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Kidney dysfunction often leads to reluctance to start or continue life-saving heart failure (HF) therapy. This study sought to examine the efficacy and safety of mineralocorticoid receptor antagonists (MRAs) in patients with HF with reduced ejection fraction experiencing significant kidney dysfunction. We pooled individual patient data from the RALES (Randomized Aldactone Evaluation Study) and EMPHASIS-HF (Eplerenone in Mild Patients Hospitalization and Survival Study in Heart Failure) trials. The association between MRA treatment and outcomes was assessed according to whether the estimated glomerular filtration rate (eGFR) declined to <30 mL/min/1.73 m2 or not. The primary outcome was cardiovascular death or HF hospitalization. Among 4,355 patients included, 295 (6.8%) experienced a deterioration of eGFR after randomization to <30 mL/min/1.73 m2. These patients had more impaired baseline cardiac and kidney function (eGFR 47.3 ± 13.4 mL/min/1.73 m2 vs 70.5 ± 21.8 mL/min/1.73 m2) and had a higher risk of the primary outcome than patients without eGFR deterioration (HR: 2.49; 95% CI: 2.01-3.08; P < 0.001). However, the risk reduction in the primary outcome with MRA therapy was similar in those who experienced a decrease in eGFR to <30 mL/min/1.73 m2 (HR: 0.65; 95% CI: 0.43-0.99) compared with those who did not (HR: 0.63; 95% CI: 0.56-0.71) (P interaction = 0.87). In patients with a decrease in eGFR to <30 mL/min/1.73 m2, 21 fewer individuals (per 100 person-years) experienced the primary outcome with MRA treatment, vs placebo, compared with an excess of 3 more patients with severe hyperkalemia (>6.0 mmol/L). Because patients experiencing a decrease in eGFR to <30 mL/min/1.73 m2 are at very high risk, the absolute risk reduction with an MRA in these patients is large and this decline in eGFR should not automatically lead to treatment discontinuation. [Display omitted] [ABSTRACT FROM AUTHOR]

Hypertension represents one of the primary and most common risk factors leading to the development of heart failure (HF) across the entire spectrum of left ventricular ejection fraction. A large body of evidence has demonstrated that adequate blood pressure (BP) control can reduce cardiovascular events, including the development of HF. Although the pathophysiological and epidemiological role of hypertension in the development of HF is well and largely known, some critical issues still deserve to be clarified, including BP targets, particularly in HF patients. Indeed, the management of hypertension in HF relies on the extrapolation of findings from high-risk hypertensive patients in the general population and not from specifically designed studies in HF populations. In patients with hypertension and HF with reduced ejection fraction (HFrEF), it is recommended to combine drugs with documented outcome benefits and BP-lowering effects. In patients with HF with preserved EF (HFpEF), a therapeutic strategy with all major antihypertensive drug classes is recommended. Besides commonly used antihypertensive drugs, different evidence suggests that other drugs recommended in HF for the beneficial effect on cardiovascular outcomes exert advantageous blood pressure-lowering actions. In this regard, type 2 sodium glucose transporter inhibitors (SGLT2i) have been shown to induce BP-lowering actions that favorably affect cardiac afterload, ventricular arterial coupling, cardiac efficiency, and cardiac reverse remodeling. More recently, it has been demonstrated that finerenone, a non-steroidal mineralocorticoid receptor antagonist, reduces new-onset HF and improves other HF outcomes in patients with chronic kidney disease and type 2 diabetes, irrespective of a history of HF. Other proposed agents, such as endothelin receptor antagonists, have provided contrasting results in the management of hypertension and HF. A novel, promising strategy could be represented by small interfering RNA, whose actions are under investigation in ongoing clinical trials. [ABSTRACT FROM AUTHOR]

With the increasing frequency of heart failure (HF) in elderly patients, polypharmacy has become a major concern owing to its adverse outcomes. However, reports on the clinical impact of polypharmacy and discharge medications in hospitalized super-aged patients with acute HF are rare. Data from 682 patients aged 80 years or older, hospitalized for treating acute HF, were analyzed. We recorded the number of medications at discharge and classified them into three groups: HF, non-HF cardiovascular, and non-cardiovascular medications. We investigated the correlation of polypharmacy, defined as daily administration of 10 or more medications at discharge, and the use of discharge medications with post-discharge prognosis. Polypharmacy was recorded in 24.3% of enrolled patients. Polypharmacy was not an independent predictor of all-cause mortality, the incidence of cardiac-related death, or HF-associated rehospitalization; however, the number of non-cardiovascular medications, multiple usage of potentially inappropriate medications, use of mineralocorticoid receptor antagonists, and doses of loop diuretics were associated with poor prognosis. Polypharmacy was significantly associated with higher mortality in patients with Barthel index ≥ 60 at discharge; hence, physical function at discharge was useful for the stratification of prognostic impacts of polypharmacy. The current study demonstrated that polypharmacy was not essentially associated with poor prognosis in super-aged patients with acute HF. Appropriate medications that consider the patient's physical function, rather than polypharmacy itself, are important for the management of HF. [ABSTRACT FROM AUTHOR]

Background: 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. Methods: 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. Results: 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). Conclusions: 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%. [ABSTRACT FROM AUTHOR]

Aggressive therapy of diabetic kidney disease (DKD) can not only slow the progression of DKD to renal failure but, if utilized at an early enough stage of DKD, can also stabilize and/or reverse the decline in renal function. The currently recognized standard of therapy for DKD is blockade of the renin‐angiotensin system with angiotensin‐converting enzyme (ACE) inhibitors or angiotensin II receptor blockers (ARBs). However, unless utilized at a very early stage, monotherapy with these drugs in DKD will only prevent or slow the progression of DKD and will neither stabilize nor reverse the progression of DKD to renal decompensation. Recently, the addition of a sodium‐glucose cotransporter‐2 inhibitor and/or a mineralocorticoid receptor blocker to ACE inhibitors or ARBs has been clearly shown to further decelerate the decline in renal function. The use of glucagon‐like peptide‐1 (GLP‐1) agonists shown promise in decelerating the progression of DKD. Other drugs that may aid in the deceleration the progression of DKD are dipeptidyl peptidase‐4 inhibitors, pentoxifylline, statins, and vasodilating beta blockers. Therefore, aggressive therapy with combinations of these drugs (stacking) should improve the preservation of renal function in DKD. [ABSTRACT FROM AUTHOR]

BACKGROUND: Empagliflozin reduces the risk of heart failure (HF) events in patients with type 2 diabetes at high cardiovascular risk, chronic kidney disease, or prevalent HF irrespective of ejection fraction. Whereas the EMPACT-MI trial (Effect of Empagliflozin on Hospitalization for Heart Failure and Mortality in Patients With Acute Myocardial Infarction) showed that empagliflozin does not reduce the risk of the composite of hospitalization for HF and all-cause death, the effect of empagliflozin on first and recurrent HF events after myocardial infarction is unknown. METHODS: EMPACT-MI was a double-blind, randomized, placebo-controlled, event-driven trial that randomized 6522 patients hospitalized for acute myocardial infarction at risk for HF on the basis of newly developed left ventricular ejection fraction of <45% or signs or symptoms of congestion to receive empagliflozin 10 mg daily or placebo within 14 days of admission. In prespecified secondary analyses, treatment groups were analyzed for HF outcomes. RESULTS: Over a median follow-up of 17.9 months, the risk for first HF hospitalization and total HF hospitalizations was significantly lower in the empagliflozin compared with the placebo group (118 [3.6%] versus 153 [4.7%] patients with events; hazard ratio, 0.77 [95% CI, 0.60, 0.98]; P =0.031, for first HF hospitalization; 148 versus 207 events; rate ratio, 0.67 [95% CI, 0.51, 0.89]; P =0.006, for total HF hospitalizations). Subgroup analysis showed consistency of empagliflozin benefit across clinically relevant patient subgroups for first and total HF hospitalizations. The need for new use of diuretics, renin-angiotensin modulators, or mineralocorticoid receptor antagonists after discharge was less in patients randomized to empagliflozin versus placebo (all P <0.05). CONCLUSIONS: Empagliflozin reduced the risk of HF in patients with left ventricular dysfunction or congestion after acute myocardial infarction. REGISTRATION: URL: https://www.clinicaltrials.gov; Unique identifier: NCT04509674. [ABSTRACT FROM AUTHOR]

• BP is uncontrolled despite the use of three drugs at optimal or best tolerated doses. • The estimated prevalence of true RH is 5 % when strict criteria are applied. • Rule out pseudo-resistance before diagnosing true drug resistance. • Consider mineralocorticoid receptor antagonists as drug number four. • Renal denervation can be considered as a treatment option in some patients. The term RH describes a subgroup of hypertensive patients whose BP is uncontrolled despite the use of at least three antihypertensive drugs in an appropriate combination at optimal or best tolerated doses. True RH is considered when appropriate lifestyle measures and treatment with optimal or best tolerated doses of three or more drugs (a thiazide/thiazide-like diuretic, plus renin-angiotensin system -RAS- blocker and a calcium channel blocker -CCB-) fail to lower office BP to <140/90 mmHg; besides the inadequate BP control should be confirmed by home blood pressure monitoring (HBPM) or 24-hour ambulatory; and evidence of adherence to therapy and exclusion of secondary causes of hypertension are required. RH patients are at a high risk of cardiovascular events and death. RH is associated with a higher prevalence of end-organ damage. When stricter criteria are applied, a reasonable estimate of the prevalence of true RH is 5 % of the total hypertensive population. The predominant hemodynamic pattern appears to be increased systemic vascular resistance and plasma volume with normal or even low cardiac output. We must rule out pseudo-resistance before diagnosing true drug resistance. RH is a therapeutic challenge, and its management includes lifestyle interventions, avoiding nonadherence to treatment, avoiding inertia, appropriate use of antihypertensive drugs based on current evidence, especially long-acting diuretics, and the addition of mineralocorticoid receptor antagonists. RCTs to identify the most protective medical therapy in RH are needed. A series of drugs in different stages of investigation could significantly impact RH treatment in the future. [ABSTRACT FROM AUTHOR]

Background and Objective Apparent mineralocorticoid excess (AME) syndrome is an ultra-rare autosomal-recessive tubulopathy, caused by mutations in HSD11B2 , leading to excessive activation of the kidney mineralocorticoid receptor, and characterized by early-onset low-renin hypertension, hypokalemia, and risk of chronic kidney disease (CKD). To date, most reports included few patients, and none described patients from Israel. We aimed to describe AME patients from Israel and to review the relevant literature. Design Retrospective cohort study. Methods Clinical, laboratory, and molecular data from patients' records were collected. Results Five patients presented at early childhood with normal estimated glomerular filtration rate (eGFR), while 2 patients presented during late childhood with CKD. Molecular analysis revealed 2 novel homozygous mutations in HSD11B2. All patients presented with severe hypertension and hypokalemia. While all patients developed nephrocalcinosis, only 1 showed hypercalciuria. All individuals were managed with potassium supplements, mineralocorticoid receptor antagonists, and various antihypertensive medications. One patient survived cardiac arrest secondary to severe hyperkalemia. At last follow-up, those 5 patients who presented early exhibited normal eGFR and near-normal blood pressure, but 2 have hypertension complications. The 2 patients who presented with CKD progressed to end-stage kidney disease (ESKD) necessitating dialysis and kidney transplantation. Conclusions In this 11-year follow-up report of 2 Israeli families with AME, patients who presented early maintained long-term normal kidney function, while those who presented late progressed to ESKD. Nevertheless, despite early diagnosis and management, AME is commonly associated with serious complications of the disease or its treatment. [ABSTRACT FROM AUTHOR]

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

Currently, the utilization patterns of medications for heart failure (HF) after worsening HF events remain unelucidated in Japan. Here, we conducted a retrospective cohort study evaluating the changes in HF drug utilization patterns in 6 months before and after hospitalizations for HF. The adherence to newly initiated HF medications was evaluated based on the proportion of days covered (PDC) and persistence as continuous treatment episodes among new users. The study included 9091 patients hospitalized for HF between January 2016 and September 2019, including 2735 (30.1%) patients who were newly prescribed at least one HF medication after hospitalization. Despite increases in the use of foundational HF therapy (beta-blockers, angiotensin-converting-enzyme inhibitors/angiotensin receptor blockers, or mineralocorticoid receptor antagonists), 35.6% and 7.6% of patients were treated with the HF foundational monotherapy or diuretics alone after hospitalization, respectively. The mean PDC of newly initiated HF medications ranged from 0.57 for thiazide diuretics to 0.77 for sodium-glucose cotransporter-2 inhibitors. Continuous use of HF medications during the first year after initiation was observed in 30–60% of patients. The mean PDC and one-year continuous HF medication use were consistently lower in patients aged ≥ 75 years and in patients with a history of HF hospitalization for all HF medication classes except for tolvaptan and digoxin. Despite the guideline recommendations of HF pharmacotherapy, both treatment and adherence were suboptimal after HF hospitalization, especially in vulnerable populations such as older patients and those with prior HF hospitalizations. [ABSTRACT FROM AUTHOR]

The immunotropic effects of aldosterone might play a role in COVID-19, as SARS-CoV-2 reportedly uses angiotensin-converting enzyme 2 receptors as an entry point into cells. Aldosterone function is closely linked to its action on mineralocorticoid receptors in kidneys; it increases the renal retention of sodium and the excretion of potassium, which increases blood pressure. Despite the large number of studies examining the effect of Ang-II and its blockers on the course of COVID-19 infection, there is still uncertainty about the role of aldosterone. The aim of the study was to assess the correlation of aldosterone, urea, creatinine, C-reactive protein (CRP), and procalcitonin (PCT) levels with 28 days of mortality in patients treated for COVID19 in an intensive care unit (ICU). This cross-selection study involved 115 adult patients who were divided into two groups: those who died within a 28-day period (n = 82) and those who survived (n = 33). The correlation of aldosterone, urea, creatinine, C-reactive protein (CRP), and procalcitonin (PCT) levels with 28 days of mortality in patients treated for COVID-19 were performed. The patients' age, sex, scores from the APACHE II, SAPS II, and SOFA scales and comorbidities like HA, IHD and DM were also analyzed. Remarkably, the individuals who survived for 28 days were of significantly lower mean age and achieved notably lower scores on the APACHE II, SAPS II, and SOFA assessment scales. Statistically significantly higher CRP levels were observed on days 3, 5, and 7 in individuals who survived for 28 days. Creatinine levels in the same group were also statistically significantly lower on days 1, 3, and 5 than those of individuals who died within 28 days. The investigation employed both univariate and multivariate Cox proportional hazard regression models to explore factors related to mortality. In the univariate analysis, variables with a p value of less than 0.50 were included in the multivariate model. Age, APACHE II, SAPS II, and SOFA demonstrated significance in univariate analysis and were considered to be associated with mortality. The outcomes of the multivariate analysis indicated that age (HR = 1.03, p = 0.033) served as a robust predictor of mortality in the entire study population. In conclusion the plasma aldosterone level is not associated with ICU mortality in patients with COVID-19. Other factors, including the patient's age, creatinine or CRP contribute to the severity and prognosis of the disease. This study was retrospectively registered in the Australian New Zealand Clinical Trials Registry (ANZCTR) with registration no. ACTRN12621001300864 (27/09/2021: https://www.anzctr.org.au/Trial/Registration/TrialReview.aspx?id=382563&isReview=true). [ABSTRACT FROM AUTHOR]

As part of a medicinal chemistry program aimed at discovering a mineralocorticoid receptor modulator for treatment of kidney and cardiovascular indications, multiple labeled versions of the lead compound, balcinrenone (AZD9977), were prepared. Four stable isotope labeled versions of the compound were prepared for clinical bioanalysis and biological investigations. Three of these stable isotope labeled compounds were tritiated as well as the parent for biology applications and DMPK investigations. They were prepared using a standard iodination–tritiodehalogentation approach. Finally, AZD9977 was prepared in carbon‐14 labeled form for preclinical and clinical applications. [ABSTRACT FROM AUTHOR]

Inflammaging, a pro-inflammatory status that characterizes aging and primarily involving macrophages, is a master driver of age-related diseases. Mineralocorticoid receptor (MR) activation in macrophages critically regulates inflammatory and fibrotic processes. However, macrophage-specific mechanisms and the role of the macrophage MR for the regulation of inflammation and fibrotic remodeling in the aging heart have not yet been elucidated. Transcriptome profiling of cardiac macrophages from male/female young (4 months-old), middle (12 months-old) and old (18 and 24 months-old) mice revealed that myeloid cell-restricted MR deficiency prevents macrophage differentiation toward a pro-inflammatory phenotype. Pathway enrichment analysis showed that several biological processes related to inflammation and cell metabolism were modulated by the MR in aged macrophages. Further, transcriptome analysis of aged cardiac fibroblasts revealed that macrophage MR deficiency reduced the activation of pathways related to inflammation and upregulation of ZBTB16, a transcription factor involved in fibrosis. Phenotypic characterization of macrophages showed a progressive replacement of the TIMD4+MHC-IIneg/low macrophage population by TIMD4+MHC-IIint/high and TIMD4–MHC-IIint/high macrophages in the aging heart. By integrating cell sorting and transwell experiments with TIMD4+/TIMD4–macrophages and fibroblasts from old MRflox/MRLysMCre hearts, we showed that the inflammatory crosstalk between TIMD4– macrophages and fibroblasts may imply the macrophage MR and the release of mitochondrial superoxide anions. Macrophage MR deficiency reduced the expansion of the TIMD4– macrophage population and the emergence of fibrotic niches in the aging heart, thereby protecting against cardiac inflammation, fibrosis, and dysfunction. This study highlights the MR as an important mediator of cardiac macrophage inflammaging and age-related fibrotic remodeling. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a chronic microvascular complication in patients with diabetes mellitus (DM) and the leading cause of end-stage kidney disease (ESKD). Although glomerulosclerosis, tubular injury and interstitial fibrosis are typical damages of DKD, the interplay of different processes (metabolic factors, oxidative stress, inflammatory pathway, fibrotic signaling, and hemodynamic mechanisms) appears to drive the onset and progression of DKD. A growing understanding of the pathogenetic mechanisms, and the development of new therapeutics, is opening the way for a new era of nephroprotection based on precision-medicine approaches. This review summarizes the therapeutic options linked to specific molecular mechanisms of DKD, including renin-angiotensin-aldosterone system blockers, SGLT2 inhibitors, mineralocorticoid receptor antagonists, glucagon-like peptide-1 receptor agonists, endothelin receptor antagonists, and aldosterone synthase inhibitors. In a new era of nephroprotection, these drugs, as pillars of personalized medicine, can improve renal outcomes and enhance the quality of life for individuals with DKD. [ABSTRACT FROM AUTHOR]

Conn's syndrome, defined as unilateral aldosterone-producing adenoma, accounts for 35-40% of cases of primary hyperaldosteronism. Primary hyperaldosteronism typically occurs in younger patients with poorly controlled arterial hypertension due to extracellular fluid retention, in whom at least a triple combination of antihypertensives, including a diuretic, is needed to maintain normotension. The clinical picture of arterial hypertension may be complemented by symptoms associated with hypokalaemia, such as weakness, fatigue, palpitations, convulsions, polydipsia, or polyuria. In addition to arterial hypertension and hypokalaemia, the diagnosis of Conn's syndrome relies on examination of serum renin and aldosterone concentrations, plasma renin activity, exercise or furosemide stimulation tests, and imaging studies, preferably computed tomography. The method of treatment of Conn's syndrome is adrenalectomy. In patients with primary hyperaldosteronism with underlying bilateral adrenal cortical hyperplasia or patients contraindicated for surgery, mineralocorticoid receptor antagonists are administered in combination with antihypertensives targeted for optimal blood pressure control. In the group of patients after kidney transplantation, the exact incidence of primary hyperaldosteronism is unknown. Based on a cross-sectional study performed in 2020, it is estimated to be approximately 15% in the group of patients with unsatisfactorily compensated arterial hypertension; in the cohort of normotensive recipients, the incidence of primary hyperaldosteronism is not documented. Diagnosis of Conn's syndrome in patients in the early period after kidney transplantation is problematic, as the prevalence of arterial hypertension in transplanted patients is high (70-90%) according to the literature. Mineral abnormalities, including hypokalaemia, are also common in the early post-transplant period, mainly due to factors such as duration of cold ischaemia, onset of graft function, donor parameters, post-transplant tubulopathy, and diuretics, the effects of immunosuppressive drugs (especially calcineurin inhibitors and corticosteroids), and possibly potassium-restricted dietary habits that the patient brings from the pre-transplant period, which may mask the effect of hyperaldosteronism on potassium. We present the case of a patient who was diagnosed with Conn's syndrome 7 months after primary kidney transplantation from a deceased donor based on persistent hypokalaemia unresponsive to replacement therapy. At the time of the first manifestation of severe hypokalaemia, the patient was treated with a dual combination of antihypertensives (amlodipine at a daily dose of 5 mg and carvedilol at a daily dose of 50 mg), without the need for a diuretics. We consider the case interesting because the spectrum of mineral and acid-base abnormalities in advanced renal failure and in the early post-transplant period, as well as acid-base and mineral imbalances, including hypokalaemia, and the high prevalence of arterial hypertension in the post-transplant period, may mask the picture of Conn's syndrome. [ABSTRACT FROM AUTHOR]

Children of parents with traumatic brain injury (TBI) are more likely to develop psychiatric disorders. This association is usually attributed to TBI-induced changes in parents' personality and families' social environment. We tested the hypothesis that offspring of young adult male rats with TBI develop neurodevelopmental abnormalities in the absence of direct social contact with sires. Male Sprague-Dawley rats (F0 generation) in the TBI group underwent moderate TBI via a midline fluid percussion injury that involved craniectomy under sevoflurane (SEVO) anesthesia for 40 min on post-natal Day 60 (P60), while F0 rats in the control group were placed in a new cage, one per cage, for the equivalent time duration. A subset of F0 rats was sacrificed on P66 to assess acute changes in hypothalamic-pituitary-adrenal (HPA) axis and inflammation markers. The remaining F0 males were mated with naive females on P90 to generate offspring (F1 generation). The F0 males and F1 males and females were sequentially evaluated in the elevated plus maze, for pre-pulse inhibition of acoustic startle, in the Morris water maze, and for resting and stress levels of serum corticosterone starting on ∼P105 (F0) and ∼P60 (F1), followed by tissue collection for further analyses. Acutely, the F0 TBI males had messenger RNA (mRNA) transcripts altered to support an increased hypothalamic and hippocampal Na+-K+-Cl- (Slc12a2) Cl- importer / K+-2Cl- (Slc12a5) Cl- exporter ratio and decreased hippocampal glucocorticoid receptors (Nr3c1), as well as increased serum levels of corticosterone, interleukin-1β (IL-1β), and biomarkers of activated hippocampal microglia and astrocytes. Long-term, F0 TBI rats exhibited increased corticosterone concentrations at rest and under stress, anxiety-like behavior, impaired sensory-motor gating, and impaired spatial memory. These abnormalities were underpinned by reduced mRNA levels of hypothalamic and hippocampal mineralocorticoid receptors (Nr3c2), hippocampal Nr3c1, and hypothalamic brain-derived neurotrophic factor (Bdnf), as well as elevated serum levels of IL-1β, and biomarkers of activated hippocampal microglia and astrocytes. F1 male offspring of TBI sires exhibited abnormalities in all behavioral tests, while their F1 female counterparts had abnormal pre-pulse inhibition responses only. F1 male offspring of TBI sires also had reduced mRNA levels of hippocampal Nr3c1 and Nr3c2, as well as hypothalamic and hippocampal Bdnf, whereas increases in inflammatory markers were more profound in F1 females. These findings suggest that offspring of sires with a history of a moderate TBI that involved craniectomy under SEVO anesthesia for 40 min, develop sex-dependent neurobehavioral abnormalities in the absence of direct social interaction between the sire and the offspring. [ABSTRACT FROM AUTHOR]

Symptoms of depression and anxiety are frequent in patients with primary aldosteronism (PA) and are supposed to be independent risk factors for cardiovascular diseases (CVD). As patients with PA have an increased cardiovascular risk compared to patients with essential hypertension, sleep disturbances, which often accompany depressive and anxiety symptoms, may be an additional contributor to the cardiometabolic consequences of PA. To clarify this possible link we investigated 132 patients with PA at baseline and after one year after initiation of treatment either by adrenalectomy (ADX) or mineralocorticoid-receptor-antagonist (MRA). Sleep disturbances and daytime sleepiness were assessed with Pittsburg sleep Inventory (PSQI) and Epworth sleepiness scale (ESS). Patients with PA showed pathological scores for sleep disturbances at baseline according to PSQI, with females being more affected (8.1 vs. 5.7 p < 0.001), which was significantly improved after initiation of specific treatment (p = 0.002). For ESS we found scores within the normal range, but higher than the general population, which significantly improved at follow-up (p < 0.001). The intensity of sleep disturbances was highly correlated with scores of anxiety and depression at baseline and follow-up. However, clinical and biochemical markers of PA (e.g. aldosterone, blood pressure) and metabolic markers did not show a consistent association with sleep changes. The degree of improvement in PSQI was significantly associated with the improvement of brief patients health questionnaire (PHQD) (p = 0.0151). Sleep disturbances seem not to be an independent risk factor for cardiovascular and metabolic problems in PA. They are strongly associated to depressive symptoms and maybe mediated by the same mineralocorticoid receptor circuits. [ABSTRACT FROM AUTHOR]

Aldosterone has been suggested to be involved in the microvascular complications observed in type 2 diabetes. We aimed to investigate the effect of mineralocorticoid receptor (MR) blockade on endothelial function in individuals with type 2 diabetes compared to healthy controls. We included 12 participants with type 2 diabetes and 14 controls. We measured leg hemodynamics at baseline and during femoral arterial infusion of acetylcholine and sodium nitroprusside before and 8 weeks into treatment with MR blockade (eplerenone). Acetylcholine infusion was repeated with concomitant n‐acetylcysteine (antioxidant) infusion. No difference in leg blood flow or vascular conductance was detected before or after the treatment with MR blockade in both groups and there was no difference between groups. Infusion of n‐acetylcysteine increased baseline blood flow and vascular conductance, but did not change the vascular response to acetylcholine before or after treatment with MR blockade. Skeletal muscle eNOS content was unaltered by MR blockade and no difference between groups was detected. In conclusion, we found no effect of MR blockade endothelial function in individuals with and without type 2 diabetes. As the individuals with type 2 diabetes did not have vascular dysfunction, these results might not apply to individuals with vascular dysfunction. [ABSTRACT FROM AUTHOR]

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

INTRODUCTION: Hyperaldosteronism (HA) is a common cause of secondary hypertension and may contribute to resistant hypertension (RH). The authors sought to determine and characterize HA screening, positivity rates, and mineralocorticoid receptor antagonist (MRA) use among patients with RH. METHODS: A cross-sectional study was performed within Kaiser Permanente Southern California (7/1/2012-6/30/2017). Using contemporary criteria, RH was defined as blood pressure uncontrolled (= 130/80) on = 3 medications or requiring = 4 antihypertensive medications. The primary outcome was screening rate for HA defined as any aldosterone and plasma renin activity measurement. Secondary outcomes were HA screen positive rates and MRA use among all patients with RH. Multivariable logistic regression analysis was used to estimate odds ratio (with 95% confidence intervals) for factors associated with HA screening and for patients that screened positive. RESULTS: Among 102,480 patients identified as RH, 1977 (1.9%) were screened for HA and 727 (36.8%) screened positive for HA. MRA use was 6.5% among all patients with RH (22.5% among screened, 31.2% among screened positive). Black race, potassium < 4, bicarbonate > 29, chronic kidney disease, obstructive sleep apnea, and systolic blood pressure were associated with HA screening, but only Black race (1.55 [1.20-2.01]), potassium (1.82 [1.48-2.24]), bicarbonate levels (1.39 [1.10-1.75]), and diastolic blood pressure (1.15 [1.03-1.29]) were associated with positive screenings. CONCLUSION: The authors' findings demonstrate low screening rates for HA among patients with difficult-to-control hypertension yet a high positivity rate among those screened. Factors associated with screening did not always correlate with screening positive. Screening and targeted use of MRA may lead to improved blood pressure control and outcomes among patients with RH. [ABSTRACT FROM AUTHOR]

Diabetic kidney disease (DKD) is a major cause of chronic kidney disease (CKD), and it heightens the risk of cardiovascular incidents. The pathogenesis of DKD is thought to involve hemodynamic, inflammatory, and metabolic factors that converge on the fibrotic pathway. Genetic predisposition and unhealthy lifestyle practices both play a significant role in the development and progression of DKD. In spite of the recent emergence of angiotensin receptors blockers (ARBs)/angiotensin converting enzyme inhibitor (ACEI), sodium-glucose cotransporter 2 (SGLT2) inhibitors, and nonsteroidal mineralocorticoid receptors antagonists (NS-MRAs), current therapies still fail to effectively arrest the progression of DKD. Glucagon-like peptide 1 receptor agonists (GLP-1RAs), a promising class of agents, possess the potential to act as renal protectors, effectively slowing the progression of DKD. Other agents, including pentoxifylline (PTF), selonsertib, and baricitinib hold great promise as potential therapies for DKD due to their anti-inflammatory and antifibrotic properties. Multidisciplinary treatment, encompassing lifestyle modifications and drug therapy, can effectively decelerate the progression of DKD. Based on the treatment of heart failure, it is recommended to use multiple drugs in combination rather than a single-use drug for the treatment of DKD. Unearthing the mechanisms underlying DKD is urgent to optimize the management of DKD. Inflammatory and fibrotic factors (including IL-1, MCP-1, MMP-9, CTGF, TNF-a and TGF-β1), along with lncRNAs, not only serve as diagnostic biomarkers, but also hold promise as therapeutic targets. In this review, we delve into the potential mechanisms and the current therapies of DKD. We also explore the additional value of combing these therapies to develop novel treatment strategies. Drawing from the current understanding of DKD pathogenesis, we propose HIF inhibitors, AGE inhibitors, and epigenetic modifications as promising therapeutic targets for the future. [ABSTRACT FROM AUTHOR]

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

Spironolactone is one of the non‐selective mineralocorticoid receptor antagonists acting as anti‐diuretic drugs. Spironolactone is reported to possess mild to severe hyperkalemia which could often result in fatal conditions. Although several analytical methods for evaluating spironolactone as tablet dosage forms have been established in human biological systems, it is crucial to highlight that these approaches are still limited to the suspension dosage form. In this study, we have quantified spironolactone suspension in human plasma with an efficient, sensitive, and optimized ultra‐performance liquid chromatography (UPLC)‐tandem mass spectrometry‐based bioanalytical method using a deuterated internal standard method. A reverse phase UPLC analysis and mass spectrometric detection was performed using electrospray ionization in positive ion mode as an interface, and multiple reaction monitoring as a mode of acquisition. The retention of Spironolactone (SL) and Spironolactone d7 (SL‐d7) was found to be around 6.15 and 6.07 min, respectively. The linearity range was 1.007–100.224 ng/mL for SL with 0.1 mL sample volume. The method was successfully applied to the pharmacokinetic study of spironolactone in healthy male volunteers by administrating 25 mg/5 mL oral suspension and is in accordance with bioanalytical guidelines. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) coexists in up to 50% of heart failure (HF) patients, affecting both those with reduced ejection fraction (HFrEF) and those with preserved ejection fraction (HFpEF). Although the efficacy of several guideline-directed medical therapies (GDMT) has been well established, the treatment recommendations are similar for those patients with HF with and without CKD. We aimed to investigate the efficacy of GDMT in patients with HF with versus those without CKD. This systematic review and meta-analysis included randomised controlled trials that compared the efficacy of GDMT (angiotensin-converting enzyme inhibitor [ACE-I], beta blocker, sodium-glucose cotransporter-2 inhibitor, mineralocorticoid receptor antagonist, angiotensin receptor-neprilysin inhibitor) in patients with HF with and without CKD. The primary outcome was the composite of cardiovascular death and HF hospitalisation. Risk ratios (RR) were pooled using random-effects meta-analysis. A total of 19 trials (15 trials in HFrEF and four trials in HFpEF) enrolling 63,677 (38% had CKD) participants were included. Among HFrEF patients, GDMT reduced the primary endpoint in those with CKD (RR 0.77, 95% confidence interval [CI] 0.72–0.82) and without CKD (RR 0.79, 95% CI 0.74–0.84). Among HFpEF patients, the pooled summary RR for GDMT reducing the primary endpoint was 0.82 (95% CI 0.74–0.91) among those with CKD and 0.88 (95% CI 0.77–0.99) among those without CKD. There was no significant difference in the efficacy of GDMT in head-to-head comparisons between those with and without CKD in HFrEF (ratio of RR 0.97, 95% CI 0.88-1.06) and HFpEF (ratio of RR 0.94, 95% CI 0.80–1.11). Among patients with HF, GDMT had a consistent effect in reducing adverse cardiovascular events in those with and without CKD. Future studies should investigate the best strategy to ensure patients with HF with CKD receive and tolerate GDMT when indicated. [ABSTRACT FROM AUTHOR]

Introduction: Acute Central Serous Chorioretinopathy (CSCR) is an important form of acquired maculopathy that usually presents as localised serous detachment of the neurosensory retina. Although, the disease is typically self limiting over a period of 2-3months, a percentage of patients ultimately develop chronic RPE changes. Eplerenone, a potential Mineralocorticoid Receptor (MR) antagonist, may play a role in regulating choroidal vascularity and modifying the disease in chronic CSCR. Aim: To assess the safety and efficacy of oral eplerenone medication in acute CSCR. Materials and Methods: This was a randomised controlled trial that included 162 eyes of 162 patients with acute CSCR. Patients were divided into two groups-Group-A, which received oral Eplerenone, and Group-B, which received Placebo therapy. Each group comprised 81 eyes. Best Corrected Visual Acuity (BCVA), Central Macular Thickness (CMT), and serum potassium (K+) levels were measured at baseline and monthly intervals for three consecutive months. Statistical analysis was performed using Statistical Package for Social Sciences (SPSS) Statistics version 20 software (IBM Corp., Armonk, NY, USA). A p-value less than 0.05 was considered statistically significant. Results: The differences in CMT in Group-A and Group-B were 279±56.41μm and 207±68.88 μm (p<0.01) at the end of the first month and 361±33.56 μm and 278±46.27 μm at three months (p<0.01), respectively. The average BCVA improvement in Group-A and Group-B was 6.05 lines and 4.21 LogMAR lines, respectively, at the conclusion (p=0.002). Deterioration to chronicity was seen in 3.7% of the eyes in Group A and 17.3% of the eyes in Group B. The increase in Serum K+ at three months was 0.61±0.27 mg/dL in Group-A and 0.1±0.21 mg/dL in Group-B (p=0.03). Conclusion: Eplerenone is a safe and effective first-line treatment option for acute CSCR, leading to faster and higher resolution with protection from progression to chronicity. [ABSTRACT FROM AUTHOR]

Conn's syndrome, defined as unilateral aldosterone-producing adenoma, accounts for 35-40% of cases of primary hyperaldosteronism. Primary hyperaldosteronism typically occurs in younger patients with poorly controlled arterial hypertension due to extracellular fluid retention, in whom at least a triple combination of antihypertensives, including a diuretic, is needed to maintain normotension. The clinical picture of arterial hypertension may be complemented by symptoms associated with hypokalaemia, such as weakness, fatigue, palpitations, convulsions, polydipsia, or polyuria. In addition to arterial hypertension and hypokalaemia, the diagnosis of Conn's syndrome relies on examination of serum renin and aldosterone concentrations, plasma renin activity, exercise or furosemide stimulation tests, and imaging studies, preferably computed tomography. The method of treatment of Conn's syndrome is adrenalectomy. In patients with primary hyperaldosteronism with underlying bilateral adrenal cortical hyperplasia or patients contraindicated for surgery, mineralocorticoid receptor antagonists are administered in combination with antihypertensives targeted for optimal blood pressure control. In the group of patients after kidney transplantation, the exact incidence of primary hyperaldosteronism is unknown. Based on a cross-sectional study performed in 2020, it is estimated to be approximately 15% in the group of patients with unsatisfactorily compensated arterial hypertension; in the cohort of normotensive recipients, the incidence of primary hyperaldosteronism is not documented. Diagnosis of Conn's syndrome in patients in the early period after kidney transplantation is problematic, as the prevalence of arterial hypertension in transplanted patients is high (70-90%) according to the literature. Mineral abnormalities, including hypokalaemia, are also common in the early post-transplant period, mainly due to factors such as duration of cold ischaemia, onset of graft function, donor parameters, post-transplant tubulopathy, and diuretics, the effects of immunosuppressive drugs (especially calcineurin inhibitors and corticosteroids), and possibly potassium-restricted dietary habits that the patient brings from the pre-transplant period, which may mask the effect of hyperaldosteronism on potassium. We present the case of a patient who was diagnosed with Conn's syndrome 7 months after primary kidney transplantation from a deceased donor based on persistent hypokalaemia unresponsive to replacement therapy. At the time of the first manifestation of severe hypokalaemia, the patient was treated with a dual combination of antihypertensives (amlodipine at a daily dose of 5 mg and carvedilol at a daily dose of 50 mg), without the need for a diuretics. We consider the case interesting because the spectrum of mineral and acid-base abnormalities in advanced renal failure and in the early post-transplant period, as well as acid-base and mineral imbalances, including hypokalaemia, and the high prevalence of arterial hypertension in the post-transplant period, may mask the picture of Conn's syndrome (Fig. 3, Ref. 19). [ABSTRACT FROM AUTHOR]

Background: Spironolactone (SPI) is a diuretic widely used to treat cardiovascular diseases (CVD) and is non-specific for mineralocorticoid receptors (MR) and with an affinity for progesterone (PR) and androgen (AR) receptors. Since 2009, it has been suggested that pharmaceuticals are emerging contaminants (called EDC), and recently, it was reported that most EDC are AR and MR antagonists and estrogen receptors (ER) agonists. Concerning SPI, endocrine-disrupting effects were observed in female western mosquitofish, but there are still no data regarding the SPI effects as a possible human EDC. Methods: In this work, aortic rings were used to analyze the contractility effects of SPI and the mode of action concerning the involvement of Ca2+ channels and endothelial pathways. Moreover, cytotoxic effects were analyzed by MTT assays. Results: SPI induces vasodilation in the rat aorta by endothelium-dependent mechanisms involving NO and by endothelium-independent mechanisms blocking Ca2+ channels. Moreover, a non-monotonic effect characteristic of EDC was observed for SPI-induced decrease in cell viability. Conclusions: Our findings suggest that SPI may act as an EDC at a human level. However, ex vivo studies with human arteries should be carried out to better understand this drug's implications for human health and future generations. [ABSTRACT FROM AUTHOR]

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

Simple Summary: Aquaculture produces fish that are then marketed to the population, but the type of production used today generates stress in fish. Constant stress, which occurs through the hormone cortisol, negatively affects the seawater adaptation of juvenile fish, which is detrimental to the aquaculture process. For many years, it was thought that only cortisol influenced physiological responses in fish. However, in recent years, the cortisol intermediary 11-deoxycorticosterone (DOC) has been considered a complementary stress-related hormone in fish. Given the above, this work aims to unravel whether DOC is involved in the regulation of early physiological and transcriptional responses in fish gills. To ascertain this, juvenile rainbow trout were injected with DOC and/or pharmacological inhibitors of corticosteroid receptors. Then, the physiological parameters and RNA sequencing of the gills were analyzed. The experiment concluded that DOC is important during stress and that it is vital for the balance between minerals and water in fish. The results of this work will help us understand the other effects of DOC in fish, as well as help improve the monitoring of animal welfare in the aquaculture industry through the incorporation of novel and potential stress molecular biomarkers. In aquaculture, stress can negatively affect fish growth. For years, the cortisol hormone has been thought to play both glucocorticoid and mineralocorticoid functions. Nevertheless, recent research has suggested that 11-deoxycorticosterone (DOC) released during stress could contribute to cortisol actions, though this process is still misunderstood. Here, we evaluated the DOC effects on physiological and early transcriptional responses by RNA-seq. Juvenile rainbow trout were treated with DOC and/or glucocorticoids (mifepristone) or mineralocorticoid (eplerenone) receptor antagonists. Subsequently, plasma was collected, and cDNA libraries were generated from the gills of vehicle (control), DOC, mifepristone, mifepristone with DOC, eplerenone, and eplerenone with DOC groups. Calcium and phosphate levels in plasma were changed. Results revealed 914 differentially expressed transcripts (DETs) induced by DOC compared with control, mainly associated with sodium ion transmembrane transport, gluconeogenesis, negative regulation of transmembrane transport, and activation of innate immune response. DOC versus eplerenone with DOC comparison displayed 444 DETs related to cell-cell junction organization, canonical glycolysis, positive regulation of immune response, and potassium ion transport. Conversely, no DETs were detected in DOC versus mifepristone with DOC comparison. These data suggest that DOC has a relevant role in gill stress response and ion transport, which is differentially regulated by mineralocorticoid receptors. [ABSTRACT FROM AUTHOR]

Aims: Heart failure (HF) medication may reduce blood pressure (BP). Low BP is associated with worse outcomes but how this association is modified by HF medication has not been studied. We evaluated the association between BP and outcomes according to HF medication dose in HF with reduced ejection fraction (HFrEF). Methods and results: We studied HFrEF patients from the Swedish HF registry (2000–2018). Associations between systolic BP (SBP) and cardiovascular death (CVD) and/or HF hospitalization (HFH) were analysed according to doses of renin–angiotensin system (RAS) inhibitors, beta‐blockers and mineralocorticoid receptor antagonists (MRA). Among 42 040 patients (median age 74.0), lower baseline SBP was associated with higher risk of CVD/HFH (adjusted hazard ratio [HR] per 10 mmHg higher SBP: 0.92, 95% confidence interval [CI] 0.92–0.93), which was less high risk under optimized RAS inhibitor and beta‐blocker doses (10% decrease in event rates per 10 mmHg SBP increase in untreated patients vs. 7% decrease in patients at maximum dose, both adjusted p < 0.02). Among the 13 761 patients with repeated measurements, 9.9% reported a SBP decrease >10 mmHg when HF medication doses were increased, whereas 24.6% reported a SBP decrease >10 mmHg with stable/decreasing doses. Decreasing SBP was associated with higher risk of CVD/HFH in patients with stable (HR 1.10, 95% CI 1.04–1.17) or decreasing (HR 1.29, 95% CI 1.18–1.42) HF medication dose but not in patients with an increase in doses (HR 0.94, 95% CI 0.86–1.02). Conclusions: The association of lower SBP with higher risk of CVD/HFH is attenuated in patients with optimized HF medication. These results suggest that low or declining SBP should not limit HF medication optimization. [ABSTRACT FROM AUTHOR]

Background: Chronic kidney disease (CKD) poses a significant health risk in contemporary society. Current CKD treatments primarily involve renin-angiotensin-aldosterone system inhibitors and mineralocorticoid receptor antagonists, albeit associated with hyperkalemia risks. A novel selective mineralocorticoid receptor antagonist, finerenone, offers a promising, safer alternative for CKD therapy. Summary: This review comprehensively assesses the role and efficacy of finerenone in CKD treatment by analyzing clinical and animal studies. Emerging evidence consistently supports finerenone's ability to effectively slow the progression of CKD. By targeting the mineralocorticoid receptor, finerenone not only mitigates renal damage but also exhibits a favorable safety profile, minimizing hyperkalemia concerns. Conclusion: Finerenone emerges as a valuable addition to CKD therapy, demonstrating potential benefits in delaying CKD progression while minimizing side effects. Nevertheless, further clinical trials are necessary to provide a comprehensive understanding of its safety and efficacy. [ABSTRACT FROM AUTHOR]

Resistant hypertension is associated with an exceedingly high cardiovascular risk and there remains an unmet therapeutic need driven by pathophysiologic pathways unaddressed by guideline‐recommended therapy. While spironolactone is widely considered as the preferable fourth‐line drug, its broad application is limited by its side effect profile, especially off‐target steroid receptor‐mediated effects and hyperkalaemia in at‐risk subpopulations. Recent landmark trials have reported promising safety and efficacy results for a number of novel compounds targeting relevant pathophysiologic pathways that remain unopposed by contemporary drugs. These include the dual endothelin receptor antagonist, aprocitentan, the aldosterone synthase inhibitor, baxdrostat and the nonsteroidal mineralocorticoid receptor antagonist finerenone. Furthermore, the evidence base for consideration of catheter‐based renal denervation as a safe and effective adjunct therapeutic approach across the clinical spectrum of hypertension has been further substantiated. This review will summarise the recently published evidence on novel antihypertensive drugs and renal denervation in the context of resistant hypertension. [ABSTRACT FROM AUTHOR]

After birth, the lungs must resorb the fluid they contain. This process involves multiple actors such as surfactant, aquaporins and ENaC channels. Preterm newborns often exhibit respiratory distress syndrome due to surfactant deficiency, and transitory tachypnea caused by a delay in lung liquid resorption. Our hypothesis is that surfactant, ENaC and aquaporins are involved in respiratory transition to extrauterine life and altered by preterm birth. We compared these candidates in preterm and term fetal sheeps. We performed cesarean sections in 8 time-dated pregnant ewes (4 at 100 days and 4 at 140 days of gestation, corresponding to 24 and 36 weeks of gestation in humans), and obtained 13 fetal sheeps in each group. We studied surfactant synthesis (SP-A, SP-B, SP-C), lung liquid resorption (ENaC, aquaporins) and corticosteroid regulation (glucocorticoid receptor, mineralocorticoid receptor and 11-betaHSD2) at mRNA and protein levels. The mRNA expression level of SFTPA , SFTPB and SFTPC was higher in the term group. These results were confirmed at the protein level for SP-B on Western Blot analysis and for SP-A, SP-B and SP-C on immunohistochemical analysis. Regarding aquaporins, ENaC and receptors, mRNA expression levels for AQP1 , AQP3 , AQP5, ENaCα, ENaCβ, ENaCγ and 11βHSD2 mRNA were also higher in the term group. Expression of surfactant proteins, aquaporins and ENaC increases between 100 and 140 days of gestation in an ovine model. Further exploring these pathways and their hormonal regulation could highlight some new explanations in the pathophysiology of neonatal respiratory diseases. [Display omitted] • Prematurity may alter birth adaptation through actors of lung liquid resorption. • Surfactant production increases during gestation in the preterm fetal sheeps. • Aquaporins, sodium channels and 11βHSD2 mRNA are also higher in term fetal sheeps. • Steroids and oxytocin regulation is worth analyzing in neonatal respiratory diseases. [ABSTRACT FROM AUTHOR]

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 <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. [ABSTRACT FROM AUTHOR]

Aim: Sodium‐glucose co‐transporter 2 inhibitors and mineralocorticoid receptor antagonists reduce albuminuria and the risk of kidney failure. The aim of this study was to investigate the effects of both agents alone and in combination on markers of the glomerular endothelial glycocalyx and tubular function. Methods: This post‐hoc analysis utilized data of the ROTATE‐3 study, a randomized cross‐over study in 46 adults with chronic kidney disease and urinary albumin excretion ≥100 mg/24 h, who were treated for 4 weeks with dapagliflozin, eplerenone or its combination. The effects of dapagliflozin, eplerenone and the combination on outcome measures such as heparan sulphate, neuro‐hormonal markers and tubular sodium handling were assessed with mixed repeated measures models. Results: The mean percentage change from baseline in heparan sulphate after 4 weeks treatment with dapagliflozin, eplerenone or dapagliflozin‐eplerenone was −34.8% (95% CI −52.2, −10.9), −5.9% (95% CI −32.5, 31.3) and −28.1% (95% CI −48.4, 0.1) respectively. The mean percentage change from baseline in plasma aldosterone was larger with eplerenone [38.9% (95% CI 2.8, 87.7)] and dapagliflozin‐eplerenone [32.2% (95% CI −1.5, 77.4)], compared with dapagliflozin [−12.5% (95% CI −35.0, 17.8)], respectively. Mean percentage change from baseline in copeptin with dapagliflozin, eplerenone or dapagliflozin‐eplerenone was 28.4% (95% CI 10.7, 49.0), 4.2% (95% CI −10.6, 21.4) and 23.8% (95% CI 6.6, 43.9) respectively. Dapagliflozin decreased proximal absolute sodium reabsorption rate by 455.9 mmol/min (95% CI −879.2, −32.6), while eplerenone decreased distal absolute sodium reabsorption rate by 523.1 mmol/min (95% CI −926.1, −120.0). Dapagliflozin‐eplerenone decreased proximal absolute sodium reabsorption [−971.0 mmol/min (95% CI −1411.0, −531.0)], but did not affect distal absolute sodium reabsorption [−9.2 mmol/min (95% CI −402.0, 383.6)]. Conclusions: Dapagliflozin and eplerenone exert different effects on markers of glomerular and tubular function supporting the hypothesis that different mechanistic pathways may account for their kidney protective effects. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) in patients with type 2 diabetes (T2D) is a major health challenge associated with a disproportionately high burden of end‐stage renal disease, cardiovascular disease and death. This review summarizes the rationale, clinical evidence and practical implementation for non‐steroidal mineralocorticoid receptor antagonists (nsMRAs), a drug class now approved and recommended for patients with T2D and CKD at risk of cardiorenal disease progression. Three nsMRAs (finerenone, esaxerenone and apararenone) have been evaluated but finerenone is currently the only approved nsMRA for this indication. Two large‐scale, placebo‐controlled, Phase 3 studies evaluated finerenone added to a maximally tolerated dose of an angiotensin‐converting enzyme inhibitor or an angiotensin II receptor blocker. Over >2 years of treatment, finerenone was associated with a significant reduction in composite endpoints of renal and cardiovascular outcomes versus placebo. Esaxerenone or apararenone have both shown significant improvements in albuminuria versus placebo. In general, nsMRAs were well tolerated. Hyperkalaemia was the most notable treatment‐related adverse event and could generally be managed through serum potassium monitoring and dose adjustments. The nsMRAs are now an important component of recommended treatment for CKD associated with T2D, providing a significant reduction in the risk of cardiorenal progression beyond what can be achieved with glucose and blood pressure control. [ABSTRACT FROM AUTHOR]

[Display omitted] [ABSTRACT FROM AUTHOR]

Diabetic Kidney Disease (DKD) is a significant complication of diabetes and primary cause of end-stage renal disease globally. The exact mechanisms underlying DKD remain poorly understood, but multiple factors, including the renin–angiotensin–aldosterone system (RAAS), play a key role in its progression. Aldosterone, a mineralocorticoid steroid hormone, is one of the key components of RAAS and a potential mediator of renal damage and inflammation in DKD. miRNAs, small noncoding RNA molecules, have attracted interest due to their regulatory roles in numerous biological processes. These processes include aldosterone signaling and mineralocorticoid receptor (MR) expression. Numerous miRNAs have been recognized as crucial regulators of aldosterone signaling and MR expression. These miRNAs affect different aspects of the RAAS pathway and subsequent molecular processes, which impact sodium balance, ion transport, and fibrosis regulation. This review investigates the regulatory roles of particular miRNAs in modulating aldosterone signaling and MR activation, focusing on their impact on kidney injury, inflammation, and fibrosis. Understanding the complex interaction between miRNAs and the RAAS could lead to a new strategy to target aldosterone signaling and MR activation using miRNAs. This highlights the potential of miRNA-based interventions for DKD, with the aim of enhancing kidney outcomes in individuals with diabetes. [ABSTRACT FROM AUTHOR]

Aldosterone (Aldo) exerts its action through binding with the mineralocorticoid receptor (MR). Clinically, a link between primary aldosteronism (PA) and thyroid diseases has been hypothesised. However, the presence and activity of MR on the thyroid have not yet been demonstrated. We investigated the gene/protein expression and activation of MR in primary thyroid cell cultures (normal rat thyroid [FRTL-5] and human papillary thyroid cancer [PTC] cell lines, BCPAP and K1) through qRT-PCR analysis, immunofluorescence, and confocal microscopy. We also studied the effects of Aldo on thyroid-specific and inflammation genes in vitro. Paired human normal and neoplastic thyroid tissues were also studied. We demonstrated both gene and protein expression and activation of MR in normal rat thyroid and human PTC lines. Incubation with Aldo induced an acute increase in IL-6 expression in both the FRTL-5 and BCPAP lines, which was antagonised by spironolactone, and an acute and late upregulation of thyroid-specific genes in FRTL-5. MR was also expressed at both gene and protein levels in normal human thyroid tissues and in PTC, with a progressive decline during neoplastic tumourigenesis, particularly in more aggressive histotypes. We present the first evidence of MR gene and protein expression in both normal and pathological thyroid cells and tissues. We have shown that MR is present and functionally activated in thyroid tissue. Binding of Aldo to MR induces the expression of inflammatory and thyroid-specific genes, and the thyroid may thus be considered a novel mineralocorticoid target tissue. [ABSTRACT FROM AUTHOR]

Background: Fas-associated factor 1 (FAF1) is a multidomain protein that interacts with diverse partners to affect numerous cellular processes. Previously, we discovered two Small Ubiquitin-like Modifier (SUMO)-interacting motifs (SIMs) within FAF1 that are crucial for transcriptional modulation of mineralocorticoid receptor. Recently, we identified Sin3A-associated protein 130 (SAP130), a putative sumoylated protein, as a candidate FAF1 interaction partner by yeast two-hybrid screening. However, it remained unclear whether SAP130 sumoylation might occur and functionally interact with FAF1. Results: In this study, we first show that SAP130 can be modified by SUMO1 at Lys residues 794, 878 and 932 both in vitro and in vivo. Mutation of these three SUMO-accepting Lys residues to Ala had no impact on SAP130 association with Sin3A or its nuclear localization, but the mutations abrogated the association of SAP130 with the FAF1. The mutations also potentiated SAP130 trans-repression activity and attenuated SAP130-mediated promotion of cell growth. Additionally, SUMO1-modified SAP130 was less stable than unmodified SAP130. Transient transfection experiments further revealed that FAF1 mitigated the trans-repression and cell proliferation-promoting functions of SAP130, and promoted SAP130 degradation by enhancing its polyubiquitination in a sumoylation-dependent manner. Conclusions: Together, these results demonstrate that sumoylation of SAP130 regulates its biological functions and that FAF1 plays a crucial role in controlling the SUMO-dependent regulation of transcriptional activity and protein stability of SAP130. [ABSTRACT FROM AUTHOR]

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. [ABSTRACT FROM AUTHOR]

Simultaneous initiation of quadruple therapy with angiotensin receptor-neprilysin inhibitor, beta-adrenergic receptor blocker, mineralocorticoid receptor antagonist, and sodium glucose cotransporter 2 inhibitor aims at prompt improvement and prevention of readmission in patients hospitalized for heart failure with reduced ejection fraction. However, titration of quadruple therapy is time consuming. Lengthy up-titration of quadruple therapy may negate the benefit of early initiation. Quadruple therapy should start with a sodium glucose cotransporter 2 inhibition and a mineralocorticoid antagonist, as both enable safe decongestion and require minimal or no titration. Depending on the level of decongestion and clinical characteristics, patients receive an angiotensin receptor-neprilysin inhibitor or a beta-adrenergic receptor blocker to be titrated after hospital discharge. Outpatient addition of an angiotensin receptor-neprilysin inhibitor to a beta-adrenergic receptor blocker or vice versa completes the quadruple therapy scheme. By focusing on decongestion and matching intervention to patients' profile, the present therapeutic sequence allows rapid implementation of quadruple therapy at fully recommended doses. [ABSTRACT FROM AUTHOR]

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

Background: The drug Finerenone, a selective the drug mineralocorticoid receptor antagonist, indicated for Chronic Kidney Disease (CKD) and Type 2 Diabetes. Recent researchers also found add on role in the management of resistant hypertension. So, this review article aims to provide an in-depth understanding of finerenone and the objective is to explore the mechanism of action, efficacy, and potential benefits of finerenone in treating (CKD) and heart failure with reduced ejection fraction (HFrEF), specifically in patients who have both type 2 diabetes (T2D) and CKD. Materials and Methods: A systematic literature search was done using IBM Micromedex, PubMed, Cochrane Library, and Scopus databases to identify relevant English-language articles published between 2000 and March 2023. Search terms included "Finerenone," "MRA," "Resistant Hypertension," "Finerenone Efficacy," and "Pharmacology of Finerenone." The selection criteria included clinical trials, randomized trials, and original articles, with references listed chronologically. Results: Finerenone's selective blockade of mineralocorticoid receptors counteracts the adverse effects of aldosterone, exhibiting anti-inflammatory and anti-fibrotic properties. Clinical trials consistently demonstrate its efficacy in reducing albuminuria, slowing CKD progression, and improving cardiovascular outcomes in patients with T2D and CKD. The recent approval of finerenone by the FDA for reducing the risk of death and abnormal cardiovascular events in adults with CKD and T2D with HFrEF highlights its therapeutic potential. Conclusion: Finerenone represents a pharmacological breakthrough in the management of resistant hypertension, offering a comprehensive therapeutic approach for patients with CKD and T2D. Its selective mineralocorticoid receptor antagonism, combined with anti-inflammatory and anti-fibrotic effects, shows promise in improving long-term renal and cardiovascular health. However, further research is needed to fully understand its long-term benefits, safety profile, and optimal utilization in the management of resistant hypertension. Finerenone's emergence provides new possibilities for patient care and signifies a significant advancement in the treatment of CKD and T2D, with the potential to enhance patient outcomes and quality of life. [ABSTRACT FROM AUTHOR]

11‐beta‐hydroxysteroid dehydrogenases (11β‐HSDs) catalyse the conversion of active 11‐hydroxy glucocorticoids (cortisol, corticosterone) and their inert 11‐keto forms (cortisone, 11‐dehydrocorticosterone). They were first reported in the body and brain 70 years ago, but only recently have they become of interest. 11β‐HSD2 is a dehydrogenase, potently inactivating glucocorticoids. In the kidney, 11β‐HSD2 generates the aldosterone‐specificity of intrinsically non‐selective mineralocorticoid receptors. 11β‐HSD2 also protects the developing foetal brain and body from premature glucocorticoid exposure, which otherwise engenders the programming of neuropsychiatric and cardio‐metabolic disease risks. In the adult CNS, 11β‐HSD2 is confined to a part of the brain stem where it generates aldosterone‐specific central control of salt appetite and perhaps blood pressure. 11β‐HSD1 is a reductase, amplifying active glucocorticoid levels within brain cells, notably in the cortex, hippocampus and amygdala, paralleling its metabolic functions in peripheral tissues. 11β‐HSD1 is elevated in the ageing rodent and, less certainly, human forebrain. Transgenic models show this rise contributes to age‐related cognitive decline, at least in mice. 11β‐HSD1 inhibition robustly improves memory in healthy and pathological ageing rodent models and is showing initial promising results in phase II studies of healthy elderly people. Larger trials are needed to confirm and clarify the magnitude of effect and define target populations. The next decade will be crucial in determining how this tale ends – in new treatments or disappointment. [ABSTRACT FROM AUTHOR]

Diabetic nephropathy (DN) and non-diabetic renal diseases (NDRD) represent intricate challenges in diagnosis and treatment within the context of the global diabetes epidemic. As the prevalence of diabetes continues to escalate, effective management of renal complications becomes paramount. Recent advancements in comprehending the multifaceted nature of renal damage, fueled by insights from histopathological investigations, offer unprecedented prospects for refining diagnostic strategies and customizing therapeutic interventions. Renal biopsies have emerged as indispensable tools for unraveling the diverse phenotypes of renal damage in diabetes. The pioneering study by Mazzucco identified three classes of renal damage in type 2 diabetes patients: classical diabetic glomerulosclerosis (DN), vascular and ischemic glomerular changes (NDRD), and other glomerulonephritides in the presence (DN + NDRD, mixed forms) or absence of DN (NDRD). The prevalence of these classes varies widely in published studies, influenced by factors such as ethnicity, geography and selection criteria for renal biopsy. Moreover, the international Renal Pathology Society consensus classification system has stratified the classical diabetic nephropathy into progressive categories of renal impairment, a breakthrough that aids in prognostication. Histopathological scrutiny, particularly the intricate correlation between glomerular and tubulointerstitial lesions, contributes profoundly to enhancing our grasp of the phenotype's heterogeneity. This amplified comprehension holds the potential to steer personalized treatment strategies. Cutting-edge interventions, encompassing sodium-glucose cotransporter 2 inhibitors, mineralocorticoid receptor antagonists and anti-endothelin receptor agents, are broadening the arsenal against renal injury in diabetes. When combined with the profound insights garnered from histopathological, omics, imaging and clinical data, these therapeutic avenues promise a transformative shift towards precision-driven care paradigms. Collaborative efforts uniting researchers, clinicians and patients are indispensable for propelling our knowledge of diabetic renal damage and ameliorating patient outcomes. The fusion of histopathological, omics and imaging findings into clinical decision-making harbors the potential to customize interventions and optimize care for individuals grappling with diabetes-associated renal complications. Furthermore, groundbreaking initiatives like the iBeat Study within the BEAt-DKD (Biomarker Enterprise to Attack Diabetic Kidney Disease) project (https://www.beat-dkd.eu/), elucidating distinct phenotypes of renal damage within diabetes, underscore the imperative necessity of integrating histopathological data into the broader framework of diabetic renal management. [ABSTRACT FROM AUTHOR]

Diabetes is the most common cause of chronic kidney disease (CKD), a condition found in 850 million persons and projected to become the fifth global cause of death by 2040. Research is needed that examines kidney tissue to characterize distinct phenotypes in patients with diabetes mellitus (DM) and CKD so as to identify non-invasive biomarker signatures and develop targeted therapeutic approaches. However, from a routine care point of view, kidney biopsy is likely overused in patients with CKD and DM, as most biopsy results are not expected to be associated with a therapeutic approach that differs from standard kidney protection with triple or quadruple therapy (renin–angiotensin system blockade, sodium-glucose cotransporter 2 inhibitors, nonsteroidal mineralocorticoid receptor antagonists and glucagon-like peptide-1 receptor agonists). Moreover, expanding the kidney biopsy criteria will increase the absolute number of complications from kidney biopsies, which may reach 27 000 to 108 000 deaths of persons that would derive little benefit from kidney biopsy if all people with DM and severe CKD were biopsied globally. Finally, limited resources should be optimally allocated. The cost of one kidney biopsy can fund 7000 semiquantitative urinary albumin:creatinine ratio assessments that could identify earlier stages of the disease and allow treatment that prevents progression to a stage at which kidney biopsy may be considered. [ABSTRACT FROM AUTHOR]

Two randomised controlled trials have reported a reduction in mortality when adjunctive hydrocortisone is administered in combination with fludrocortisone compared with placebo in septic shock. A third trial did not support this finding when hydrocortisone administered in combination with fludrocortisone was compared with hydrocortisone alone. The underlying mechanisms for this mortality benefit remain poorly understood. We review the clinical implications and potential mechanisms derived from laboratory and clinical data underlying the beneficial role of adjunctive fludrocortisone with hydrocortisone supplementation in septic shock. Factors including distinct biological effects of glucocorticoids and mineralocorticoids, tissue-specific and mineralocorticoid receptor-independent effects of mineralocorticoids, and differences in downstream signalling pathways between mineralocorticoid and glucocorticoid binding at the mineralocorticoid receptor could contribute to this interaction. Furthermore, pharmacokinetic and pharmacodynamic disparities exist between aldosterone and its synthetic counterpart fludrocortisone, potentially influencing their effects. Pending publication of well-designed, randomised controlled trials, a molecular perspective offers valuable insights and guidance to help inform clinical strategies. [ABSTRACT FROM AUTHOR]

Coronary microvascular dysfunction (CMD) is associated with cardiac dysfunction and predictive of cardiac mortality in obesity, especially in females. Clinical data further support that CMD associates with development of heart failure with preserved ejection fraction and that mineralocorticoid receptor (MR) antagonism may be more efficacious in obese female, versus male, HFpEF patients. Accordingly, we examined the impact of smooth muscle cell (SMC)-specific MR deletion on obesity-associated coronary and cardiac diastolic dysfunction in female mice. Obesity was induced in female mice via western diet (WD) feeding alongside littermates fed standard diet. Global MR blockade with spironolactone prevented coronary and cardiac dysfunction in obese females and specific deletion of SMC-MR was sufficient to prevent obesity-associated coronary and cardiac diastolic dysfunction. Cardiac gene expression profiling suggested reduced cardiac inflammation in WD-fed mice with SMC-MR deletion independent of blood pressure, aortic stiffening, and cardiac hypertrophy. Further mechanistic studies utilizing single-cell RNA sequencing of non-cardiomyocyte cell populations revealed novel impacts of SMC-MR deletion on the cardiac cellulome in obese mice. Specifically, WD feeding induced inflammatory gene signatures in non-myocyte populations including B/T cells, macrophages, and endothelium as well as increased coronary VCAM-1 protein expression, independent of cardiac fibrosis, that was prevented by SMC-MR deletion. Further, SMC-MR deletion induced a basal reduction in cardiac mast cells and prevented WD-induced cardiac pro-inflammatory chemokine expression and leukocyte recruitment. These data reveal a central role for SMC-MR signaling in obesity-associated coronary and cardiac dysfunction, thus supporting the emerging paradigm of a vascular origin of cardiac dysfunction in obesity. [ABSTRACT FROM AUTHOR]

Chronic kidney disease patients are at increased risk of cardiovascular disease, which is the leading cause of mortality among this population. In addition, chronic kidney disease is a major risk factor for the development of coronary artery disease and is widely regarded as a coronary artery disease risk equivalent. Medical therapy is the cornerstone of coronary artery disease management in the general population. However, there are few trials to guide medical therapy of coronary artery disease in chronic kidney disease, with most data extrapolated from clinical trials of mainly non-chronic kidney disease patients, which were not adequately powered to evaluate this subgroup. There is some evidence to suggest that the efficacy of certain therapies such as aspirin and statins is attenuated with declining estimated glomerular filtration rate, with questionable benefit among end-stage renal disease (ESRD) patients. Furthermore, chronic kidney disease and ESRD patients are at higher risk of potential side effects with therapy, which may limit their use. In this review, we summarize the available evidence supporting the safety and efficacy of medical therapy of coronary artery disease in chronic kidney disease and ESRD patients. We also discuss the data on new emerging therapies, including PCSK9i, SGLT2i, GLP1 receptor agonists, and nonsteroidal mineralocorticoid receptor antagonists, which show promise at reducing risk of cardiovascular events in the chronic kidney disease population and may offer additional treatment options. Overall, dedicated studies directly evaluating chronic kidney disease patients, particularly those with advanced chronic kidney disease and ESRD, are greatly needed to establish the optimal medical therapy for coronary artery disease and improve outcomes in this vulnerable population. [ABSTRACT FROM AUTHOR]