Mineralocorticoid Receptor Research Articles

7836 Targeting of Mineralocorticoid Receptor Expression by miR-124-3p-Loaded Extracellular Vesicles as Potential Therapy for Vascular Cognitive Impairment

7836 Targeting of Mineralocorticoid Receptor Expression by miR-124-3p-Loaded Extracellular Vesicles as Potential Therapy for Vascular Cognitive Impairment

Efficacy, Safety and Mechanistic Impact of a Heart Failure Guideline-Directed Medical Therapy Clinic

BackgroundAlthough clinical evidence supports rapid institution of guideline-directed medical therapy (GDMT) for heart failure (HF), in actual practice, there remain large gaps in adherence to guideline recommendations. Recent data support safety and efficacy of rapid GDMT implementation; however, rapid GDMT deployment within a general cardiology environment remains unexplored. ObjectivesThe purpose of this study was to evaluate the efficacy and safety of a GDMT clinic within a general cardiology practice relative to usual care, the impact on prescription of GDMT, HF symptoms, N-terminal pro–B-type natriuretic peptide concentrations and echocardiographic parameters of remodeling. MethodsIndividuals with HF with an abnormal ejection fraction (<50%) referred to the GDMT clinic underwent rapid GDMT titration with close monitoring of clinical data. Rates of GDMT prescription were compared with a matched reference group. Patients underwent echocardiography at baseline and after GDMT clinic completion. ResultsA total of 114 persons were treated in GDMT clinic. The mean age was 67.6 ± 14.6 years, and 32 (28%) were women. Among those referred, 100 (87.7%) had no contraindications for 4-drug GDMT. From baseline to clinic completion (median 15.8 weeks [Q1-Q3: 10.7-23.0 weeks]), patients without medication contraindications experienced significant increases in 4-drug GDMT use (from 21% to 88%; P < 0.001); of 4-drug GDMT recipients, 92% received angiotensin receptor neprilysin inhibitor. GDMT clinic participants achieved higher medication doses than those in usual care, with greater achievement of ≥50% target dose of angiotensin receptor neprilysin inhibitor (52% vs 8%), beta-blocker (78% vs 6.2%), mineralocorticoid receptor antagonist (98% vs 15.6%), and sodium-glucose cotransporter 2 inhibitors (92% vs 6.2%). Target doses of all 4 drugs were reached in nearly 1 in 4 participants. HF symptoms improved (94% to 75% NYHA functional class II/III; P < 0.001) and N-terminal pro–B-type natriuretic peptide concentration decreased (median 587 to 534 ng/L; P = 0.03) despite loop diuretic reduction. Additionally, we observed an absolute 6% LVEF increase (from 37% [Q1-Q3: 31%-41%] to 43% [Q1-Q3: 38%-53%]; P < 0.001) and substantial decrease in moderate or severe mitral regurgitation. GDMT titration was well-tolerated. ConclusionsRapid GDMT implementation via an outpatient GDMT clinic was effective, safe, and associated with improvement in key clinical parameters. The more widespread role of GDMT clinics to improve HF care warrants further study.

Design and cohort characteristics of TRACK, a prospective study of hyperkalaemia management decision-making.

Guideline-recommended hyperkalaemia management includes dietary potassium (K+) restriction, bicarbonate correction, diuretics and K+ binders with dose reduction of renin-angiotensin-aldosterone system inhibitors as a last resort. The extent to which these recommendations are implemented is uncertain, as real-world data on hyperkalaemia management are limited. The Tracking Treatment Pathways in Adult Patients with Hyperkalemia (TRACK) study is a multinational, prospective, longitudinal study that is being conducted to address this knowledge gap. We report the design and baseline cohort characteristics of this real-world study of hyperkalaemia management decision-making. This study enrolled participants within 21days of an episode of hyperkalaemia in four European countries (UK, Spain, Germany, Italy) and the USA. During the 12-month follow up, data collected will include participant and healthcare provider characteristics (specialty and practice setting), hyperkalaemia treatment objectives and strategies, rationale for management decisions and indicators of response and patient-reported perceptions of their hyperkalaemia treatment. The enrolled cohort includes 1330 participants, mean age 68years, of whom 31% were women. At baseline, 6% reported heart failure, 55% chronic kidney disease, 29% both and 9% neither. Most participants (57%) were taking an angiotensin-converting enzyme inhibitor, angiotensin receptor blocker or angiotensin receptor/neprilysin inhibitor at baseline. Mineralocorticoid receptor antagonist use was lower (14%). The prospective TRACK study will shed light on practitioners' hyperkalaemia management decision-making and assess the impact of their decisions on hyperkalaemia recurrence. Understanding practitioners' underlying thought processes will facilitate efforts to improve hyperkalaemia management.ClinicalTrials.gov: NCT05408039.

Low-dose spironolactone and cardiovascular outcomes in moderate stage chronic kidney disease: a randomized controlled trial.

Chronic kidney disease (CKD) is associated with a substantial risk of progression to end-stage renal disease and vascular events. The nonsteroidal mineralocorticoid receptor antagonist (MRA), finerenone, offers cardiorenal protection for people with CKD and diabetes, but there is uncertainty if the steroidal MRA, spironolactone, provides the same protection. In this prospective, randomized, open, blinded endpoint trial, we assessed the effectiveness of 25 mg spironolactone in addition to usual care or usual care alone for reducing cardiovascular outcomes in stage 3b CKD among an older community cohort (mean age = 74.8 years and s.d. = 8.1). We recruited 1,434 adults from English primary care, of whom 1,372 (96%) were included in the primary analysis. The primary outcome was time from randomization until the first occurrence of death, hospitalization for heart disease, stroke, heart failure, transient ischemic attack or peripheral arterial disease, or first onset of any condition listed not present at baseline. Across 3 years of follow-up, the primary endpoint occurred in 113 of 677 participants randomized to spironolactone (16.7%) and 111 of 695 participants randomized to usual care (16.0%) with no significant difference between groups (hazard ratio = 1.05, 95% confidence interval: 0.81-1.37). Two-thirds of participants randomized to spironolactone stopped treatment within 6 months, predominantly because they met prespecified safety stop criteria. The most common reason for stopping spironolactone was a decrease in the estimated glomerular filtration rate that met prespecified stop criteria (n = 239, 35.4%), followed by participants being withdrawn due to treatment side effects (n = 128, 18.9%) and hyperkalemia (n = 54, 8.0%). In conclusion, we found that spironolactone was frequently discontinued due to safety concerns, with no evidence that it reduced cardiovascular outcomes in people with stage 3b CKD. Spironolactone should not be used for people with stage 3b CKD without another explicit treatment indication. ClinicalTrials.gov registration: ISRCTN44522369 .

Recovery of complete left bundle branch block in dilated cardiomyopathy after optimal heart failure treatment: a case report

Complete left bundle branch block (CLBBB) is a significant cardiac conduction abnormality often associated with dilated cardiomyopathy (DCM). This case report highlights the improvement in CLBBB and symptom relief through reverse cardiac remodeling in a patient diagnosed with DCM following an optimized heart failure treatment regimen consisting of an angiotensin-converting enzyme inhibitor, beta-blocker, and mineralocorticoid receptor antagonist. This case highlights the potential of electrical remodeling and conduction system improvement in patients with DCM receiving optimized medical therapy.

First interim results from FINE-REAL: a prospective, non-interventional, phase 4 study providing insights into the use and safety of finerenone in a routine clinical setting.

Finerenone, a selective non-steroidal mineralocorticoid receptor antagonist, improves kidney and cardiovascular outcomes in patients with chronic kidney disease (CKD) associated with type 2 diabetes (T2D). The FINE-REAL study (NCT05348733) aims to evaluate the characteristics and treatment patterns of participants treated with finerenone in clinical practice. FINE-REAL is a prospective, single-arm, non-interventional study of patients initiated on finerenone as part of their routine care in accordance with country-approved labels. The study, initiated in June 2022, is expected to be completed by January 2028. The cutoff for this pre-specified interim analysis was June 13, 2023. Participants were recruited across nephrology, endocrinology, cardiology, and primary care settings. Of 556 participants enrolled in the study by the cut-off date, 504 were included in this analysis (median follow-up duration of 7months [finerenone treatment initiation to last recorded observation]). At baseline, 76.1% of participants were in the high or very high (KDIGO) CKD risk categories. Angiotensin converting enzyme inhibitors/angiotensin receptor blockers and sodium-glucose cotransporter 2 inhibitors were prescribed to 71.8% and 46.6% of participants, respectively. Based on prescribing information, 87.9% and 12.1% of participants initiated finerenone at doses of 10 and 20mg, respectively. Finerenone treatment was uninterrupted in 92.3% of participants after 7months' median follow-up. Treatment-emergent adverse events occurred in 110 (21.8%) participants. Hyperkalemia occurred in 25 (5.0%) participants, with no cases leading to death, dialysis, or hospitalization. At this interim analysis, finerenone was initiated in patients with CKD and T2D across various clinical practices participating in the study. Treatment discontinuation and hyperkalemia occurred infrequently.

Effects of the Non-Steroidal MRA Finerenone with and without Concomitant SGLT2 Inhibitor Use in Heart Failure.

Patients with heart failure (HF) with mildly reduced or preserved ejection fraction face heightened long-term risks of morbidity and mortality. The sodium glucose-co-transporter-2 inhibitors (SGLT2i) and the non-steroidal mineralocorticoid receptor antagonist (MRA) finerenone have both been shown to reduce the risk of cardiovascular events in this population, but the effects of their combined use are not known. FINEARTS-HF was a randomized, double-blind, placebo-controlled trial of finerenone in patients with HF and left ventricular ejection fraction (LVEF) ≥40%. Baseline SGLT2i use was a prespecified subgroup. The primary outcome was a composite of total (first and recurrent) worsening HF events and cardiovascular death. We first assessed for evidence of treatment heterogeneity based on baseline SGLT2i use. We further examined SGLT2i uptake during the trial and evaluated the treatment effects of finerenone accounting for baseline and during trial use of SGLT2i in time-varying analyses. Among 6,001 participants, 817 (13.6%) were treated with an SGLT2i at baseline. During 2.6-years median follow-up, treatment with finerenone similarly reduced the risk of the primary outcome in participants treated with an SGLT2i (rate ratio 0.83; 95% confidence interval 0.60 to 1.16) and without an SGLT2i at baseline (rate ratio 0.85; 95% confidence interval 0.74 to 0.98); Pinteraction=0.76. In follow-up, 980 participants initiated SGLT2i, which was less frequent in the finerenone arm compared with placebo (17.7% vs. 20.1%; hazard ratio 0.86; confidence interval 0.76 to 0.97). Time-updated analyses accounting for baseline and subsequent use of SGLT2i did not meaningfully alter the treatment effects of finerenone on the primary endpoint. The treatment benefits of the non-steroidal MRA finerenone were observed irrespective of concomitant use of an SGLT2i. These data suggest that the combined use of SGLT2i and a non-steroidal MRA may provide additive protection against cardiovascular events in patients with HF with mildly reduced or preserved ejection fraction.

Guideline-directed medical therapy implementation during hospitalization for cardiogenic shock.

Despite significant morbidity and mortality, recent advances in cardiogenic shock (CS) management have been associated with increased survival. However, little is known regarding the management of patients who survive CS with heart failure (HF) with reduced left ventricular ejection fraction (LVEF, HFrEF), and the utilization of guideline-directed medical therapy (GDMT) in these patients has not been well described. To fill this gap, we investigated the use of GDMT during an admission for CS and short-term outcomes using the Inova single-centre shock registry. We investigated the implementation of GDMT for patients who survived an admission for CS with HFrEF using data from our single-centre shock registry from January 2017 to December 2019. Baseline characteristics, discharge clinical status, data on GDMT utilization and 30day, 6month and 12month patient outcomes were collected by retrospective chart review. Among 520 patients hospitalized for CS during the study period, 185 (35.6%) had HFrEF upon survival to discharge. The median age was 64years [interquartile range (IQR) 56, 70], 72% (n=133) were male, 22% (n=40) were Black and 7% (n=12) were Hispanic. Forty-one per cent of patients (n=76) presented with shock related to acute myocardial infarction (AMI), while 59% (n=109) had HF-related CS (HF-CS). The median length of hospital stay was 12days (IQR 7, 18). At discharge, the proportions of patients on beta-blockers, angiotensin-converting enzyme inhibitors (ACEis)/angiotensin receptor blockers (ARBs)/angiotensin receptor/neprilysin inhibitors (ARNIs) and mineralocorticoid receptor antagonists (MRAs) were 78% (n=144), 58% (n=107) and 55% (n=101), respectively. Utilization of three-drug GDMT was 33.0% (n=61). Ten per cent of CS survivors with HFrEF (n=19) were not prescribed any component of GDMT at discharge. Multivariable logistic regression adjusted for baseline GDMT use revealed that patients with lower LVEF and those who transferred to our centre from an outside hospital were more likely to experience GDMT addition (P<0.05). Patients prescribed at least one additional class of GDMT during admission had higher odds of 6month and 1year survival (P<0.01): On average, 6month survival odds were 7.1 times greater [confidence interval (CI) 1.9, 28.5] and 1year survival odds were 6.0 times greater than those who did not have at least one GDMT added (CI 1.9, 20.5). Most patients who survived CS admission with HFrEF in this single-centre CS registry were not prescribed all classes or goal doses of GDMT at hospital discharge. These findings highlight an urgent need to augment multidisciplinary efforts to enhance the post-discharge medical management and outcomes of patients who survive CS with HFrEF.

ENaCγ in Urinary Extracellular Vesicles as an Indicator of MR Signaling in PA.

Aldosterone and the MR (mineralocorticoid receptor) are important therapeutic targets for hypertension and cardiovascular diseases. However, biomarkers of tissue MR signaling are not fully established. Extracellular vesicles released from eukaryotic cells can provide information on tissue signaling. Using samples from patients with primary aldosteronism (PA), we explored the potential of urinary extracellular vesicles (uEVs) as a noninvasive indicator of MR signaling to guide treatment. We analyzed proteins contained in PA uEVs by liquid chromatography tandem mass spectrometry. We narrowed down candidate biomarkers by referring to an existing database of urinary exosomes. The results were validated through Western blot analysis involving 63 patients with PA and 11 healthy volunteers. We identified a total of 1940 proteins in PA uEVs. Comparative analysis with the existing database narrowed down the pathways enriched in PA uEVs, which were related to diabetic complications, Rac1 signaling, and aldosterone-regulated sodium reabsorption. A closer look at the identified proteins revealed ENaCγ (epithelial Na+ channel γ) peptides near the proteolytic cleavage sites, and Western blot analysis confirmed the predominant presence of cleaved ENaCγ, a marker of aldosterone signaling in renal tubules. In PA uEVs, cleaved ENaCγ showed a 4.8-fold increase compared with healthy volunteers and was significantly correlated with the aldosterone-to-renin ratio, aldosterone levels, and fractional excretion of K+. Targeted treatment in PA reduced the abundance of cleaved ENaCγ, suggesting a causal role for MR in its induction. This study provides a list of proteins contained in PA uEVs and suggests that ENaCγ in uEVs is a promising biomarker for renal MR signaling.

Translating the 2021 ESC heart failure guideline recommendations in daily practice: Results from a heart failure survey. A scientific statement of the ESC Council for Cardiology Practice and the Heart Failure Association of the ESC.

Real-world data show that guidelines are insufficiently implemented, and particularly guideline-directed medical therapies (GDMT) are underused in patients with heart failure and reduced ejection fraction (HFrEF) in clinical practice. The Council for Cardiology Practice and the Heart Failure Association of the European Society of Cardiology (ESC) developed a survey aiming to (i) evaluate the perspectives of the cardiology community on the 2021 ESC heart failure (HF) guidelines, (ii) pinpoint disparities in disease management, and (iii) propose strategies to enhance adherence to HF guidelines. A 22-question survey regarding the diagnosis and treatment of HFrEF was delivered between March and June 2022. Of 457 physicians, 54% were general cardiologists, 19.4% were HF specialists, 18.9% other cardiac specialists, and 7.7% non-cardiac specialists. For diagnosis, 52.1% employed echocardiography and natriuretic peptides (NPs), 33.2% primarily used echocardiography, and 14.7% predominantly relied on NPs. The first drug class initiated in HFrEF was angiotensin-converting enzyme inhibitors/angiotensin receptor-neprilysin inhibitor (ACEi/ARNi) (91.2%), beta-blockers (BB) (73.8%), mineralocorticoid receptor antagonists (MRAs) (53.4%), and sodium-glucose cotransporter 2 (SGLT2) inhibitors (48.1%). The combination ACEi/ARNi + MRA+ BB was preferred by 39.3% of physicians, ACEi/ARNi + SGLT2 inhibitors + BB by 33.3%, and ACEi/ARNi + BB by 22.2%. The time required to initiate and optimize GDMT was estimated to be <1 month by 8.3%, 1-3 months by 52%, 3-6 months by 31.8%, and >6 months by 7.9%. Compared to general cardiologists, HF specialists/academic cardiologists reported lower estimated time-to-initiation, and more commonly preferred a parallel initiation of GDMT rather than a sequential approach. Participants generally followed diagnostic and treatment guidelines, but variations in HFrEF management across care settings or HF specialties were noted. The survey may raise awareness and promote standardized HF care.

Progressive 11β-Hydroxysteroid Dehydrogenase Type 2 Insufficiency as Kidney Function Declines.

It has been postulated that chronic kidney disease (CKD) is a state of relative 11β-hydroxysteroid dehydrogenase type 2 (11βHSD2) insufficiency, resulting in increased cortisol-mediated mineralocorticoid receptor (MR) activation. We hypothesized that relative 11βHSD2 insufficiency manifests across a wide spectrum of progressively declining kidney function, including within the normal range. Adult participants were recruited at two academic centers. A discovery cohort (n=500) enrolled individuals with estimated glomerular filtration rate (eGFR) ranging from normal to CKD stage 5, in whom serum cortisol-to-cortisone (F/E) was measured as a biomarker of 11βHSD2 activity. A validation cohort (n=101) enrolled only individuals with normal kidney function (eGFR ≥ 60 mL/min/1.73 m2) in whom 11βHSD2 activity was assessed via serum F/E and 11-hydroxy-to-11-keto androgen (11OH/K) ratios following multiple maneuvers: oral sodium suppression test (OSST), dexamethasone suppression test (DST), and ACTH-stimulation test (ACTHstim). In the discovery cohort, lower eGFR was associated with higher F/E (P-trend<0.001). Similarly, in the validation cohort, with normal eGFR, an inverse association between eGFR and both F/E and 11OH/K ratios was observed (P-trend<0.01), which persisted following DST (P-trend<0.001) and ACTHstim (P-trend< 0.05). The fractional excretion of potassium, a marker of renal MR activity, was higher with higher F/E (P-trend < 0.01) and with lower eGFR (P-trend<0.0001). A continuum of declining 11βHSD2 activity was observed with progressively lower eGFR in individuals spanning a wide spectrum of kidney function, including those with apparently normal kidney function. These findings implicate cortisol-mediated MR activation in the pathophysiology of hypertension and cardiovascular disease in CKD.

Optimizing heart failure therapy with enhanced medical management: focus on heart rate management

Heart failure (HF) is a significant global health issue, affecting over 60 million people worldwide, with its prevalence expected to rise due to aging populations and the increasing incidence of comorbidities like hypertension and diabetes. Despite therapeutic advances, including quadruple therapy with renin-angiotensin-system inhibitors, beta blockers (BB), mineralocorticoid receptor antagonists, and sodium-glucose cotransporter 2 inhibitors, HF remains a condition with a poor prognosis, particularly for those with reduced ejection fraction (HFrEF), who are predominantly found in low- and middle-income countries like India. Elevated resting heart rate (HR) is a critical prognostic factor in HF, correlating strongly with cardiovascular mortality and morbidity. For every five-beat increase in HR, there is a 16% rise in cardiovascular mortality and HF hospitalization, emphasizing the need for effective HR management. However, challenges persist in optimizing HF treatment, such as the underutilization of BBs, despite their proven efficacy in reducing mortality. In India, the "double burden" of age-related and contemporary diseases complicates HF management further. Addressing unmet needs in HF care requires optimizing therapeutic strategies and improving treatment adherence, particularly in the context of HR control. Studies indicate that tailored approaches, including the use of BBs and ivabradine, could reduce HR and improve clinical outcomes. The ongoing challenges in accessing guideline-directed therapy and ensuring adherence highlight the need for comprehensive strategies to enhance patient outcomes, while personalized treatments and further research remain essential in navigating the complex landscape of HF management.

A comprehensive review of finerenone-a third-generation non-steroidal mineralocorticoid receptor antagonist.

Multiple studies have shown that finerenone (BAY 94-8862), a third-generation non-steroidal mineralocorticoid receptor antagonist (MRA), possesses different or superior mechanisms of action to traditional MRAs. Specifically, animal and cell-based experiments have demonstrated that this compound exerts multiple effects including fibrosis inhibition, reduced pulmonary artery pressure, improved diabetic retinopathy, enhanced endothelial functions, metabolic optimization as well as reduced oxidative stress, thereby exerting overall positive effects on renal and cardiovascular diseases. Consequently, clinical research, such as the FIGARO-DKD and FIDELIO-DKD trials, has demonstrated dual benefits for patients with type 2 diabetes mellitus and chronic kidney disease (T2DM-CKD), especially by validating MRAs' potential in reducing risks of renal and cardiovascular composite endpoints. Currently, cardiovascular indications for finerenone are limited to patients with T2DM-CKD, while its use in non-T2DM CKD patients remains at clinical trial stages. Despite showing good safety and efficacy in T2DM-CKD patients, there are insufficient corresponding data for those presenting chronic kidney disease without diabetes (ndCKD). Furthermore, the application of this compound in diseases such as primary aldosteronism and its association with cancer risk need to be further validated through larger-scale and longer-term clinical studies. Nevertheless, the development of finerenone provides an additional option for treating cardiovascular and renal diseases. With further research, it is expected that finerenone will be relevant to a broader range of CKD patient populations by addressing current knowledge gaps to comprehensively evaluate its clinical value and potentially alter existing treatment strategies. The current review aims to comprehensively analyze the basic research and clinical advancements involving finerenone in order to explore its prospects for treating cardiovascular and renal diseases, while addressing unmet needs in current treatment strategies. Additionally, through a comprehensive analysis of relevant research findings, a deeper understanding of finerenone's drug characteristics will be provided alongside scientific guidance for future treatment strategies and their clinical significance.

Mineralocorticoid Receptor Antagonists in Diabetic Kidney Disease: Clinical Evidence and Potential Adverse Events

Diabetic kidney disease (DKD) is the leading cause of chronic kidney disease (CKD) globally and is associated with an increased risk of developing cardiovascular disease (CVD). DKD management requires a multipronged approach to decrease the progression of CKD and CVD. Mineralocorticoid receptor antagonists (MRAs) added to renin-angiotensin-aldosterone system blockade and sodium–glucose cotransporter 2 inhibitor therapy reduce the incidence of cardiovascular outcomes and progression of CKD. This review examines the cardiorenal benefits of MRAs and summarizes evidence on potential risks for acute kidney injury, hyperkalemia, and sexual dysfunction for steroidal and nonsteroidal MRAs.

The renin-angiotensin-aldosterone system: An old tree sprouts new shoots

The intricate physiological and pathological diversity of the Renin-Angiotensin-Aldosterone System (RAAS) underpins its role in maintaining bodily equilibrium. This paper delves into the classical axis (Renin-ACE-Ang II-AT1R axis), the protective arm (ACE2-Ang (1–7)-MasR axis), the prorenin-PRR-MAP kinases ERK1/2 axis, and the Ang IV-AT4R-IRAP cascade of RAAS, examining their functions in both physiological and pathological states. The dysregulation or hyperactivation of RAAS is intricately linked to numerous diseases, including cardiovascular disease (CVD), renal damage, metabolic disease, eye disease, Gastrointestinal disease, nervous system and reproductive system diseases. This paper explores the pathological mechanisms of RAAS in detail, highlighting its significant role in disease progression. Currently, in addition to traditional drugs like ACEI, ARB, and MRA, several novel therapeutics have emerged, such as angiotensin receptor-enkephalinase inhibitors, nonsteroidal mineralocorticoid receptor antagonists, aldosterone synthase inhibitors, aminopeptidase A inhibitors, and angiotensinogen inhibitors. These have shown potential efficacy and application prospects in various clinical trials for related diseases. Through an in-depth analysis of RAAS, this paper aims to provide crucial insights into its complex physiological and pathological mechanisms and offer valuable guidance for developing new therapeutic approaches. This comprehensive discussion is expected to advance the RAAS research field and provide innovative ideas and directions for future clinical treatment strategies.

A commentary from the European Renal Best Practice (ERBP) on the Kidney Disease Improving Global Outcomes (KDIGO) 2024 Clinical Practice Guideline for the Evaluation and Management of Chronic Kidney Disease in children and adults

Abstract The Kidney Disease: Improving Global Outcomes (KDIGO) 2024 Guidelines for identification and management of chronic kidney disease (CKD) are a welcome development coming 12 years after the paradigm changing 2012 guidelines. We are living in an unprecedented era in nephrology with novel therapies, including sodium-glucose cotransporter-2 inhibitors, glucagon-like peptide-1 receptor agonists and non-steroidal mineralocorticoid receptor antagonists now being proven in multiple randomised controlled clinical trials to reduce both the progression of CKD and cardiovascular morbidity and mortality. The KDIGO 2024 CKD guideline is aimed at a broad audience looking after children and adults with CKD and provide practical and actionable steps to improve care. This commentary reviews the guideline sections pertaining to the evaluation and risk assessment of individuals with CKD from a European perspective. We feel that despite the last guideline being published 12 years ago, and that the assessment of CKD has been emphasized by many other national/international nephrology, cardiology and diabetology guidelines and societies, the diagnosis and treatment of CKD remains poor across Europe. As such the KDIGO 2024 CKD Guidelines should be seen as an urgent call to action to improve diagnosis and care of children and adults with CKD across Europe. We know what we need to do. We now need to get on and do it.

Molecular Therapeutics for Diabetic Kidney Disease: An Update.

Diabetic kidney disease (DKD) is a common microvascular complication of diabetes mellitus (DM). With the increasing prevalence of DM worldwide, the incidence of DKD remains high. If DKD is not well controlled, it can develop into chronic kidney disease or end-stage renal disease (ESRD), which places considerable economic pressure on society. Traditional therapies, including glycemic control, blood pressure control, blood lipid control, the use of renin-angiotensin system blockers and novel drugs, such as sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor inhibitors and glucagon-like peptide-1 receptor agonists, have been used in DKD patients. Although the above treatment strategies can delay the progression of DKD, most DKD patients still ultimately progress to ESRD. Therefore, new and multimodal treatment methods need to be explored. In recent years, researchers have continuously developed new treatment methods and targets to delay the progression of DKD, including miRNA therapy, stem cell therapy, gene therapy, gut microbiota-targeted therapy and lifestyle intervention. These new molecular therapy methods constitute opportunities to better understand and treat DKD. In this review, we summarize the progress of molecular therapeutics for DKD, leading to new treatment strategies.

Early metabolic and transcriptomic regulation in rainbow trout (Oncorhynchus mykiss) liver by 11-deoxycorticosterone through two corticosteroid receptors pathways

Cortisol hormone is considered the main corticosteroid in fish stress, acting through glucocorticoid (GR) or mineralocorticoid (MR) receptor. The 11-deoxycorticosterone (DOC) corticosteroid is also secreted during stress and could complement the cortisol effects, but this still not fully understood. Hence, we evaluated the early transcriptomic response of rainbow trout (Oncorhynchus mykiss) liver by DOC through GR or MR. Thirty juvenile trout were pretreated with an inhibitor of endogenous cortisol synthesis (metyrapone) by intraperitoneal injection in presence or absence of GR (mifepristone) and MR (eplerenone) pharmacological antagonists for one hour. Then, fish were treated with a physiological DOC dose or vehicle (DMSO-PBS1X as control) for three hours (n = 5 per group). We measured several metabolic parameters in plasma, together with the liver glycogen content. Additionally, we constructed cDNA libraries from liver of each group, sequenced by HiseqX Illumina technology and then analyzed by RNA-seq. Plasma pyruvate and cholesterol levels decreased in DOC-administered fish and only reversed by eplerenone. Meanwhile, DOC increased liver glycogen contents depending on both corticosteroid receptor pathways. RNA-seq analysis revealed differential expressed transcripts induced by DOC through GR (448) and MR (1901). The enriched biological processes to both were mainly related to stress response, protein metabolism, innate immune response and carbohydrates metabolism. Finally, we selected sixteen genes from enriched biological process for qPCR validation, presenting a high Pearson correlation (0.8734 average). These results describe novel physiological effects of DOC related to early metabolic and transcriptomic responses in fish liver and differentially modulated by MR and GR.

Urinary proteomic signature of mineralocorticoid receptor antagonism by spironolactone: evidence from the HOMAGE trial

ObjectiveHeart failure (HF) is characterised by collagen deposition. Urinary proteomic profiling (UPP) followed by peptide sequencing identifies parental proteins, for over 70% derived from collagens. This study aimed to refine...

The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF): Rationale and design.

Benefits of mineralocorticoid receptor antagonists (MRAs) in heart failure with preserved and mildly reduced ejection fraction (HFpEF/HFmrEF) have not been established. Conventional randomized controlled trials are complex and expensive. The Spironolactone Initiation Registry Randomized Interventional Trial in Heart Failure with Preserved Ejection Fraction (SPIRRIT-HFpEF) is a unique pragmatic registry-based randomized controlled trial. SPIRRIT-HFpEF is a multicentre, prospective, randomized, open-label, blinded endpoint trial conducted on platforms in the Swedish Heart Failure Registry (SwedeHF) and the United States (US) Trial Innovation Network. Patients with HFpEF/HFmrEF are randomized 1:1 to spironolactone (or eplerenone) in addition to usual care, versus usual care alone. The primary outcome is total number of cardiovascular deaths and hospitalizations for heart failure. Outcomes are collected from Swedish administrative complete coverage registries and a US call centre and subsequently adjudicated. Simple eligibility criteria were based on data available in SwedeHF: heart failure as outpatient or at discharge from hospital, left ventricular ejection fraction ≥40%, N-terminal pro-B-type natriuretic peptide >300 ng/L (in sinus rhythm) or >750 ng/L (in atrial fibrillation), with pre-specified adjustment for elevated body mass index, and chronic loop diuretic use. Power and sample size assessments were based on an event-driven design allowing enrolment over approximately 6 years, and application of hazard ratios from the TOPCAT trial, Americas subset. The final sample size is expected to be approximately 2400 patients. SPIRRIT-HFpEF will be informative on the effectiveness of generic MRAs in HFpEF and HFmrEF, and on the feasibility of conducting pragmatic and registry-based trials in heart failure and other chronic conditions.