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Background Mineralocorticoid receptor antagonists (MRAs) reduce systolic blood pressure (SBP) and increase serum potassium concentration ([K+]). This indirect comparison investigated any differences in SBP-lowering and hyperkalemia risk between finerenone, a nonsteroidal MRA, and the steroidal MRA spironolactone ± a potassium binder. Methods In FIDELITY (a pooled analysis of FIDELIO-DKD and FIGARO-DKD), a subgroup of patients with treatment-resistant hypertension (TRH) and chronic kidney disease meeting eligibility criteria of the AMBER trial were identified (FIDELITY-TRH). The main outcomes were mean change in SBP, incidence of serum [K+] ≥5.5 mmol/L and hyperkalemia-associated treatment discontinuation. Results at ∼17 weeks were compared with 12 weeks from AMBER. Results In 624 FIDELITY-TRH patients and 295 AMBER patients, the least squares mean change in SBP (mmHg) from baseline was −7.1 for finerenone and −1.3 for placebo {between-group difference −5.74 [95% confidence interval (CI) −7.99 to −3.49], P < .0001} versus −11.7 for spironolactone + patiromer and −10.8 for spironolactone + placebo [between-group difference −1.0 (95% CI −4.4–2.4), P = .58]. The incidence of serum [K+] ≥5.5 mmol/L was 12% for finerenone and 3% for placebo versus 35% with spironolactone + patiromer and 64% with spironolactone + placebo. Treatment discontinuation due to hyperkalemia was 0.3% for finerenone and 0% for placebo versus 7% for spironolactone + patiromer and 23% for spironolactone + placebo. Conclusions In patients with TRH and chronic kidney disease compared with spironolactone with or without patiromer, finerenone was associated with a lower SBP reduction and lower risk of hyperkalemia and treatment discontinuation. Trial Registration: AMBER (NCT03071263), FIDELIO-DKD (NCT02540993), FIGARO-DKD (NCT02545049) Graphical Abstract Graphical Abstract Video Abstract 10.1093/ckj/sfac234 Video Abstract sfac234media1 6314668222112

Jianwei Ma,1,2,* Qin Su,1,* Hanlu Wang,1 Jiayan Xu,1,3 Chenyi Yuan,1 Guicai Fan,1,3 Jiapei Ying,1 Xueyan Bian1 1Department of Nephrology, The First Affiliated Hospital of Ningbo University, Ningbo, 315010, People’s Republic of China; 2Department of Clinical Medicine, Tongji University School of Medicine, Shanghai, 200092, People’s Republic of China; 3Health Science Center, Ningbo University, Ningbo, 315211, People’s Republic of China*These authors contributed equally to this workCorrespondence: Xueyan Bian, Department of Nephrology, The First Affiliated Hospital of Ningbo University, 59 Liuting Street, Haishu District, Ningbo, 315010, People’s Republic of China, Email fyybianxueyan@nbu.edu.cnBackground: The combination of non-steroidal mineralocorticoid receptor antagonists (nsMRAs) and sodium-glucose cotransporter-2 (SGLT2) inhibitors has shown renoprotective benefits in diabetic kidney disease; however, their synergistic effects in non-diabetic chronic kidney disease (CKD) remain underexplored. This study evaluated the efficacy and safety of finerenone combined with dapagliflozin versus dapagliflozin monotherapy in patients with non-diabetic CKD.Methods: A single-center, retrospective cohort study was conducted on 121 patients with biopsy- or clinically confirmed non-diabetic CKD treated with either dapagliflozin alone (n = 77) or in combination with finerenone (n = 44) for ≥ 6 months. Propensity score matching (PSM) yielded 33 well-balanced pairs. The primary outcomes were changes in the urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR) over 6 months. Secondary outcomes included Blood Pressure, biochemical parameters, and treatment-related adverse events. Repeated-measures ANOVA and mediation analyses were used to assess longitudinal changes and mechanistic relationships.Results: Finerenone Combined with Dapagliflozin therapy significantly enhanced UACR reduction at 3 months (median 63.4% vs 47.8%, P = 0.007) and 6 months (66.9% vs 40.8%, P = 0.002), compared with dapagliflozin alone, with a higher proportion of patients achieving ≥ 50% reduction (84.9% vs 45.5%, P < 0.001). The eGFR was preserved or improved with combination therapy (+2.06% vs – 5.08%, P < 0.001), whereas dapagliflozin alone therapy was associated with a decline. Mediation analysis indicated that early UACR reduction explained only 1.45% of the treatment effect on eGFR changes, suggesting albuminuria-independent mechanisms. The incidence of adverse events, including hyperkalemia, did not differ significantly between the groups, and all events were mild and manageable.Conclusion: Finerenone combined with dapagliflozin yielded superior proteinuria reduction and better preservation of renal function compared with dapagliflozin alone in patients with non-diabetic CKD, without compromising safety. These findings provide real-world evidence for the potential additive renoprotective effects of dual therapy and underscore the need for prospective trials to validate its efficacy in non-diabetic populations.Keywords: finerenone, dapagliflozin, non-diabetic chronic kidney disease, albuminuria, estimated glomerular filtration rate

The overactivation of the mineralocorticoid receptor (MR) promotes pathophysiological processes related to multiple physiological systems, including the heart, vasculature, adipose tissue and kidneys. The inhibition of the MR with classical MR antagonists (MRA) has successfully improved outcomes most evidently in heart failure. However, real and perceived risk of side effects and limited tolerability associated with classical MRA have represented barriers to implementing MRA in settings where they have been already proven efficacious (heart failure with reduced ejection fraction) and studying their potential role in settings where they might be beneficial but where risk of safety events is perceived to be higher (renal disease). Novel non-steroidal MRA have distinct properties that might translate into favourable clinical effects and better safety profiles as compared with MRA currently used in clinical practice. Randomised trials have shown benefits of non-steroidal MRA in a range of clinical contexts, including diabetic kidney disease, hypertension and heart failure. This review provides an overview of the literature on the systemic impact of MR overactivation across organ systems. Moreover, we summarise the evidence from preclinical studies and clinical trials that have set the stage for a potential new paradigm of MR antagonism. Graphical Abstract

Diabetic nephropathy (DN) could impair the function of the glomerular filtration barrier by damaging the podocytes. Extant research has demonstrated that aldosterone plays a crucial role in this progression. Finerenone is a novel, high-selective mineralocorticoid receptor antagonist that has been demonstrated to be efficacious in renal protection in DN patients, albeit with an unclear underlying mechanism. Podocytes were stimulated with RPMI 1640 medium containing different concentrations of glucose and treated with finerenone to evaluate the protective effect of finerenone on podocytes in high glucose environment. Intraperitoneal injection of STZ was used to induce diabetic nephropathy rats and intragastric administration with finerenone or vehicles, and the changes of renal function, renal pathological changes and renal tissue protein expression were assayed. Cell experiment showed that high glucose could induce epithelial-mesenchymal transition (EMT). After finerenone treatment, we accessed the EMT-related protein and found EMT was reversed. Besides, the cell migration capacity and cytoskeleton were also ameliorated. To further explore the mechanism, we found that finerenone could upregulate the expression of Krüppel-like factor 5 (KLF5) which was downregulated in a high glucose environment. After the silence of KLF5 in the presence of finerenone, the rescue experiment showed the protective function of finerenone is counteracted by KLF5. In animal experiment, after the treatment of finerenone, the level of blood creatinine decreased compared with the DN group while blood urea nitrogen (BUN) and potassium showed no significant difference. The pathological alterations of the treatment group also got ameliorated. Finerenone could normalize the level of EMT-related protein, nephrin, and KLF5 of kidney tissue in DN rats. Our results suggest that finerenone could alleviate high glucose-induced podocyte EMT via regulating KLF5. Further investigation is warranted to elucidate the precise underlying mechanism.

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 2.4 mg once weekly administered for 1 year decreased body weight and significantly improved quality of life and the 6 min 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.

Heart failure (HF) is one of the greatest problems in healthcare and it often coexists with declining renal function. The pathophysiology between the heart and the kidneys is bidirectional. Common mechanisms leading to the dysfunction of these organs result in a vicious cycle of cardiorenal deterioration. It is also associated with difficulties in the treatment of aggravating HF and chronic kidney disease (CKD) and, as a consequence, recurrent hospitalizations and death. As the worsening of renal function has an undeniably negative impact on the outcomes in patients with HF, searching for new treatment strategies and identification of biomarkers is necessary. This review is focused on the pathomechanisms in chronic kidney disease in patients with HF and therapeutic strategies for co-existing CKD and HF.

Chronic kidney disease (CKD) in individuals with type 2 diabetes (T2D) represents a major public health issue; it develops in about 30%–40% of patients with diabetes mellitus and is the most common cause of CKD worldwide. Patients with CKD and T2D are at high risk of both developing kidney failure and of cardiovascular events. Renin–angiotensin system (RAS) blockers were considered the cornerstone of treatment of albuminuric CKD in T2D for more than 20 years. However, the residual risk of progression to more advanced CKD stages under RAS blockade remains high, while in major studies with these agents in patients with CKD and T2D no significant reductions in cardiovascular events and mortality were evident. Steroidal mineralocorticoid receptor antagonists (MRAs) are known to reduce albuminuria in individuals on RAS monotherapy, but their wide clinical use has been curtailed by the significant risk of hyperkalemia and absence of trials with hard renal outcomes. In recent years, non-steroidal MRAs have received increasing interest due to their better pharmacologic profile. Finerenone, the first compound of this class, was shown to effectively reduce the progression of kidney disease and of cardiovascular outcomes in participants with T2D in phase 3 trials. This clinical practice document prepared from a task force of the European Renal Best Practice board summarizes current knowledge on the role of MRAs in the treatment of CKD in T2D aiming to support clinicians in decision-making and everyday management of patients with this condition.

Background: The Colombian Association of Endocrinology, Diabetes and Metabolism (ACE) developed this clinical practice guideline with the aim of providing updated recommendations for the management and follow-up of individuals living with type 2 diabetes mellitus (T2DM) in Colombia. This update responds to the need to revise the recommendations established in the national guideline published in 2016, in light of recent and robust global scientific evidence that has substantially modified the therapeutic approach.Objective: The guideline emphasizes the preventive approach to cardiovascular and renal outcomes, as well as the integration of lifestyle interventions and the incorporation of technology as an essential component of a holistic approach to T2DM care.Methods: The guideline was developed using the GRADE methodology, in accordance with the AGREE II and Institute of Medicine standards. The process included the formulation of nine PICO questions, systematic literature searches, critical appraisal of evidence, and formulation of recommendations by an interdisciplinary panel with patient participation. Transparency was ensured through conflict-of-interest management and external international review.Main recommendations: Combination therapy with metformin and either a sodiumglucose cotransporter-2 inhibitor (SGLT2i) or a dipeptidyl peptidase-4 inhibitor (DPP-4i) is recommended for patients with significantly elevated HbA1c levels, while combinations with sulfonylureas are discouraged.In patients who do not reach glycemic targets with metformin monotherapy, adding an SGLT2i or a glucagon-like peptide-1 receptor agonist (AR GLP-1) is suggested, the latter being particularly indicated in individuals with overweight, obesity, or markedly elevated HbA1c.For patients with inadequate glycemic control despite oral antidiabetic therapy, the preferred next step is the addition of a AR GLP-1, especially in those with a body mass index (BMI) >27 kg/m². Basal insulin should be considered when glycemic control is not achieved with a AR GLP-1.In cases of T2DM associated with overweight or obesity, the use of AR GLP-1s or dual GLP-1/GIP receptor agonists is recommended. In individuals with class II or higher obesity, metabolic or bariatric surgery may be considered, provided it is accompanied by patient education, individualized risk–benefit assessment, and performed in specialized reference centers.Cardiorenal protective therapies (SGLT2i, AR GLP-1, finerenone) should be prioritized and initiated regardless of glycemic control or concomitant therapy, in individuals with atherosclerotic cardiovascular disease, heart failure, or chronic kidney disease, according to individual clinical profiles.The use of real-time continuous glucose monitoring (CGM) systems is recommended in patients receiving multiple daily insulin doses and experiencing hypoglycemia or inadequate glycemic control.Finally, the guideline underscores the importance of continuous diabetes education and a multidisciplinary approach as cornerstones of comprehensive care for all individuals with T2DM.Conclusions: This guideline provides a practical and rigorous framework for the comprehensive management of T2DM in Colombia, with recommendations tailored to the national context and high potential to improve quality of life and reduce disease burden.

Aldosterone is a mineralocorticoid hormone with a well-known effect on the renal tubule leading to water retention and potassium reabsorption. Other major effects of the hormone include the induction of proinflammatory activity that leads to progressive fibrotic damage of the target organs, heart and kidney. Blocking the aldosterone receptor therefore represents an important pharmacological strategy to avoid the clinical conditions deriving from heart failure (CHF) and chronic kidney disease (CKD). However, steroidal mineralocorticoid receptor antagonists (MRA) have a low safety profile, especially in CKD patients due to the high incidence of hyperkalemia. A new generation of nonsteroidal MRA has recently been developed to obtain a selective receptor block avoiding side-effects like hyperkalemia and thereby making the drugs suitable for administration to CKD patients. This review summarizes the results of published preclinical and clinical studies on the nonsteroidal MRA, apararenone esaxerenone and finerenone. The trials showed a better safety profile with maintained drug efficacy compared with steroidal MRA. For this reason, nonsteroidal MRA represent an interesting new therapeutic approach for the prevention of CHF and CKD progression. Some basic research findings also yielded interesting results in acute clinical settings such as myocardial infarction and acute kidney injury.

The study aimed to retrospectively evaluate the efficacy and safety of finerenone in patients diagnosed with IgA nephropathy. 42 IgA nephropathy patients treated with finerenone combined with renin-angiotensin system inhibitor (RASI) and 42 patients who received RASI monotherapy were included in this study. The follow-up duration was 3 months. The efficacy and safety of finerenone were assessed based on key parameters, including urine protein creatinine ratio (UPCR), estimated glomerular filtration rate (eGFR), serum creatinine, serum albumin, hematuria, and serum potassium at 1 and 3 months after treatment initiation. This study demonstrated that finerenone combined with RASI significantly reduced proteinuria in IgA nephropathy patients. Two-way repeated measures ANOVA revealed a significant time * treatment interaction ( = 0.032), and subsequent one-way repeated measures ANOVA showed a marked decline in log-transformed UPCR over time in the combination group (P < 0.001) but not in the monotherapy group (P = 0.187). Correspondingly, the combination group achieved a 27.29% reduction in UPCR at one month (95% CI: 13.47-39.68%, P = 0.017) and a 34.17% reduction at three months (95% CI: 21.84-52.75%, P < 0.001) compared to baseline, whereas RASI monotherapy failed to show any significant proteinuria-reduction effects. Notably, the antiproteinuric effect was consistent across subgroups. Serum potassium and creatinine levels remained stable, and no adverse events related to hyperkalemia were observed. The retrospective evaluation suggests that finerenone combined with RASI effectively reduced proteinuria in IgA nephropathy patients, underscoring its potential as a viable treatment option for this patient population.