Obesity, along with type 2 diabetes mellitus (T2DM), is a major contributor to hypertension. The renin-angiotensin-aldosterone system is involved in the occurrence of diabetes and hypertension. However, the mechanism by which obesity is related to T2DM induced hypertension is unclear. In this study, we observed that blood pressure and serum renin content were increased in patients with diabetes and hypertension. Hydrogen sulfide (H2S), as an endogenous bioactive molecule, has been shown to be a vasodilator. Db/db mice, characterized by obesity and T2DM, and juxtaglomerular (JG) cells, which line the afferent arterioles at the entrance of the glomeruli to produce renin, treated with glucose, palmitic acid (PA) and oleic acid (OA), were used as animal and cellular models. NaHS, the H2S donor, was administered to db/db mice through intraperitoneal injection. NaHS significantly alleviated blood pressure in db/db mice, decreased the renin content in the serum of db/db mice and reduced renin secretion from JG cells. NaHS modulated renin release via cAMP and soluble N-ethylmaleimide-sensitive factor attachment protein receptors (SNAREs), including synaptosome-associated protein 23 (SNAP23) and vesicle-associated membrane protein 2 (VAMP2), which mediate renin exocytosis. Furthermore, NaHS increased the levels of autophagy-related proteins and colocalization with EGFP-LC3 puncta with renin-containing granules and VAMP2 to consume excessive renin to maintain intracellular homeostasis. Therefore, exogenous H2S attenuates renin release and promotes renin-vesicular autophagy to relieve diabetes-induced hypertension.

The elevated aldosterone in primary aldosteronism (PA) is associated with increased insulin resistance and prevalence of diabetes mellitus (DM). Both aldosterone excess and DM lead to left ventricular (LV) pathological remodeling. In this study, we investigated the impact of DM on LV non-hemodynamic remodeling in patients with PA. We enrolled 665 PA patients, of whom 112 had DM and 553 did not. Clinical, biochemical, and echocardiographic data were analyzed at baseline and 1 year after adrenalectomy. LV non-hemodynamic remodeling was represented by inappropriate excess left ventricular mass index (ieLVMI), which was defined as the difference between left ventricular mass index (LVMI) and predicted left ventricular mass index (pLVMI). Propensity score matching (PSM) was used with age, sex, systolic, and diastolic blood pressure to adjust for baseline variables. After PSM, the patient characteristics were balanced between the DM and non-DM groups, except for fasting glucose, HbA1c, and lipid profile. A total of 111 DM and 419 non-DM patients were selected for further analysis. Compared to the non-DM group, the DM group had significantly higher ieLVMI and LVMI. After multivariable linear regression analysis, the presence of DM remained a significant predictor of increased ieLVMI. After adrenalectomy, ieLVMI decreased significantly in the non-DM group but not in DM group. The presence of DM in PA patients was associated with more prominent non-hemodynamic LV remodeling and less recovery after adrenalectomy.

About one-fourth of the global population is either overweight or obese, both of which increase the risk of insulin resistance, cardiovascular diseases, and infections. In obesity, both immune cells and adipocytes produce an excess of pro-inflammatory cytokines that may play a significant role in disease progression. In the recent coronavirus disease 2019 (COVID-19) pandemic, important pathological characteristics such as involvement of the renin-angiotensin-aldosterone system, endothelial injury, and pro-inflammatory cytokine release have been shown to be connected with obesity and associated sequelae such as insulin resistance/type 2 diabetes and hypertension. This pathological connection may explain the severity of COVID-19 in patients with metabolic disorders. Many studies have also reported an association between type 2 diabetes and persistent viral infections. Similarly, diabetes favors the growth of various microorganisms including protozoal pathogens as well as opportunistic bacteria and fungi. Furthermore, diabetes is a risk factor for a number of prion-like diseases. There is also an interesting relationship between helminths and type 2 diabetes; helminthiasis may reduce the pro-inflammatory state, but is also associated with type 2 diabetes or even neoplastic processes. Several studies have also documented altered circulating levels of neutrophils, lymphocytes, and monocytes in obesity, which likely modifies vaccine effectiveness. Timely monitoring of inflammatory markers (e.g., C-reactive protein) and energy homeostasis markers (e.g., leptin) could be helpful in preventing many obesity-related diseases.

Hypertension (HT) is a major cardiovascular risk factor that affects 10% to 40% of the general population in an age-dependent manner. Detection of secondary forms of HT is particularly important because it allows the targeted management of the underlying disease. Among hypertensive patients, the prevalence of endocrine HT reaches up to 10%. Adrenal diseases are the most frequent cause of endocrine HT and are associated with excess production of mineralocorticoids (mainly primary aldosteronism), glucocorticoids (Cushing syndrome), and catecholamines (pheochromocytoma). In addition, a few rare diseases directly affecting the action of mineralocorticoids and glucocorticoids in the kidney also lead to endocrine HT. Over the past years, genomic and genetic studies have allowed improving our knowledge on the molecular mechanisms of endocrine HT. Those discoveries have opened new opportunities to transfer knowledge to clinical practice for better diagnosis and specific treatment of affected subjects. In this review, we describe the physiology of adrenal hormone biosynthesis and action, the clinical and biochemical characteristics of different forms of endocrine HT, and their underlying genetic defects. We discuss the impact of these discoveries on diagnosis and management of patients, as well as new perspectives related to the use of new biomarkers for improved patient care.

The pathophysiology of genetic hypokalemia is close to that of non-genetic hypokalemia. New molecular pathways physiologically involved in renal and extrarenal potassium homeostasis have been highlighted. A physiological approach to diagnosis is illustrated here, with 6 cases. Mechanisms generating and sustaining of hypokalemia are discussed. After excluding acute shift of extracellular potassium to the intracellular compartment, related to hypokalemic periodic paralysis, inappropriate kaliuresis (> 40 mmol/24h) concomitant to hypokalemia indicates renal potassium wasting. Clinical analysis distinguishes hypertension-associated hypokalemia, due to hypermineralocorticism or related disorders. Genetic hypertensive hypokalemia is rare. It includes familial hyperaldosteronism, Liddle syndrome, apparent mineralocorticoid excess,11beta hydroxylase deficiency and Geller syndrome. In case of normo- or hypo-tensive hypokalemia, two etiologies are to be considered: chloride depletion or salt-wasting tubulopathy. Diarrhea chlorea is a rare disease responsible for intestinal chloride depletion. Due to the severity of hypokalemic metabolic alkalosis, this disease can be misdiagnosed as pseudo-Bartter syndrome. Gitelman syndrome is the most frequent cause of genetic hypokalemia. It typically associates renal sodium and potassium wasting, hypomagnesemia, conserved chloride excretion (>40 mmol/24h), and low-range calcium excretion (urinary Ca/creatinine ratio < 0.20 mmol/mmol). Systematic analysis of hydroelectrolytic disorder and dynamic hormonal investigation optimizes indications for and orientation of genotyping of hereditary salt-losing tubulopathy.

A 76-year-old man was evaluated in our emergency department (ED) for right toe swelling and pain. His initial ED workup revealed volume overload, uncontrolled hypertension, slow atrial fibrillation, refractory hypokalemia, mixed metabolic alkalosis and respiratory acidosis, with a normal plasma pH, and hypernatremia. His medical chart revealed long standing hyperkalemia and metabolic acidosis, related to his diabetic kidney disease. We hypothesized that a short course of daily SPS ingestion (Sodium Polystyrene Sulfonate, "Kayexalate") was the sole etiology for the compound electrolyte abnormalities and the electrolyte "flip flop". SPS ingestion can cause hypokalemia by excessive potassium binding in the gut. SPS exchanging potassium for sodium caused excessive sodium retention leading to hypernatremia, hypertension and volume overload. Volume overload worsened his chronic obstructive sleep apnea and yielded respiratory acidosis. Finally hypokalemia by itself was the main trigger for generation and maintenance of metabolic alkalosis. Urinary electrolytes, and renin and aldosterone levels taken at the ED ruled out primary aldosteronism and renal potassium and hydrogen loss. The patient's potassium was replenished by both PO and IV routes. He was treated for his volume overload and hypertension with furosemide. Spironolactone and amiloride, potassium sparing diuretics, were cautiously given only during his hypokalemic phase. His plasma sodium and potassium levels, blood pressure and volume status gradually improved. "Kayexalate" effect should be suspected in a patient presenting with unexplained hypokalemia and alkalosis, accompanied by volume overload rather than volume depletion, developing shortly after SPS ingestion. ED doctors should specifically ask CKD or ESRD patients on SPS, as it otherwise can skip the medication reconciliation process.

Liddle syndrome is an inherited form of arterial hypertension with autosomal dominant pattern of inheritance. It is caused by activating mutation of genes coding of the epithelial sodium channel in distal nephron. Mutation leads to excessive reabsorbtion of sodium ions and volume expansion resulting in arterial hypertension. Antoher typical laboratory findings are hypokalaemia, low levels of serum aldosteron and metabolic alkalosis. Phenotypic variability makes it difficult to identify patients with Liddle syndrome, often resulting in misdiagnosis and severe complications at early age. Genetic studies should be done to confirm the diagnosis. Therapy of Liddle syndrome is based on administration of epithelial sodium channel blocker amilorid.

Patients with primary bilateral macronodular adrenal hyperplasia (PBMAH) usually present bilateral benign adrenocortical macronodules at imaging and variable levels of cortisol excess. PBMAH is a rare cause of primary overt Cushing's syndrome, but may represent up to one third of bilateral adrenal incidentalomas with evidence of cortisol excess. The increased steroidogenesis in PBMAH is often regulated by various G-protein coupled receptors aberrantly expressed in PBMAH tissues; some receptor ligands are ectopically produced in PBMAH tissues creating aberrant autocrine/paracrine regulation of steroidogenesis. The bilateral nature of PBMAH and familial aggregation, led to the identification of germline heterozygous inactivating mutations of the ARMC5 gene, in 20-25% of the apparent sporadic cases and more frequently in familial cases; ARMC5 mutations/pathogenic variants can be associated with meningiomas. More recently, combined germline mutations/pathogenic variants and somatic events inactivating the KDM1A gene were specifically identified in patients affected by GIP-dependent PBMAH. Functional studies demonstrated that inactivation of KDM1A leads to GIP-receptor (GIPR) overexpression and over or down-regulation of other GPCRs. Genetic analysis is now available for early detection of family members of index cases with PBMAH carrying identified germline pathogenic variants. Detailed biochemical, imaging, and co-morbidities assessment of the nature and severity of PBMAH is essential for its management. Treatment is reserved for patients with overt or mild cortisol/aldosterone or other steroid excesses taking in account co-morbidities. It previously relied on bilateral adrenalectomy; however recent studies tend to favor unilateral adrenalectomy, or less frequently, medical treatment with cortisol synthesis inhibitors or specific blockers of aberrant GPCR.

Renal tubulointerstitial fibrosis (TIF) is a hallmark in the continuous progression of chronic kidney disease (CKD), in which excessive activation of the renin‑angiotensin‑-aldosterone system serves a crucial role. Currently, there are no targeted therapies for the progression of TIF. microRNA (miR)‑26a may be an ideal anti‑fibrosis candidate molecule; however, the effect of miR‑26 on aldosterone (ALD)‑induced TIF remains unclear. This study aimed to elucidate the role of miR‑26a in ALD‑induced TIF. In the present study, we hypothesized that delivery of miR‑26a by exosomes could attenuate ALD‑induced TIF. miR‑26a expression was downregulated in the kidney of ALD‑induced mice compared with the mice in the sham group. Exosome‑encapsulated miR‑26a (Exo‑miR‑26a) was manufactured and injected into ALD‑treated mice through the tail vein. In vivo experiments showed that Exo‑miR‑26a alleviated the downregulated miR‑26a expression in the kidney, tubular injury and ALD‑induced TIF, which was determined using Masson's trichrome staining and assessment of lipocalin 2, α‑smooth muscle actin, collagen I and fibronectin expression. Moreover, in vitro experiments revealed that Exo‑miR‑26a inhibited epithelial‑mesenchymal transition and extracellular matrix deposition in mouse tubular epithelial cells. Mechanistically, overexpressing miR‑26a led to decreased expression levels of connective tissue growth factor by directly binding to its 3'‑UTR and inhibiting the activation of SMAD3. These findings demonstrated that the exosomal delivery of miR‑26a may alleviate ALD‑induced TIF, which may provide new insights into the treatment of CKD.

Primary aldosteronism is the most common form of secondary arterial hypertension, due to excessive aldosterone production from the adrenal gland. Although somatic mutations have been identified in aldosterone producing adenoma, the exact mechanisms leading to increased cell proliferation and nodule formation remain to be established. One hypothesis is that changes in vascular supply to the adrenal cortex, due to phenomena of atherosclerosis or high blood pressure, may influence the morphology of the adrenal cortex, resulting in a compensatory growth and nodule formation in response to local hypoxia. In this review, we will summarize our knowledge on the mechanisms regulating adrenal cortex development and function, describe adrenal vascularization in normal and pathological conditions and address the mechanisms allowing the cross-talk between the hormonal and vascular components to allow the extreme tissue plasticity of the adrenal cortex in response to endogenous and exogenous stimuli. We will then address recent evidence suggesting a role for alterations in the vascular compartment that could eventually be involved in nodule formation and the development of primary aldosteronism.

This study aims to investigate the effects and the underlying mechanism of Huangqi Shengmai Decoction(HQSMD) in the treatment of fatigue and myocardial injury in a joint rat model. Wistar rats were assigned into 4 groups: sham, model, diltiazem hydrochloride(positive control), and HQSMD. The joint model of fatigue and myocardial injury was established by 14-day exhausted swimming followed by high ligation of the left anterior descending coronary artery. The rats in the sham group underwent a sham operation without coronary artery ligation or swimming. Since the fourth day after the ligation, swimming was continued in the model group and the drug-treated groups for the following 4 weeks. Meanwhile, the rats in the positive control group and the HQSMD group were respectively administrated intragastrically with diltiazem hydrochloride(20 mg·kg~(-1)·d~(-1)) and HQSMD(0.95 g·kg~(-1)·d~(-1)) for 4 weeks, while the shams and the models were given the same volume of normal saline. The left ventricular ejection fraction(LVEF), left ventricular fractional shortening(LVFS), grip strength, and myocardial pathophysiological changes were measured to evaluate the anti-fatigue and cardioprotective effects of HQSMD. The protein levels of PTEN-induced putative kinase 1(PINK1) and parkin in the myocardium were measured by Western blot to preliminarily elucidate the mechanism of HQSMD in ameliorating myocardial injury by suppressing mitochondrial autophagy. Compared with the shams, the models showed weakened heart function(LVEF and LVFS, P<0.01), decreased grasping ability(P<0.05), elevated blood urea nitrogen(BUN) and aldosterone(ALD) levels(P<0.01), aggravated myocardial fibrosis and connective tissue hyperplasia(P<0.01), and up-regulated protein levels of PINK1(P<0.01) and parkin(P<0.05). Four-week treatment with HQSMD increased the LVEF and LVFS levels(P<0.01), enhanced the grip strength(P<0.01), reduced the serum levels of BUN(P<0.01) and ALD(P<0.05), alleviated the pathological injury and fibrosis in the myocardium(P<0.01), and down-regulated the protein levels of PINK1(P<0.01) and parkin(P<0.05) in heart tissue. The results demonstrate that HQSMD may alleviate myocardial fibrosis and protect myocardium by suppressing the excessive mitochondrial auto-phagic activity and reducing the excessively elevated ALD level, thereby ameliorating fatigue and myocardial injury.

Aldosterone, an effector molecule of the renin-angiotensin-aldosterone system (RAAS), has been receiving more attention in the field of ophthalmology because of its possible role in the pathogenesis of various eye diseases or abnormalities; it may even become a target for their treatment. Primary aldosteronism, a typical model of a systemic aldosterone excess, may cause vision loss due to various ocular diseases, such as retinal vein occlusion, central serous chorioretinopathy, and, possibly glaucoma. RAAS components are present in various parts and types of cells present in the eye. Investigations of the local RAAS in various animal models of diabetic macular edema, retinal vein occlusion, retinopathy of prematurity, central serous chorioretinopathy, and glaucoma have found evidence that aldosterone or mineralocorticoid receptors may exacerbate the pathology of these disorders. Further studies are needed to elucidate whether the modulation of aldosterone or mineralocorticoid receptors is an effective treatment for preventing vision loss in patients with eye diseases.

In this review, we describe previous basic and clinical studies on autonomous aldosterone production. Over the past decades, mineralocorticoid receptor antagonists (MRAs) have been found to concentration-dependently inhibit steroidogenesis in different degrees. However, many studies have proven the suppressive effects of MRAs on the activities of hormone synthase. The probable factors of cytochrome P-450 reduction, both in microsomes and mitochondria, have also been considered: (1) one of the spironolactone metabolite forms had destructive function, except canrenone, (2) 7α-thio-spironolactone was an obligatory intermediate in the spironolactone-induced CYP450 decrease, and (3) the contributing steroids should have 7α-methylthio or 7α-methylsulfone groups. In previous clinical research, spironolactone-body-containing cells showed a type II pattern of enzyme activity (i.e., enhanced 3β-hydroxysteroid dehydrogenase, glucose-6-phosphate, and NADP-isocitrate dehydrogenase activities and weaken succinate dehydrogenase activity), and the subcapsular micronodules composed of spironolactone-body-containing cells also exhibited a type II pattern and excess aldosterone secretion, indicating that the subcapsular micronodules might be the root of aldosterone-producing adenoma. Moreover, combined with the potential impeditive function to aldosterone secretion, a few cases of spontaneous remission of primary aldosteronism, with normal ranges of blood pressure, plasma potassium, plasma renin activity, and aldosterone renin ratio, have been reported after long-term treatment with MRAs.

Connshing syndrome (CoSh) (adrenal-related synchronous aldosterone (A) and cortisol (C) excess) represents a distinct entity among PA (primary hyperaldosteronisms) named by W. Arlt et al. in 2017, but the condition has been studied for more than 4 decades. Within the last few years, this is one of the most dynamic topics in hormonally active adrenal lesions due to massive advances in steroids metabolomics, molecular genetics from CYP11B1/B2 immunostaining to genes constellations, as well as newly designated pathological categories according to the 2022 WHO classification. In gross, PA causes 4-10% of all high blood pressure (HBP) cases, and 20% of resistant HBP; subclinical Cushing syndrome (SCS) is identified in one-third of adrenal incidentalomas (AI), while CoSh accounts for 20-30% to 77% of PA subjects, depending on the tests used to confirm autonomous C secretion (ACS). The clinical picture overlaps with PA, hypercortisolemia being mild. ACS is suspected in PA if a more severe glucose and cardiovascular profile is identified, or there are larger tumours, ACS being an independent factor risk for kidney damage, and probably also for depression/anxiety and osteoporotic fractures. It seems that one-third of the PA-ACS group harbours mutations of C-related lines like PRKACA and GNAS. A novel approach means we should perform CYP11B2/CYP11B1 immunostaining; sometimes negative aldosteronoma for CYP11B1 is surrounded by micronodules or cell clusters with positive CYP11B1 to sustain the C excess. Pitfalls of hormonal assessments in CoSh include the index of suspicion (check for ACS in PA patients) and the interpretation of A/C ratio during adrenal venous sample. Laparoscopic adrenalectomy is the treatment of choice. Post-operative clinical remission rate is lower in CoSh than PA. The risk of clinically manifested adrenal insufficiency is low, but a synthetic ACTH stimulating testing might help to avoid unnecessary exposure to glucocorticoids therapy. Finally, postponing the choice of surgery may impair the outcome, having noted that long-term therapy with mineralocorticoids receptors antagonists might not act against excessive amounts of C. Awareness of CoSh improves management and overall prognosis.

Background The pathobiology of heart failure with preserved ejection fraction (HFpEF) is still poorly understood, and effective therapies remain limited. Diabetes and mineralocorticoid excess are common and important pathophysiological factors that may synergistically promote HFpEF. The authors aimed to develop a novel animal model of HFpEF that recapitulates key aspects of the complex human phenotype with multiorgan impairments. Methods and Results The authors created a novel HFpEF model combining leptin receptor-deficient db/db mice with a 4-week period of aldosterone infusion. The HFpEF phenotype was assessed using morphometry, echocardiography, Ca2+ handling, and electrophysiology. The sodium-glucose cotransporter-2 inhibitor empagliflozin was then tested for reversing the arrhythmogenic cardiomyocyte phenotype. Continuous aldosterone infusion for 4 weeks in db/db mice induced marked diastolic dysfunction with preserved ejection fraction, cardiac hypertrophy, high levels of B-type natriuretic peptide, and significant extracardiac comorbidities (including severe obesity, diabetes with marked hyperglycemia, pulmonary edema, and vascular dysfunction). Aldosterone or db/db alone induced only a mild diastolic dysfunction without congestion. At the cellular level, cardiomyocyte hypertrophy, prolonged Ca2+ transient decay, and arrhythmogenic action potential remodeling (prolongation, increased short-term variability, delayed afterdepolarizations), and enhanced late Na+ current were observed in aldosterone-treated db/db mice. All of these arrhythmogenic changes were reversed by empagliflozin pretreatment of HFpEF cardiomyocytes. Conclusions The authors conclude that the db/db+aldosterone model may represent a distinct clinical subgroup of HFpEF that has marked hyperglycemia, obesity, and increased arrhythmia risk. This novel HFpEF model can be useful in future therapeutic testing and should provide unique opportunities to better understand disease pathobiology.

The term dialysis is derived from the Greek words dia, meaning "through", and lysis meaning "loosening or splitting". It is a form of renal replacement therapy, where the kidney's role of filtration of the blood is supplemented by artificial equipment, which removes excess water, solutes, and toxins. Dialysis ensures maintenance of homeostasis (a stable internal environment) in people experiencing a rapid loss of kidney function i.e., acute kidney injury (AKI), or a prolonged, gradual loss that is chronic kidney disease (CKD). It is a measure to tide over acute kidney injury, to buy time until a kidney transplant can be carried out, or for sustaining those ineligible for it. The incidence of renal replacement therapy (RRT) depends on the incidence and prevalence of conditions causing end-stage renal disease (ESRD), early diagnosis of chronic kidney disease (CKD), and measures to slow progression to end-stage renal disease (ESRD). Systematic identification of patients with a declining estimated glomerular filtration rate (eGFR), heavy proteinuria, and history of acute kidney injury episodes facilitates planned RRT commencement, thus slowing the rising trend in RRT incidence. All patients who are likely to end up with ESRD and their caregivers must be adequately prepared physically and psychologically and provided with accessible education about future treatment options. Advanced preparation helps avoid dialysis associated complications such as a malfunctioning catheter or poorly functioning fistula, causing temporary vascular access insertion culminating in sepsis, thrombosis, bleeding, and accelerated mortality. Patients who are provided with the educational programs are more likely to choose home-based dialysis therapy with societal benefits, less expenditure, and improved quality of life. These programs should commence no later than stage 4 CKD for the patient to have sufficient time and cognition to make informed choices and implement preparatory measures for RRT. In 2010, approximately 2.5 million people worldwide received chronic RRT, with high absolute rates in North America and maximum prevalence in Taiwan and Japan. Maintenance of regional and national dialysis registries with details on rates, outcomes, and national dialysis practice patterns help keep track of the population dependent on RRT. They also include hospital-specific information, safety, and quality reporting and provide resources for clinical research. Access to dialysis is affected by sociocultural and socioeconomic factors. ESRD is disproportionately higher in African Americans and CKD among the White population. ESRD disease burden is attributed to diabetes mellitus (45%) and hypertension (30%) besides rarer causes like polycystic kidney disease, obstructive uropathy, and glomerulonephritis. Women are at higher risk for CKD, while men have a higher risk of ESRD. Race disparities can limit access to health care due to its impact on income or the availability of health insurance. Indigenous people in Australia, New Zealand, United States, and Canada have high rates of kidney disease, less access to transplantation, and poorer outcomes. There are three broad types of dialysis: Hemodialysis (HD). Peritoneal dialysis (PD). Continuous renal replacement therapy (CRRT). Dynamics of this particular form of renal replacement therapy vary across countries with longer dialysis sessions and slower blood flow rates in Japan. PD is highly prevalent in Hong Kong and the Jalisco region of Mexico, while Home HD is widely adopted in New Zealand and Australia. The timing for initiation of dialysis is decided after considering the complications of early initiation (unnecessary exposure to IV lines and invasive procedure with risks of infection) against late initiation causing avoidable volume, metabolic and electrolyte complications of AKI. It is not advisable to assign an arbitrary urea nitrogen or creatinine level for dialysis initiation due to individual variability in uremia symptom severity and renal function. Despite optimal CKD management, patients progress to needing RRT, especially when their eGFR drops below 20 ml/ min/1.73 m2 and/or they rapidly deteriorate to ESRD within 12 months. The eGFR at dialysis initiation has steadily increased in recent times. In 1996, in the United States, 13% of incident ESRD patients started RRT at an eGFR of 10 ml/min/1.73 m2 or higher. This increased to 43% in 2010 and dropped to 39% in 2015. Waiting for uremic symptoms to set in before commencing RRT had added risks of the patient being malnourished with an increased risk of mortality. Asking patients to compare their current eating habits and physical activity levels with those 6 to 12 months back helps avoid the lack of awareness. The concept of 'healthy start,' with dialysis commencing before the onset of severe uremia symptoms, is associated with prolonged survival. An early start will prepone the need for a change of modality or further procedures without any improvement in the quality of life while adding to healthcare costs. The Renal Physicians Association's (RPA) criteria for identifying dialysis patients with a poor prognosis beyond 75 years of age includes: 1. Clinician's estimation of the likelihood of patient mortality in the next six months. 2. Greatly impaired functional status. 3. High comorbidity score. 4. Severe chronic malnutrition (low serum albumin). Quality of life also strongly predicts mortality. It provides a comprehensive toolkit to encourage shared decision making. Mortality rates among dialysis patients are markedly higher among younger age groups, primarily attributed to cardiovascular (40%) and infectious causes (10%). High cardiovascular mortality in dialysis patients could be related to shared risk factors such as chronic inflammation, significant changes in extracellular volume, dystrophic vascular calcification, and altered cardiovascular dynamics during dialysis. The study of heart and renal protection (SHARP) having both dialysis and non-dialysis requiring CKD patients showed a 17% reduction in cardiovascular death and major cardiovascular events with simvastatin-ezetimibe treatment. Conventional cardioprotective strategies such as beta-blockers, aspirin, renin-angiotensin-aldosterone system inhibitors are recommended in dialysis patients based on their cardiovascular risk profile. Hypertension has a graded association with ESRD risk as it is both a cause and a consequence of CKD. The first three months after dialysis initiation, especially among older patients, has the highest mortality rates. This could be due to risks associated with the commencement of dialysis (central venous catheter placement) and more severe comorbidities causing deterioration of renal function.

In recent studies, primary aldosteronism (PA) has been reported as the most common etiology for secondary hypertension of endocrine origin, accounting for approximately 10% of cases. In PA, excess aldosterone production can lead to deleterious effects at the cardiovascular (CV) and renal levels by activating mineralocorticoid receptors, which involves an increase in pro-inflammatory and pro-fibrotic mediators. Among these mediators, neutrophil gelatinase-associated lipocalin (NGAL), a secretion glycoprotein belonging to the lipocalin superfamily, has been closely linked to CV and renal damage in several pathological conditions. Because NGAL can be detected in biofluids such as plasma and urine, it has been proposed as a damage biomarker for target tissues and has also been studied for its role in hypertension and associated with PA. NGAL is produced by many different cell types, can be carried on extracellular vesicles, and is modulated by microRNAs, which would support its use as a biomarker for endocrine hypertension due to PA. Over the last decade, studies have shown that NGAL is necessary for the development of aldosterone-induced hypertension and that is associated with end-organ damage. In addition, it has been proposed that some mechanisms are dependent on the activation of immune cells, such as dendritic cells and macrophages, where the release of specific cytokines (i.e., interleukin [IL]-23) or chemokines (i.e., CCL-5) induced by aldosterone would depend on NGAL. Subsequently, this activates the T helper (Th) lymphocytes, such as Th17 and Th2, resulting in CV and renal fibrosis due to the high aldosterone levels. Although the immune system has been closely associated with essential hypertension, its participation in endocrine hypertension has not been fully elucidated. This review discusses the link between NGAL and endocrine hypertension, particularly in the context of PA, and their possible regulators and mechanisms, with a focus on its role as an immunomodulator.

Primary aldosteronism (PA) is a disease characterized by hypertension and hypokalemia due to the excessive aldosterone secretion from the adrenal cortex, which leads to the retention of both water and sodium, and the inhibition of the renin-angiotensin system as well. Familial hyperaldosteronism type II (FH-II) is known as an autosomal dominant hereditary disease, which is a scarce cause of PA. In this report, we cllected the clinical data of a patient with repeated hypertension and hypokalemia of uncertain diagnosis since 2014. Nevertheless, we discovered by genetic sequencing in 2021 that the CLCN2 and WFS1 gene mutation of the patient, whose mother belongs to heterozygote genotype and father belongs to wild-type genotype. Combined with a series of endocrine function tests and imaging studies, the patient was finally certified her suffering from FH-II and WFS1 gene mutation. By summarizing and analyzing the characteristics and genetic test results of this case, we recommended gene sequencing for patients with PA whose etiology is difficult to be determined clinically. This case also provides new clinical data for subsequent genetic studies of the disease.

Phosphorus, present as phosphate in biological systems, is an essential mineral for various biological activities and biochemical processes. Numerous studies have indicated that disturbed phosphate balance may contribute to the development of metabolic syndrome (MetS). However, no consistent result was found on the association between phosphorus intake and serum phosphate concentration with MetS. It is believed that both positive and negative impacts of phosphorus/phosphate co-exist in parallel during MetS condition. Reduced phosphate level contributed to the development of obesity and hyperglycaemia. Low phosphate is believed to compromise energy production, reduce exercise capacity, increase food ingestion, and impair glucose metabolism. On the other hand, the effects of phosphorus/phosphate on hypertension are rather complex depending on the source of phosphorus and subjects' health conditions. Phosphorus excess activates sympathetic nervous system, renin-angiotensin-aldosterone system, and induces hormonal changes under pathological conditions, contributing to the blood pressure-rising effects. For lipid metabolism, adequate phosphate content ensures a balanced lipid profile through regulation of fatty acid biosynthesis, oxidation, and bile acid excretion. In conclusion, phosphate metabolism serves as a potential key feature for the development and progression of MetS. Dietary phosphorus and serum phosphate level should be under close monitoring for the management of MetS.

Primary aldosteronism (PA) is the most frequent form of secondary endocrine hypertension, which is characterized by excessive aldosterone secretion and suppressed renin. The currently recommended diagnostic algorithm is very clear, and the plasma aldosterone-to-renin ratio (ARR) is considered the first-line screening test. However, this indicator is influenced by many factors, some of which may cause false-negative results, consequently leading to underdiagnosed PA. Here, we report the rare case of a 38-year-old man who presented with bilateral accessory renal arteries and aldosterone-producing adenoma but had a negative ARR test result.

Primary aldosteronism (PA) is considered the most common form of secondary hypertension, which is associated with excessive aldosterone secretion in the adrenal cortex. The cause of excessive aldosterone secretion is the induction of aldosterone synthase gene (CYP11B2) expression by depolarization of adrenocortical cells. In this study, we found that YM750, an Acyl-coenzyme A: cholesterol acyltransferase (ACAT) inhibitor, acts on adrenocortical cells to suppress CYP11B2 gene expression and aldosterone secretion. YM750 inhibited the induction of CYP11B2 gene expression by KCl stimulation, but not by angiotensin II and forskolin stimulation. Interestingly, YM750 did not inhibit KCl-stimulated depolarization via an increase in intracellular calcium ion concentration. Moreover, ACAT1 expression was relatively abundant in the zona glomerulosa (ZG) including these CYP11B2-positive cells. Thus, YM750 suppresses CYP11B2 gene expression by suppressing intracellular signaling activated by depolarization. In addition, ACAT1 was suggested to play an important role in steroidogenesis in the ZG. YM750 suppresses CYP11B2 gene expression and aldosterone secretion in the adrenal cortex, suggesting that it may be a potential therapeutic agent for PA.

Apparent mineralocorticoid excess is an autosomal recessive form of monogenic disease characterized by juvenile resistant low-renin hypertension, marked hypokalemic alkalosis, low aldosterone levels, and high ratios of cortisol to cortisone metabolites. It is caused by defects in the HSD11B2 gene, encoding the enzyme 11β-hydroxysteroid dehydrogenase type 2 (11β-HSD2), which is primarily involved in the peripheral conversion of cortisol to cortisone. To date, over 50 deleterious HSD11B2 mutations have been identified worldwide. Multiple molecular mechanisms function in the lowering of 11β-HSD2 activity, including damaging protein stability, lowered affinity for the substrate and cofactor, and disrupting the dimer interface. Genetic polymorphism, environmental factors as well as epigenetic modifications may also offer an implicit explanation for the molecular pathogenesis of AME. A precise diagnosis depends on genetic testing, which allows for early and specific management to avoid the morbidity and mortality from target organ damage. In this review, we provide insights into the molecular genetics of classic and non-classic apparent mineralocorticoid excess and aim to offer a comprehensive overview of this monogenic disease.

Soluble (pro)renin receptor (sPRR), the extracellular domain of (pro)renin receptor (PRR), is primarily generated by site-1 protease and furin. It has been reported that sPRR functions as an important regulator of intrarenal renin contributing to angiotensin II (ANG II)-induced hypertension. Relatively, less is known for the function of sPRR in ANG II-independent hypertension such as mineralocorticoid excess. In the present study, we used a novel mouse model with mutagenesis of the cleavage site in PRR (termed as PRRR279V/L282V or mutant) to examine the phenotype during aldosterone (Aldo)-salt treatment. The hypertensive response of mutant mice to Aldo-salt treatment was blunted in parallel with the attenuated response of plasma volume expansion and renal medullary α-epithelial Na+ channel expression. Moreover, Aldo-salt-induced hypertrophy in the heart and kidney as well as proteinuria were improved, accompanied by blunted polydipsia and polyuria. Together, these results represent strong evidence favoring endogenous sPRR as a mediator of Aldo-salt-induced hypertension and renal injury.NEW & NOTEWORTHY We used a novel mouse model with mutagenesis of the cleavage site of PRR to support soluble PRR as an essential mediator of aldosterone-salt-induced hypertension and also as a potential therapeutic target for patients with mineralocorticoid excess. We firstly report that soluble PRR-dependent pathway medicates the Na+-retaining action of aldosterone in the distal nephron, which opens up a new area for a better understanding of the molecular basis of renal handling of Na+ balance and blood pressure.

The coronavirus 2019 pandemic has affected many healthcare systems worldwide. While acute respiratory distress syndrome (ARDS) has been well-documented in COVID-19, there are several cardiovascular complications, such as myocardial infarction, ischaemic stroke, and pulmonary embolism, leading to disability and death. The link between COVID-19 and increasing thrombogenicity potentially occurs due to numerous different metabolic mechanisms, ranging from endothelial damage for direct virus infection, associated excessive formation of neutrophil extracellular traps (NETs), pathogenic activation of the renin-angiotensin-aldosterone system (RAAS), direct myocardial injury, and ischemia induced by respiratory failure, all of which have measurable biomarkers. A search was performed by interrogating three databases (MEDLINE; MEDLINE In-Process and Other Non-Indexed Citations, and EMBASE). Evidence from randomized controlled trials (RCT), prospective series, meta-analyses, and unmatched observational studies were evaluated for the processing of the algorithm and treatment of thromboembolic disease and cardiac thrombotic complications related to COVID-19 during SARS-CoV-2 infection. Studies out with the SARS-Cov-2 infection period and case reports were excluded. A total of 58 studies were included in this analysis. The role of the acute inflammatory response in the propagation of the systemic inflammatory sequelae of the disease plays a major part in determining thromboembolic disease and cardiac thrombotic complication in COVID-19. Some of the mechanisms of activation of these pathways, alongside the involved biomarkers noted in previous studies, are highlighted. Inflammatory response led to thromboembolic disease and cardiac thrombotic complications in COVID-19. NETs play a pivotal role in the pathogenesis of the inflammatory response. Despite moving into the endemic phase of the disease in most countries, thromboembolic complications in COVID-19 remain an entity that substantially impacts the health care system, with long-term effects that remain uncertain. Continuous monitoring and research are required.

Increased dietary phosphate intake has been associated with severity of coronary artery disease, increased carotid intima-media thickness, left ventricular hypertrophy (LVH), and increased cardiovascular mortality and morbidity in individuals with normal renal function as well as in patients suffering from chronic kidney disease. However, the underlying mechanisms are still unclear. To further elucidate the cardiovascular sequelae of long-term elevated phosphate intake, we maintained male C57BL/6 mice on a calcium, phosphate, and lactose-enriched diet (CPD, 2% Ca, 1.25% P, 20% lactose) after weaning them for 14 months and compared them with age-matched male mice fed a normal mouse diet (ND, 1.0% Ca, 0.7% P). Notably, the CPD has a balanced calcium/phosphate ratio, allowing the effects of elevated dietary phosphate intake largely independent of changes in parathyroid hormone (PTH) to be investigated. In agreement with the rationale of this experiment, mice maintained on CPD for 14 months were characterized by unchanged serum PTH but showed elevated concentrations of circulating intact fibroblast growth factor-23 (FGF23) compared with mice on ND. Cardiovascular phenotyping did not provide evidence for LVH, as evidenced by unchanged LV chamber size, normal cardiomyocyte area, lack of fibrosis, and unchanged molecular markers of hypertrophy (Bnp) between the two groups. However, intra-arterial catheterization revealed increases in systolic pressure, mean arterial pressure, and pulse pressure in mice fed the CPD. Interestingly, chronically elevated dietary phosphate intake stimulated the renin-angiotensin-aldosterone system (RAAS) as evidenced by increased urinary aldosterone in animals fed the CPD, relative to the ND controls. Furthermore, the catecholamines epinephrine, norepinephrine, and dopamine as well as the catecholamine metabolites metanephrine. normetanephrine and methoxytyramine as measured by mass spectrometry were elevated in the urine of mice on CPD, relative to mice on the ND. These changes were partially reversed by switching 14-month-old mice on CPD back to ND for 2 weeks. In conclusion, our data suggest that excess dietary phosphate induces a rise in blood pressure independent of secondary hyperparathyroidism, and that this effect may be mediated through activation of the RAAS and stimulation of the sympathetic tone.