use of diuretics and lower eGFR as risk factors of IDT. To inform patients optimally, pre-implant assessment of those factors could help identify patients at higher risk of IDT. Furthermore, it could dictate more cautious device programming and consequently reduce rates of IDT, reducing the negative influence of IDT on QoL and wellbeing in the ICD population.

Mineralocorticoid receptor overactivation in diabetes mellitus: role of O-GlcNAc modification.

Hypertension is a significant risk factor for microangiopathy and cardiovascular complications in diabetic patients. The efficacy of mineralocorticoid receptor (MR) antagonists in impeding the advancement of diabetic nephropathy, along with the reduction in active renin concentration observed in diabetic retinopathy, strongly implies the involvement of MR overactivation in diabetic complications. This review provides a comprehensive review of various mechanisms proposed for MR overactivation in diabetes mellitus. In particular, it focuses on post-translational MR modifications, including O-linkedN-acetylglucosamine modification and phosphorylation, which have been implicated in MR protein stabilization and overactivation under conditions of high glucose. Given the role of MR overactivation in hyperglycemia, it emerges as a promising therapeutic target for preventing diabetic complications. Post-translational modifications (PTMs), such as O-GlcNAcylation and phosphorylation, are related to MR overactivation in diabetes and metabolic syndrome. Aldosterone binding promotes the proteasomal degradation of MR. Under conditions of high glucose, O-GlcNAcylation, and PKCβ-mediated MR phosphorylation are increased. Salt loading and oxidative stress also increase MR phosphorylation through the EGER/ERK pathway. PTMs inhibit ubiquitin attachment to the MR and interfere with the receptor's aldosterone-induced proteasomal degradation. Consequently, they increase the sensitivity of the MR to aldosterone and exacerbate aldosterone-associated complications.

#694 Effects of nonsteroidal mineralocorticoid receptor antagonists on kidney of cirrhotic rats

Abstract Background and Aims Aldosterone binds to renal mineralocorticoid receptors (MRs) to regulate fluid and electrolytes homeostasis. In addition, aldosterone can be deleterious as a driver of inflammation and tissue fibrosis in several organs. Thus, blockade of aldosterone represents an important option to mitigate the target-organ damage. Mineralocorticoid receptor antagonists (MRAs) have been widely used as diuretic drugs for the management of hypertension, cirrhosis, and heart failure. However, the use of MRAs is limited by adverse events such as hyperkalemia. More recently, novel nonsteroidal selective MRAs with improved safety profiles have been developed. This nonsteroidal MRA (finerenone) has higher selectivity and stronger affinity for the MR, leading to lower risk of hyperkalemia. Recent evidences showed that finerenone reduces albuminuria, risk of CKD progression, and cardiovascular events in patients with chronic kidney disease and type 2 diabetes with a low incidence of hyperkalemia related treatment discontinuation. The pathophysiology of cirrhosis is very similar to that of cardiac failure. Decompensated cirrhosis is frequently treated with the MRAs. In addition to fluid management, MRAs showed hepatoprotective actions via reducing oxidative stress and inflammatory responses in CCl4-induced and common bile duct ligation (CBDL)-induced liver injury models. The potential beneficial effects of nonsteroidal MRA on cirrhosis had never been studied. This study aims to explore the renal protective role of nonsteroidal selective MRA and associated mechanisms in common bile duct ligation-related liver injury in rat model. Method CBDL was used to create liver injury in the Male Sprague-Dawley Drats. Finerenone (10 mg/kg/day) or vehicle was administered since the 1st day after CBDL. The effects of nonsteroidal selective MRA on kidneys were surveyed in two paralleled series on the 7th day (inflammation) and the 28th day (cirrhosis), respectively. The following parameters were evaluated: (a) hemodynamic parameters; (b) serum potassium, liver and renal function; (c) in-situ kidney perfusion; (d) western analyses of renal cortex and medulla. Results Compared with the vehicle-treated group, there was significantly lower renal vascular responsiveness to ET-1 in CBDL rats receiving 28 days of MRA (p&amp;lt;0.05) (Fig. 1B), but not in those receiving 7 days of MRA (Fig. 1A). MRA treatment led to no significant change in mean arterial pressure, portal pressure, serum potassium, liver, and renal function in CBDL rats (Table 1). The expressions of vasoactive mediators, such as iNOS, eNOS, ETA, and ETB in both renal cortex and medulla showed no significant change in CBDL rats following 28 days of MRA treatment (Fig. 2). Conclusion MRA treatment led to no significant effects on hemodynamics, liver, and renal function, but lower renal vascular responsiveness to ET-1 in CBDL rats receiving 28 days of MRA. The exact mechanisms remained to be further studied.

Salt substitute recommendations for heart failure patients may influence guideline-directed medical therapies titration.

Reducing sodium intake is necessary for patients with chronic heart failure (CHF). Salt substitutes (saltSubs) have become increasingly popular as recommendations by healthcare professionals (HCPs) as well as options for patients and their caregivers. However, their consumption is generally potassium based and remains poorly evaluated in CHF management. Their impact on guideline-directed medical therapies (GDMTs) also remains unknown. The primary objective of this study was to provide a description and estimate of HCP recommendations and reported use of saltSubs in France. Secondary objectives were to identify if there was an association between these recommendations by HCPs and the use of GDMTs. A nationwide, questionnaire-based, cross-sectional, epidemiological study was conducted from September 2020 to July 2021. Data collection included baseline characteristics, the use and recommendations of saltSubs, and the use of GDMTs, which included (i) angiotensin-converting enzyme inhibitors (ACEis) and angiotensin receptor blockers (ARBs) or angiotensin receptor-neprilysin inhibitors (ARNis), (ii) mineralocorticoid receptor antagonists (MRAs), and/or (iii) beta-blockers (BBs). In total, 13% of HCPs advised saltSubs and 17% of patients and 22% of caregivers reported their consumption. CHF patients advised to take saltSubs did not differ in terms of left ventricular ejection fraction (EF) <40%, ischaemic origin, and New York Heart Association III-IV class, but were more recently hospitalized for acute HF (P=0.004). HCPs who recommended saltSubs to patients were more likely to advise an anti-diabetic diet (P<0.001), cholesterol-lowering diet (P<0.001), and exercise (P=0.018). In the overall population, ACEi/ARB/ARNi use was less frequent in case of saltSub recommendations (74% vs. 82%, P=0.012). The concomitant prescription of none, one, two, or three GDMTs was less favourable in case of saltSub recommendations (P=0.046). There was no significant difference for the presence of MRA (56% vs. 58%) and/or BB (78% vs. 82%). The under-prescription of ACEi/ARB/ARNi was found when patients had EF<40% (P=0.029) and/or EF≥40% (P=0.043). In the subgroup with left ventricular EF≥40%, we found a higher thiazide use (P=0.014) and a less frequent use of low EF GDMTs (P=0.044) in case of being recommended saltSubs. Beyond the well-established risk for hyperkalaemia, our preliminary results suggest a potentially negative impact of saltSubs on GDMT use, especially for ACEis/ARBs/ARNis in CHF management. saltSub recommendations and their availability from open sale outlets should be considered to avoid possible misuse or deference from GDMTs in the future. Informed advice to consumers should also be considered from HCPs or pharmacists.

#1485 Hypertension management of CKD patients referred to Hypertension Excellence centres in 27 countries: on behalf of the ESH Hypertension and Kidney WG

Abstract Background and Aims Real-life management of hypertensive patients with chronic kidney disease (CKD) is unclear and may vary across countries. Our aim was to identify unmet needs and heterogeneity of management in this population of patients in Europe and the Middle-East through our network of European Society of Hypertension (ESH) Excellence Centers. Method A survey was conducted in 2023 by the ESH to assess management of CKD patients referred to ESH-Hypertension Excellence Centres (ESH-ECs) at first referral visit. The questionnaire contained 64 questions with which ESH-ECs representatives were asked to estimate pre-existing CKD management quality and data for their management are reported here. Results Overall, 88 ESH-ECs from 27 countries participated (fully completed surveys: 66/88 (75.0%)). ESH-ECs reported that 28% (median, interquartile range: 15-50%) had pre-existing CKD, of whom 10% (5- 30%) were previously referred to a nephrologist, while 30% (15-40%) had resistant hypertension. The reported rate of previous recent (&amp;lt;6 months) estimated glomerular filtration rate (eGFR) and urine Albumin- Creatinine Ratio (UACR) testing were 80% (50-95%) and 30% (15-50%), respectively. The reported use of renin-angiotensin system blockers was 80% (70-90%). When a nephrologist was part of the ESH-EC teams the reported rates for SGLT2 inhibitors (27.5% (20-40%) vs 15% (10-25), p = 0.003), GLP1-RA (10% (10-20%) vs 5% (5-10%), p = 0.003) and mineralocorticoid receptor antagonists (20% (10-30%) vs 15% (10-20%), p = 0.05) use were greater as compared to ESH-ECs without nephrologist participation. The rate of reported resistant hypertension, recent eGFR and UACR results and management of CKD patients prior to referral varied widely across centres in Europe countries and in the Middle East. Conclusion Our results indicate deficits regarding CKD screening, use of nephroprotective drugs and referral to nephrologists before referral to ESH-ECs but results varied widely across centres. This information can be used to build specific programs to improve care in hypertensives with CKD.

#1626 The role of sodium-glucose cotransporter 2 inhibitors in diabetic nephropathy and non diabetic renal disease in diabetes mellitus type 2 patients

Abstract Background and Aims Diabetes Mellitus type 2 (DM2) leads to chronic kidney disease in a 30-40% of diabetic patients and it is the major cause of end stage renal disease (ESRD). The clinical course of diabetic kidney disease is very heterogeneous and there is a lack of agreement between clinical parameters and renal histology. Besides, lesions of non-diabetic kidney disease (NDRD) can coexist with lesions of diabetic nephropathy (DN) in two-thirds of kidney biopsies in patients with diabetes. There is not a specific treatment against diabetic kidney disease, treatment based in the blockade of renin-angiotensin-aldosterone system has demonstrated a delay of kidney function decline but the diabetic kidney disease is still the main cause of renal replacement by dialysis. Recently, a new class of oral glucose -lowering drugs, sodium-glucose cotransporter 2 (SGLT2) inhibitors, have shown beneficial effects into cardiovascular protection and chronic kidney disease in diabetic patients but it is not clear the beneficial effect in DN. The aim of this study is to evaluate the role of SGLT2 inhibitors in diabetic patients with DN biopsy-confirmed and compare with a group of diabetic patients with NDRD (DN and superimposed non diabetic renal disease lesions, NDRD). Method This is a retrospective study with DM2 patients and kidney biopsy performed. Patient demographic characteristics were recorded and diagnosis of Hypertension, duration of DM2, presence or absence of diabetic retinopathy (DR), macrovascular disease and treatment with renin–angiotensin– aldosterone system blockers (RAASB), oral hypoglycaemic agents, insulin, and aldosterone antagonists. Histological lesions were recorded according to the pathologic classification of DN. Renal function was based on estimated filtration rate CKD-EPI (eGFR mil/min/m2), the urine albumin-creatinine ratio (UACR mg/gr) and the 24 h proteinuria (g/24 h). Diabetic patients were classified according to the kidney biopsies in DN and NDRD. The follow up was assessed at the time of sodium-glucose cotransporter 2 (SGLT2) inhibitors started, 6, 12 and 24 months. Results A total of 64 DM2 patients with kidney biopsy were included in the study. Basal characteristics are summarized in Table 1. DN was diagnosed in 47% and NDRD in 53% of DM2 patients. DM2 patients with NDRD were older (64 ± 10 vs 70 ± 10, p = 0.017), and with more macrovascular disease than patients with DN, 6 (20%) vs 15 (44%), p = 0.04. Instead, DM2 patients with DN showed higher uACR levels than NDRD (2355 ± 2540 vs 706 ± 730, p = 0.02). A 40% of DM2 patients with DN were classified in nodular sclerosis class III of glomerular classification of DN. Interstitial fibrosis and tubular atrophy score were higher in DN versus NDRD patients, (interstitial fibrosis 12 (40%) vs 3 (9%), p = 0.006, tubular atrophy 10 (33%) vs 3 (9%), p = 0.02, Table 2. At the end of follow up, 20% of DM2 patients developed ESRD. According SGLT2 inhibitors treatment, a higher proportion of ESRD and death were observed in DM2 patients without SGLT2 inhibitors than patients with SGLT2 inhibitors, ESRD 11 (39%) vs 2 (6%), p = 0.001, death 9 (32%) vs 4 (11%), p = 0.03. Serum creatinine levels were lower in DM2 patients with SGLT2 inhibitors (118 ± 63.7 vs 203 ± 80.7, p = 0.001), but no differences was observed in uACR between groups. A significant reduction in serum creatinine levels with better eGFR were observed in both groups (DN and NDRD) under SGLT2 inhibitors comparing to group without SGLT2 inhibitors, serum creatinine levels 124 ± 78 vs 236 ± 83, p = 0.008, 107 ± 40 vs 201 ± 110, p = 0.02, and eGFR mil/min/m2 60.9 ± 27.5 vs 25.1 ± 7.2, p = 0.004, 62.6 ± 21.2 vs 33.7 ± 16.2, p = 0.005, Table 3. Conclusion A higher proportion of DM2 showed NDRD lesions in kidney biopsy. Treatment with SGLT2 inhibitors reduced progression of chronic renal disease in DN and NDRD DM2 patients. A reduced progression to ESRD and death were also observed in NDRD DM2 patients with SGLT2 treatment.

#2551 Treatment and prognosis for myocardial infarction in patients with chronic kidney disease 2010-2022: a nationwide cohort study

Abstract Background and Aims Chronic kidney disease (CKD) is present in &amp;gt;30% of patients with acute coronary syndrome. Although prognosis following myocardial infarction (MI) has improved throughout the last decades, patients with CKD remain at considerably increased risk of recurrent cardiovascular events. We investigate use of guideline-directed cardiovascular interventions and cardioprotective medical therapy and associated cardiovascular outcomes in patients with and without CKD. Method From 2010 to 2022, all adult patients hospitalized with first-time MI (ICD10: DI21) were identified in nationwide Danish health care registers. CKD was defined by an estimated glomerular filtration rate (eGFR) &amp;lt;60 ml/min/1.73 m2. Study outcomes were evaluated in multiple logistic and cause-specific Cox regression models with computation of standardized risks/probabilities of outcomes. The probability of referral for interventional work-up was evaluated based on 30-days probability of cardiovascular interventions, i.e. coronary angiography (CAG) and/or revascularization. Guideline-directed cardioprotective medical therapy, i.e. lipid-lowering treatment, dual antiplatelet therapy, renin-angiotensin-system inhibitors, aldosterone antagonists, beta blockers, calcium channel blockers, and nitrates, was evaluated as 90-days probability of treatment in 90-days survivors. Lastly, one-year standardized risk of mortality was evaluated. All models were adjusted for age, sex, kidney transplant, congestive heart failure, hypertension, diabetes, cancer, thromboembolism, and any arrhythmia. Results In total, 21 009 patients were included; median age 72 years (IQR 63; 81), 60.8% males, median eGFR 82 ml/min/1.73 m2, 20.9% CKD. Patients with CKD were older, less likely to be male, had a longer admission time, had more comorbidities, and received more medical treatment compared with patients without CKD. The 30-days probability of CAG was 77.8% (95% CI 77.2%-78.5%) and 65.8% (95% CI 64.1%-67.3%), p &amp;lt; 0.001, and of revascularization 58.2% (95% CI 57.3%-59.0%) and 48.8% (95% CI46.9%-50.5%), p &amp;lt; 0.001, in patients without and with CKD, respectively. Development in probability of cardiovascular interventions and risk of 1-year mortality during the study period is depicted in Fig. 1. Probability of cardioprotective medical therapy in 90-days survivors is presented in Fig. 2. The 1-year risk of mortality was 16.4% (95% CI 15.7%-17.0%) and 20.9% (95% CI 19.9%-22.0%) in patients without and with CKD. Conclusion Although prognosis following first-time myocardial infarction has been improved for all patients, CKD continues to be associated with lower rates of guideline-directed cardiovascular interventions and cardioprotective medical therapy and increased 1-year mortality compared with patients without CKD.

Safety of Antiandrogens for the Treatment of Female Androgenetic Alopecia with Respect to Gynecologic Malignancies

The most common type of alopecia in women is female androgenetic alopecia (FAGA), characterized by progressive hair loss in a patterned distribution. Many oral therapies, including spironolactone (an aldosterone antagonist), androgen receptor blockers (e.g., flutamide/bicalutamide), 5-alpha-reductase inhibitors (e.g., finasteride/dutasteride), and oral contraceptives, target the mechanism of androgen conversion and binding to its respective receptor and therefore could be administered for the treatment of FAGA. Despite significant advances in the oral treatment of FAGA, its management in patients with a history of gynecological malignancies, the most common cancers in women worldwide, may still be a concern. In this review, we focus on the safety of antiandrogens for the treatment of FAGA patients. For this purpose, a targeted literature review was conducted on PubMed, utilizing the relevant search terms. To sum up, spironolactone seems to be safe for the systemic treatment of FAGA, even in high-risk populations. However, a general uncertainty remains regarding the safety of other medications in patients with a history of gynecologic malignancies, and further studies are needed to evaluate their long-term safety in patients with FAGA and risk factors to establish an optimal risk assessment and treatment selection protocol.

#417 Targeting parietal epithelial cell activation with mineralocorticoid receptor antagonism controls FSGS and crescentic glomerulonephritis

Abstract Background and Aims We have recently demonstrated that targeting specific pathways in parietal epithelial cells (PEC) can markedly alleviate experimental extracapillary glomerular injury [1]. Accumulating evidence has indicated the potential contributions of the mineralocorticoid receptor (MR) to the pathophysiology of chronic kidney disease. MR is expressed in endothelial cells, glomerular mesangial cells, podocytes, and distal tubular cells. Previous studies have shown that administering mineralocorticoid receptor antagonists has beneficial effects in various renal injury animal models, the role of the MR in extracapillary glomerulopathies is still elusive and mechanistically unclear. Methods To investigate the cell-specific role of the MR in PEC in the course of focal segmental glomerulosclerosis (FSGS) and crescentic glomerulonephritis (GN), we generated chimeric mice specifically lacking MR (Pec Cre Nr3c2lox/lox) in PECs using an inducible Cre recombinase system. Maladaptive FSGS was induced by combining a high-salt diet and deoxycorticosterone acetate (DOCA) with unilateral nephrectomy (DOCA-UniN). Crescentic glomerulonephritis (GN) was induced using the anti-glomerular basement membrane nephrotoxic serum (NTS) model. Results At baseline, Pec Cre Nr3c2wt/wt and Pec Cre Nr3c2lox/lox mice displayed no kidney morphology and function differences. When challenged by DOCA-UniN, PEC-selective Nr3c2 targeting significantly inhibited the expression of PEC activation markers Ki67, CD44, and FSGS lesions. Importantly, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function compared to Pec Cre Nr3c2 wt/wt counterparts. Likewise, Pec Cre Nr3c2lox/lox mice showed less albuminuria and preserved renal function in the NTS-induced CGN model. Crescents were also more numerous and organised in Pec Cre Nr3c2wt/wt mice than in Pec Cre Nr3c2lox/lox animals. Next, we examined whether pharmacological MR inhibition could alleviate the severity of crescentic GN. When Pec Cre Nr3c2wt/wt mice were orally given eplerenone for 14 days after the onset of the crescentic GN, they were significantly protected from renal injury and failure (decreased proteinuria, normal BUN and reduced number of crescent). Such global action was associated with less expression of the CD44 activation marker on PECs. Thus, genetic disruption of MR in PEC and pharmacological inhibition using eplerenone reduced glomerular expression of CD44 and crescent formation. Furthermore, kidney biopsies of individuals diagnosed with crescentic glomerulonephritis displayed increased expression of MR in PEC within FSGS and crescents. We next evaluated PEC migration under various conditions (DMSO, HB-EGF, Eplerenone, or HB-EGF+Eplerenone) for 24 hours. Eplerenone fully abrogated HB-EGF-induced PEC migration and Pcna, Snai1, and Vim mRNA expressions. Conclusion Altogether, these results indicate the critical role of MR in PEC activation during crescentic glomerulonephritis, along with the recently discovered CD9/EGFR/PDGFR [1] and CLDN1 pathways. This further supports the idea that the PEC phenotype switch is not a bystander event but plays a targetable critical active pathogenic role in FGSS and, more surprisingly, in crescentic GN. MR modulation using eplerenone may be a new therapeutic option for the management of such severe disease.

#615 Generalisability of cardiovascular RCTs to patients with chronic kidney disease in clinical practice: a comparison between RCTs and real-world data

Abstract Background and Aims Randomised controlled trials (RCTs) often apply stringent eligibility criteria, which could limit the external applicability of RCTs to patients in routine clinical practice. This is specifically troublesome in the setting of chronic kidney disease (CKD) given that kidney disease is commonly used as an ineligibility criterion in RCTs. In this pilot study we estimated the eligibility of patients with CKD in routine clinical practice in five major cardiovascular outcome trials - CREDENCE, DAPA-CKD, CIBIS II, CIBIS III, and AUGUSTUS - and described reasons for ineligibility. Method We included patients with CKD (defined as an estimated glomerular filtration rate (eGFR) &amp;lt;60 ml/min/1.73 m2 or an urinary albumin creatinine ratio (UACR) &amp;gt;3 mg/mmol present for &amp;gt;3 months) from the Utrecht Patient Oriented Database (UPOD) who visited a cardiovascular outpatient clinic in the University Medical Centre Utrecht between 2012 and 2019. The eligibility criteria were extracted from the selected RCTs and consequently modelled on the patients from UPOD. The percentage of eligible patients and reasons for ineligibility were described descriptively. The percentage of eligible patients for CIBIS II and CIBIS III were only calculated for patients with heart failure, and for the AUGUSTUS trial for patients with coronary artery disease as patients with these conditions were targeted. Patients could not fulfil multiple inclusion criteria and or meet multiple exclusion criteria or both. Results In total, 9005 UPOD patients with CKD were included. Patients had a mean age of 65 ± 14 years, 42% was female, mean eGFR was 49 ± 17, 1741 (19%) had a history of atherosclerotic cardiovascular disease, and 765 (8%) of heart failure. Overall, 0.05% of patients would be eligible for the DAPA-CKD trial and 0% for the CREDENCE trial. Of included patients with heart failure, 2% would have been eligible for CIBIS II and 3% for CIBIS III. Of included patients with coronary artery disease, 2% would have been eligible for the AUGUSTUS trial. Main reasons for ineligibility for DAPA-CKD were not fulfilling the inclusion criteria for UACR (52%), eGFR (20%), or the prescription of RAAS-inhibitors (arb) (49%) or meeting the exclusion criteria for primary kidney disease (PRD, 6%), or a kidney transplant (15%), or other comorbidities. Similarly, patients were often ineligible for the CREDENCE trial because they did not fulfill the inclusion criteria for UACR (48%), eGFR (18%), HbA1c (35%), or prescription of a RAAS-inhibitor (43%) or met one of the exclusion criteria for PRD (29%), cardiovascular disease (23%), or prescription of a mineralocorticoid receptor antagonist (10%). For CIBIS II, main reasons for ineligibility were not fulfilling the inclusion criteria for left-ventricular ejection fraction (LVEF, 50%) or prescription of an ace-inhibitor (42%) or diuretic (33%) or meeting the exclusion criteria of coronary artery disease (17%) or prescription of a calcium-channel blocker (16%). For CIBIS III, patients were also ineligible because they were not fulfilling the inclusion criteria for age (46%), LVEF (46%), or prescription of diuretics (31%) or met the exclusion criteria for serum creatinine (9%) or prescription of an angiotension receptor blocker (14%). Lastly, for the AUGUSTUS trial, patients were mainly ineligible due to not fulfilling the inclusion criteria of atrial fibrillation (79%) or percutaneous coronary interventions (PCI, 91%) or meeting the eGFR exclusion criteria (14%). Conclusion Based on this pilot study, less than 3% of patients with CKD in routine clinical practice would be eligible to participate in cardiovascular RCTs. Patients were often ineligible because they did not fulfil the inclusion criteria and a substantial number of patients was ineligible due to kidney disease. The low eligibility rate of patients with CKD in cardiovascular trials could limit the generalisability of results to patients with CKD treated in practice. To improve generalisability, RCTs in patients with CKD should aim to include more patients who reflect the patients with CKD treated in practice.

Balcinrenone plus dapagliflozin in patients with heart failure and chronic kidney disease: Results from the phase 2b MIRACLE trial.

Many patients with heart failure (HF) have chronic kidney disease (CKD) and may not tolerate mineralocorticoid receptor antagonists. We investigated the efficacy and safety of the novel mineralocorticoid receptor modulator balcinrenone in combination with dapagliflozin in a phase 2b study. From January 2021 to October 2023, we randomized 133 adults with symptomatic HF, ejection fraction <60%, estimated glomerular filtration rate (eGFR) ≥30 to ≤60 ml/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) ≥30 to <3000 mg/g, to receive balcinrenone 15, 50 or 150 mg/day plus dapagliflozin 10 mg/day, or dapagliflozin 10 mg/day plus placebo, for 12 weeks. Enrolment was stopped early because of slow recruitment. Relative reductions in UACR from baseline to week 12 (primary endpoint) were not significantly different between the balcinrenone plus dapagliflozin groups versus dapagliflozin plus placebo. There was no clear balcinrenone dose-response relationship. There were possible dose-dependent increases in serum potassium levels, reduced eGFR in the highest dose group, and non-significant trends towards reduced N-terminal pro-B-type natriuretic peptide levels. Hyperkalaemia adverse events led to discontinuation in two participants receiving balcinrenone plus dapagliflozin and none in those receiving dapagliflozin plus placebo. While the smaller than planned sample size limits interpretation, we did not see significant reduction in UACR in patients treated with balcinrenone plus dapagliflozin compared with dapagliflozin plus placebo.