Nonsteroidal Mineralocorticoid Receptor Antagonist Finerenone Improves Diastolic Dysfunction in Preclinical Nondiabetic Chronic Kidney Disease.

BACKGROUND: The mineralocorticoid receptor plays a significant role in the development of chronic kidney disease (CKD) and associated cardiovascular complications. Classic steroidal mineralocorticoid receptor antagonists are a therapeutic option, but their use in the clinic is limited due to the associated risk of hyperkalemia in patients with CKD. Finerenone is a nonsteroidal mineralocorticoid receptor antagonist that has been recently investigated in 2 large phase III clinical trials (FIDELIO-DKD [Finerenone in Reducing Kidney Failure and Disease Progression in Diabetic Kidney Disease] and FIGARO-DKD [Finerenone in Reducing Cardiovascular Mortality and Morbidity in Diabetic Kidney Disease]), showing reductions in kidney and cardiovascular outcomes. METHODS AND RESULTS: We tested whether finerenone improves renal and cardiac function in a preclinical nondiabetic CKD model. Twelve weeks after 5/6 nephrectomy, the rats showed classic signs of CKD characterized by a reduced glomerular filtration rate and increased kidney weight, associated with left ventricular (LV) diastolic dysfunction and decreased LV perfusion. These changes were associated with increased cardiac fibrosis and reduced endothelial nitric oxide synthase activating phosphorylation (ser 1177). Treatment with finerenone prevented LV diastolic dysfunction and increased LV tissue perfusion associated with a reduction in cardiac fibrosis and increased endothelial nitric oxide synthase phosphorylation. Curative treatment with finerenone improves nondiabetic CKD-related LV diastolic function associated with a reduction in cardiac fibrosis and increased cardiac phosphorylated endothelial nitric oxide synthase independently from changes in kidney function. Short-term finerenone treatment decreased LV end-diastolic pressure volume relationship and increased phosphorylated endothelial nitric oxide synthase and nitric oxide synthase activity. CONCLUSIONS: We showed that the nonsteroidal mineralocorticoid receptor antagonist finerenone reduces renal hypertrophy and albuminuria, attenuates cardiac diastolic dysfunction and cardiac fibrosis, and improves cardiac perfusion in a preclinical nondiabetic CKD model.

Eplerenone reduces lymphangiogenesis in the contralateral kidneys of UUO rats.

Inflammation and fibrosis often occur in the kidney after acute injury, resulting in chronic kidney disease and consequent renal failure. Recent studies have indicated that lymphangiogenesis can drive renal inflammation and fibrosis in injured kidneys. However, whether and how this pathogenesis affects the contralateral kidney remain largely unknown. In our study, we uncovered a mechanism by which the contralateral kidney responded to injury. We found that the activation of mineralocorticoid receptors and the increase in vascular endothelial growth factor C in the contralateral kidney after unilateral ureteral obstruction could promote lymphangiogenesis. Furthermore, mineralocorticoid receptor activation in lymphatic endothelial cells resulted in the secretion of myofibroblast markers, thereby contributing to renal fibrosis. We observed that this process could be attenuated by administering the mineralocorticoid receptor blocker eplerenone, which, prevented the development of fibrotic injury in the contralateral kidneys of rats with unilateral ureteral obstruction. These findings offer valuable insights into the intricate mechanisms underlying kidney injury and may have implications for the development of therapeutic strategies to mitigate renal fibrosis in the context of kidney disease.

Drug Therapy for Acute and Chronic Heart Failure with Preserved Ejection Fraction with Hypertension: A State-of-the-Art Review.

In this comprehensive state-of-the-art review, we provide an evidence-based analysis of current drug therapies for patients with heart failure with preserved ejection fraction (HFpEF) in the acute and chronic phases with concurrent hypertension. Additionally, we explore the latest developments and emerging evidence on the efficacy, safety, and clinical outcomes of common and novel drug treatments in the management of HFpEF with concurrent hypertension. During the acute phase of HFpEF, intravenous diuretics, mineralocorticoid receptor antagonists (MRAs), and vasodilators are pivotal, while in the chronic phase, angiotensin-converting enzyme inhibitors and angiotensin receptor blockers have proven effective in enhancing clinical outcomes. However, the use of calcium channel blockers in HFpEF with hypertension should be approached with caution, owing to their potential negative inotropic effects. We also explored emerging drug therapies for HFpEF, such as sodium-glucose co-transporter 2 (SGLT2) inhibitors, angiotensin receptor-neprilysin inhibitor (ARNI), soluble guanylate cyclase (sGC) stimulators, novel MRAs, and ivabradine. Notably, SGLT2 inhibitors have shown promise in reducing heart failure hospitalizations and cardiovascular mortality in patients with HFpEF, regardless of their diabetic status. Additionally, ARNI and sGC stimulators have demonstrated potential in improving symptoms, functional capacity, and quality of life. Nonetheless, additional research is necessary to pinpoint optimal treatment strategies for HFpEF with concurrent hypertension. Furthermore, long-term studies are essential to assess the durability and sustained benefits of emerging drug therapies. Identification of novel targets and mechanisms underlying HFpEF pathophysiology will pave the way for innovative drug development approaches in the management of HFpEF with concurrent hypertension.

Prediction of endogenous mineralocorticoid receptor activity by depressor effects of mineralocorticoid receptor antagonists in patients with primary aldosteronism.

Patients with primary aldosteronism have an increased risk of developing cardiovascular disease. The response to mineralocorticoid receptor antagonists varies among individuals, indicating diverse mineralocorticoid receptor activities in these patients. This study explored the factors linked to the efficacy of blood pressure reduction through mineralocorticoid receptor antagonists in patients with primary aldosteronism. We examined the relationship between the reduction in blood pressure and patient characteristics in a group of 41 patients with primary aldosteronism (24 males, mean age 55 ± 13 years, including 34 patients diagnosed with bilateral primary aldosteronism) before and after undergoing treatment with mineralocorticoid receptor antagonists. Significant reductions in office blood pressure were observed 3 and 6 months after treatment initiation. Single correlation analyses showed that the urinary chloride-to-potassium ratio displayed the strongest positive association with blood pressure reduction, surpassing plasma aldosterone concentration, plasma renin activity, and urinary sodium-to-potassium ratio, at 3 and 6 months. Multiple correlation analyses revealed a consistent and independent positive correlation between the urinary chloride-to-potassium ratio and blood pressure reduction at 3 and 6 months. The optimal threshold for the urinary chloride-to-potassium ratio with respect to its ability to lower blood pressure, was determined as 3.18. These results imply that the urinary chloride-to-potassium ratio may be independently associated with the effectiveness of blood pressure reduction facilitated by mineralocorticoid receptor antagonists. Moreover, it could potentially serve as a valuable predictor of the effectiveness of these agents and function as an indicator of endogenous mineralocorticoid receptor activity in patients with primary aldosteronism.

Cardiorenal Benefits of Finerenone in Different Races and Kidney Function in Patients with Chronic Kidney Disease.

BACKGROUND: The mineralocorticoid receptor plays an important pathophysiological role in cardiorenal diseases by causing inflammation and fibrosis. Mineralocorticoid receptor antagonists (MRAs) are well known in treating cardiovascular disease and diverse nephropathies. However, the first-generation MRA (spironolactone) and the second-generation MRA (eplerenone) remain underutilized because of the risk of inducing severe adverse events. As a selective nonsteroidal MRA, finerenone is safer and more effective and improves cardiorenal outcomes in patients with chronic kidney disease (CKD) and type 2 diabetes mellitus (T2DM). However, the effect of finerenone on cardiorenal outcomes in patients of different races and kidney function (estimated glomerular filtration rate) is unclear. SUMMARY: In this review, we summarized the impact of finerenone on patients with CKD and T2DM from randomized controlled trials. The synthesis of published data aims to address the questions pertaining to the cardiorenal benefits of finerenone among various racial groups and different levels of kidney function. KEY MESSAGE: Finerenone presents racial differences and effects associated with kidney function in CKD and T2DM patients. Due to the limited data for subgroups, it is prudent to approach the conclusion with caution.

Comprehensive characterization of the effect of mineralocorticoid receptor antagonism with spironolactone on the renin-angiotensin-aldosterone system in healthy dogs.

OBJECTIVE: To characterize the dose-exposure-response effect of spironolactone on biomarkers of the classical and alternative arms of the renin-angiotensin-aldosterone system (RAAS) in healthy dogs. ANIMALS: Ten healthy purpose-bred Beagle dogs. PROCEDURES: Study dogs were randomly allocated to 2 spironolactone dosing groups (2 mg/kg PO q24hr, 4 mg/kg PO q24hr). The dogs received 7-day courses of spironolactone followed by a 14-day washout period in a crossover (AB/BA) design. Angiotensin peptides and aldosterone were measured in serum using equilibrium analysis, and plasma canrenone and 7-α-thiomethyl spironolactone (TMS) were quantified via liquid chromatography-mass spectrometry/mass spectroscopy (LC-MS/MS). Study results were compared before and after dosing and between groups. RESULTS: Following spironolactone treatment, dogs had a significant increase in serum aldosterone concentration (P = 0.07), with no statistical differences between dosing groups. Significant increases in angiotensin II (P = 0.09), angiotensin I (P = 0.08), angiotensin 1-5 (P = 0.08), and a surrogate marker for plasma renin activity (P = 0.06) were detected compared to baseline following spironolactone treatment during the second treatment period only. Overall, changes from baseline did not significantly differ between spironolactone dosages. RAAS analytes were weakly correlated (R < 0.4) with spironolactone dosage and plasma canrenone or plasma TMS. There were no adverse clinical or biochemical effects seen at any spironolactone dosage during treatment. CONCLUSIONS: Treatment with spironolactone increased serum aldosterone concentration in healthy dogs and impacted other biomarkers of the classical and alternative arms of the RAAS. There was no difference in effect on the RAAS between 2 and 4 mg/kg/day dosing. Dosage of 4 mg/kg/day was safe and well-tolerated in healthy dogs.

Mineralocorticoid Receptor Antagonism Reduces Inflammatory Pain Measures in Mice Independent of the Receptors on Sensory Neurons.

Corticosteroids are commonly used in the treatment of inflammatory low back pain, and their nominal target is the glucocorticoid receptor (GR) to relieve inflammation. They can also have similar potency at the mineralocorticoid receptor (MR). The MR has been shown to be widespread in rodent and human dorsal root ganglia (DRG) neurons and non-neuronal cells, and when MR antagonists are administered during a variety of inflammatory pain models in rats, pain measures are reduced. In this study we selectively knockout (KO) the MR in sensory neurons to determine the role of MR in sensory neurons of the mouse DRG in pain measures as MR antagonism during the local inflammation of the DRG (LID) pain model. We found that MR antagonism using eplerenone reduced evoked mechanical hypersensitivity during LID, but MR KO in paw-innervating sensory neurons only did not. This could be a result of differences between prolonged (MR KO) versus acute (drug) MR block or an indicator that non-neuronal cells in the DRG are driving the effect of MR antagonists. MR KO unmyelinated C neurons are more excitable under normal and inflamed conditions, while MR KO does not affect excitability of myelinated A cells. MR KO in sensory neurons causes a reduction in overall GR mRNA but is protective against reduction of the anti-inflammatory GRα isoform during LID. These effects of MR KO in sensory neurons expanded our understanding of MR's functional role in different neuronal subtypes (A and C neurons), and its interactions with the GR.

Effects of the mineralocorticoid receptor antagonist eplerenone in experimental autoimmune encephalomyelitis.

There is growing evidence indicating that mineralocorticoid receptor (MR) expression influences a wide variety of functions in metabolic and immune response. The present study explored if antagonism of the MR reduces neuroinflammation in the spinal cord of mice with experimental autoimmune encephalomyelitis (EAE). Eplerenone (EPLE) (100 mg/kg dissolved in 30% 2-hydroxypropyl-ß-cyclodextrin) was administered intraperitoneally (i.p.) daily from EAE induction (day 0) until sacrificed on day 17 post-induction. The MR blocker (a) significantly decreased the inflammatory parameters TLR4, MYD88, IL-1ß, and iNOS mRNAs; (b) attenuated HMGB1, NLRP3, TGF-ß mRNAs, microglia, and aquaporin4 immunoreaction without modifying GFAP. Serum IL-1ß was also decreased in the EAE+EPLE group. Moreover, EPLE treatment prevented demyelination and improved clinical signs of EAE mice. Interestingly, MR was decreased and GR remained unchanged in EAE mice while EPLE treatment restored MR expression, suggesting that a dysbalanced MR/GR was associated with the development of neuroinflammation. Our results indicated that MR blockage with EPLE attenuated inflammation-related spinal cord pathology in the EAE mouse model of Multiple Sclerosis, supporting a novel therapeutic approach for immune-related diseases.

Renin as a Biomarker to Guide Medical Treatment in Primary Aldosteronism Patients. Findings from the SPAIN-ALDO Registry.

INTRODUCTION: Primary aldosteronism (PA) is associated with several cardiometabolic comorbidities. Specific treatment by mineralocorticoid receptor antagonists (MRA) or adrenalectomy has been reported to reduce the cardiometabolic risk. However, the cardiovascular benefit could depend on plasma renin levels in patients on MRA. AIM: To compare the development of cardiovascular, renal and metabolic complications between medically treated patients with PA and those who underwent adrenalectomy, taking the renin status during MRA treatment into account. METHODS: A multicenter retrospective study (SPAIN-ALDO Register) of patients with PA treated at 35 Spanish tertiary hospitals. Patients on MRA were divided into two groups based on renin suppression (n = 90) or non-suppression (n = 70). Both groups were also compared to unilateral PA patients (n = 275) who achieved biochemical cure with adrenalectomy. RESULTS: Adrenalectomized patients were younger, had higher plasma aldosterone concentration, and lower potassium levels than MRA group. Patients on MRA had similar baseline characteristics when stratified into treatment groups with suppressed and unsuppressed renin. 97 (55.1%) of 176 patients without comorbidities at diagnosis, developed at least one comorbidity during follow-up (median 12 months vs. 12.5 months' follow-up after starting MRA and surgery, respectively). Surgery group had a lower risk of developing new cardiovascular events (HR 0.40 [95% CI 0.18-0.90]) than MRA group. Surgical treatment improved glycemic and blood pressure control, increased serum potassium levels, and required fewer antihypertensive drugs than medical treatment. However, there were no differences in the cardiometabolic profile or the incidence of new comorbidities between the groups with suppressed and unsuppressed renin levels (HR 0.95 [95% CI 0.52-1.73]). CONCLUSION: Cardiovascular, renal, and metabolic events were comparable in MRA patients with unsuppressed and suppressed renin. Effective surgical treatment of PA was associated with a decreased incidence of new cardiovascular events when compared to MRA therapy.

Effects of esaxerenone on blood pressure, urinary albumin excretion, serum levels of NT-proBNP, and quality of life in patients with primary aldosteronism.

Primary aldosteronism (PA) is typically managed with mineralocorticoid receptor antagonists (MRAs) barring adrenalectomy. The efficacy of esaxerenone, a nonsteroidal MRA, were explored in patients with PA. Various parameters such as the urinary albumin to creatinine ratio (UACR) and serum levels of N-terminal prohormone of brain natriuretic peptide (NT-proBNP) were evaluated in 25 PA patients before and 3 and 6 months after esaxerenone treatment. Systolic and diastolic blood pressure (BP), and the estimated glomerular filtration rate decreased after treatment, while serum levels of potassium and active renin increased. Significant reductions were observed in UACR 3 and 6 months after treatment. A significant decrease in NT-proBNP was evident at 6 months but not 3 months after treatment. Correlation analysis indicated that the reductions in BP and UACR at 3 months were independent of estimated daily salt intake. Furthermore, the effect of esaxerenone treatment on lowering UACR and NT-proBNP levels was independent of BP reduction. Responders whose systolic BP decreased 6 months after esaxerenone treatment by more than 10 mmHg compared to pretreatment had higher pretreatment NT-proBNP and similar UACR before and after treatment when compared with nonresponders. Esaxerenone improved mental, physical, and social quality of life (QOL) 6 months after treatment compared to healthy controls and increased over time. No patients discontinued treatment due to severe hyperkalemia or renal dysfunction. In conclusion, esaxerenone is a safe and effective MRA for PA treatment, offering significant benefits in terms of hypertension, albuminuria, NT-proBNP levels, and QOL improvement. Esaxerenone effectively lowers BP, UACR, and serum levels of NT-proBNP independent of dietary salt intake in mild PA patients. ARC active renin concentration, DBP diastolic blood pressure, MR mineralocorticoid receptor, MRA mineralocorticoid receptor antagonist, NT-proBNP N-terminal pro-brain natriuretic peptide, PA primary aldosteronism, QOL quality of life, SBP systolic blood pressure, SF-36 Medical Outcomes Study 36-Item Short-Form Health Survey, UACR urinary albumin to creatinine ratio.

Characteristics of women with type 2 diabetes and heart failure in Spain. The DIABET-IC study.

BACKGROUND: Heart failure (HF) is the second most common initial presentation of cardiovascular disease in people with type 2 diabetes mellitus (T2DM). T2DM carries an increased risk of HF in women. The aim of this study is to analyze the clinical characteristics and the treatment received by women with HF and T2DM in Spain. METHODS: The DIABET-IC study included 1517 patients with T2DM in 2018-2019 in Spain, in 30 centers, which included the first 20 patients with T2DM seen in cardiology and endocrinology clinics. They underwent clinical evaluation, echocardiography, and analysis, with a 3-year follow-up. Baseline data are presented in this study. RESULTS: 1517 patients were included (501 women; aged 67.28 ± 10.06 years). Women were older (68.81 ± 9.90 vs. 66.53 ± 10.06 years; p < 0.001) and had a lower frequency of a history of coronary disease. There was a history of HF in 554 patients, which was more frequent in women (38.04% vs. 32.86%; p < 0.001), and preserved ejection fraction being more frequent in them (16.12% vs. 9.00%; p < 0.001). There were 240 patients with reduced ejection fraction. Women less frequently received treatment with angiotensin converting enzyme inhibitors (26.20% vs. 36.79%), neprilysin inhibitors (6.00% vs. 13.51%), mineralocorticoid receptor antagonists (17.40% vs. 23.08%), beta-blockers (52.40% vs. 61.44%), and ivabradine (3.60% vs. 7.10%) (p < 0.001 for all), and 58% received guideline-directed medical therapy. CONCLUSIONS: A selected cohort with HF and T2DM attending cardiology and endocrinology clinics did not receive optimal treatment, and this finding was more pronounced in women.

Renoprotective Effects of Mineralocorticoid Receptor Antagonists Against Diabetic Kidney Disease.

Diabetic kidney disease (DKD) is a growing epidemic worldwide and a leading cause of end-stage kidney disease. Mineralocorticoid receptor (MR) blockade using Finerenone is a recently approved therapeutic approach to slow down the progression of DKD in patients with type 2 diabetes in addition to other therapies such as angiotensin-II converting enzyme inhibitors (ACEIs), angiotensin II receptor blockers (ARBs), sodium-glucose co-transporter 2 (SGLT2) inhibitors, and glucagon-like peptide 1 (GLP-1) analogs. This review elaborates on the pathophysiologic pathways activated by aldosterone (the human mineralocorticoid) in DKD, the pharmacology of three different generations of mineralocorticoid receptor antagonists (MRAs), specifically, spironolactone, eplerenone, and finerenone, and the mechanisms by which these MRAs elicit their protective effects on the kidney under diabetic settings.

The influence of pharmacological mineralocorticoid and glucocorticoid receptor blockade on the cortisol response to psychological stress.

The glucocorticoid cortisol is the end product of the hypothalamic-pituitary-adrenal (HPA) axis and crucial for the stress response in humans. Cortisol regulates numerous biological functions by binding to two different types of receptors: the mineralocorticoid receptor (MR) and the glucocorticoid receptor (GR). Both receptors are found in the brain where they are crucially involved in various mental functions and in feedback inhibition of cortisol release. The precise role of both receptors in the human stress response is not completely understood. In this study, we examined the effects of pharmacological blockade of the MR or the GR on stress-induced cortisol release in a sample of 318 healthy young men (M = 25.42, SD = 5.01). Participants received the MR antagonist spironolactone (300 mg), the GR antagonist mifepristone (600 mg), or a placebo and were subjected 90 min later to a social-evaluative stressor (Trier Social Stress Test) or a non-stressful control condition. We found significantly higher stress-induced cortisol release in the spironolactone group, whereas participants after mifepristone administration did not differ from the control groups. These results suggest that MR blockade results in attenuated fast negative feedback processes and emphasize the important role of the MR during the early phase of the stress response.

Sacubitril/valsartan compared to ramipril in high-risk post-myocardial infarction patients stratified according to use of mineralocorticoid receptor antagonists: Insight from the PARADISE MI trial.

AIM: It is unknown whether safety and clinical endpoints by use of sacubitril/valsartan (an angiotensin receptor-neprilysin inhibitor [ARNI]) are affected by mineralocorticoid receptor antagonists (MRA) in high-risk myocardial infarction (MI) patients. The aim of this study was to examine whether MRA modifies safety and clinical endpoints by use of sacubitril/valsartan in patients with a MI and left ventricular systolic dysfunction (LVSD) and/or pulmonary congestion. METHODS AND RESULTS: Patients (n = 5661) included in the PARADISE MI trial (Prospective ARNI vs. ACE Inhibitor Trial to Determine Superiority in Reducing Heart Failure Events After MI) were stratified according to MRA. Primary outcomes in this substudy were worsening heart failure or cardiovascular death. Safety was defined as symptomatic hypotension, hyperkalaemia >5.5 mmol/L, or permanent drug discontinuation. A total of 2338 patients (41%) were treated with MRA. Safety of ARNI compared to ramipril was not altered significantly by ± MRA, and both groups had similar increase in symptomatic hypotension with ARNI. In patients taking MRA, the risk of hyperkalaemia or permanent drug discontinuation was not significantly altered by ARNI (p > 0.05 for all comparisons). The effect of ARNI compared with ramipril was similar in those who were and were not taking MRA (hazard ratio [HR]MRA 0.96, 95% confidence interval [CI] 0.77-1.19 and HRMRA- 0.87, 95% CI 0.71-1.05, for the primary endpoint; p = 0.51 for interaction [Clinical Endpoint Committee adjudicated]); similar findings were observed if investigator-reported endpoints were evaluated (p = 0.61 for interaction). CONCLUSIONS: Use of a MRA did not modify safety or clinical endpoints related to initiation of ARNI compared to ramipril in the post-MI setting in patients with LVSD and/or congestion.

Single-cell transcriptomics and chromatin accessibility profiling elucidate the kidney-protective mechanism of mineralocorticoid receptor antagonists.

Mineralocorticoid excess commonly leads to hypertension (HTN) and kidney disease. In our study, we used single-cell expression and chromatin accessibility tools to characterize the mineralocorticoid target genes and cell types. We demonstrated that mineralocorticoid effects were established through open chromatin and target gene expression, primarily in principal and connecting tubule cells and, to a lesser extent, in segments of the distal convoluted tubule cells. We examined the kidney-protective effects of steroidal and nonsteroidal mineralocorticoid antagonists (MRAs), as well as of amiloride, an epithelial sodium channel inhibitor, in a rat model of deoxycorticosterone acetate, unilateral nephrectomy, and high-salt consumption-induced HTN and cardiorenal damage. All antihypertensive therapies protected against cardiorenal damage. However, finerenone was particularly effective in reducing albuminuria and improving gene expression changes in podocytes and proximal tubule cells, even with an equivalent reduction in blood pressure. We noted a strong correlation between the accumulation of injured/profibrotic tubule cells expressing secreted posphoprotein 1 (Spp1), Il34, and platelet-derived growth factor subunit b (Pdgfb) and the degree of fibrosis in rat kidneys. This gene signature also showed a potential for classifying human kidney samples. Our multiomics approach provides fresh insights into the possible mechanisms underlying HTN-associated kidney disease, the target cell types, the protective effects of steroidal and nonsteroidal MRAs, and amiloride.

Aldosterone and aldosterone synthase inhibitors in cardiorenal disease.

Modulation of the renin-angiotensin-aldosterone system is a foundation of therapy for cardiovascular and kidney diseases. Excess aldosterone plays an important role in cardiovascular disease, contributing to inflammation, fibrosis, and dysfunction in the heart, kidneys, and vasculature through both genomic and mineralocorticoid receptor (MR)-mediated as well as nongenomic mechanisms. MR antagonists have been a key therapy for attenuating the pathologic effects of aldosterone but are associated with some side effects and may not always adequately attenuate the nongenomic effects of aldosterone. Aldosterone is primarily synthesized by the CYP11B2 aldosterone synthase enzyme, which is very similar in structure to other enzymes involved in steroid biosynthesis including CYP11B1, a key enzyme involved in glucocorticoid production. Lack of specificity for CYP11B2, off-target effects on the hypothalamic-pituitary-adrenal axis, and counterproductive increased levels of bioactive steroid intermediates such as 11-deoxycorticosterone have posed challenges in the development of early aldosterone synthase inhibitors such as osilodrostat. In early-phase clinical trials, newer aldosterone synthase inhibitors demonstrated promise in lowering blood pressure in patients with treatment-resistant and uncontrolled hypertension. It is therefore plausible that these agents offer protection in other disease states including heart failure or chronic kidney disease. Further clinical evaluation will be needed to clarify the role of aldosterone synthase inhibitors, a promising class of agents that represent a potentially major therapeutic advance.

Advances in the management of chronic kidney disease.

Chronic kidney disease (CKD) represents a global public health crisis, but awareness by patients and providers is poor. Defined as persistent abnormalities in kidney structure or function for more than three months, manifested as either low glomerular filtration rate or presence of a marker of kidney damage such as albuminuria, CKD can be identified through readily available blood and urine tests. Early recognition of CKD is crucial for harnessing major advances in staging, prognosis, and treatment. This review discusses the evidence behind the general principles of CKD management, such as blood pressure and glucose control, renin-angiotensin-aldosterone system blockade, statin therapy, and dietary management. It additionally describes individualized approaches to treatment based on risk of kidney failure and cause of CKD. Finally, it reviews novel classes of kidney protective agents including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists, non-steroidal selective mineralocorticoid receptor antagonists, and endothelin receptor antagonists. Appropriate, widespread implementation of these highly effective therapies should improve the lives of people with CKD and decrease the worldwide incidence of kidney failure.

Emerging Preventive Strategies in Chronic Kidney Disease: Recent Evidence and Gaps in Knowledge.

PURPOSE OF REVIEW: Chronic kidney disease (CKD) is increasingly prevalent worldwide and is associated with increased cardiovascular risk. New therapeutic options to slow CKD progression and reduce cardiovascular morbidity and mortality have recently emerged. This review highlights recent evidence and gaps in knowledge in emerging CKD preventive strategies. RECENT FINDINGS: EMPA-Kidney trial found that empagliflozin, a sodium-glucose co-transporter 2 inhibitor (SGLT2i) led to 28% lower risk of progression of kidney disease or death from cardiovascular causes, compared to placebo. This reinforced the previous findings from DAPA-CKD and CREDENCE trials and led to inclusion of SGLT2i as the cornerstone of CKD preventive therapy in both diabetic and non-diabetic CKD. Finerenone, a selective nonsteroidal mineralocorticoid receptor antagonist, slowed diabetic kidney disease progression by 23% compared to placebo in a pool analysis of FIDELIO-DKD and FIGARO-DKD trials. Non-pharmacological interventions, including low protein diet, and early CKD detection and risk stratification strategies based on novel biomarkers have also gained momentum. Ongoing efforts to explore the wealth of molecular mechanisms in CKD, added to integrative omics modeling are well posed to lead to novel therapeutic targets in kidney care. While breakthrough pharmacological interventions continue to improve outcomes in CKD, the heterogeneity of kidney diseases warrants additional investigation. Further research into specific kidney disease mechanisms will facilitate the identification of patient populations most likely to benefit from targeted interventions.

Non-steroidal mineralocorticoid receptor antagonist finerenone ameliorates mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in diabetic tubulopathy.

Diabetic tubulopathy (DT) is a recently recognized key pathology of diabetic kidney disease (DKD). The mitochondria-centric view of DT is emerging as a vital pathological factor in different types of metabolic diseases, such as DKD. Finerenone (FIN), a novel non-steroidal mineralocorticoid receptor antagonist, attenuates kidney inflammation and fibrosis in DKD, but the precise pathomechanisms remain unclear. The role of mineralocorticoid receptor (MR) in perturbing mitochondrial function via the PI3K/Akt/eNOS signaling pathway, including mitochondrial dynamics and mitophagy, was investigated under a diabetic state and high glucose (HG) ambiance. To elucidate how the activation of MR provokes mitochondrial dysfunction in DT, human kidney proximal tubular epithelial (HK-2) cells were exposed to HG, and then mitochondrial dynamics, mitophagy, mitochondrial ROS (mitoROS), signaling molecules PI3K, Akt, Akt phosphorylation and eNOS were probed. The above molecules or proteins were also explored in the kidneys of diabetic and FIN-treated mice. FIN treatment reduced oxidative stress, mitochondrial fragmentation, and apoptosis while restoring the mitophagy via PI3K/Akt/eNOS signaling pathway in HK-2 cells exposed to HG ambiance and tubular cells of DM mice. These findings linked MR activation to mitochondrial dysfunction via PI3K/Akt/eNOS signaling pathway in DT and highlight a pivotal but previously undiscovered role of FIN in alleviating renal tubule injury for the treatment of DKD.