Nonsteroidal Mineralocorticoid Receptor Antagonist Research Articles

Effectiveness and safety of finerenone in Chinese CKD patients without diabetes: a retrospective, real-world study.

Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has previously demonstrated its efficacy and safety in chronic kidney disease (CKD) associated with diabetes mellitus. Given its therapeutic potential, finerenone has been preliminarily explored in clinical practice for non-diabetic CKD patients. The effectiveness and safety in this population require further investigation in a real-world setting. This retrospective, real-world analysis included non-diabetic CKD patients receiving finerenone. The main clinical outcomes assessed were changes in urinary albumin-to-creatinine ratio (UACR) and estimated glomerular filtration rate (eGFR). Serum potassium (sK+) levels were also monitored. Data were collected at baseline, and then at 1month and 3months following treatment initiation. Totally, 16 patients were included. There was a notable decrease in UACR from 1-month post-treatment, with a further reduction at 3months, resulting in a median reduction of 200.41mg/g (IQR, 84.04-1057.10mg/g; P = 0.028; percent change, 44.52% [IQR, 31.79-65.42%]). The average eGFR at baseline was 80.16ml/min/1.73m2, with no significant change after 1month (80.72ml/min/1.73m2, P = 0.594) and a slight numerical increase to 83.45ml/min/1.73m2 (P = 0.484) after 3months. During the 3-month follow-up, sK+ levels showed only minor fluctuations, with no significant differences compared to baseline, and remained within the normal range throughout the treatment period. No treatment discontinuation or hospitalization due to hyperkalemia was observed. In non-diabetic CKD patients, finerenone showed good effectiveness and safety within a 3-month follow-up period. This study provides valuable real-world evidence supporting the use of finerenone in non-diabetic CKD and highlights the need for future large-scale prospective research to further validate its efficacy.

Finerenone: Who should prescribe it for CKD? The physician associate's perspective.

Diabetic kidney disease (DKD) affects 30-40% of all patients with diabetes and contributes significantly to the cardiovascular burden of chronic kidney disease (CKD). Despite the availability of evidence-based medications like finerenone and simple screening tests such as Urinary Albumin-to-Creatinine Ratio (UACR), more resources are still needed to care for DKD patients. Physician Associates (PAs) play a crucial role in the multidisciplinary team responsible for DKD diagnosis, monitoring, and management. A nonsteroidal mineralocorticoid receptor antagonist, namely finerenone, was approved by the FDA in adults with CKD associated with type 2 diabetes to reduce the risk of renal and cardiovascular outcomes. Finerenone is considered among the pillars of care for DKD, furthermore, the addition of finerenone in combination with renin-angiotensin system inhibitors and/or other renal protective medications may offer additional benefits. Primary care providers prescribe finerenone less frequently than specialized care providers, indicating a need to empower physician associates in medication prescription and other renal protection strategies. As part of a multidisciplinary team, physician associates can play an important role in evaluating risk factors that contribute to heart disease and metabolic health. They can also monitor not only kidney function by ordering tests, such as serum creatinine and urinary albumin-to-creatinine ratio every 3-12months, but also serum potassium levels. Additionally, physician associates can encourage patients to take responsibility for their health by regularly monitoring their blood pressure, blood glucose levels, and body weight. With early detection and management, kidney failure and cardiovascular events may be preventable. Specialized physician associates also play a significant role in the comprehensive care of DKD patients, especially in the later stages. DKD care can be hindered by numerous factors such as lack of patient engagement during counseling, cost disparities, and a complex referral system that requires multidisciplinary guidelines to improve professional communication. It is necessary to re-envision the physician associates' role in primary care and empower them in goal-directed therapies.

A review of novel endothelin antagonists and overview of non-steroidal mineralocorticoid antagonists for treating resistant hypertension: An update

Several agents are emerging from five different novel classes of antihypertensive medications. We will focus on endothelin antagonists and non-steroidal mineralocorticoid receptor antagonists. While several agents exist in this later class, only a couple have demonstrated superior efficacy in resistant hypertension management. Endothelin receptor antagonists are effective therapy for primary and resistant hypertension, but they are not widely used. This is due to side effects demonstrated in large clinical trials, specifically increased peripheral edema and worsening heart failure in some cases, as well as the availability of many alternative agents to manage blood pressure effectively. However, the relationship between endothelin and its close ties to hypertension is evolving. Recent pre-clinical work explores new applications of more selective endothelin receptor antagonists. They suggest that specific subtypes of hypertension may benefit more from endothelin receptor blockade than simply those with primary hypertension. We review this topic and other related data. Lastly, we also provide a brief overview of non-steroidal mineralocorticoid receptor antagonists as some in the class show promise as antihypertensive agents.

The Early Diagnosis and Treatment of Chronic Renal Insufficiency.

Chronic renal insufficiency (CRI) is becoming more common and has an increasing impact on public health. In Germany, approximately one in ten adults has CRI. Its most serious consequence is generally not the development of end-stage renal failure, but rather the markedly increased cardiovascular risk as kidney function declines. This review is based on the findings of a selective search in PubMed for literature about the treatment options for CRI, and on our overview of the existing guideline recommendations on diagnostic testing. Patients with diabetes mellitus and arterial hypertension are at especially high risk of developing CRI. For these patients, some of the guidelines recommend regular testing for albuminuria and measurement of the glomerular filtration rate (GFR), though sometimes only when specific risk constellations are present. The treatment of CRI has evolved in recent years. At first, aside from general measures, only RAS inhibitors were available as a specific therapy for CRI. With the extension of the approval of SGLT-2 inhibitors to non-diabetic CRI patients, the options for treatment have become wider. Two randomized controlled trials have revealed the benefit of SGLT-2 inhibitors with respect to their primary combined endpoints: time to a specified eGFR reduction and renal/cardiovascular death (HR 0.61 [0.51; 0.72] and 0.72 [0.64; 0.82]). The potential side effects and contraindications of SGLT-2 inhibitors must be taken into account. A further treatment option for diabetics with CRI has become available with the approval of the non-steroidal mineralocorticoid receptor antagonist finerenone. In patients with risk factors, renal function should be regularly tested.

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

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. 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. 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.

#694 Effects of nonsteroidal mineralocorticoid receptor antagonists on kidney of cirrhotic rats

Abstract Background and Aims Aldosterone binds to renal mineralocorticoid receptors (MRs) to regulate fluid and electrolytes homeostasis. In addition, aldosterone can be deleterious as a driver of inflammation and tissue fibrosis in several organs. Thus, blockade of aldosterone represents an important option to mitigate the target-organ damage. Mineralocorticoid receptor antagonists (MRAs) have been widely used as diuretic drugs for the management of hypertension, cirrhosis, and heart failure. However, the use of MRAs is limited by adverse events such as hyperkalemia. More recently, novel nonsteroidal selective MRAs with improved safety profiles have been developed. This nonsteroidal MRA (finerenone) has higher selectivity and stronger affinity for the MR, leading to lower risk of hyperkalemia. Recent evidences showed that finerenone reduces albuminuria, risk of CKD progression, and cardiovascular events in patients with chronic kidney disease and type 2 diabetes with a low incidence of hyperkalemia related treatment discontinuation. The pathophysiology of cirrhosis is very similar to that of cardiac failure. Decompensated cirrhosis is frequently treated with the MRAs. In addition to fluid management, MRAs showed hepatoprotective actions via reducing oxidative stress and inflammatory responses in CCl4-induced and common bile duct ligation (CBDL)-induced liver injury models. The potential beneficial effects of nonsteroidal MRA on cirrhosis had never been studied. This study aims to explore the renal protective role of nonsteroidal selective MRA and associated mechanisms in common bile duct ligation-related liver injury in rat model. Method CBDL was used to create liver injury in the Male Sprague-Dawley Drats. Finerenone (10 mg/kg/day) or vehicle was administered since the 1st day after CBDL. The effects of nonsteroidal selective MRA on kidneys were surveyed in two paralleled series on the 7th day (inflammation) and the 28th day (cirrhosis), respectively. The following parameters were evaluated: (a) hemodynamic parameters; (b) serum potassium, liver and renal function; (c) in-situ kidney perfusion; (d) western analyses of renal cortex and medulla. Results Compared with the vehicle-treated group, there was significantly lower renal vascular responsiveness to ET-1 in CBDL rats receiving 28 days of MRA (p<0.05) (Fig. 1B), but not in those receiving 7 days of MRA (Fig. 1A). MRA treatment led to no significant change in mean arterial pressure, portal pressure, serum potassium, liver, and renal function in CBDL rats (Table 1). The expressions of vasoactive mediators, such as iNOS, eNOS, ETA, and ETB in both renal cortex and medulla showed no significant change in CBDL rats following 28 days of MRA treatment (Fig. 2). Conclusion MRA treatment led to no significant effects on hemodynamics, liver, and renal function, but lower renal vascular responsiveness to ET-1 in CBDL rats receiving 28 days of MRA. The exact mechanisms remained to be further studied.

Renal effects and safety between Asian and non-Asian chronic kidney disease and type 2 diabetes treated with nonsteroidal mineralocorticoid antagonists.

Asians bear a heavier burden of chronic kidney disease (CKD), a common comorbidity of type 2 diabetes mellitus (T2DM), than non-Asians. Nonsteroidal mineralocorticoid receptor antagonists (MRAs) have garnered attention for their potential advantages in renal outcomes. Nevertheless, the impact on diverse ethnic groups remains unknown. The PubMed, Embase, Cochrane Library, China National Knowledge Infrastructure (CNKI), Wanfang database, and clinical trial registries were searched through August 2023 with the following keywords: nonsteroidal MRAs (finerenone, apararenone, esaxerenone, AZD9977, KBP-5074), CKD, T2DM, and randomized controlled trial (RCT). A random effects model was used to calculate overall effect sizes. Seven RCTs with 14 997 participants were enrolled. Nonsteroidal MRAs reduced urinary albumin to creatinine ratio (UACR) significantly more in Asians than non-Asians: (weighted mean difference [WMD], -0.59, 95% CI, -0.73 to -0.45, p < .01) vs (WMD, -0.29, 95% CI, -0.32 to -0.27, p < .01), respectively. The average decline of estimated glomerular filtration rate (eGFR) was similar in Asians and non-Asians (p > .05). Regarding systolic blood pressure (SBP), nonsteroidal MRAs had a better antihypertension performance in Asians (WMD, -5.12, 95% CI, -5.84 to -4.41, p < .01) compared to non-Asians (WMD, -3.64, 95% CI, -4.38 to -2.89, p < .01). A higher incidence of hyperkalemia and eGFR decrease ≥30% was found in Asians than non-Asians (p < .01). Nonsteroidal MRAs exhibited significant renal benefits by decreasing UACR and lowering SBP in Asian than that of non-Asian patients with CKD and T2DM, without increase of adverse events except hyperkalemia and eGFR decrease ≥30%.

Finerenone in patients with heart failure with mildly reduced or preserved ejection fraction: Rationale and design of the FINEARTS-HF trial.

Steroidal mineralocorticoid receptor antagonists (MRAs), spironolactone and eplerenone, are strongly recommended in the treatment of patients with chronic heart failure (HF) with reduced left ventricular ejection fraction (LVEF), but the balance of efficacy and safety in those with higher LVEF has not been well established. Broad use of steroidal MRAs has further been limited in part due to safety concerns around risks of hyperkalaemia, gynecomastia, and kidney dysfunction. These risks may be mitigated by the unique pharmacological properties of the non-steroidal MRA finerenone. The FINEARTS-HF trial is designed to evaluate the long-term efficacy and safety of the selective non-steroidal MRA finerenone among patients with HF with mildly reduced or preserved ejection fraction. FINEARTS-HF is a global, multicentre, event-driven randomized trial evaluating oral finerenone versus matching placebo in symptomatic patients with HF with LVEF ≥40%. Adults (≥40 years) with HF with New York Heart Association class II-IV symptoms, LVEF ≥40%, evidence of structural heart disease, and diuretic use for at least the previous 30 days were eligible. All patients required elevated natriuretic peptide levels: for patients in sinus rhythm, N-terminal pro-B-type natriuretic peptide (NT-proBNP) ≥300 pg/ml (or B-type natriuretic peptide [BNP] ≥100 pg/ml) were required, measured within 30 days (in those without a recent worsening HF event) or within 90 days (in those with a recent worsening HF event). Qualifying levels of NT-proBNP or BNP were tripled if a patient was in atrial fibrillation at screening. Estimated glomerular filtration rate <25 ml/min/1.73 m2 or serum potassium >5.0 mmol/L were key exclusion criteria. Patients were enrolled irrespective of clinical care setting (whether hospitalized, recently hospitalized, or ambulatory). The primary endpoint is the composite of cardiovascular death and total (first and recurrent) HF events. The trial started on 14 September 2020 and has validly randomized 6001 participants across 37 countries. Approximately 2375 total primary composite events are targeted. The FINEARTS-HF trial will determine the efficacy and safety of the non-steroidal MRA finerenone in a broad population of hospitalized and ambulatory patients with HF with mildly reduced or preserved ejection fraction. ClinicalTrials.gov NCT04435626 and EudraCT 2020-000306-29.

Baseline characteristics of patients with heart failure with mildly reduced or preserved ejection fraction: The FINEARTS-HF trial.

To describe the baseline characteristics of participants in the FINEARTS-HF trial, contextualized with prior trials including patients with heart failure (HF) with mildly reduced and preserved ejection fraction (HFmrEF/HFpEF). The FINEARTS-HF trial is comparing the effects of the non-steroidal mineralocorticoid receptor antagonist finerenone with placebo in reducing cardiovascular death and total worsening HF events in patients with HFmrEF/HFpEF. Patients with symptomatic HF, left ventricular ejection fraction (LVEF) ≥40%, estimated glomerular filtration rate ≥ 25 ml/min/1.73 m2, elevated natriuretic peptide levels and evidence of structural heart disease were enrolled and randomized to finerenone titrated to a maximum of 40 mg once daily or matching placebo. We validly randomized 6001 patients to finerenone or placebo (mean age 72 ± 10 years, 46% women). The majority were New York Heart Association functional class II (69%). The baseline mean LVEF was 53 ± 8% (range 34-84%); 36% of participants had a LVEF <50% and 64% had a LVEF ≥50%. The median N-terminal pro-B-type natriuretic peptide (NT-proBNP) was 1041 (interquartile range 449-1946) pg/ml. A total of 1219 (20%) patients were enrolled during or within 7 days of a worsening HF event, and 3247 (54%) patients were enrolled within 3 months of a worsening HF event. Compared with prior large-scale HFmrEF/HFpEF trials, FINEARTS-HF participants were more likely to have recent (within 6 months) HF hospitalization and greater symptoms and functional limitations. Further, concomitant medications included a larger percentage of sodium-glucose cotransporter 2 inhibitors and angiotensin receptor-neprilysin inhibitors than previous trials. FINEARTS-HF has enrolled a broad range of high-risk patients with HFmrEF and HFpEF. The trial will determine the safety and efficacy of finerenone in this population.

Mineralocorticoid receptor antagonists and reno-protection: What's the evidence & where do they fit? A guide for non-specialists.

The role of aldosterone has yet to be well appreciated in chronic kidney disease (CKD). Two variables define CKD: an estimated glomerular filtration rate of <60 ml/min/1.73 m2 and a spot urine albumin-creatinine ratio of >30 mg/g. Both are needed for an accurate diagnosis. The presence of CKD at this level is associated with an elevated risk of cardiovascular death and a greater risk of CKD progression to kidney failure and subsequent dialysis. This paper presents an overview of aldosterone's importance in CKD and its contribution to the inflammatory processes involved in CKD development. Data on outcomes, both surrogate and hard, related to outcomes on CKD progression will also be discussed in the context of mineralocorticoid blockade. Based on recent epidemiological data as well as data examining markers of diabetic kidney disease progression, it is clear that use of both renin-angiotensin system inhibitors and aldosterone receptor antagonists have a significant role in altering the natural history of kidney disease progression itself, as well as reducing the risk of cardiovascular events that generally accompany long-standing kidney disease. This paper will discuss these issues and the management of consequent hyperkalaemia when both steroidal and non-steroidal mineralocorticoid receptor antagonists are used in detail.

Detecting and managing the patient with chronic kidney disease in primary care: A review of the latest guidelines.

Chronic kidney disease (CKD) is a major global health problem, affecting about 9.5% of the population and 850 million people worldwide. In primary care, most CKD is caused by diabetes and/or hypertension, but a substantial proportion of cases may have alternative causes. During the early stages, CKD is asymptomatic, and many people are unaware that they are living with the disease. Despite the lack of symptoms, CKD is associated with elevated risks of cardiovascular disease, progressive kidney disease, kidney failure and premature mortality. Risk reduction strategies are effective and cost-effective but require early diagnosis through testing of the estimated glomerular filtration rate and albuminuria in high-risk populations. Once diagnosed, the treatment of CKD centres around lifestyle interventions, blood pressure and glycaemic control, and preventative treatments for cardiovascular disease and kidney disease progression. Most patients with CKD should be managed with statins, renin-angiotensin-aldosterone system inhibitors and sodium-glucose cotransporter-2 inhibitors. Additional treatment options to reduce cardiorenal risk are available in patients with diabetes, including glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists. The Kidney Failure Risk Equation is a new tool that can support the identification of patients at high risk of progressive kidney disease and kidney failure and can be used to guide referrals to nephrology. This review summarizes the latest guidance relevant to managing adults with, or at risk of, CKD and provides practical advice for managing patients with CKD in primary care.

Intellectual landscapes and emerging trends of non-steroidal mineralocorticoid receptor antagonists: a bibliometric and visual analysis.

With increasing studies, non-steroidal mineralocorticoid receptor (MR) antagonists have been increasingly recognized as a major novel dimension in cardiorenal disease therapy. This bibliometric analysis aimed to uncover current research status and identify future research directions in the study of non-steroidal MR antagonists to inform subsequent investigations. Relevant English-language literature was retrieved from the Science Citation Index Expanded of the Web of Science Core Collection on January 10, 2024. Analyses of countries, institutions, authors, journals, documents, cited references and keywords were performed by the CiteSpace and VOSviewer software. Overall, 498 documents, including 297 articles and 201 reviews, were included and analyzed. The United States (n = 188), Bayer AG (n = 78), and Professor Peter Kolkhof (n = 59) were the most prolific country, institution, and author in this field, respectively. Cluster analysis of cited references identified major clusters like cardiovascular disease, chronic kidney disease, and omecamtiv mecarbil. Keyword analysis indicated that sodium-glucose transport protein (SGLT)-2 inhibitors, pharmacotherapy, clinical trial, and guideline have emerged recently. The field of non-steroidal MR antagonists is gradually gaining momentum as a novel pharmacotherapy in cardiorenal diseases, especially diabetic kidney disease, hypertension, and heart failure. Future studies will focus on add-on pharmacotherapy by combining non-steroidal MR antagonists with SGLT-2 inhibitors and the development and publication of clinical guidelines to facilitate patient management.

Finerenone: From the Mechanism of Action to Clinical Use in Kidney Disease.

Diabetic kidney disease is a frequent microvascular complication of diabetes and is currently the leading cause of chronic kidney disease and end-stage kidney disease worldwide. Although the prevalence of other complications of diabetes is falling, the number of diabetic patients with end-stage kidney disease in need of kidney replacement therapy is rising. In addition, these patients have extremely high cardiovascular risk. It is more than evident that there is a high unmet treatment need in patients with diabetic kidney disease. Finerenone is a novel nonsteroidal mineralocorticoid receptor antagonist used for treating diabetic kidney disease. It has predominant anti-fibrotic and anti-inflammatory effects and exhibits several renal and cardiac protective effects. This review article summarizes the current knowledge and future prospects of finerenone in treating patients with kidney disease.

Finerenone cardiovascular and kidney outcomes by age and sex: FIDELITY post hoc analysis of two phase 3, multicentre, double-blind trials

ObjectivesThis study aimed to evaluate the efficacy and safety of finerenone, a selective, non-steroidal mineralocorticoid receptor antagonist, on cardiovascular and kidney outcomes by age and/or sex.DesignFIDELITY post hoc analysis; median...

A New Hope on the Horizon for Kidney and Cardiovascular Protection with SGLT2 Inhibitors, GLP-1 Receptor Agonists, and Mineralocorticoid Receptor Antagonists in Type 2 Diabetic and Chronic Kidney Disease Patients.

Type 2 diabetes (T2D) is the leading cause of chronic kidney disease (CKD). In addition, the cardiovascular prevalence in diabetic patients is around 32.2%, with a two-fold increased mortality risk compared to those without diabetes. Recent investigations have shed light on the promising cardioprotective and nephroprotective benefits of sodium-glucose cotransporter-2 inhibitors (SGLT2i), glucagon-like peptide-1 receptor agonists (GLP-1RA), and nonsteroidal mineralocorticoid receptor antagonists (nsMRAs) for individuals with T2D. The evidence robustly indicates that SGLT2i and GLP-1RA significantly reduce the risk of CKD and cardiovascular disease (CVD), all while effectively managing blood glucose levels. Furthermore, combining SGLT2i with nsMRAs amplifies the benefits, potentially offering a more profound reduction in cardiovascular and renal outcomes. The data analysis strongly supports the integration of these pharmacological agents in the management strategies for CKD and CVD prevention among T2D patients, highlighting the importance of awareness among nephrologists, especially in regions with limited healthcare resources.

The changing landscape of mineralocorticoid receptor antagonists – finerenone in cardiovascular and renal health

Finerenone is a novel non-steroidal mineralocorticoid receptor antagonist (MRA) with high selectivity and affinity to mineralocorticoid receptor (MR). Steroidal MRAs, like spironolactone and eplerenone, have been in use for decades. They have an established position in the management of hypertension and heart failure with reduced ejection fraction (HFrEF). There are studies showing that MR antagonism has anti-inflammatory and anti-fibrotic effects resulting in cardiovascular and renal protection. However, broader use of steroidal MRAs is seriously limited by antiandrogenic side effects and the risk of hyperkalemia. The differences in structure as well as pharmacokinetic and pharmacodynamic properties between steroidal and non-steroidal MRAs result in reduced risk of side effects while offering the benefit of cardiorenal protection. Finerenone is currently the only non-steroidal MRA approved by European Medicines Agency (EMA). It is indicated for patients with chronic kidney disease (CKD) with albuminuria and type 2 diabetes mellitus (DM2). Several studies showed a reduction of the risk of cardiovascular and renal events in this group of patients compared to placebo. The risk of hyperkalemia was increased resulting in discontinuation of treatment in more patients than placebo, but the risk of serious adverse events did not differ significantly. The other indications for finerenone, including heart failure (HF) management, are currently being researched.

Use of ACEi/ARBs, SGLT2 inhibitors and MRAs can help us reach the therapeutic ceiling in CKD

ABSTRACT Chronic kidney disease (CKD) is increasing in prevalence worldwide, posing major implications for public health such as kidney failure requiring dialysis, and increased risk of cardiovascular and all-cause mortality. Diabetic and hypertensive kidney disease represent the two most common causes of CKD. Until a few years ago, lifestyle modifications, blood pressure, glycaemic and lipid control, along with angiotensin-converting enzyme inhibitor or angiotensin-receptor blocker monotherapy were the only measures for retarding these two diseases and were the cornerstone of treatment for CKD of any aetiology. Effective application of all these measures could reduce the estimated glomerular filtration rate (eGFR) decline in proteinuric CKD roughly from 10–12 to 5–6 mL/min/1.73 m2/year, hence leaving a large unmet need in CKD treatment. In recent years, major kidney outcome trials showed that the addition of sodium–glucose cotransporter-2 inhibitors (SGLT2i) in patients with CKD with or without type 2 diabetes (T2D) and of the non-steroidal mineralocorticoid receptor antagonist finerenone in patients with CKD with T2D can largely improve kidney and cardiovascular outcomes. Elegant analyses of these trials shed further light on these effects, showing that SGLT2i or finerenone use on top of standard-of-care treatment in patients with albuminuric CKD can further reduce chronic eGFR annual loss to 2–2.5 mL/min/1.73 m2, while SGLT2is in normoalbuminuric CKD can reduce this loss &amp;lt;0.5 mL/min/1.73 m2, i.e. well below the aging-related GFR loss. Therefore, current evidence suggests that available treatments, if properly implemented, can help us reach the therapeutic ceiling in the majority of CKD patients.

Kidney Fibrosis and Oxidative Stress: From Molecular Pathways to New Pharmacological Opportunities.

Kidney fibrosis, diffused into the interstitium, vessels, and glomerulus, is the main pathologic feature associated with loss of renal function and chronic kidney disease (CKD). Fibrosis may be triggered in kidney diseases by different genetic and molecular insults. However, several studies have shown that fibrosis can be linked to oxidative stress and mitochondrial dysfunction in CKD. In this review, we will focus on three pathways that link oxidative stress and kidney fibrosis, namely: (i) hyperglycemia and mitochondrial energy imbalance, (ii) the mineralocorticoid signaling pathway, and (iii) the hypoxia-inducible factor (HIF) pathway. We selected these pathways because they are targeted by available medications capable of reducing kidney fibrosis, such as sodium-glucose cotransporter-2 (SGLT2) inhibitors, non-steroidal mineralocorticoid receptor antagonists (MRAs), and HIF-1alpha-prolyl hydroxylase inhibitors. These drugs have shown a reduction in oxidative stress in the kidney and a reduced collagen deposition across different CKD subtypes. However, there is still a long and winding road to a clear understanding of the anti-fibrotic effects of these compounds in humans, due to the inherent practical and ethical difficulties in obtaining sequential kidney biopsies and the lack of specific fibrosis biomarkers measurable in easily accessible matrices like urine. In this narrative review, we will describe these three pathways, their interconnections, and their link to and activity in oxidative stress and kidney fibrosis.

Assessment of renal and cardiovascular risks in patients with type 2 diabetes when using non-steroidal mineralocorticoid receptor antagonists

Background. Given the proven excessive activation of the renin-angiotensin-aldosterone system and the clinical manifestations of hypertension, mostly of renal origin, there is a need to optimize antihypertensive therapy aimed at an active nephroprotection. The purpose of the study is to carry out a comprehensive assessment of kidney and heart risk factors in patients with type 2 diabetes mellitus and chronic kidney disease (CKD) and to justify the administration of non-steroidal mineralocorticoid receptor antagonists to these patients. Materials and methods. In a prospective cohort study, 88 patients with type 2 diabetes were examined: group 1 — estimated glomerular filtration rate (eGFR) &lt; 60 ml/min/m2, group 2 — eGFR ≥ 60 ml/min/m2. eGFR was evaluated according to the CKD-EPI (Chronic Kidney Disease Epidemiology Colla­boration) formula based on serum creatinine. GFR category was defined according to the KDIGO (Kidney Disease: Improving Global Outcomes) criteria. The albumin-creatinine ratio was calcula­ted. The level of glycated hemoglobin (HbA1c) was assessed by the method of high-performance liquid chromatography. Aldosterone was evaluated by immunoenzymatic method. Results. In patients with eGFR &lt; 60 ml/min/m2, the albumin-creatinine ratio in daily urine is statistically significantly higher compared to group 2. Patients with eGFR &lt; 60 ml/min/m2 had an average uric acid level of 410.3 ± 98.8 μmol/l, which is statistically significantly higher than in those with eGFR ≥ 60 ml/min/m2 — 321.10 ± 74.54 μmol/l. A statistically significant correlation between the level of uric acid and markers of renal dysfunction was found only in patients with eGFR &lt; 60 ml/min/m2. Aldosterone levels were higher in the first group. No statistical difference was found between the average value of HbA1c in the studied groups. Conclusions. Numerous factors of unfavorable prognosis regarding kidney and heart risks have been identified: hypertension, increased albumin-creatinine ratio and cholesterol, unsatisfactory compensation of diabetes, obesity. There is an increase in the frequency of resistant hypertension, hyperuricemia, and hyperaldosteronism in patients with decreased eGFR. In patients with diabetic kidney damage on the background of type 2 diabetes, the administration of finerenone, a non-steroidal mine­ralocorticoid receptor antagonist, at a dose of 10–20 mg/day is pathogenetically justified.

A fluorescence chemo sensor approach for determination of finerenone in pharmaceutical formulation and human plasma: Method development and validation

Finerenone, a non-steroidal mineralocorticoid receptor antagonist, has gained recent approval for treating cardiovascular and kidney-related conditions. Herein, an innovative fluorescence chemo sensor was developed for the determination of finerenone in the pharmaceutical dosage form and the plasma matrix. The method is basically based on chemical transformation of finerenone into a fluorescent product through sequential reactions. This transformation occurs through a sequence of steps involving the interaction of finerenone with trimethylamine, resulting in the formation of a nucleophilic intermediate that subsequently reacts with bromoacetyl bromide to form fluorescent product, (S)-N-(2-bromoacetyl)-4-(4-cyano-2-methoxyphenyl)-5-ethoxy-2,8-dimethyl-1,4-dihydro-1,6-naphthyridine-3-carboxamide. The formed fluorescent product exhibits defined emission peak at 338 nm when excited at 248 nm. Significant concentration-dependent fluorescence enhancement was obtained enabling precise finerenone determination in the pharmaceutical formulation and plasma matrix. The method was optimized and validated providing sensitive determination over linearity range of 1–200 ng/mL with a lower limit of detection at 0.280 ng/mL. This strategy provides an efficient, economical substitute and straightforward, more sensitive analytical method for finerenone assessment in various matrices, in contrast to the previously published method, high-performance liquid chromatography-tandem mass spectrometry, which is expensive and time-consuming.