Search Results (63)

Diabetic kidney disease (DKD) remains a primary driver of end-stage kidney disease and cardiovascular morbidity despite the optimized use of renin–angiotensin system (RAS) inhibitors and sodium-glucose cotransporter-2 (SGLT2) inhibitors. Recent evidence identifies the overactivation of the mineralocorticoid receptor (MR) as a critical, independent pathway leading to persistent renal inflammation and fibrosis. In the diabetic milieu, MR overactivation—driven by both aldosterone and ligand-independent factors such as Rac1 GTPase and oxidative stress—triggers pro-inflammatory and pro-fibrotic gene networks. Unlike traditional steroidal mineralocorticoid receptor antagonists (MRAs), the novel non-steroidal MRA finerenone exhibits a distinct binding mode that more effectively blocks the recruitment of transcriptional co-activators, thereby silencing detrimental downstream signaling in podocytes, fibroblasts, and myeloid cells. Preclinical models have demonstrated that MR blockade significantly reduces albuminuria and preserves podocyte integrity independent of systemic blood pressure. These findings translated into landmark clinical trials; the FIDELIO-DKD and FIGARO-DKD trials established that finerenone significantly reduces the risk of kidney disease progression and cardiovascular events across a broad spectrum of chronic kidney disease stages in type 2 diabetes. Furthermore, recent data from the FINEARTS-HF and CONFIDENCE trials suggest a synergetic benefit when combined with SGLT2 inhibitors, offering more robust cardiorenal protection with a manageable risk of hyperkalemia. This review synthesizes the current understanding of MR pathophysiology and clinical evidence, providing a comprehensive framework for the integration of MRAs into the evolving standard of care for patients with diabetic kidney disease. Full article

Cardiac arrest is a way of demise of patients who are affected by heart failure (HF), being more frequent in those with HF with a reduced left ventricular ejection fraction (HFrEF), and is, as such, responsible for 30–50% of cardiac death. Specific data on the risk of sudden cardiac death (SCD) related to HF with a preserved ejection fraction (HFpEF) and HF with a mildly reduced ejection fraction (HFmrEF) are lacking, as well as data regarding ventricular arrhythmias in this population. Considering the 0.3% person/year incidence rate of investigator-reported ventricular tachycardia (VT) and ventricular fibrillation (VF), the rate of SCD in the analyzed population seems to be 1.3% per year. Age, gender, history of diabetes and myocardial infarction, left bundle branch block (LBBB) on electrocardiogram (ECG), and a natural logarithm of N-terminal pro B-type natriuretic peptide (NT-proBNP), identified a subgroup of HFpEF patients with a higher risk (5-year cumulative incidence of 11%) of sudden death (SD). In HFpEF patients, both glifozins and finerenone did not demonstrate a beneficial effect on SCD incidence in comparison to placebo. A significantly lower rate of SCD emerged in patients who were treated with dapaglifozin (10 vs. 26 pts) among patients with HF with an improved ejection fraction (HFimpEF), who were defined as patients with a previous left ventricular ejection fraction (LVEF) < 40%. Promising methods discussed include cardiac magnetic resonance, myocardial scintigraphy, genetic assessment, and electrophysiologic studies for predicting SCD in those patients. In conclusion, arrhythmic SCD in HFpEF patients should not be considered merely as an effect of VT/VF; bradyarrhythmia is probably more frequent and dangerous. The effects of drugs in preventing SCD in HFpEF have not been demonstrated yet. Full article

Chronic Kidney Disease (CKD) is a global health crisis, projected to be the fifth leading cause of death by 2040. Its progression is driven by a reinforcing loop of mitochondrial dysfunction, oxidative stress, and chronic inflammation. The AMPK-NRF2–FOXO axis serves as a central “redox-metabolic rheostat” that maintains renal homeostasis but is commonly dysfunctional in CKD. Herein, we explore the molecular crosstalk within this network, where AMPK acts as a metabolic and redox sensor, NRF2 governs the cytoprotective response, and FOXO isoforms regulate autophagy, antioxidative defense, and senescence. We highlight the functional paradoxes within the axis and evaluate the benefits and drawbacks of nutraceuticals and pharmacological agents, such as NRF2 inducer bardoxolone methyl, underscoring the necessity for context-dependent modulation. Furthermore, we examine the AMPK–NRF2–FOXO axis within the current clinical management, according to the 2024/2026 KDIGO guidelines. These guidelines reflect a shift toward a multi-targeted pharmacological approach involving metformin, SGLT2 inhibitors, GLP-1 receptor agonists, finerenone, and hypoxia-inducible factor-prolyl hydroxylase (HIF-PH) inhibitors. Full article

This study aimed to validate the health economic model for finerenone in the treatment of patients with heart failure (HF) and left ventricular ejection fraction (LVEF) ≥40% in the United Kingdom. A Markov model informed by the pivotal FINEARTS-HF trial compared finerenone + standard of care (SoC) to SoC alone. Cross-validation was performed on the results (life years [LYs] and quality adjusted life years [QALYs]) for the SoC arm against three models in HF with LVEF >40%. External validation compared cardiovascular (CV) mortality and the number of total HF events (hospitalisation for heart failure [HFF] and urgent heart failure visit [UHFV]) against FINEARTS-HF. The model estimated similar discounted outcomes to other models in HF (6.47 vs. 6.63–7.91 LYs and 4.78 vs. 4.63–5.27 QALYs). CV deaths (22 vs. 27) and UHFV events (60 vs. 61) avoided with finerenone were similar between the model and FINEARTS-HF. The broad estimated range of avoided HHF events (205–303 vs. 219 in FINEARTS-HF) was largely driven by baseline patient age. This comprehensive validation exercise demonstrated that the finerenone model accurately estimated observed clinical data and was well aligned in its projections with previous models assessing similar populations. Full article

Mineralocorticoid receptor antagonism represents a therapeutic cornerstone in patients with HFrEF. However, the efficacy of MRAs in patients HFmrEF or HFpEF remains unclear. While the TOPCAT trial did not demonstrate a statistically significant reduction in cardiovascular mortality or hospitalizations for HF in this patient population, post hoc data suggested potential clinical benefits of MRAs in specific patient subgroups. More recently, the landscape has evolved with the FINEARTS-HF trial, which generated novel evidence regarding finerenone, a non-steroidal MRA, in the HFmrEF and HFpEF cohorts. This investigation established a statistically significant decrease in the primary composite endpoint, comprising cardiovascular death and worsening heart failure events. This positive outcome was principally attributable to a lower incidence of total WHF events. Key findings also highlighted the therapy’s rapid onset of action and favorable safety profile. Notably, finerenone’s benefit was consistent across the entire LVEF spectrum and was not influenced by baseline SGLT2i use, sex, or age. Finerenone’s established indication is for patients with type 2 diabetes mellitus and chronic kidney disease to reduce heart failure risk. However, based on the findings of the FINEARTS-HF trial, finerenone may represent a novel therapeutic pillar for patients with HFpEF and HFmrEF. In this review, we aim to describe the potential benefits of MRAs in the pathophysiology of HFpEF and HFmrEF and in different patient phenotypes, the results of the FINEARTS-HF trial, and the most important subanalyses of the study. Full article

Despite the clinical efficacy of doxorubicin (DOX), effective strategies to prevent its cardiotoxicity are still lacking. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist (MRA), has demonstrated cardioprotective properties; however, its role and mechanism in DOX-induced cardiotoxicity (DIC) remain unclear. In this study, Finerenone treatment was found to significantly alleviate DOX-induced cardiac dysfunction and pathological remodeling in both mouse models and cultured cells. Mechanistically, molecular docking suggests that Finerenone may directly bind to Latent Transforming Growth Factor Beta Binding Protein 2 (LTBP2), a key regulator of TGF-β bioavailability. This potential binding could inhibit the LTBP2–TGF-β axis, thereby suppressing DOX-induced activation and subsequent Smad3 phosphorylation. The importance of this pathway was supported by the similar anti-fibrotic effects observed with the TGF-β inhibitor LY2109761. However, our findings on the direct binding of Finerenone to LTBP2 are preliminary and require further validation through additional experimental approaches. These results identify LTBP2 as a novel direct target of Finerenone and reveal an additional mechanism underlying its cardioprotective action, suggesting its potential repurposing for the prevention of DIC. Full article

Patients with diabetes and chronic kidney disease (CKD-DM) often have residual albuminuria despite pharmacological treatment. Finerenone targets mineralocorticoid overactivation, but real-world evidence remains limited. This study evaluated the impact of finerenone in a cohort of patients with CKD-DM. This was a real-life study including patients with CKD-DM and an estimated glomerular filtration rate (eGFR) ≥ 20 mL/min/1.73 m², treated with finerenone, aged ≥ 18 years, and followed at the Nephrology Department of Vall d’Hebron Hospital. Clinical and laboratory data were collected at baseline and at 1, 3, and 6 months of treatment. Changes in albuminuria and eGFR were analyzed in patients who completed 6 months of follow-up. A total of 60 patients were included in the analysis; 39 (65%) were male, with a median age of 79 ± 10.12 years. Finerenone was initiated at 10 mg daily in 57 patients (95%), with 38.3% escalating to 20 mg after 1 month. After 6 months, the urinary albumin-to-creatinine ratio (UACR) decreased by 37.1% (p = 0.012, n = 34). Patients with an initial eGFR drop > 20% showed a greater UACR decrease of around 43% at 3 (p = 0.012) and 6 months (p = 0.013). A significant 9.5% decline in eGFR was observed at 1 month, followed by stabilization at 3 and 6 months. Finerenone was discontinued in 10% of the patients due to adverse events. Hyperkalemia occurred in 18.3% of the patients, but no hospitalizations for adverse events or heart failure were reported. In summary, finerenone induced a significant 37.1% reduction in albuminuria after 6 months of treatment. This reduction was more pronounced in patients who experienced an initial eGFR dip ≥ 20%. Finerenone was generally well tolerated and appears to be a promising therapeutic strategy for reducing albuminuria in this population. Full article

Diabetes mellitus (DM) continues to be a global world health problem. Despite medical advances, both DM and chronic kidney disease (CKD) remain global health issues with high mortality and limited options to prevent end-stage renal failure. Current therapies encompass five classes of drugs: (1) angiotensin-converting-enzyme inhibitors (ACEI) or angiotensin II receptor blockers (AIIRB); (2) sodium-glucose-transporter 2 (SGLT2) inhibitors; (3) glucagon-like peptide-1 receptor agonists (GLP-1 RA); and (4) an antagonist of type 1 endothelin receptor (ET1R) with proven efficacy to reduce albuminuria and proteinuria. (5) The mineralocorticoid receptor antagonist (MRA) finerenone has been tested in RCTs as a kidney protective agent. In our review, we summarize many of the principal trials that have generated evidence in this regard. Many novel agents—many of them proven not only for DM management but also for the treatment of obesity with or without DM or heart failure (HF)—are now in development and may be added to the five classical pillars: other non-steroidal MRA (balcinrenone); aldosterone synthase inhibitors (baxdrostat and vicadrostat); other GLP-1 RA (tirzepatide, survodutide, retatrutide, and cagrilintide); ET1 R antagonists, (zibotentan); and soluble guanylate cyclase activators (avenciguat). These new agents aim to slow disease progression further and reduce cardiovascular risk. Future strategies rely on integrated, patient-centered approaches and personalized therapy to curb renal disease and its related complications. Full article

Background: Finerenone has emerged as a promising nonsteroidal mineralocorticoid receptor antagonist for patients with chronic kidney disease (CKD), yet its safety and efficacy in kidney transplant recipients remain unstudied. Methods: A total of 1750 kidney transplant recipients were screened, and 39 were prescribed finerenone alongside angiotensin-converting enzyme inhibitors or angiotensin II receptor blockers. Fifteen patients who met inclusion criteria and used finerenone consistently for at least six months were compared with 15 matched controls. Proteinuria, renal function, serum potassium, and other laboratory and clinical parameters were assessed at baseline and at 1, 3, and 6 months. Results: Finerenone was discontinued in two patients (5.1%) due to flushing and headache. Severe hyperkalemia occurred in four patients (10.2%). In the finerenone group, proteinuria significantly decreased at all time points (p < 0.05), with a 40% reduction at six months. No significant changes in estimated glomerular filtration rate or serum creatinine were observed. Conclusions: Finerenone is a promising adjunct therapy in kidney transplant patients for reducing proteinuria without impairing renal function for those patients who can tolerate it. However, in the early phase of treatment initiation, patients should be closely monitored for adverse effects including hyperkalemia. Full article

Background/Objectives: Recent randomized controlled trial evidence in adults with type 2 diabetes (T2D) and chronic kidney disease (CKD) indicates that adding finerenone to empagliflozin provides additive clinical benefit. A prespecified analysis demonstrates that this benefit is consistent irrespective of prior glucagon-like peptide-1 receptor agonist (GLP-1 RA) use. We aimed to assess the effectiveness of adding finerenone to existing sodium-glucose cotransporter-2 inhibitor (SGLT2i) and GLP-1 RA therapy in a real-world setting. Methods: We performed a retrospective cohort study of adults with T2D and CKD from Maccabi Healthcare Services diabetes, endocrinology, and nephrology clinics in Haifa, Israel. Included individuals initiated finerenone between 1 August 2023, and 31 January 2025, and met the following criteria: estimated glomerular filtration rate (eGFR) of 25–60 mL/min/1.73 m²; urinary albumin-to-creatinine ratio (UACR) > 300 mg/g; and a history of ≥12 weeks of SGLT2i (empagliflozin or dapagliflozin) and GLP-1 RA (liraglutide, dulaglutide, or semaglutide) use prior to finerenone initiation. Outcomes were assessed at the last measurement taken within 26 ± 10 weeks of finerenone initiation. The primary outcome was adjusted percent change in log-transformed UACR from baseline to follow-up. Secondary outcomes were adjusted mean changes in eGFR and serum potassium. We used multiple linear regression models. Prespecified subgroup analyses examined the UACR change by age, sex, body mass index (BMI), baseline eGFR, and baseline UACR. Results: Fifty-one individuals were included in the study, with a mean age of 66.0 ± 9.5 years and a mean BMI 30.9 ± 5.2 kg/m². The median eGFR was 45 mL/min/1.73 m² (IQR 36–52), and the median UACR was 1001 mg/g (IQR 515–1599). 94% were receiving a renin–angiotensin system inhibitor. Finerenone was initiated at 10 mg/day and titrated to 20 mg/day in eight individuals. Over a median follow-up of 27 weeks, the adjusted percent change in UACR was −51.3% (p < 0.001), consistent across prespecified subgroups. The adjusted mean eGFR change was −3.92 mL/min/1.73 m² (p < 0.001). Serum potassium increased by +0.34 mmol/L (p < 0.001). Conclusions: In adults with T2D and albuminuric CKD already receiving an SGLT2i and a GLP-1 RA, adding finerenone substantially reduced albuminuria. Full article

Background: Heart failure (HF) remains a major global health challenge with substantial morbidity, mortality, and healthcare burden. Finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), has demonstrated cardiovascular and renal benefits in patients with diabetes mellitus (DM) and chronic kidney disease (CKD), as well as reduced HF events, in patients with HF with preserved or mildly reduced ejection fraction (HFpEF/HFmrEF). However, its efficacy and safety in patients with HF with reduced EF (HFrEF) or HFmrEF, DM, and CKD, remain unclear. Notably, finerenone is currently reimbursed only for DM and CKD but not for HF itself. Methods: We conducted a retrospective, single-center study of patients with HFrEF/HFmrEF who received finerenone between August 2022 and June 2025. Clinical data were obtained 6 months before, at baseline, and 6 months after the initiation of finerenone. The primary outcome was the change in serum NT pro-B-type natriuretic peptide (BNP). Results: Among 37 patients screened, 22 who initiated finerenone on a de novo basis were included. Median age was 75 years, 73% were male, and all had DM and CKD, which are current indications of finerenone. NT pro-BNP decreased significantly during the on-treatment period compared with the pre-treatment period (p < 0.001). Left ventricular end-diastolic diameter and left ventricular ejection fraction remained unchanged during the pre-treatment period but improved significantly during the on-treatment period (p < 0.001 for both). Renal function and serum potassium remained stable during the whole study period (p > 0.05 for both). Conclusions: In this real-world study of patients with HFrEF/HFmrEF complicated by DM and CKD, finerenone was associated with significant improvements in NT pro-BNP and cardiac remodeling indices without worsening renal function or hyperkalemia. Full article

Through the mineralocorticoid receptor, aldosterone controls extracellular volume and arterial blood pressure by stimulating Na⁺ absorption and K⁺ secretion in epithelial cells of the kidney, colon, and several glands. Hyperaldosteronism promotes fibrosis and inflammation in epithelial and non-epithelial tissues, thereby favoring loss of kidney and heart function. Mineralocorticoid receptor blockade therefore gains relevance especially in renal and cardiac disease. Kidney-derived Klotho is a powerful anti-aging protein with anti-fibrosis and anti-inflammatory effects providing cardio- and nephroprotection. We wondered whether Klotho expression and production is influenced by mineralocorticoid receptor agonists and antagonists. Using four renal cell lines, Madin-Darby canine kidney (MDCK), normal rat kidney, subtype 52E (NRK-52E), human kidney 2 (HK2) cells, and primary renal proximal tubule epithelial cells (RPTECs), and the four most frequently prescribed mineralocorticoid receptor blockers, spironolactone, eplerenone, finerenone, and esaxerenone, we assessed Klotho gene expression by qRT-PCR and Klotho protein by Western blotting. Aldosterone and eplerenone did not significantly affect Klotho expression in either cell line. Spironolactone enhanced Klotho expression in MDCK and NRK-52E cells and downregulated Klotho in HK2 cells and RPTECs. Novel non-steroidal mineralocorticoid receptor antagonist finerenone downregulated Klotho expression in MDCK, NRK-52E, and low-dose finerenone in HK2 cells. To conclude, common mineralocorticoid receptor antagonists are characterized by highly diverse effects on Klotho in four renal cell lines. Further studies are needed to define the role of mineralocorticoid receptor blockade for Klotho production. Full article

Diabetic nephropathy (DN) remains the leading cause of end-stage renal disease worldwide, with proximal tubular epithelial cells (PTECs) playing a central role in its pathogenesis. Under hyperglycemic conditions, PTECs drive a pathological triad of inflammation, apoptosis, and fibrosis. Recent advances reveal that these processes interact synergistically to form a self-perpetuating vicious cycle, rather than operating in isolation. This review systematically elucidates the molecular mechanisms underlying this crosstalk in PTECs. Hyperglycemia induces reactive oxygen species (ROS) overproduction, advanced glycation end products (AGEs) accumulation, and endoplasmic reticulum stress (ERS), which collectively activate key inflammatory pathways (NF-κB, NLRP3, cGAS-STING). The resulting inflammatory milieu triggers apoptosis via death receptor and mitochondrial pathways, while apoptotic cells release damage-associated molecular patterns (DAMPs) that further amplify inflammation. Concurrently, fibrogenic signaling (TGF-β1/Smad, Hippo-YAP/TAZ) promotes epithelial–mesenchymal transition (EMT) and extracellular matrix (ECM) deposition. Crucially, the resulting fibrotic microenvironment reciprocally exacerbates inflammation and apoptosis through mechanical stress and hypoxia. Quantitative data from preclinical and clinical studies are integrated to underscore the magnitude of these effects. Current therapeutic strategies are evolving toward multi-target interventions against this pathological network. We contrast the paradigm of monotargeted agents (e.g., Finerenone, SGLT2 inhibitors), which offer high specificity, with that of multi-targeted natural product-based formulations (e.g., Huangkui capsule, Astragaloside IV), which provide synergistic multi-pathway modulation. Emerging approaches (metabolic reprogramming, epigenetic regulation, mechanobiological signaling) hold promise for reversing fibrosis. Future directions include leveraging single-cell technologies to decipher PTEC heterogeneity and developing kidney-targeted drug delivery systems. We conclude that disrupting the inflammation–apoptosis–fibrosis vicious cycle in PTECs is central to developing next-generation therapies for DN. Full article

Background & Objectives: Data on the efficacy and adverse effects of finerenone in patients with nondiabetic chronic kidney disease (CKD) are limited, particularly regarding ethnic diversity. This study aimed to evaluate the outcomes of finerenone in patients with nondiabetic CKD previously treated with standard therapies and investigate associated adverse effects, including hyperkalemia and hypotension. Methods: This is a retrospective exploratory study. It is a single-center study including patients with nondiabetic CKD who visited King Fahad Medical City in Riyadh, Saudi Arabia. The primary exposure was finerenone treatment, assessing its effects on albuminuria, kidney function, and blood pressure (BP), following prior use of renin–angiotensin–aldosterone system and sodium–glucose transport protein 2 inhibitors. The measured outcomes were the urine albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). The UACR (primary endpoint) was calculated as the mean of two morning spot urine samples collected consecutively 1 day apart. During each 4-week treatment period, secondary endpoints included changes in UACR, as determined by a 24 h urine sample, BP, and eGFR. The Wilcoxon signed-rank test was used to compare changes in continuous variables before and after therapy initiation. Statistical significance was set at p < 0.05. Results: This study included 16 patients with nondiabetic CKD (median age, 38.5 years [range, 35–50 years]; 56.3% male). The baseline eGFR was 66 mL/min/1.73 m² (47–82.5), with a UACR of 90.0 mg/g (58.8–132.5). No hyperkalemia was observed (potassium level, 4 mmol/L [3.8–4.4]). However, significant reductions in systolic and diastolic BPs were observed. Albuminuria improved significantly: the UACR decreased from 90.0 to 39.3 mg/g (p = 0.04). No adverse events, including hyperkalemia or hypotension, were reported. Conclusions: Finerenone showed promise in reducing albuminuria and blood pressure among patients with nondiabetic chronic kidney disease, with no significant adverse effects reported. These findings suggest potential benefits for this patient population, warranting further investigation. Full article

Heart failure represents a complex clinical syndrome characterized by progressive ventricular dysfunction, systemic congestion, and high mortality despite significant advances in pharmacological and device-based therapy. This review explores recent developments across the heart failure continuum, with a focus on therapeutic advances across the continuum of care, with emphasis on both established and emerging strategies. In patients with reduced ejection fraction, early initiation of the four pillars markedly lowers cardiovascular events, yet real-world implementation remains limited by therapeutic inertia and underdosing. Novel agents such as finerenone provide cardiorenal benefits in patients with diabetes and chronic kidney disease, while glucagon-like peptide-1 receptor agonists show promise in preserved or mildly reduced ejection fraction, particularly with obesity. Tricuspid regurgitation, once considered a secondary phenomenon, is now recognized as a modifiable contributor to disease progression, with transcatheter interventions offering new therapeutic avenues. In advanced disease, innovations including donation after circulatory death and the development of total artificial heart systems offer promising solutions to overcome organ shortages and improve access to transplantation. Together, these advances highlight a shift toward precision-guided, multidisciplinary heart failure care. Full article