Nonsteroidal Mineralocorticoid Receptor Research Articles

New Paradigms for CKD Management in Patients With T2D.

At the end of the activity, participants will be able to: Identify the risks of kidney disease and their consequences in patients with type 2 diabetes (T2D). Appropriately screen for the presence of chronic kidney disease (CKD) in patients with T2D. Initiate evidence-based therapy to slow the progression of kidney disease in patients with T2D and CKD. Become familiar with the novel nonsteroidal mineralocorticoid receptor antagonist finerenone and its role in the treatment of patients with T2D and CKD.

What is central to renal nutrition: protein or sodium intake?

Historically, nutrition intervention has been primarily focused on limiting kidney injury, reducing generation of uraemic metabolites, as well as maintaining nutrition status and preventing protein-energy wasting in patients with chronic kidney disease (CKD). This forms an important rationale for prescribing restricted protein diet and restricted salt diet in patients with CKD. However, evidence supporting a specific protein intake threshold or salt intake threshold remains far from compelling. Some international or national guidelines organizations have provided strong or 'level 1' recommendations for restricted protein diet and restricted salt diet in CKD. However, it is uncertain whether salt or protein restriction plays a more central role in renal nutrition management. A key challenge in successful implementation or wide acceptance of a restricted protein diet and a restricted salt diet is patients' long-term dietary adherence. These challenges also explain the practical difficulties in conducting randomized trials that evaluate the impact of dietary therapy on patients' outcomes. It is increasingly recognized that successful implementation of a restricted dietary prescription or nutrition intervention requires a highly personalized, holistic care approach with support and input from a dedicated multidisciplinary team that provides regular support, counselling and close monitoring of patients. With the advent of novel drug therapies for CKD management such as sodium-glucose cotransporter-2 inhibitors or non-steroidal mineralocorticoid receptor antagonist, it is uncertain whether restricted protein diet and restricted salt diet may still be necessary and have incremental benefits. Powered randomized controlled trials with novel design are clearly indicated to inform clinical practice on recommended dietary protein and salt intake threshold for CKD in this new era.

Cardiorenal interactions in heart failure: insights from recent therapeutic advances.

Heart failure is a syndrome that may develop when cardiovascular disease progresses or is insufficiently treated and associated with a poor quality of life, high mortality rates, and increased healthcare expenditures. Prevention and treatment of heart failure are therefore of utmost importance. New therapies in patients with cardiovascular disease have recently been shown to be effective in the prevention and sometimes treatment of heart failure, and additional research is underway. Specifically, in high-risk patients with either (a combination of) diabetes, chronic kidney disease, and/or heart failure, three specific drug classes [sodium-glucose co-transporter 2 inhibitors (SGLT2i), glucagon-like peptide 1 receptor agonists (GLP-1-RAs), and non-steroidal mineralocorticoid receptor antagonists (MRAs)] have taken centre stage in therapeutic approach for these high cardiovascular risk patients. The commonality of these drugs is the finding that they improve cardiovascular and renal endpoints across the cardiorenal continuum and SGTL2i have already proved effective in all subtypes of heart failure, while we await data on non-steroidal MRA therapy in heart failure. The story may be different for GLP-1-RA in patients with established heart failure, but these drugs are effective in reducing cardiovascular events in patients with diabetes. Taken together, these new therapies advance the treatment and improve the associated outcomes of patients with cardiorenal disease and diabetes, with similar characteristics and effectiveness in different conditions.

Pharmacokinetics and Drug-Drug Interaction of Ocedurenone (KBP-5074) in vitro and in vivo.

Ocedurenone (KBP-5074) is a novel nonsteroidal mineralocorticoid receptor antagonist that has demonstrated safety and efficacy in clinical trials in patients with uncontrolled hypertension and stage 3b/4 chronic kidney disease. This study evaluated the involvement of cytochrome P450 (CYP) isozymes and drug transporters in the biotransformation of ocedurenone, and whether ocedurenone inhibited or induced CYP enzymes and transporters. Clinical pharmacokinetic drug-drug interaction (DDI) of ocedurenone with CYP3A inhibitor and inducer were investigated in healthy volunteers. In vitro tests were conducted to determine which CYP enzymes were involved in ocedurenone's metabolism and whether ocedurenone inhibited or induced these CYP enzymes; ocedurenone substrate characteristics for efflux and uptake transporters and its inhibitory potential on major drug transporters were also assessed. A clinical DDI study was conducted in healthy volunteers to evaluate the effects of a strong CYP3A inhibitor (itraconazole) and inducer (rifampin) on ocedurenone's pharmacokinetics. The in vitro study showed that ocedurenone was primarily metabolized by CYP3A4 and that it did not inhibit CYP enzymes. Ocedurenone appeared to be a substrate of BCRP and P-gp efflux transporters and inhibited BCRP, BSEP, MDR1, MATE1 and 2-K, OATP1B1/3, and OCT1. The clinical DDI study showed that itraconazole reduced ocedurenone's oral clearance by 51% and increased area under the plasma concentration-time curve extrapolated to infinity(AUC0-inf) by104%, while rifampin increased its oral clearance by 6.4-fold and decreased plasma AUC0-inf by 84%. Ocedurenone was shown to be a CYP3A substrate, with no inhibition potential on major drug metabolizing CYP enzymes and transporters at clinical efficacious doses. Ocedurenone did not induce CYP1A2 and 3A4 activity in cultured human primary hepatocytes. Clinical DDI study indicated ocedurenone was well tolerated when administered as a single 0.5-mg dose both alone and with itraconazole or rifampin, and while itraconazole had a weak effect on ocedurenone's pharmacokinetics, rifampin had a significant effect reducing systemic exposures.

407-P: Efficacy of Finerenone in Patients with Abnormal Markers of Liver Steatosis and Fibrosis—A FIDELITY Subgroup Analysis

Introduction: Finerenone, a selective, nonsteroidal mineralocorticoid receptor antagonist, showed cardiorenal benefits vs placebo in patients with chronic kidney disease and type 2 diabetes. Here, we analyzed patients with liver function abnormalities in FIDELITY, a prespecified pooled dataset from the FIDELIO-DKD and FIGARO-DKD trials. Methods: Patients with urine albumin-to-creatinine ratio ≥30-≤5000 mg/g and estimated glomerular filtration rate (eGFR) ≥25 mL/min/1.73 m2 and type 2 diabetes were analyzed according to elevated transaminases, high risk of steatosis (hepatic steatosis index [HSI] >36), and risk of intermediate to advanced fibrosis (Fibrosis-4 Index [FIB-4] scores >1.30, >2.67, and >3.25). Changes in liver function and in kidney (kidney failure, sustained 57% eGFR decline, or renal death) and cardiovascular (CV; CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) composite outcomes were assessed. Results: Across 13,026 patients, finerenone reduced the risk of kidney and CV outcomes compared with placebo in patients with elevated transaminases (HR=0.75; 95% CI 0.50-1.13 and HR=0.81; 95% CI 0.62-1.07, respectively), at high risk of steatosis (HR=0.75; 95% CI 0.64-0.88 and HR=0.85; 95% CI 0.77-0.95, respectively), and at high risk of intermediate fibrosis (HR=0.75; 95% CI 0.60-0.93 and HR=0.76; 95% CI 0.67-0.87, respectively), with stronger reductions in the risk of the CV composite outcome at higher FIB-4 scores (HR=0.61; 95% CI 0.41-0.92; p-value for interaction=0.13 and HR=0.48; 95% CI 0.25-0.90; p-value for interaction=0.03 for FIB-4 >2.67 and >3.25, respectively). Liver transaminase levels remained consistent between treatment groups throughout the study. Conclusions: Finerenone demonstrated robust and consistent cardiorenal benefits in patients with abnormal liver function and even more profound CV benefits in patients with higher FIB-4 scores. Disclosure N.Perakakis: Advisory Panel; Bayer Inc., Other Relationship; Novo Nordisk, Novo Nordisk. P.Kolkhof: Employee; BAYER AG. R.Lawatscheck: Employee; Bayer Inc. C.Scott: None. G.Bakris: Advisory Panel; Janssen Pharmaceuticals, Inc., Consultant; AstraZeneca, Boehringer Ingelheim (Canada) Ltd., Other Relationship; Bayer Inc. S.R.Bornstein: None. A.L.Birkenfeld: None. A.Linkermann: None. S.Anker: Advisory Panel; AstraZeneca, Novartis AG, Consultant; Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Vifor Pharma Management Ltd., Research Support; Abbott, Vifor Pharma Management Ltd. G.Filippatos: Other Relationship; Boehringer-Ingelheim, Bayer Inc., Amgen Inc., Medtronic, Vifor Pharma Management Ltd., Novartis, Servier Laboratories. B.Pitt: Consultant; Bayer Inc., AstraZeneca, Boehringer Ingelheim International GmbH, Vifor Pharma Management Ltd., Lexicon Pharmaceuticals, Inc., PhaseBio Pharmaceuticals, Inc., KBP Bioscience, Merck & Co., Inc. P.Rossing: Other Relationship; Abbott Diagnostics, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Novo Nordisk, Merck KGaA, Gilead Sciences, Inc., Sanofi. L.M.Ruilope: Advisory Panel; Bayer Inc.

829-P: Outcomes with Finerenone in People with CKD and T2D by Baseline Insulin Resistance—A FIDELITY Subgroup Analysis

Introduction Insulin resistance (IR) is associated with increased risk of T2D, CV disease and CKD. Finerenone, a nonsteroidal mineralocorticoid receptor antagonist, has shown cardiorenal benefits in people with CKD and T2D. We investigated if IR is associated with risk of cardiorenal outcomes and if IR modifies finerenone efficacy in the pooled FIDELITY dataset. Methods People with T2D and CKD (UACR ≥30-<300 mg/g + eGFR ≥25-≤90 mL/min/1.73 m2 or UACR ≥300-≤5000 mg/g + eGFR ≥25 mL/min/1.73 m2) and optimized RAS blockade were randomized to finerenone or placebo. Estimated glucose disposal rate (eGDR), an inverse marker of IR, was calculated by 21.158 + (-0.09 × waist circumference [cm]) + (-3.407 × presence of hypertension) + (-0.551 × HbA1c [%]). Risk of CV (time to CV death, nonfatal myocardial infarction, nonfatal stroke, or hospitalization for heart failure) and kidney (time to kidney failure, sustained ≥57% eGFR decline, or renal death) composite outcomes, and safety, were assessed by eGDR. Results Median baseline eGDR was 4.1 mg/kg/min in 12,964 participants. Analysis by continuous baseline eGDR showed a significantly lower risk of CV events at 3.5 years with increasing eGDR (HR 0.88 [95% CI 0.86-0.91] p<0.01); whereas eGDR was not associated with kidney outcomes. Analyses by eGDR subgroups showed no significant heterogeneity for the effect of finerenone on CV (eGDR <median: HR 0.82 [95% CI 0.72-0.92]; eGDR ≥median: HR 0.91 [95% CI 0.78-1.06]; p-interaction=0.29) or kidney outcomes (eGDR <median: HR 0.85 [95% CI 0.70-1.04]; eGDR ≥median: HR 0.69 [95% CI 0.57-0.84]; p-interaction=0.18). Consistent strength and direction of the associations were observed across sensitivity analyses. Adverse events were similar across eGDR subgroups; hyperkalaemia events were higher with finerenone than placebo. Conclusions A higher risk of CV, but not kidney, outcomes was observed with greater IR in people with T2D and CKD. Finerenone efficacy and safety were not modified by baseline IR. Disclosure T.Ebert: Advisory Panel; Sanofi, Bayer Inc., Research Support; AstraZeneca, Speaker's Bureau; CME-Verlag, Santis, Fresenius Medical Care. K.Rohwedder: Employee; Bayer Inc., AstraZeneca. P.Rossing: Other Relationship; Abbott Diagnostics, AstraZeneca, Bayer Inc., Boehringer Ingelheim Inc., Novo Nordisk, Merck KGaA, Gilead Sciences, Inc., Sanofi. S.Anker: Advisory Panel; AstraZeneca, Novartis AG, Consultant; Bayer Inc., Boehringer Ingelheim Pharma GmbH&Co.KG, Vifor Pharma Management Ltd., Research Support; Abbott, Vifor Pharma Management Ltd. L.M.Ruilope: Advisory Panel; Bayer Inc. P.Fioretto: Advisory Panel; Eli Lilly and Company, Novo Nordisk, Speaker's Bureau; AstraZeneca, Boehringer-Ingelheim, Bayer Inc. V.Fonseca: Consultant; Abbott, Corcept Therapeutics, Eli Lilly and Company, Other Relationship; BRAVO4HEALTH, LLC, Research Support; Fractyl Health, Inc., Stock/Shareholder; Amgen Inc. G.Umpierrez: Research Support; Abbott, Dexcom, Inc., Baxter. A.L.Birkenfeld: None. R.Lawatscheck: Employee; Bayer Inc. C.Scott: None.

#3484 A NETWORK META-ANALYSIS COMPARING INTENSIVE GLYCEMIC CONTROL AND SGLT-2 INHIBITORS IN PREVENTING RENAL OUTCOMES

Abstract Background and Aims Type 2 diabetes (T2D) is one of the prominent causes for chronic kidney disease (CKD) leading to end-stage renal failure. Traditionally, prevention and retardation of CKD was attempted with effective glycemic and blood pressure control. In recent times sodium glucose co-transporter 2 inhibitors (SGLT-2is), glucagon-like peptide 1 receptor agonists (GLP1-RA), and non-steroidal mineralocorticoid receptor (MRA) inhibitors have proved to be excellent agents in preventing cardio-renal outcomes in patients with T2D, independent of baseline glucose control. SGLT-2is rank the highest in recent network meta-analysis-based scoring. We conducted this network meta-analysis to explore the ranking of intensive glucose therapy in comparison to SGLT-2is, to better understand the present position of the traditional approach and its relevance. Method A database search was conducted using the Cochrane library to identify relevant citations. Analysis was conducted using RStudio (2022.07.1, Build 554). Using progression of macroalbuminuria and end-stage kidney disease (ESKD) as the outcomes of interest, scoring was performed comparing intensive glycemic control (IGC) and SGLT-2is. Using a frequentist approach P-score was conducted and corroborated using the Surface Under the Cumulative Ranking (SUCRA) using Bayesian network meta-analysis. Results A pooled population of 62,742 patients from twelve citations were included for analysis. The Cochrane risk of bias was used to assess quality of the studies. IGC scored higher than SGLT-2is as far as retardation of progression of macroalbuminuria was concerned while using both the P-score (0.99 Vs 0.50) as well as the SUCRA (0.97 Vs 0.52). A similar trend was also observed with ESRD as the end point with both the P-score (0.84 Vs 0.65) and the SUCRA (0.81 Vs 0.68) rankings favoring IGC (Fig. 1). Conclusion The importance of achieving glycemic targets should be emphasized in recommendations in the same footing as the choice of individual reno-protective agents.

#2505 CHARACTERISTICS OF MEDICATION-INITIATOR COHORTS OF PATIENTS WITH CHRONIC KIDNEY DISEASE AND TYPE 2 DIABETES IN JAPAN: A REPORT FROM FOUNTAIN PLATFORM

Abstract Background and Aims The clinical landscape for the treatment of patients with chronic kidney disease (CKD) and type 2 diabetes (T2D) is rapidly evolving with the introduction of new treatments such as sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonist (GLP-1 RA), and non-steroidal mineralocorticoid receptor antagonists (nsMRA). However, limited information is available regarding the utilization patterns of these new therapies in worldwide clinical practice. The FINEGUST study (EUPAS48148; NCT05526157) is a multinational observational cohort study and part of the FOUNTAIN multi-database research platform. It aims to describe drug utilization and temporal changes of different treatments in adults with CKD and T2D in two time periods (before and after finerenone approval) using secondary data from population-based data sources in Europe, Japan, China, the United Kingdom, and the United States. Method In this country-specific analysis, four separate medication-specific cohorts of adults with CKD and T2D, including new users of SGLT2i, GLP-1 RA, steroidal MRA (sMRA), or esaxerenone as a nsMRA available in the study period, were retrospectively identified from the Japan Chronic Kidney Disease Database Extension (J-CKD-DB-Ex) between January 1st 2014 and June 30th 2021 (pre-finerenone period). The presence of T2D and CKD was assessed based on ICD-10 diagnostic codes, and lab measurement values, i.e., serum creatinine to calculate estimated glomerular filtration rate (CKD-EPI) or urine albumin-creatinine ratio (UACR). The CKD stage was categorized based on the KDIGO definition. Patients with type 1 diabetes, kidney cancer or kidney failure at baseline were excluded. The index date was the date of initial prescription of each drug class. Patient characteristics and baseline medication patterns were summarized overall and by presence or absence of UACR results in the previous year. Results Of 251,659 patients recorded in J-CKD-DB-Ex in the study period, we identified 6,934, 2,991, 18,974, and 301 patients with recorded use of SGLT2i, GLP-1 RA, sMRA, and nsMRA, respectively. After applying inclusion and exclusion criteria, 1,157 SGLT-2i (16.7%), 329 GLP-1 RA (11.0%), 1,769 sMRA (9.3%), and 63 nsMRA (20.9%) new users were included in the analysis. The mean age ranged from 66 years in the GLP-1 RA cohort to 74 years in the sMRA cohort (Table 1). All medication classes were most prescribed in patients with CKD stage 3 followed by patients with CKD stage 2. Insulin was most frequently prescribed in the GLP-1 RA cohort (65.3%). Patients in the sMRA cohort were most comorbid based on the prevalence of congestive heart failure (40.2%), coronary heart disease (26.9%), and cerebrovascular disease (16.1%). Compared to patients without UACR measurements, those with a UACR measurement in year prior to the index date were more likely to receive other treatments of interest in combination during the 90 days prior to index (Figure 1). Among the drug classes summarized, angiotensin-converting enzyme inhibitors or angiotensin-receptor blockers were the most prescribed drug class in all cohorts (43.0% in SGLT2i cohort, 28.9% in GLP-1 RA cohort, 30.4% in sMRA cohort, and 50.8% in nsMRA cohort, respectively). Conclusion Treatment initiation with either SGLT2i, GLP-1RA, sMRA or nsMRA occurred most frequently in patients with CKD stage 2–3 with variations in characteristics for each medication class, including the patterns of anti-hyperglycemic therapies and cardiovascular complications. Differences by UACR test result availability 1-year prior to index may indicate a possible association between treatment choice and the availability of UACR test results. Subsequent analyses from the FOUNTAIN program, including longitudinal drug utilization patterns and geographic variations across regions, will provide further insights about the clinical use of different treatment options for patients with CKD and T2D.

#4486 VALIDATION OF A CKD PROGRESSION RISK PREDICTION MODEL IN THE FIDELITY TRIAL POPULATION

Abstract Background and Aims Chronic kidney disease (CKD) is often underrecognised until later stages when most of the kidney function is lost and the therapeutic window for disease-modifying therapy is narrow [1]. We previously developed a lab-based risk prediction model to accurately predict CKD progression in adults at all stages of CKD [2]. Here, we describe a validation of our model in the clinical trial population of FIDELITY, a prespecified pooled analysis of the phase III FIDELIO-DKD (NCT02540993) and FIGARO-DKD (NCT02545049) trials for the nonsteroidal mineralocorticoid receptor antagonist finerenone [3]. Method We performed a post hoc analysis of all participants from the FIDELITY database, irrespective of estimated glomerular filtration rate (eGFR) or albuminuria stage. Baseline values for the underlying laboratory tests required for the model, Klinrisk, were extracted from the complete blood count, comprehensive metabolic panel and urine albumin-to-creatinine ratio (UACR). The predicted outcome was a ≥40% decline in eGFR or kidney failure. We calculated discrimination ability of the model and calibration using area under the curve (AUC), Brier scores and calibration plots in the overall population, and stratified by treatment assignment. Sensitivity analyses examined the accuracy of the models in predicting ≥57% decline in eGFR, as well as the change in risk score over time. Kidney Disease: Improving Global Outcomes (KDIGO) heat map categories were used as the reference standard. Results We included 13,026 participants with a mean age of 64.8 ± 9.5 years, mean eGFR of 57.6 ± 21.7 ml/min/1.73 m2, and median UACR of 58.2 mg/mmol (interquartile range 22.4–129.6). At time horizons of 2 and 4 years, 984 and 1795 patients experienced a primary outcome event, respectively. The Klinrisk model predicted progression accurately, with an AUC of 0.81 (95% confidence interval [CI] 0.79–0.82) at 2 years and 0.86 (95% CI 0.84–0.87) at 4 years, compared with the KDIGO heatmap categories (AUC of 0.59 [95% CI 0.58–0.60] at 2 years and 0.66 [95% CI 0.65–0.68] at 4 years). Calibration was appropriate (Brier score of 0.067 [95% CI 0.064–0.070] at 2 years and 0.115 [95% CI 0.109–0.120] at 4 years). Similar discrimination accuracy was seen for the ≥57% decline outcome (C-statistic 0.88, 95% CI 0.87–0.90) at 3 years. Conclusion Based on routinely collected lab data, our machine learning model (Klinrisk) accurately predicts CKD progression events in a well characterized global clinical trial population. Prospective implementation of the model in clinical trial enrolment as well as clinical care pathways is needed.

Population pharmacokinetics of esaxerenone, a novel non-steroidal mineralocorticoid receptor blocker, in patients with essential hypertension, patients with diabetic nephropathy, and healthy volunteers

ObjectivesEsaxerenone is a novel, non-steroidal mineralocorticoid receptor (MR) blocker with improved selectivity and affinity for MR. The objectives of this study were to model the population pharmacokinetics of esaxerenone in a diverse population and to evaluate the effect of covariates on pharmacokinetics parameters. MethodsA total of 8263 plasma esaxerenone concentrations from 166 healthy volunteers, 1097 hypertensive patients and 360 patients with diabetic nephropathy were pooled. A three-compartment model with sequential zero- and first-order absorption was used to describe the time-courses of plasma esaxerenone following single and multiple doses once daily for up to 12 weeks. Covariate effects were estimated using the full covariate modeling approach. Clinical relevance of covariates was ascertained using tornado plots. ResultsEsaxerenone was estimated to have high bioavailability (85.3%), low clearance (3.28 L/h) and relatively large distribution volume at steady state (94.8 L). Body weight (−26 to +36%) and coadministration of itraconazole (+64%) or rifampicin (−68%) were associated with a greater influence on esaxerenone exposure. ConclusionsThe most influential covariates on esaxerenone exposure were coadministrations of itraconazole and rifampicin, followed by body weight. The clinical relevance of effects of renal impairment, mild to moderate hepatic impairment, and age is limited.

Recent understandings about hypertension management in type 2 diabetes: What are the roles of SGLT2 inhibitor, GLP-1 receptor agonist, and finerenone?

Diabetes and hypertension often coexist, with about half of patients with diabetes also having hypertension. The risk of cardiovascular disease increases by three to six-fold with the coexistence of diabetes and hypertension; therefore, the management of blood pressure to prevent cardiovascular disease is a particularly important issue in patients with diabetes. Clinical trial findings have resulted in recommendations to control blood pressure to <130/80 mmHg in Japanese patients with diabetes. However, the target blood pressure and selection of anti-hypertensive medications should vary depending on the duration of diabetes and comorbidities, and guidelines and clinical trial results should be interpreted flexibly to provide anti-hypertensive treatment tailored to individual patients. In recent years, a number of drugs have emerged that have significant cardio-renal protective effects in patients with diabetes, and a typical example is sodium-glucose cotransporter 2 inhibitor (SGLT2i), glucagon-like peptide-1 receptor agonist (GLP-1RA), and nonsteroidal mineralocorticoid receptor antagonist, finerenone. They have also shown modest but significant blood pressure-lowering effects. In the future, beyond considering the thresholds for how far to lower blood pressure, blood pressure management in patients with diabetes will require understanding the additive cardioprotective value of drugs aimed at lowering blood pressure and the quality of blood pressure lowering. Clinical questions of blood pressure lowering in patients with diabetes GLP-1RA, glucagon-like peptide-1 receptor agonist; SGLT2i, sodium-glucose cotransporter 2 inhibitor.

Therapeutic perspective: evolving evidence of nonsteroidal mineralocorticoid receptor antagonists in diabetic kidney disease.

Approximately 30%-40% of patients with type 1 or type 2 diabetes (T1D/T2D) develop diabetic kidney disease (DKD), which can lead to end-stage kidney disease (ESKD). Angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and sodium-glucose cotransporter 2 (SGLT2) inhibitors have been investigated as treatments for DKD. However, these drugs do not prevent overactivation of the mineralocorticoid receptor (MR). Studies have shown a correlation between MR hyperactivation, renal injury, and DKD. Finerenone, a novel and selective nonsteroidal mineralocorticoid receptor antagonist (NS-MRA), was approved for the treatment of patients with DKD, and is associated with lower rates of hyperkalemia. Other NS-MRAs (such as KBP-5074, BR-4628, esaxerenone, and apararenone) may also be effective drugs for the treatment of DKD. This review summarizes the effects of pharmacological MR blockade on diabetes and diabetes-associated CKD, with a particular focus on the therapeutic mechanisms of NS-MRAs in preclinical studies and ongoing clinical studies. Further investigation of combined treatment with renoprotective drugs and NS-MRAs to improve the treatment of DKD is needed.

An analysis of DPV and DIVE registry patients with chronic kidney disease according to the finerenone phase III clinical trial selection criteria

BackgroundThe FIDELIO-DKD and FIGARO-DKD randomized clinical trials (RCTs) showed finerenone, a novel non-steroidal mineralocorticoid receptor antagonist (MRA), reduced the risk of renal and cardiovascular events in patients with type 2 diabetes mellitus (T2DM) and chronic kidney disease (CKD). Using RCT inclusion and exclusion criteria, we analyzed the RCT coverage for patients with T2DM and CKD in routine clinical practice in Germany.MethodsGerman patients from the DPV/DIVE registries who were ≥ 18 years, had T2DM and CKD (an estimated glomerular filtration rate [eGFR] < 60 mL/min/1.73 m2OR eGFR ≥ 60 mL/min/1.73m2 and albuminuria [≥ 30 mg/g]) were included. RCT inclusion and exclusion criteria were then applied, and the characteristics of the two populations compared.ResultsOverall, 65,168 patients with T2DM and CKD were identified from DPV/DIVE. Key findings were (1) Registry patients with CKD were older, less often male, and had a lower eGFR, but more were normoalbuminuric vs the RCTs. Cardiovascular disease burden was higher in the RCTs; diabetic neuropathy, lipid metabolism disorders, and peripheral arterial disease were more frequent in the registry. CKD-specific drugs (e.g., angiotensin-converting enzyme inhibitors [ACEi] and angiotensin receptor blocker [ARBs]) were used less often in clinical practice; (2) Due to the RCT’s albuminuric G1/2 to G4 CKD focus, they did not cover 28,147 (43.2%) normoalbuminuric registry patients, 4,519 (6.9%) albuminuric patients with eGFR < 25, and 6,565 (10.1%) patients with microalbuminuria but normal GFR (≥ 90 ml/min); 3) As RCTs required baseline ACEi or ARB treatment, the number of comparable registry patients was reduced to 28,359. Of these, only 12,322 (43.5%) registry patients fulfilled all trial inclusion and exclusion criteria. Registry patients that would have been eligible for the RCTs were more often male, had higher eGFR values, higher rates of albuminuria, more received metformin, and more SGLT-2 inhibitors than patients that would not be eligible.ConclusionsCertain patient subgroups, especially non-albuminuric CKD-patients, were not included in the RCTs. Although recommended by guidelines, there was an undertreatment of CKD-patients with renin-angiotensin system (RAS) blockers. Further research into patients with normoalbuminuric CKD and a wider prescription of RAS blocking agents for CKD patients in clinical practice appears warranted.

The emerging pillars of chronic kidney disease: no longer a bystander in metabolic medicine

Chronic kidney disease (CKD) represents an enormous healthcare burden, the management of which has been stagnant for the last couple of decades, with blockade of the renin-angiotensin-aldosterone system (RAAS) the most potent tool available to retard kidney disease progression. In the new cardiometabolic era, sodium-glucose cotransporter-2 inhibitors (SGLT2i) have emerged as forerunners in addressing combined cardiorenal risk. This review summarises the evidence for SGLT2i use in diabetic and non-diabetic CKD and examines the risk:benefit profile in this population. Novel non-steroidal mineralocorticoid receptor antagonists are also considered as an emerging pillar of CKD management, and their role in optimising the cardiorenal health of patients with diabetic kidney disease is discussed.

Hypertension as Cardiovascular Risk Factor in Chronic Kidney Disease

Hypertension is the leading modifiable cause of premature death and hence one of the global targets of World Health Organization for prevention. Hypertension also affects the great majority of patients with chronic kidney disease (CKD). Both hypertension and CKD are intrinsically related, as hypertension is a strong determinant of worse renal and cardiovascular outcomes and renal function decline aggravates hypertension. This bidirectional relationship is well documented by the high prevalence of hypertension across CKD stages and the dual benefits of effective antihypertensive treatments on renal and cardiovascular risk reduction. Achieving an optimal blood pressure (BP) target is mandatory and requires several pharmacological and lifestyle measures. However, it also requires a correct diagnosis based on reliable BP measurements (eg, 24-hour ambulatory BP monitoring, home BP), especially for populations like patients with CKD where reduced or reverse dipping patterns or masked and resistant hypertension are frequent and associated with a poor cardiovascular and renal prognosis. Even after achieving BP targets, which remain debated in CKD, the residual cardiovascular risk remains high. Current antihypertensive options have been enriched with novel agents that enable to lower the existing renal and cardiovascular risks, such as SGLT2 (sodium-glucose cotransporter-2) inhibitors and novel nonsteroidal mineralocorticoid receptor antagonists. Although their beneficial effects may be driven mostly from actions beyond BP control, recent evidence underline potential improvements on abnormal 24-hour BP phenotypes such as nondipping. Other promising novelties are still to come for the management of hypertension in CKD. In the present review, we shall discuss the existing evidence of hypertension as a cardiovascular risk factor in CKD, the importance of identifying hypertension phenotypes among patients with CKD, and the traditional and novel aspects of the management of hypertensives with CKD.

Benefits and harms of drug treatment for type 2 diabetes: systematic review and network meta-analysis of randomised controlled trials

ObjectiveTo compare the benefits and harms of drug treatments for adults with type 2 diabetes, adding non-steroidal mineralocorticoid receptor antagonists (including finerenone) and tirzepatide (a dual glucose dependent insulinotropic polypeptide...

Ocedurenone: A Novel Therapy for Uncontrolled Hypertension in Advanced Chronic Kidney Disease

Patients with advanced-stage chronic kidney disease (CKD) have a high burden of disease, which is compounded by serious comorbidities, including diabetes, cardiovascular disease (CVD), and, most commonly, hypertension. Control of hypertension is vital in patients with advanced CKD to reduce the associated risks of morbidity and mortality, but treatment options are limited, largely due to safety concerns for the use of existing antihypertensive agents in patients with poor renal function. During interviews conducted by EMJ in November 2022, two leading specialists in nephrology and cardiology, George Bakris, American Heart Association Comprehensive Hypertension Center, Department of Medicine, The University of Chicago Medicine, Illinois, USA, and Faiez Zannad, Clinical Investigation Centre (CIC 1493 Inserm-CHU), Université de Lorraine, Nancy, France; and Regional and University Hospital Center (CHRU) Nancy, France, discussed the challenges of treating uncontrolled hypertension in advanced CKD. These two experts described the complicated relationship between cardiovascular and renal disease, and identified significant unmet needs for patients with uncontrolled hypertension and advanced CKD. In this context, new agents in the field were viewed with interest, including the emerging class of non-steroidal mineralocorticoid receptor antagonists (MRA). The experts highlighted data from recent studies on the novel non-steroidal MRA, ocedurenone (KBP-5074), and discussed its potential as a treatment for uncontrolled hypertension in patients with advanced CKD.

Therapieoptionen bei diabetischer Nephropathie

Diabetic nephropathy is a serious complication of diabetes mellitus caused by metabolic and hemodynamic changes. Both supportive and drug therapies have been limited to treatment of cardiovascular risk factors and blockade of the renin–angiotensin–aldosterone system. With the development of sodium–glucose linked transporter 2 (SGLT2) inhibitors and nonsteroidal mineralocorticoid receptor blockers, two classes of drugs that suppress the proinflammatory and profibrotic nature of diabetic nephropathy are available after years of stagnation. In addition, glucagon-like peptide 1 (GLP-1) receptor agonists may soon expand the therapeutic portfolio. Atrasentan, selonsertib, and stimulators and activators of soluble guanylate cyclase present themselves as promising future therapeutic options.

Upregulation of Piezo2 in the mesangial, renin, and perivascular mesenchymal cells of the kidney of Dahl salt-sensitive hypertensive rats and its reversal by esaxerenone.

The recent discovery of mechanosensitive ion channels has promoted mechanobiological research in the field of hypertension and nephrology. We previously reported Piezo2 expression in mouse mesangial and juxtaglomerular renin-producing cells, and its modulation by dehydration. This study aimed to investigate how Piezo2 expression is altered in hypertensive nephropathy. The effects of the nonsteroidal mineralocorticoid receptor blocker, esaxerenone, were also analyzed. Four-week-old Dahl salt-sensitive rats were randomly assigned to three groups: rats fed a 0.3% NaCl diet (DSN), rats fed a high 8% NaCl diet (DSH), and rats fed a high salt diet supplemented with esaxerenone (DSH + E). After six weeks, DSH rats developed hypertension, albuminuria, glomerular and vascular injuries, and perivascular fibrosis. Esaxerenone effectively decreased blood pressure and ameliorated renal damage. In DSN rats, Piezo2 was expressed in Pdgfrb-positive mesangial and Ren1-positive cells. Piezo2 expression in these cells was enhanced in DSH rats. Moreover, Piezo2-positive cells accumulated in the adventitial layer of intrarenal small arteries and arterioles in DSH rats. These cells were positive for Pdgfrb, Col1a1, and Col3a1, but negative for Acta2 (αSMA), indicating that they were perivascular mesenchymal cells different from myofibroblasts. Piezo2 upregulation was reversed by esaxerenone treatment. Furthermore, Piezo2 inhibition by siRNA in the cultured mesangial cells resulted in upregulation of Tgfb1 expression. Cyclic stretch also upregulated Tgfb1 in both transfections of control siRNA and Piezo2 siRNA. Our findings suggest that Piezo2 may have a contributory role in modulating the pathogenesis of hypertensive nephrosclerosis and have also highlighted the therapeutic effects of esaxerenone on salt-induced hypertensive nephropathy. Mechanochannel Piezo2 is known to be expressed in the mouse mesangial cells and juxtaglomerular renin-producing cells, and this was confirmed in normotensive Dahl-S rats. In salt-induced hypertensive Dahl-S rats, Piezo2 upregulation was observed in the mesangial cells, renin cells, and notably, perivascular mesenchymal cells, suggesting its involvement in kidney fibrosis.

New guideline on diabetes management in chronic kidney disease

In autumn 2022, an update of the Kidney Disease: Improving Global Outcomes (KDIGO) Clinical Practice Guideline on diabetes management in chronic kidney disease (CKD) was published. This article presents in aclear manner and discusses the new aspects compared to the 2020 guideline. Innovations are seen in the area of general and all-encompassing treatment as well as in relation to blood glucose-lowering and organ-protective treatments with sodium-glucose cotransporter2 inhibitors, non-steroidal mineralocorticoid receptor antagonists, and glucagon-like peptide‑1 receptor agonists. Anew feature is also the top 10 recommendations on diabetes management in CKD for both patients and physicians. The KDIGO guideline on diabetes management in CKD represents the current evidence-based standard of care for patients with diabetes mellitus and CKD. It is now important to implement the guideline in order to provide patients with the benefits of the treatments and thus improve their lives.