eplerenone and Renal-Insufficiency--Chronic

Approximately 40% of people with type 2 diabetes (T2D) also have chronic kidney disease (CKD), which substantially increases their risk of cardiovascular (CV)-related complications and mortality. Until recently, no approved therapies have directly targeted inflammatory and fibrotic pathways that drive disease progression and organ damage in patients with CKD associated with T2D.. Finerenone is a potent, selective, nonsteroidal mineralocorticoid receptor antagonist (MRA) that targets fibrosis and inflammation by blocking overactivation of the MR in the kidneys and heart. Finerenone has been associated with significant reductions in kidney- and CV-related endpoints compared with placebo and minimal effects on serum potassium and kidney function in phase III trials involving >13,000 patients with diabetic kidney disease (DKD). In addition to reviewing the clinical data, this review compares the properties of finerenone with those of the older steroidal MRAs spironolactone and eplerenone.. Unlike spironolactone and eplerenone, finerenone has demonstrated a favorable benefit-risk profile offering an effective new treatment for patients with CKD associated with T2D. Increases in serum potassium are predictable and manageable and should not discourage the use of finerenone in clinical practice. It is important to discuss where finerenone 'fits best' within the current DKD management landscape.

Topics: Diabetes Mellitus, Type 2; Eplerenone; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Potassium; Renal Insufficiency, Chronic; Spironolactone

Diabetic kidney disease (DKD) represents a leading cause of morbidity and mortality in subjects with diabetes and develops in more than one third of diabetic patients. Steroidal mineralocorticoid receptor antagonists (MRAs - eplerenone and spironolactone) reduce mortality in patients with heart failure with reduced ejection fraction (HFrEF). However, in clinical practice the use of steroidal MRAs is limited by the significant risk of hyperkalemia, especially in patients with impaired renal function. Finerenone, a novel nonsteroidal MRA, shows a higher selectivity and binding affinity for mineralocorticoid receptor (MR) compared to steroidal MRAs and has been shown to reduce chronic kidney disease (CKD) progression and cardiovascular mortality in patients with CKD and T2DM.. This review summarizes the current evidence on efficacy and safety of finerenone in the treatment of patients with CKD and T2DM, and discusses its mechanisms of action investigated in preclinical studies.. Pharmacological properties of finerenone and its unique tissue distribution are responsible for a lower risk of hyperkalemia. Therefore, finerenone represents a valuable therapeutic tool in patients with CKD/diabetic kidney disease (DKD). Recent studies have shown that finerenone delays the progression of CKD and reduce cardiovascular events in patients with DKD, highlighting its safety and efficacy in this high-risk population.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eplerenone; Heart Failure; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Spironolactone; Stroke Volume

Finerenone is a novel non-steroidal mineralocorticoid antagonist (MRA) recently approved for the treatment of chronic kidney disease (CKD) in people with type 2 diabetes (T2D). We aim to conduct a systematic review of finerenone to know the efficacy and safety of finerenone in CKD with or without T2D.. A systematic search in the electronic database of PubMed and Google Scholar was made from inception until September 09, 2022, using several MeSH keywords related to finerenone. Ongoing trials were additionally searched from ClinicalTrials.Gov.. Five phase 2 and three phase 3, randomized, double-blind, placebo- or active-controlled studies of finerenone have been published to date and several other randomized and real-world studies of finerenone are currently undergoing.. In short-term studies in patients with CKD and reduced ejection heart failure, with or without T2D, finerenone 20 mg appears to have a better renal outcome compared with spironolactone and a better mortality outcome compared with eplerenone, with significantly lesser hyperkalemia compared to both spironolactone and finerenone. In long-term studies in patients with CKD and T2D, finerenone 10/20 mg significantly reduces the progression of renal disease and reduced CV endpoints (especially heart failure hospitalization) compared to placebo. Finerenone has no effect on HbA1c, body weight, and sexual side effects including gynecomastia, and has only a modest effect on blood pressure. However, hyperkalemia leading to drug withdrawal was significantly higher with finerenone compared to placebo. Safety data in real-world settings is a pressing priority.

Topics: Diabetes Mellitus, Type 2; Diabetic Nephropathies; Eplerenone; Glycated Hemoglobin; Heart Failure; Humans; Hyperkalemia; Male; Mineralocorticoid Receptor Antagonists; Randomized Controlled Trials as Topic; Renal Insufficiency, Chronic; Spironolactone

Even though five to 11% of child-to-parent abuse (CPA) perpetrators are emerging adults (age 18-23 years), relevant risk factors underlying CPA in this group are understudied.. A multilevel meta-analysis was performed on nine studies (450 effect sizes,. This was the first multilevel meta-analysis focusing exclusively on CPA displayed by emerging adults. The results can be used as a basis for further research into relevant risk factors for CPA in this group and hopefully contribute to the development of health care interventions to reduce chances of CPA occurring.. The online version contains supplementary material available at 10.1007/s10896-022-00469-4.. This study revealed that DEX can alleviate intestinal I/R injury through a microbiota-related mechanism, providing a potential avenue for the management of intestinal I/R injury.

Topics: Aldosterone; Animals; Antihypertensive Agents; Cat Diseases; Cats; Eplerenone; Renal Insufficiency, Chronic; Retrospective Studies

People with chronic kidney disease (CKD) requiring dialysis are at a particularly high risk of cardiovascular death and morbidity. Several clinical studies suggested that aldosterone antagonists would be a promising treatment option for people undergoing dialysis. However, the clinical efficacy and potential harm of aldosterone antagonists for people with CKD on dialysis has yet to be determined.. This review aimed to evaluate the benefits and harms of aldosterone antagonists, both non-selective (spironolactone) and selective (eplerenone), in comparison to control (placebo or standard care) in people with CKD requiring haemodialysis (HD) or peritoneal dialysis (PD).. We searched the Cochrane Kidney and Transplant Register of Studies up to 5 August 2020 using search terms relevant to this review. Studies in the Register are identified through searches of CENTRAL, MEDLINE, and EMBASE, conference proceedings, the International Clinical Trials Register (ICTRP) Search Portal and ClinicalTrials.gov.. We included parallel randomised controlled trials (RCTs), cross-over RCTs, and quasi-RCTs (where group allocation is by a method that is not truly random, such as alternation, assignment based on alternate medical records, date of birth, case record number, or other predictable methods) that compared aldosterone antagonists with placebo or standard care in people with CKD requiring dialysis.. Two review authors independently extracted data and assessed risk of bias for included studies. We used a random-effects model meta-analysis to perform a quantitative synthesis of the data. We used the I² statistic to measure heterogeneity among the studies in each analysis. We indicated summary estimates as a risk ratio (RR) for dichotomous outcomes, mean difference (MD) for continuous outcomes, or standardised mean differences (SMD) if different scales were used, with their 95% confidence interval (CI). We assessed the certainty of the evidence for each of the main outcomes using the GRADE (Grades of Recommendation, Assessment, Development, and Evaluation) approach.. We included 16 studies (14 parallel RCTs and two cross-over RCTs) involving a total of 1446 participants. Thirteen studies compared spironolactone to placebo or standard care and one study compared eplerenone to a placebo. Most included studies had an unclear or high risk of bias. Compared to control, aldosterone antagonists probably reduced the risk of death (any cause) for people with CKD requiring dialysis (9 studies, 1119 participants: RR 0.45, 95% CI 0.30 to 0.67; I² = 0%; moderate certainty of evidence). Aldosterone antagonist probably decreased the risk of death due to cardiovascular disease (6 studies, 908 participants: RR 0.37, 95% CI 0.22 to 0.64; I² = 0%; moderate certainty of evidence) and cardiovascular and cerebrovascular morbidity (3 studies, 328 participants: RR 0.38, 95% CI 0.18 to 0.76; I² = 0%; moderate certainty of evidence). While aldosterone antagonists probably increased risk of gynaecomastia compared with control (4 studies, 768 participants: RR 5.95, 95% CI 1.93 to 18.3; I² = 0%; moderate certainty of evidence), aldosterone antagonists may make little or no difference to the risk of hyperkalaemia (9 studies, 981 participants: RR 1.41, 95% CI 0.72 to 2.78; I² = 47%; low certainty of evidence). Aldosterone antagonists had a marginal effect on left ventricular mass among participants undergoing dialysis (8 studies, 633 participants: SMD -0.42, 95% CI -0.78 to 0.05; I² = 77%). In people with CKD requiring dialysis received aldosterone antagonists compared to control, there were 72 fewer deaths from all causes per 1000 participants (95% CI 47 to 98) with a number needed to treat for an additional beneficial outcome (NNTB) of 14 (95% CI 10 to 21) and for gynaecomastia were 26 events per 1000 participants (95% CI 15 to 39) with a number need to treat for an additional harmful outcome (NNTH) of 38 (95% CI 26 to 68).. Based on moderate certainty of the evidence, aldosterone antagonists probably reduces the risk of all-cause and cardiovascular death and probably reduces morbidity due to cardiovascular and cerebrovascular disease in people with CKD requiring dialysis. For the adverse effect of gynaecomastia, the risk was increased compared to control. For this outcome, the absolute risk was lower than the absolute risk of death. It is hoped the three large ongoing studies will provide better certainty of evidence.

Topics: Bias; Cardiovascular Diseases; Cause of Death; Cerebrovascular Disorders; Eplerenone; Gynecomastia; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Placebos; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Spironolactone

Cardiovascular and renal diseases are one of the main health problems in all industrialized countries. Their incidence is constantly increasing due to the aging of the population and the greater prevalence of obesity and type 2 diabetes. Clinical evidence suggests that aldosterone and the activation of mineralocorticoid receptors (MR) have a role in the pathophysiology of cardiovascular and renal diseases. Moreover, clinical studies demonstrate the benefits of mineralocorticoid receptor antagonists (MRAs) on mortality and progression of heart and kidney disease. In addition to renal effects on body fluid homeostasis, aldosterone has multiple extrarenal effects including the induction of inflammation, vascular rigidity, collagen formation and stimulation of fibrosis. Given the fundamental role of MR activation in renal and cardiac fibrosis, effective and selective blocking of the signal with MRAs can be used in the clinical practice to prevent or slow down the progression of heart and kidney diseases. The aim of the present work is to review the role of MRAs in light of the new evidence as well as its potential use as an antifibrotic in chronic kidney disease (CKD). The initial clinical results suggest that MRAs are potentially useful in treating patients with chronic kidney disease, particularly in cases of diabetic nephropathy. We don't yet have efficacy and safety data on the progression of kidney disease up to the end stage (ESRD) and filling this gap represents an important target for future trials.

Topics: Aldosterone; Body Fluids; Cardiovascular Diseases; Clinical Trials as Topic; Cytokines; Diabetic Nephropathies; Eplerenone; Fibrosis; Heart; Heart Diseases; Homeostasis; Humans; Kidney; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Spironolactone

Mineralocorticoid receptor antagonists (MRAs) that block aldosterone's effects on both epithelial and non-epithelial receptors have become a mainstay of therapy for chronic heart failure. Given that cardiovascular events remain the leading cause of death for patients with end-stage renal disease (ESRD), the question of whether these MRAs can be employed in dialysis patients arises. This review summarizes the rationale for blocking aldosterone in patients with chronic and end-stage kidney disease and surveys the data on both the efficacy and safety of using MRAs in the ESRD population. A small but growing body of literature suggests that use of MRAs by ESRD patients is associated with lower blood pressure, reduced left ventricular (LV) mass, and improved LV ejection fraction. Recently, a large randomized trial found an overall 3-year mortality rate of 6.4% in ESRD patients on spironolactone 25 mg daily vs. 19.7% in ESRD patients on no MRA therapy (p = 0.002), without a significantly increased risk of hyperkalemia.

Topics: Aldosterone; Blood Pressure; Disease Progression; Eplerenone; Heart Failure; Humans; Kidney Failure, Chronic; Mineralocorticoid Receptor Antagonists; Patient Safety; Randomized Controlled Trials as Topic; Renal Dialysis; Renal Insufficiency, Chronic; Spironolactone; Stroke Volume; Survival Analysis; Treatment Outcome; Ventricular Remodeling

Blockade of the renin-angiotensin-aldosterone system (RAAS) is a standard therapeutic intervention in diabetic patients with chronic kidney disease (CKD). Concomitant mineralocorticoid receptor blockade has been studied as a novel approach to further slow down CKD progression. We used PubMed and EMBASE databases to search for relevant literature. We included in our review eight studies in patients of at least 18 years of age, with a diagnosis of type 1 or type 2 diabetes mellitus and diabetic nephropathy, under an angiotensin converting enzyme inhibitor (ACEI) and/or an angiotensin II receptor blocker (ARB) as standard treatment. A subset of patients in each study also received a mineralocorticoid receptor blocker (MRB) (either spironolactone or eplerenone) in addition to standard treatment. Combined treatment with a mineralocorticoid receptor blocker further reduced albuminuria by 23 to 61% compared with standard treatment. Estimated glomerular filtration rate values upon study completion slightly decreased under combined treatment. Blood pressure levels upon study completion were significantly lower with combined treatment in three studies. Hyperkalemia prevalence increased in patients under combined treatment raising dropout rate up to 17%. Therefore, combined treatment by an ACEI/ARB and a MRB may further decrease albuminuria in diabetic nephropathy. This effect may be due to the specific properties of the MRB treatment. Clinicians should regularly check potassium levels because of the increased risk of hyperkalemia. Available evidence should be confirmed by an adequately powered comparative trial of the standard treatment (ACEI or ARB) versus combined treatment by an ACEI/ARB and a MRB.

Topics: Albuminuria; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Diabetic Nephropathies; Drug Therapy, Combination; Eplerenone; Glomerular Filtration Rate; Humans; Hyperkalemia; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Spironolactone; Treatment Outcome

Aldosterone-receptor antagonists dose-dependently reduce both the epithelial and nonepithelial actions of aldosterone. These compounds are used commonly in the treatment of hypertension, with or without aldosteronism, and in the volume-overload periods of various forms of heart failure, cirrhosis, and renal failure. In this regard, the relevant site of action for these compounds is compartmentalized to the distal nephron. The cardiac benefits of aldosterone-receptor blockade now are sufficiently well established to warrant routine use of these compounds for their survival benefits in moderate to advanced stages of heart failure. Aldosterone-receptor antagonists spironolactone and eplerenone commonly are used in the treatment of resistant forms of hypertension. Spironolactone, but not eplerenone, is a commonly used add-on diuretic that provides incremental benefit for salt-and-water excretion in excess of what may be seen with a loop diuretic given together with a thiazide-type diuretic. The dose-response relationship for natriuresis with spironolactone has not been explored completely as to its combination therapy responses. The quite high doses of spironolactone used in patients with cirrhosis and ascites would infer that the overall treatment effect with this compound exceeds simple receptor blockade and may include a nervous system effect that operationally reduces renal sympathetic nerve traffic. The adverse electrolyte and renal function side effects with aldosterone-receptor antagonists are not uncommon in at-risk patients, such as those with chronic kidney disease, and require that dosing be mindful of the tendency of these drugs to importantly increase serum potassium levels.

Topics: Aldosterone; Area Under Curve; Diuretics; Eplerenone; Heart Failure; Humans; Hypertension; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Spironolactone

Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, was evaluated in Japanese patients with heart failure (HF) with reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.. ARTS-HF Japan was a randomized, double-blind, phase 2b study. Patients (n=72) received oral, once-daily (o.d.) finerenone (2.5, 5, 7.5, 10 or 15 mg, up-titrated to 5, 10, 15, 20, or 20 mg, respectively, on day 30) or eplerenone (25 mg every other day, increased to 25 mg o.d. on day 30, and 50 mg on day 60) for 90 days. The primary endpoint was the proportion of individuals with a decrease of >30% in plasma NT-proBNP at day 90. Safety endpoints included the incidence of hyperkalemia. Decreases in NT-proBNP occurred in 23.1% of patients in the eplerenone group and 15.4%, 23.1%, 45.5%, 27.3% and 45.5% in the 2.5→5 mg, 5→10 mg, 7.5→15 mg, 10→20 mg and 15→20 mg finerenone groups, respectively (all P=NS). Mean changes in serum potassium levels were similar between groups.. Because of the small sample size, limited conclusions can be drawn. Considering the results of ARTS-HF and that finerenone was well tolerated in Japanese patients in ARTS-HF Japan, the safety and efficacy of finerenone should be further explored in a large outcomes trial including Japanese patients. (Circ J 2016; 80: 1113-1122).

Topics: Adult; Chronic Disease; Diabetes Mellitus; Double-Blind Method; Eplerenone; Heart Failure; Humans; Hyperkalemia; Japan; Naphthyridines; Natriuretic Peptide, Brain; Patient Safety; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

To evaluate oral doses of the non-steroidal mineralocorticoid receptor antagonist finerenone given for 90 days in patients with worsening heart failure and reduced ejection fraction and chronic kidney disease and/or diabetes mellitus.. Miner Alocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF) was a randomized, double-blind, phase 2b multicentre study (ClinicalTrials.gov: NCT01807221). Of 1286 screened patients, 1066 were randomized. Patients received oral, once-daily finerenone (2.5, 5, 7.5, 10, or 15 mg, uptitrated to 5, 10, 15, 20, or 20 mg, respectively, on Day 30) or eplerenone (25 mg every other day, increased to 25 mg once daily on Day 30, and to 50 mg once daily on Day 60) for 90 days. The primary endpoint was the percentage of individuals with a decrease of >30% in plasma N-terminal pro-B-type natriuretic peptide (NT-proBNP) from baseline to Day 90. A key exploratory endpoint was a composite clinical endpoint of death from any cause, cardiovascular hospitalizations, or emergency presentation for worsening HF until Day 90. Mean age ranged from 69.2 to 72.5 years in different treatment groups (standard deviation 9.7-10.6 years). Decreases in NT-proBNP of >30% from baseline occurred in 37.2% of patients in the eplerenone group and 30.9, 32.5, 37.3, 38.8, and 34.2% in the 2.5→5, 5→10, 7.5→15, 10→20, and 15→20 mg finerenone groups, respectively (P = 0.42-0.88). Except for the 2.5→5 mg finerenone group, the composite clinical endpoint occurred numerically less frequently in finerenone-treated patients compared with eplerenone; this difference reached nominal statistical significance in the 10→20 mg group (hazard ratio 0.56, 95% confidence interval, CI, 0.35; 0.90; nominal P = 0.02), despite the fact that this phase 2 study was not designed to detect statistical significant differences. A potassium level increase to ≥5.6 mmol/L at any time point occurred in 4.3% of patients, with a balanced distribution among all treatment groups.. Finerenone was well tolerated and induced a 30% or greater decrease in NT-proBNP levels in a similar proportion of patients to eplerenone. The finding of reduced clinical events in the finerenone 10→20 mg group should be further explored in a large outcomes trial.

Topics: Aged; Chronic Disease; Diabetes Mellitus; Double-Blind Method; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

To investigate the safety and potential efficacy of the novel non-steroidal mineralocorticoid receptor antagonist finerenone in patients with worsening chronic heart failure and reduced left ventricular ejection fraction (HFrEF) and at high risk of hyperkalaemia and worsening renal dysfunction.. The MinerAlocorticoid Receptor antagonist Tolerability Study-Heart Failure (ARTS-HF; NCT01807221) is a multicentre, randomized, double-blind, active-comparator-controlled, six-parallel-group, phase 2b dose-finding study. In total, 1060 patients with HFrEF and concomitant type 2 diabetes mellitus and/or chronic kidney disease (CKD) will be randomized within 7 days of emergency presentation to hospital for worsening chronic HF to receive finerenone (one of five doses in the range 2.5-20.0 mg once daily) or eplerenone (25 mg every second day to 50 mg once daily for 90 days). The primary objective is to investigate the safety and potential efficacy (measured as the percentage of individuals with a decrease in plasma N-terminal pro-B-type natriuretic peptide [NT-proBNP] of more than 30% relative to baseline at day 90 ± 2) of different oral doses of finerenone compared with eplerenone. Other objectives are to assess the effects of finerenone on a composite clinical endpoint (death from any cause, cardiovascular hospitalizations, or emergency presentations for worsening chronic HF), and on changes in health-related quality of life from baseline.. ARTS-HF is the first phase 2b clinical trial to investigate the effects of finerenone on plasma NT-proBNP in a high-risk population of patients who have worsening chronic HF with type 2 diabetes mellitus and/or CKD presenting at the emergency department.

Topics: Comorbidity; Diabetes Mellitus, Type 2; Double-Blind Method; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Naphthyridines; Natriuretic Agents; Natriuretic Peptide, Brain; Peptide Fragments; Renal Insufficiency, Chronic; Spironolactone

Renin-angiotensin system inhibitors have renoprotective effects in patients with chronic kidney disease, but most patients treated with these drugs have residual urinary albumin excretion. Some small clinical studies show that mineralocorticoid receptor blockade reduces albuminuria. Our study aimed to examine the beneficial effects of addition of a selective aldosterone antagonist, eplerenone, to renin-angiotensin system inhibitors in hypertensive patients with non-diabetic chronic kidney disease.. In this double-blind, randomised, placebo-controlled trial, we enrolled hypertensive patients, aged 20–79 years, with albuminuria (urinary albumin-to-creatinine ratio [UACR] in the first morning void urine of 30–599 mg/g), an estimated glomerular filtration rate of 50 mL/min per 1·73 m2 or more, and who had received an angiotensin-converting enzyme inhibitor, an angiotensin receptor blocker, or both, for at least 8 weeks. Participants were from 59 clinics and hospitals in Japan. Eligible patients were randomly assigned (1:1), stratified by baseline characteristics, to either low-dose eplerenone (50 mg/day) or placebo, with continuation of standard antihypertensive treatment to attain therapeutic goals (<130/80 mm Hg) for 52 weeks. We assessed efficacy in all patients who received allocated treatment, provided a baseline and post-treatment urine sample, and remained in follow-up. We assessed safety in all patients who received allocated treatment. The primary efficacy measure was percent change in UACR in the first morning void urine at week 52 from baseline. The trial is registered at the clinical trials registry of University Hospital Medical Information Network (UMIN), trial identification number UMIN000001803.. Between April 1, 2009, and March 31, 2012, we randomly allocated 170 patients to the eplerenone group and 166 patients to the placebo group. In the primary efficacy analysis, mean percent change in UACR from baseline was −17·3% (95% CI −33·65 to −0·94) for 158 patients in the eplerenone group compared with 10·3% (−6·75 to 22·3) for 146 patients in the placebo group (absolute difference −27·6% [–51·15 to −3·96]; p=0·0222). In the safety analyses, 53 (31%) of 169 patients in the eplerenone group had adverse events (five serious), as did 49 (30%) of 163 in the placebo group (seven serious). Although mean serum potassium concentration was higher in the eplerenone group than the placebo group, severe hyperkalaemia (>5·5 mmol/L) was not recorded in either group.. Addition of low-dose eplerenone to renin-angiotensin system inhibitors might have renoprotective effects through reduction of albuminuria in hypertensive patients with non-diabetic chronic kidney disease, without serious safety concerns.. Pfizer.

Topics: Adult; Aged; Albuminuria; Antihypertensive Agents; Creatinine; Double-Blind Method; Eplerenone; Female; Humans; Hypertension; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Protective Agents; Renal Insufficiency, Chronic; Spironolactone

Patients with chronic kidney disease (CKD) have high cardiovascular mortality and morbidity associated with increased arterial stiffness. Plasma aldosterone levels are increased in CKD, and aldosterone has been found to increase vascular inflammation and fibrosis. It was hypothesized that aldosterone receptor inhibition with eplerenone could reduce arterial stiffness in CKD stage 3-4.. The design was randomized, open, parallel group. Measurements of arterial stiffness markers were undertaken at weeks 1 and 24.. 24 weeks of add-on treatment with 25-50 mg eplerenone or standard medication.. Primary outcome parameter was carotid-femoral pulse wave velocity (cfPWV). Secondary outcomes were augmentation index (AIx), ambulatory arterial stiffness index (AASI) and urinary albumin excretion.. Fifty-four CKD patients (mean eGFR 36 mL/min/1.73 m(2), SD 11) were randomized. Forty-six patients completed the trial. The mean difference in cfPWV changes between groups was 0.1 m/s (95%CI: -1.0, 1.3), P = 0.8. The mean difference in AIx changes between groups was 4.4% (0.1, 8.6), P = 0.04. AASI was unchanged in both groups. The ratio of change in urinary albumin excretion in the eplerenone group compared to the control was 0.61 (0.37, 1.01), P = 0.05. Four patients were withdrawn from the eplerenone group including three because of possible side effects; one was withdrawn from the control group. Mild hyperkalemia was seen on three occasions and was easily managed.. The full planned number of patients was not attained. The duration of the trial may have been too short to obtain full effect of eplerenone on the arteries.. Add-on treatment with eplerenone in CKD stage 3-4 did not significantly reduce cfPWV. There may be beneficial vascular effects leading to attenuated pulse wave reflection. Treatment was well-tolerated.. ClinicalTrials.govNCT01100203.

Topics: Blood Pressure; Demography; Eplerenone; Female; Heart Rate; Humans; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Pulse Wave Analysis; Renal Insufficiency, Chronic; Spironolactone; Vascular Stiffness

The study sought to investigate the safety and efficacy of eplerenone in patients at high risk for hyperkalemia or worsening renal function (WRF) in EMPHASIS-HF, a trial that enrolled patients at least 55 years old with heart failure and reduced ejection fraction (HF-REF), in New York Heart Association (NYHA) functional class II and with an estimated glomerular filtration rate (eGFR) >30 ml/min/1.73 m(2) and serum potassium <5.0 mmol/l. Patients were receiving optimal therapy and most had been hospitalized for a cardiovascular reason within 180 days of inclusion.. Underuse of eplerenone in patients with HF-REF may be due to fear of inducing hyperkalemia or WRF in high-risk patients.. This was a pre-specified analysis of subgroups of patients at high risk of hyperkalemia or WRF (patients ≥ 75 years of age, with diabetes, with eGFR <60 ml/min/1.73 m(2), and with systolic blood pressure < median of 123 mm Hg), examining the major safety measures (potassium >5.5, >6.0, and <3.5 mmol/l; hyperkalemia leading to study-drug discontinuation or hospitalization; and hospitalization for WRF) as well as the primary outcome (hospitalization for HF or cardiovascular mortality).. In all high-risk subgroups, patients treated with eplerenone had an increased risk of potassium >5.5 mmol/l but not of potassium >6.0 mmol/l, and of hospitalization for hyperkalemia or discontinuation of study medication due to adverse events. Eplerenone was effective in reducing the primary composite endpoint in all subgroups.. In patients with chronic HF-REF, in NYHA functional class II, and meeting specific inclusion and exclusion criteria, including an eGFR >30 ml/min/1.73 m(2) and potassium <5.0 mmol/l, eplerenone was both efficacious and safe when carefully monitored, even in subgroups at high risk of developing hyperkalemia or WRF. (A Comparison Of Outcomes In Patients In New York Heart Association [NYHA] Class II Heart Failure When Treated With Eplerenone Or Placebo In Addition To Standard Heart Failure Medicines [EMPHASIS-HF Study]; NCT00232180).

Topics: Aged; Aged, 80 and over; Eplerenone; Female; Heart Failure; Hospitalization; Humans; Hyperkalemia; Kidney Function Tests; Male; Middle Aged; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Risk Factors; Spironolactone; Survival Rate; Treatment Outcome

Pharmacological inhibition of renin-angiotensin-aldosteron system (RAAS) may reduce proteinuria and the rate of chronic kidney disease progression. The aim was to compare the effects on albuminuria of the therapy with either: (i) telmisartan 80 mg and aliskiren 300 mg, (ii) telmisartan 80 mg and eplerenone 50 mg, (iii) telmisartan 160 mg as monotherapy.. Randomized, double-center, double-blind, cross-over, three treatments-three periods of 8 weeks each study. 18 patients with non-diabetic proteinuric CKD stage 1-3 completed the protocol.. There was significant difference in albuminuria between studied therapies (ANOVA; p<0.01). The combination therapy with telmisartan plus aliskiren decreased albuminuria more effectively than the treatment with telmisartan plus eplerenone and monotherapy with telmisartan 160 mg OD [376 mg/g creatinine (286-686) vs. 707 (502-1204) vs. 525 (318-763); post-hoc p<0.01 and p<0.05, respectively].. The study demonstrated that the combination therapy with angiotensin receptor blocker (ARB) and renin inhibitor was more effective in albuminuria lowering than the concomitant usage of ARB and mineralocorticoid receptor antagonist as well as than ARB in doses two-fold higher than usually used in treatment of hypertension in patients with non-diabetic CKD and that this higher antiproteinuric efficacy was independent on changes in blood pressure.

Topics: Adult; Albuminuria; Amides; Angiotensin Receptor Antagonists; Benzimidazoles; Benzoates; Comorbidity; Cross-Over Studies; Disease Progression; Dose-Response Relationship, Drug; Double-Blind Method; Drug Therapy, Combination; Eplerenone; Female; Fumarates; Humans; Hypertension; Male; Mineralocorticoid Receptor Antagonists; Prospective Studies; Proteinuria; Renal Insufficiency, Chronic; Renin; Renin-Angiotensin System; Severity of Illness Index; Spironolactone; Telmisartan; Treatment Outcome

Cardiorenal syndrome (CRS) is the leading cause of death associated with chronic kidney disease (CKD) and end-stage renal disease (ESRD). However, the underlying mechanisms of CRS are still poorly understood. Here, we studied a CKD model of unilateral ureteral obstruction (UUO) and observed pathological cardiac fibrosis and lymphangiogenesis in 180-day old UUO rats, in which inflammatory injury plays a major role. In addition, treatment of UUO rats with eplerenone, a mineralocorticoid receptor blocker (MRB), significantly reduced cardiac lymphangiogenesis and fibrosis. In conclusion, our experimental results showed that cardiac lymphangiogenesis in long-term UUO rats may be involved in the formation of cardiac fibrosis and that eplerenone can alleviate lymphangiogenesis and cardiac fibrosis by inhibiting inflammation.

Topics: Animals; Disease Models, Animal; Eplerenone; Fibrosis; Kidney; Lymphangiogenesis; Rats; Renal Insufficiency, Chronic; Ureteral Obstruction

Renal fibrosis is the inevitable pathway of the progression of chronic kidney disease to end-stage renal disease, which manifests as progressive glomerulosclerosis and renal interstitial fibrosis. In a previous study, we observed severe interstitial fibrosis in the contralateral kidneys of 6-month unilateral ureteral obstruction (UUO) rats, which was accompanied by increased macrophage infiltration and phenotypic transformation; after eplerenone administration, these effects were reduced. Therefore, we hypothesized that this effect was closely related to mineralocorticoid receptor (MR) activation induced by the increased aldosterone (ALD) level. In this study, we used uninephrectomy plus continuous aldosterone infusion in mice to observe whether aldosterone induced macrophage-to-myofibroblast transition (MMT) and renal fibrosis and investigated the signaling pathways. Notably, aldosterone induced predominantly M1 macrophage-to-myofibroblast transition by activating MR and upregulating TGF-β1 expression, which promoted renal fibrosis. These effects were antagonized by the MR blocker esaxerenone. These findings suggest that targeting the MR/TGF-β1 pathway may be an effective therapeutic strategy for renal fibrosis.

Topics: Aldosterone; Animals; Eplerenone; Fibrosis; Macrophages; Mice; Myofibroblasts; Pyrroles; Rats; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Sulfones; Transforming Growth Factor beta1

Cardiovascular disease constitutes the leading cause of mortality in patients with chronic kidney disease (CKD), which is termed cardiorenal syndrome type 4 (CRS-4). Here, we report the development of pathological cardiac remodeling and fibrosis in unilateral urinary obstruction (UUO) rats.. Hematoxylin and eosin (H&E) staining was performed to observe the pathology of myocardial tissue. The degree of myocardial tissue fibrosis was observed by Masson and Sirius red staining. Immunohistochemical staining was applied to detect the expression of CD34 and CD105 in myocardial tissue, and immunofluorescent staining was performed to examine the expression of CD34, collagen I/collagen III, and alpha smooth muscle actin (. The results showed the development of pathological cardiac remodeling and cardiac dysfunction in UUO rats. Moreover, there was more angiogenesis and endothelial-mesenchymal transition (End-MT) in the UUO group, and these effects were inhibited by eplerenone.

Topics: Actins; Aldosterone; Animals; Collagen; Eosine Yellowish-(YS); Eplerenone; Fibrosis; Glucocorticoids; Hematoxylin; Interleukin-1beta; Kidney; NF-kappa B; Rats; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; RNA, Messenger; Ureteral Obstruction; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factor Receptor-2; Ventricular Remodeling

Topics: Diabetes Mellitus, Type 2; Eplerenone; Heart Failure; Humans; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic

Yiqi Huoxue Tongluo recipe (YHTR) is a traditional Chinese medicine for the treatment of chronic kidney disease, but its exact mechanism is not clear.. To monitor the potential improvement of renal mitochondrial function in unilateral ureteral obstruction (UUO) rats by regulating NR4A1 using the YHTR.. Wistar rats were randomly divided into four groups: sham, UUO (left ureteral ligation for 14 days), eplerenone (EPL) (UUO + EPL), and YHTR (UUO + YHTR). UUO rats were established and intragastrically administered EPL (100 mg/day/kg) or YHTR (11.7 g/day/kg) for 14 days. The expression of related proteins in kidneys was detected by immunohistochemistry, western blot, RT-PCR, and chemical colorimetric assay, respectively.. YHTR significantly improved the development of CKD; this study may provide new ideas for the pathogenesis of CKD and new strategies for the development of new drugs against CKD.

Topics: Animals; Eplerenone; Mitochondria; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Ureteral Obstruction

Cardiovascular complications are the leading causes of death in patients with chronic kidney disease (CKD), accounting for approximately 50% of deaths. Despite significant advances in the understanding of cardiac disease due to CKD, the underlying mechanisms involved in many pathological changes have not been fully elucidated. In our previous study, we observed severe fibrosis in the contralateral kidney of a 6-month-old rat UUO model. In the present experiment, we also observed severe fibrosis in the hearts of rats subjected to UUO and the macrophage-to-myofibroblast transition (MMT). These effects were inhibited by the mineralocorticoid receptor (MR) blocker eplerenone. Notably, in vitro, aldosterone-activated MR induced the MMT and subsequently promoted the secretion of CTGF, the target of MR, from macrophages; these changes were inhibited by eplerenone. The CTGF also induced the MMT and both the aldosterone and CTGF-induced MMT could be alleviated by the CTGF blocker. In conclusion, our results suggest that targeting the MR/CTGF pathway to inhibit the MMT may be an effective therapeutic strategy for the treatment of cardiac fibrosis.

Topics: Aldosterone; Animals; Cardio-Renal Syndrome; Eplerenone; Fibrosis; Heart Diseases; Macrophages; Myofibroblasts; Rats; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic

Progression of chronic kidney disease (CKD) to uremia is often accompanied by varying degrees of lung damage and this is also an important cause of death. Although there are many studies on the mechanism of lung injury, it is not clearly understood. Inflammatory macrophages may associated with fibrosis in the lungs. Here, we investigated the role of macrophage-myofibroblast transition (MMT) in lung fibrosis with unilateral ureteral obstruction (UUO) rats. We found that cells undergoing MMT accounted for an important part of the myofibroblast population, and correlated with lung fibrosis, MMT cells in lungs have a predominant M2 phenotype, and this process was attenuated after treatment with eplerenone. In conclusion, our studies provide a possible mechanism for UUO-induced kidney damage and lung injury, indicating the possibility of using eplerenone, a mineralocorticoid receptor blocker, to treat UUO to reduce kidney damage and protect lung function.

Topics: Animals; Cell Differentiation; Disease Models, Animal; Eplerenone; Humans; Macrophages; Male; Mineralocorticoid Receptor Antagonists; Myofibroblasts; Protective Agents; Pulmonary Fibrosis; Rats; Rats, Wistar; Renal Insufficiency, Chronic; Ureteral Obstruction

Excess mineralocorticoid receptor (MR) activation promotes target organ dysfunction, vascular injury and fibrosis. MR antagonists like eplerenone are used for treating heart failure, but their use is limited due to the compound class-inherent hyperkalemia risk. Here we present evidence that AZD9977, a first-in-class MR modulator shows cardio-renal protection despite a mechanism-based reduced liability to cause hyperkalemia. AZD9977 in vitro potency and binding mode to MR were characterized using reporter gene, binding, cofactor recruitment assays and X-ray crystallopgraphy. Organ protection was studied in uni-nephrectomised db/db mice and uni-nephrectomised rats administered aldosterone and high salt. Acute effects of single compound doses on urinary electrolyte excretion were tested in rats on a low salt diet. AZD9977 and eplerenone showed similar human MR in vitro potencies. Unlike eplerenone, AZD9977 is a partial MR antagonist due to its unique interaction pattern with MR, which results in a distinct recruitment of co-factor peptides when compared to eplerenone. AZD9977 dose dependently reduced albuminuria and improved kidney histopathology similar to eplerenone in db/db uni-nephrectomised mice and uni-nephrectomised rats. In acute testing, AZD9977 did not affect urinary Na+/K+ ratio, while eplerenone increased the Na+/K+ ratio dose dependently. AZD9977 is a selective MR modulator, retaining organ protection without acute effect on urinary electrolyte excretion. This predicts a reduced hyperkalemia risk and AZD9977 therefore has the potential to deliver a safe, efficacious treatment to patients prone to hyperkalemia.

Topics: Administration, Oral; Aldosterone; Animals; Benzoates; Cell Line, Tumor; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Eplerenone; Humans; Kidney; Male; Mice, Mutant Strains; Mineralocorticoid Receptor Antagonists; Molecular Structure; Oxazines; Potassium; Rats, Sprague-Dawley; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic; Sodium; Sodium, Dietary; Spironolactone

Managing the cardiovascular complications of renal failure is a major therapeutic challenge in clinical practice. Mineralocorticoid Receptor (MR) blockade is a highly effective strategy for the management of heart failure, but the use of MR antagonists (MRA) is limited by their side effects rendering them contraindicated in patients with renal failure. Finerenone is a new non-steroidal MRA that shows fewer hyperkaliaemic events than the traditional steroidal MRAs and could therefore represent an alternative to these molecules in patients with damaged kidney function. The aim of this study is to characterize the effects of Finerenone on the cardiac complications of renal failure in a mouse model of chronic kidney disease (CKD). CKD was induced by subtotal nephrectomy (Nx), and finerenone was administered at a low dose (2.5 mg/kg/d) from week 4 to week 10 post-Nx. Cardiac function was assessed by echocardiography and invasive hemodynamics while cardiac fibrosis was measured by Sirius Red staining. Renal failure induced cardiac systolic and diastolic dysfunctions in the untreated CKD mice, as well as minor changes on cardiac structure. We also observed alterations in the phosphorylation of proteins playing key roles in the calcium handling (Phospholamban, Calmodulin kinase II) in these mice. Finerenone prevented most of these lesions with no effects on neither the renal dysfunction nor kaliemia. The benefits of finerenone suggest that activation of MR is involved in the cardiac complication of renal failure and strengthen previous studies showing beneficial effects of MRA in patients with CKD.

Topics: Animals; Disease Models, Animal; Eplerenone; Heart Failure, Diastolic; Hemodynamics; Humans; Mice; Mineralocorticoid Receptor Antagonists; Naphthyridines; Receptors, Mineralocorticoid; Renal Insufficiency, Chronic

Aldosterone antagonists slow the progression of chronic kidney disease (CKD), but their use is limited by hyperkalemia, especially when associated with RAS inhibitors. We examined the renoprotective effects of Ly, a novel non-steroidal mineralocorticoid receptor (MR) blocker, through two experimental protocols: In Protocol 1, male Munich-Wistar rats underwent 5/6 renal ablation (Nx), being divided into: Nx+V, receiving vehicle, Nx+Eple, given eplerenone, 150 mg/kg/day, and Nx+Ly, given Ly, 20 mg/kg/day. A group of untreated sham-operated rats was also studied. Ly markedly raised plasma renin activity (PRA) and aldosterone, and exerted more effective anti-albuminuric and renoprotective action than eplerenone. In Protocol 2, Nx rats remained untreated until Day 60, when they were divided into: Nx+V receiving vehicle; Nx+L treated with losartan, 50 mg/kg/day; Nx+L+Eple, given losartan and eplerenone, and Nx+L+Ly, given losartan and Ly. Treatments lasted for 90 days. As an add-on to losartan, Ly normalized blood pressure and albuminuria, and prevented CKD progression more effectively than eplerenone. This effect was associated with strong stimulation of PRA and aldosterone. Despite exhibiting higher affinity for the MR than either eplerenone or spironolactone, Ly caused no hyperkalemia. Ly may become a novel asset in the effort to detain the progression of CKD.

Topics: Albuminuria; Aldosterone; Animals; Blood Pressure; Eplerenone; Losartan; Mineralocorticoid Receptor Antagonists; Nephrectomy; Rats, Wistar; Renal Insufficiency, Chronic; Renin; Treatment Outcome

Topics: Eplerenone; Female; Heart Failure; Hospitalization; Humans; Hyperkalemia; Male; Mineralocorticoid Receptor Antagonists; Renal Insufficiency, Chronic; Spironolactone

Topics: Eplerenone; Female; Follow-Up Studies; Humans; Hypertension; Middle Aged; Mineralocorticoid Receptor Antagonists; Myocardial Infarction; Renal Insufficiency, Chronic; Spironolactone; Treatment Outcome