MicroRNA and renal fibrosis in autosomal dominant polycystic kidney disease: a longitudinal study.

BACKGROUND: Autosomal dominant polycystic kidney disease (ADPKD) is a hereditary kidney disorder that may progress to kidney failure, accounting for 5-10% of all patients with end-stage kidney disease (ESKD). Clinical data, as well as molecular genetics and advanced imaging techniques have provided surrogate prognostic biomarkers to predict rapid decline in kidney function, nonetheless enhanced tools for assessing prognosis for ADPKD are still needed. The aim of this study was to analyze specific microRNAs involved in the pathogenesis of ADPKD and in the development of renal fibrosis, evaluating their potential role as predictors of renal function loss. METHODS: We evaluated kidney function by estimated glomerular filtration rate (eGFR) in 32 ADPKD patients in different stages of kidney disease at T0 and after a 24-month follow up (T1). Patients were divided into two groups: Rapid disease progression ([RP], n 15) and Non-rapid disease progression ([NRP], n 17), according to the Mayo Clinic classification criteria. At T0, ADPKD patients underwent plasma sampling for quantitative analysis of h-miR-17-5p, h-miR-21-5p and h-miR-199a-5p microRNA expression, using the quantitative reverse transcriptase-polymerase chain reaction (qRT-PCR) method and a 3 T magnetic resonance imaging (MRI), using an advanced MRI imaging protocol, for the quantification of total kidney volume (TKV), total perfusion volume (TPV) and total fibrotic volume (TFV). RESULTS: The expression of h-miR17-5p was higher (p < 0.05) in ADPKD patients with rapid disease progression. h-miR-17-5p, h-miR-21-5p and h-mir-199-5p showed a positive and significant correlation with the eGFR slope (mL/min/1.73 m2/year) (p < 0.05) but not with the eGFR at both T0 and T1. Both total fibrotic volume (cm3) and height-adjusted total fibrotic volume (cm3/m) were positively and significantly correlated to h-miR 21-5p and h-miR 199-5p (p < 0.05), but not to total kidney volume (cm3) and height-adjusted total kidney volume (cm3/m). CONCLUSIONS: The microRNAs we studied were associated with fibrosis and renal damage, suggesting their possible role as biomarkers able to identify ADPKD patients at high risk of disease progression regardless of the degree of kidney function, and therefore suitable for medical therapy, and may help uncovering new molecular mechanisms underlying cystogenesis.

Potential Mechanisms Underlying COVID-19-Mediated Central and Peripheral Demyelination: Roles of the RAAS and ADAM-17.

Demyelination is among the most conspicuous neurological sequelae of SARS-CoV-2 infection (COVID-19) in both the central (CNS) and peripheral (PNS) nervous systems. Several hypotheses have been proposed to explain the mechanisms underlying demyelination in COVID-19. However, none have considered the SARS-CoV-2's effects on the renin-angiotensin-aldosterone system (RAAS). Therefore, our objective in this review is to evaluate how RAAS imbalance, caused by direct and indirect effects of SARS-CoV-2 infection, could contribute to myelin loss in the PNS and CNS. In the PNS, we propose that demyelination transpires from two significant changes induced by SARS-CoV-2 infection, which include upregulation of ADAM-17 and induction of lymphopenia. Whereas, in the CNS, demyelination could result from RAAS imbalance triggering two alterations: (1) a decrease in angiotensin type II receptor (AT2R) activity, responsible for restraining defense cells' action on myelin; (2) upregulation of ADAM-17 activity, leading to impaired maturation of oligodendrocytes and myelin formation. Thus, we hypothesize that increased ADAM-17 activity and decreased AT2R activity play roles in SARS-CoV-2 infection-mediated demyelination in the CNS.

Transient secondary pseudo-hypoaldosteronism in infants with urinary tract infections: systematic literature review.

Infants with a congenital anomaly of the kidney and urinary tract sometimes present with hyponatremia, hyperkalemia, and metabolic acidosis due to under-responsiveness to aldosterone, hereafter referred to as secondary pseudo-hypoaldosteronism. The purpose of this report is to investigate pseudo-hypoaldosteronism in infant urinary tract infection. A systematic review was conducted following PRISMA guidelines after PROSPERO (CRD42022364210) registration. The National Library of Medicine, Excerpta Medica, Web of Science, and Google Scholar without limitations were used. Inclusion criteria involved pediatric cases with documented overt pseudo-hypoaldosteronism linked to urinary tract infection. Data extraction included demographics, clinical features, laboratory parameters, management, and course. Fifty-seven reports were selected, detailing 124 cases: 95 boys and 29 girls, 10 months or less of age (80% of cases were 4 months or less of age). The cases exhibited hyponatremia, hyperkalemia, acidosis, and activated renin-angiotensin II-aldosterone system. An impaired kidney function was found in approximately every third case. Management included antibiotics, fluids, and, occasionally, emergency treatment of hyperkalemia, hyponatremia, or acidosis. The recovery time averaged 1 week for electrolyte, acid-base imbalance, and kidney function. Notably, anomalies of the kidney and urinary tract were identified in 105 (85%) cases. CONCLUSIONS: This review expands the understanding of overt transient pseudo-hypoaldosteronism complicating urinary tract infection. Management involves antimicrobials, fluid replacement, and consideration of electrolyte imbalances. Raising awareness of this condition within pediatric hospitalists is desirable. WHAT IS KNOWN: • Infants affected by a congenital anomaly of the kidney and urinary tract may present with clinical and laboratory features resembling primary pseudo-hypoaldosteronism. • Identical features occasionally occur in infant urinary tract infection. WHAT IS NEW: • Most cases of secondary pseudo-hypoaldosteronism associated with a urinary tract infection are concurrently affected by a congenital anomaly of the kidney and urinary tract. • Treatment with antibiotics and parenteral fluids typically results in the normalization of sodium, potassium, bicarbonate, and creatinine within approximately 1 week.

Pathophysiological role of Na-Cl cotransporter in kidneys, blood pressure, and metabolism.

The Na-Cl cotransporter (NCC) is a well-recognized regulator of ion transportation in the kidneys that facilitates Na+ reabsorption in the distal convoluted tubule. It is also the pharmacologic inhibitory target of thiazide diuretics, a class of front-line antihypertensive agents that have been widely used for decades. NCC is a potent regulator of Na+ reabsorption and homeostasis. Hence, its overactivation and suppression lead to hypertension and hypotension, respectively. Genetic mutations that affect NCC function contribute to several diseases such as Gordon and Gitelman syndromes. We summarized the role of NCC in various physiologic processes and pathological conditions, such as maintaining ion and water homeostasis, controlling blood pressure, and influencing renal physiology and injury. In addition, we discussed the recent advancements in understanding cryo-EM structure of NCC, the regulatory mechanisms and binding mode of thiazides with NCC, and novel physiologic implications of NCC in regulating the cross-talk between the immune system and adipose tissue or the kidneys. This review contributes to a comprehensive understanding of the pivotal role of NCC in maintaining ion homeostasis, regulating blood pressure, and facilitating kidney function and NCC's novel role in immune and metabolic regulation.

Novel homozygous mutation in SCNN1A gene in an Iranian boy with PHA1B.

OBJECTIVES: Pseudohypoaldosteronism type 1 (PHA1) has two genetically distinct variants, including renal and systemic forms. Systemic PHA type I (PHA1B) has varying degrees of clinical presentation and results from mutations in genes encoding subunits of the epithelial sodium channel (ENaC) including the alpha, beta, and gamma subunits. To date, about 45 variants of PHA1B have been identified. CASE PRESENTATION: We report a boy with PHA1B, who presented with vomiting, lethargy, and poor feeding due to salt wasting six days after birth. The patient had electrolyte imbalances. A novel SCNN1A (sodium channel epithelial subunit alpha) gene mutation, NM_001038.6:c.1497G>C, with an autosomal recessive pattern, was identified by whole exosome sequencing. This variant was inherited as a homozygote from both heterozygous parents. CONCLUSIONS: PHA should be considered in neonates with hyponatremia and hyperkalemia. This case report presents a patient with a novel mutation in SCNN1A that has not been previously reported. Long-term follow-up of identified patients to understand the underlying phenotype--genotype link is necessary.

Differential effects of angiotensin II and aldosterone on human neutrophil adhesion and concomitant secretion of proteins, free amino acids and reactive oxygen and nitrogen species.

Invasion and adhesion of neutrophils into tissues and their concomitant secretion play an important role in the development of vascular pathologies, including abdominal aortic aneurysm (AAA). Chronic administration of angiotensin II is used to initiate AAA formation in mice. The role of aldosterone in this process is being studied. We conducted for the first time a complex comparative study of the effects of angiotensin II and aldosterone on the adhesion of human neutrophils to fibronectin and the concomitant secretion of proteins, free amino acids as well as reactive oxygen (ROS) and nitrogen (NO) species. Neither angiotensin II nor aldosterone affected the attachment of neutrophils to fibronectin and the concomitant production of ROS. We showed for the first time that aldosterone stimulated the release of amino acid hydroxylysine, a product of lysyl hydroxylase, the activity of which is positively correlated with cell invasiveness. Aldosterone also initiates the secretion of matrix metalloproteinase 9 (MMP-9) and cathepsin G, which may reorganize the extracellular matrix and stimulate the recruitment and adhesion of neutrophils to the aortic walls. Angiotensin II did not affect protein secretion. It may contribute to neutrophil-induced vascular injury by inhibiting the production of NO or by increasing the secretion of isoleucine. Our results suggest that it is aldosterone-induced neutrophil secretion that may play a significant role in neutrophil-induced vascular wall destruction in angiotensin II-induced AAA or other vascular complications.

Impact of RAAS Receptors and Membrane-Bound Transporter System in the Left Ventricle during the Long-Term Control of Hypertension.

The Renin-Angiotensin-Aldosterone System (RAAS) has been implicated in systemic and neurogenic hypertension. The infusion of RAAS inhibitors blunted arterial pressure and efficacy of use-dependent synaptic transmission in sympathetic ganglia. The current investigation aims to elucidate the impact of RAAS-mediated receptors on left ventricular cardiomyocytes and the role of the sarcolemma-bound carrier system in the heart of the hypertensive transgene model. A significant increase in mRNA and the protein expression for angiotensin II (AngII) receptor subtype-1 (AT1R) was observed in (mREN2)27 transgenic compared to the normotensive rodents. Concurrently, there was an upregulation in AT1R and a downregulation in the MAS1 proto-oncogene protein receptor as well as the AngII subtype-2 receptor in hypertensive rodents. There were modifications in the expressions of sarcolemma Na+-K+-ATPase, Na+-Ca2+ exchanger, and Sarcoendoplasmic Reticulum Calcium ATPase in the transgenic hypertensive model. These observations suggest chronic RAAS activation led to a shift in receptor balance favoring augmented cardiac contractility and disruption in calcium handling through modifications of membrane-bound carrier proteins and blood pressure. The study provides insight into mechanisms underlying RAAS-mediated cardiac dysfunction and highlights the potential value of targeting the protective arm of AngII in hypertension.

Aprotinin (II): Inhalational Administration for the Treatment of COVID-19 and Other Viral Conditions.

Aprotinin is a broad-spectrum inhibitor of human proteases that has been approved for the treatment of bleeding in single coronary artery bypass surgery because of its potent antifibrinolytic actions. Following the outbreak of the COVID-19 pandemic, there was an urgent need to find new antiviral drugs. Aprotinin is a good candidate for therapeutic repositioning as a broad-spectrum antiviral drug and for treating the symptomatic processes that characterise viral respiratory diseases, including COVID-19. This is due to its strong pharmacological ability to inhibit a plethora of host proteases used by respiratory viruses in their infective mechanisms. The proteases allow the cleavage and conformational change of proteins that make up their viral capsid, and thus enable them to anchor themselves by recognition of their target in the epithelial cell. In addition, the activation of these proteases initiates the inflammatory process that triggers the infection. The attraction of the drug is not only its pharmacodynamic characteristics but also the possibility of administration by the inhalation route, avoiding unwanted systemic effects. This, together with the low cost of treatment (≈2 Euro/dose), makes it a good candidate to reach countries with lower economic means. In this article, we will discuss the pharmacodynamic, pharmacokinetic, and toxicological characteristics of aprotinin administered by the inhalation route; analyse the main advances in our knowledge of this medication; and the future directions that should be taken in research in order to reposition this medication in therapeutics.

Gene expression in heart, kidney, and liver identifies possible mechanisms underpinning fetal resistance and susceptibility to in utero PRRSV infection.

Porcine reproductive and respiratory syndrome (PRRS) is one of the costliest diseases to pork producers worldwide. We tested samples from the pregnant gilt model (PGM) to better understand the fetal response to in-utero PRRS virus (PRRSV) infection. Our goal was to identify critical tissues and genes associated with fetal resilience or susceptibility. Pregnant gilts (N=22) were infected with PRRSV on day 86 of gestation. At 21 days post maternal infection, the gilts and fetuses were euthanized, and fetal tissues collected. Fetuses were characterized for PRRS viral load in fetal serum and thymus, and preservation status (viable or meconium stained: VIA or MEC). Fetuses (N=10 per group) were compared: uninfected (UNIF; <1 log/µL PRRSV RNA), resilient (HV_VIA, >5 log virus/µL but viable), and susceptible (HV_MEC, >5 log virus/µL with MEC). Gene expression in fetal heart, kidney, and liver was investigated using NanoString transcriptomics. Gene categories investigated were hypothesized to be involved in fetal response to PRRSV infection: renin- angiotensin-aldosterone, inflammatory, transporter and metabolic systems. Following PRRSV infection, CCL5 increased expression in heart and kidney, and ACE2 decreased expression in kidney, each associated with fetal PRRS susceptibility. Liver revealed the most significant differential gene expression: CXCL10 decreased and IL10 increased indicative of immune suppression. Increased liver gene expression indicated potential associations with fetal PRRS susceptibility on several systems including blood pressure regulation (AGTR1), energy metabolism (SLC16A1 and SLC16A7), tissue specific responses (KL) and growth modulation (TGFB1). Overall, analyses of non-lymphoid tissues provided clues to mechanisms of fetal compromise following maternal PRRSV infection.

Effects of sacubitril-valsartan on aging-related cardiac dysfunction.

Heart failure (HF) remains a huge medical burden worldwide, with aging representing a major risk factor. Here, we report the effects of sacubitril/valsartan, an approved drug for HF with reduced EF, in an experimental model of aging-related HF with preserved ejection fraction (HFpEF). Eighteen-month-old female Fisher 344 rats were treated for 12 weeks with sacubitril/valsartan (60 mg/kg/day) or with valsartan (30 mg/kg/day). Three-month-old rats were used as control. No differential action of sacubitril/valsartan versus valsartan alone, either positive or negative, was observed. The positive effects of both sacubitril/valsartan and valsartan on cardiac hypertrophy was evidenced by a significant reduction of wall thickness and myocyte cross-sectional area. Contrarily, myocardial fibrosis in aging heart was not reduced by any treatment. Doppler echocardiography and left ventricular catheterization evidenced diastolic dysfunction in untreated and treated old rats. In aging rats, both classical and non-classical renin-angiotensin-aldosterone system (RAAS) were modulated. In particular, with respect to untreated animals, both sacubitril/valsartan and valsartan showed a partial restoration of cardioprotective non-classical RAAS. In conclusion, this study evidenced the favorable effects, by both treatments, on age-related cardiac hypertrophy. The attenuation of cardiomyocyte size and hypertrophic response may be linked to a shift towards cardioprotective RAAS signaling. However, diastolic dysfunction and cardiac fibrosis persisted despite of treatment and were accompanied by myocardial inflammation, endothelial activation, and oxidative stress.

Increased adrenocortical activity in patients with vasovagal syncope.

OBJECTIVE: Syncope is a transient loss of consciousness resulting from cerebral hypoperfusion. Vasovagal syncope (VVS) is a form of orthostatic intolerance (OI). Its clinical signs such as dizziness and hypotension may mimic symptoms of adrenal insufficiency. The objective of this study was to evaluate the adrenal gland function in patients with vasovagal syncope after stimulation with synthetic adrenocorticotropic hormone (ACTH). DESIGN: Case-control study on patients with VVS and healthy controls. METHODS: The study involved 42 participants, including 27 patients diagnosed with VVS using the head-up tilt test and 15 healthy individuals with no history of syncope or any orthostatic symptoms. Serum cortisol and aldosterone concentrations were measured under basal conditions and at 30 and 60 min after intramuscular ACTH stimulation. RESULTS: Patients with VVS had significantly higher cortisol levels at baseline (441 ± 143 vs. 331 ± 84.7 nmol/L, p = 0.01), at 30 min (802 ± 143 vs. 686 ± 105 nmol/L, p = 0.01) and at 60 min (931 ± 141 nmol/L vs. 793 ± 147 nmol/L, p = 0.001) after ACTH administration (Synacthen 250 µg). Plasma aldosterone increased after ACTH stimulation, but did not show significant differences among groups. Furthermore, there was also no significant correlation between cortisol levels and blood pressure or heart rate. CONCLUSION: Patients diagnosed with VVS have higher cortisol levels both at baseline and after ACTH stimulation. This finding indicates that individuals with VVS have higher adrenocortical activity potentially as a response to the orthostatic stress induced by syncope, which acts as a stressful stimulus on the autonomic nervous system.

Tetrandrine inhibits aldosterone synthesis by covalently targeting CYP11A1 to attenuate hypertension.

Introduction: Tetrandrine (Tet) is the main pharmacological component of Stephania tetrandra S. Moore, which is a well-documented traditional Chinese medicine known for its diuretic and antihypertensive properties. Unraveling the specific targets and mechanisms of Tet involved in inducing diuresis and mitigating hypertension can provide valuable insights into its therapeutic effects. This study aimed to explore the diuretic and antihypertensive targets and mechanisms of Tet using chemical biology coupled with activity analyses in vivo and in vitro. Methods: The diuretic effects of Tet were evaluated using a water-loaded mouse model. The direct target proteins for the diuretic and antihypertensive effects of Tet were determined using chemical biology. Furthermore, the molecular mechanism of Tet binding to target proteins was analyzed using a multidisciplinary approach based on the structure and function of the proteins. Finally, the effects of the Tet-targeted protein on downstream signaling pathways and blood pressure were evaluated in hypertensive model rats. Results: Tet exhibited significant antihypertensive and potassium-preserving diuretic effects. The mechanism underlying these effects involves the modulation of the enzyme activity by covalent binding of Tet to Cys423 of CYP11A1. This interaction alters the stability of heme within CYP11A1, subsequently impeding electron transfer and inhibiting aldosterone biosynthesis. Discussion: This study not only revealed the mechanism of the diuretic and antihypertensive effects of Tet but also discovered a novel covalent inhibitor of CYP11A1. These findings contribute significantly to our understanding of the therapeutic potential of Tet and provide a foundation for future research in the development of targeted treatments for hypertension.

Nephrotic syndrome and adrenoleukodystrophy in a 5-year-old boy.

Nephrotic syndrome is a common condition characterized by filtration of large amounts of protein, hypoalbuminemia, reduced plasma oncotic pressure, sodium retention, and edema. The mechanism responsible for sodium retention in this condition is still controversial. Two different pathophysiological pathways have been proposed to explain edema formation: activation of neurohumoral effector mechanisms, including the renin-angiotensin-aldosterone system, or abnormal intrinsic/primary renal sodium retention. A 5-year-old boy with X-linked adrenoleukodystrophy presented with bilateral leg swelling, massive proteinuria, and hypoalbuminemia. Minimal change disease was diagnosed. The patient was initially treated with corticosteroids and experienced several relapses. The progression of fractional excretion of sodium correlated with proteinuria and undetectable aldosterone levels. This unusual finding suggests that the mechanism of tubular sodium avidity in this child with mineralocorticoid insufficiency was independent of the renin-angiotensin-aldosterone system.

Sparing confirmatory testing in primary aldosteronism (SCIPA): a multicenter retrospective diagnostic accuracy study.

BACKGROUND: The diagnosis of primary aldosteronism (PA) is comprehensive, which includes case-detection testing, case confirmation followed by subtype classification. In certain instances, such as in the setting of spontaneous hypokalemia, suppressed renin activity (PRA) plus plasma aldosterone concentration (PAC) of > 15 ng/dL, one may not proceed with confirmatory tests. However, the quality of evidence behind this approach is very low. This study sought to evaluate the proposed "simplified confirmatory pathway" that can spare confirmatory testing for primary aldosteronism by evaluating the diagnostic performances of the various pre-specified PAC thresholds in combination with findings of suppressed renin and spontaneous hypokalemia. METHODS: This is a multi-center, retrospective diagnostic accuracy cohort-selected cross-sectional study. A total of 133 participants aged 18 years and above underwent saline infusion test between January 2010 to March 2024. The outcome measures comprise of the diagnostic performances of the different index test combinations (baseline PAC, baseline PRA and presence of spontaneous hypokalemia): sensitivity, specificity, negative predictive value, positive predictive value, positive likelihood ratio, negative likelihood ratio, and diagnostic accuracy. Data analysis was performed using SPSS 29.0.1.0 & MedCalc 20.218. RESULTS: Of the 133 patients who underwent saline infusion test, 88 (66.17%) were diagnosed with PA. A PAC of > 25 ng/dL plus PRA < 1.0 ng/dL/hr with spontaneous hypokalemia showed the highest specificity at 100% (95% CI 90.51%, 100.00%) and positive predictive value at 100% (85.18 - 100.00%). The minimum acceptable combination criteria were determined to be a PAC of > 20 ng/dL plus PRA < 0.6 ng/dL/hr, and presence of spontaneous hypokalemia. It has high specificity (94.59%; 95% CI 81.81%, 99.34%), positive predictive value (93.55%, 95% CI 78.49%, 98.29%), and moderate positive likelihood ratio (LR+) (6.39, 95% CI 1.61, 25.38) CONCLUSION: A hypertensive patient with spontaneous hypokalemia and screening findings of PAC > 20 ng/dL and suppressed PRA of < 0.6 ng/ml/hr, may be classified as "overt primary aldosteronism confirmed" and may not need to proceed with dynamic confirmatory testing. PROTOCOL REGISTRATION NUMBER: SRCTN34186253.

Prevalence and impact of diabetes and prediabetes on presentation and complications of primary hyperaldosteronism at diagnosis.

BACKGROUND: Primary hyperaldosteronism (PH) is considered to contribute to increased risk of developing type 2 diabetes mellitus (T2DM) and prediabetes. Both PH and DM are associated with increased risk for hypertension, cardiovascular diseases, and chronic kidney diseases. However, data on prevalence of T2DM and prediabetes in PH, and impact of T2DM and prediabetes on presentation and cardio renal complications in PH at presentation is sparse. AIM: To determine the prevalence of T2DM and prediabetes in PH at diagnosis and impact on presentation and complications of PH. METHODS: A retrospective cohort study was conducted in tertiary care settings in individuals with confirmed diagnosis of PH at presentation. Demographic variables, clinical presentations, duration and degree of hypertension, complications, laboratory parameters including sodium, potassium levels, plasma aldosterone concentration (PAC), plasma renin activity (PRA), and aldosterone to renin ratio (ARR) and cardio-renal parameters were collected. Comparison was done between three groups: PH with no DM (Group A) or with pre-diabetes (Group B) or with T2DM (Group C). P < 0.05 was statistically significant. RESULTS: Among 78 individuals with confirmed PH, 62% had pre-diabetes or diabetes; with 37% having DM. Mean duration of T2DM was 5.97 ± 4.7 years. The mean levels of glycaemic parameters among the group A vs B vs C individuals were fasting plasma glucose (mg/dL): 87.9 ± 6.5, 105.4 ± 9.02, 130.6 ± 21.1; post prandial plasma glucose (mg/dL): 122.7 ± 9.8, 154.9 ± 14, 196.7 ± 38.0; glycated haemoglobin (%) (5.3 ± 0.2, 5.9 ± 0.2, 7.5 ± 0.6, P < 0.05), respectively. There was no significant difference in the biochemical parameters (PAC, PRA, ARR, sodium, potassium levels), presentation and complications between the groups. Cardio renal parameters or degree and duration of hypertension were comparable between the groups. CONCLUSION: Significant prevalence of T2DM and prediabetes in PH at diagnosis does not impact its presentation or complications. Early screening for undetected PH in T2DM and prediabetes subjects with hypertension may prevent complications.

Increased daytime and awakening salivary free aldosterone in essential hypertensive men.

Background: While aldosterone plays an important role in blood pressure regulation, its role in essential hypertension (EHT) remains unclear. Here, we systematically investigated the secretion of biologically-active free aldosterone in saliva in response to awakening (AldAR) and during the day (AldDay) in EHT compared to normotensive controls (NT). Methods: In 30 men with EHT and 30 age-matched NT, AldAR saliva samples were collected immediately after awakening and 15, 30, 45, and 60 min thereafter and AldDay samples were collected from 08:30-22:00 h on two consecutive days. Results: Over the course of the day, men with EHT had higher repeated AldDay levels compared to NT (p = .002) with higher concentrations in the morning hours (p's ≤ .047), a steeper decline over the course of the day (p's ≤ .018), and similar concentrations in the evening (p's ≥ .21). Regarding AldAR, we observed higher concentrations in EHT at awakening (p = .017) and borderline higher concentrations at 15 min (p = .086). No differences were found 30-60 min after awakening (p's ≥ .34). Analyses with repeated and aggregated AldAR levels resulted in borderline significantly higher free aldosterone in EHT (p's ≤ .077). Complementary analyses confirmed linear associations between higher blood pressure and higher AldAR and AldDay levels. Conclusions: Our data point to elevated salivary free aldosterone secretion in EHT over the course of the day, particularly in the morning hours. As the free aldosterone fraction is considered biologically active, our data may point to a biological mechanism underlying EHT.

Dose and Time Effects of Renin-Angiotensin Inhibitors on Patients With Advanced Stages 4 to 5 of Diabetic Kidney Disease.

Context: Limited evidence exists regarding the cumulative dosing and duration impact of renin-angiotensin system inhibitors (RASis) on cardiorenal and mortality outcomes in patients with advanced stages (predominantly in stage 5 and a minority in stage 4) of diabetic kidney disease (DKD). Objective: To retrospectively investigate whether there are dose- and time-dependent relationships between RASis and cardiorenal and mortality outcomes in this population. Methods: Using Taiwan's national health insurance data in 2000-2017, we analyzed 2196 RASi users and 2196 propensity-matched nonusers among 8738 patients living with diabetes and newly diagnosed with advanced chronic kidney disease (23% stage 4, 77% stage 5). Cox proportional hazards regression models were used to estimate adjusted hazard ratios (aHRs) and 95% CI. Results: RASi use was significantly associated with reduced risks of all-cause mortality (aHR, 0.53; 95% CI 0.47-0.60) and cardiovascular mortality (0.68; 0.56-0.83) with the degree of benefit depending on therapeutic dosage and duration, despite a nonsignificant increase in acute kidney injury risk (1.16; 0.98-1.38) and a significant increase in hyperkalemia risk (1.45; 1.19-1.77). Significant differences in proteinuria risk (1.32; 1.21-1.43) were observed, while there were no significant differences in end-stage renal disease risk (1.01; 0.88-1.15) and no dose- or time-response relationships for either end-stage renal disease or proteinuria risks. Sensitivity analyses confirmed cardiovascular and survival benefits, even in patients with stage 5 DKD. Conclusion: This real-world study suggests that RASi use in advanced stages 4 to 5 DKD may provide dose- and time-dependent cardioprotection and improved survival, without excess renal harms.

Efficacy and safety of adrenal arterial embolization for primary aldosteronism: a systematic review and meta-analysis.

Background: Primary aldosteronism (PA) is related with resistant hypertension and cardiovascular events. Adrenal artery embolization (AAE) is a choice for patients who refused surgery and medical therapy. However, whether AAE can effectively and safely treat PA is unclear. We performed this meta-analysis to determine the efficacy and safety of AAE for patients with PA. Methods: Databases including Cochrane Library, Embase, PubMed and Web of Science were used to obtain relevant articles published before July 30, 2023. The primary outcome was blood pressure before and after AAE. The second outcomes included changes in plasma aldosterone level, serum potassium level, and plasma cortisol level. Results: Finally, 7 prospective studies with 222 patients were included. The results showed that systolic and diastolic blood pressure was reduced by 21.68 mmHg (P<0.001) and 10.54 mmHg (P=0.007) respectively after AAE. The change in plasma aldosterone and serum potassium level was -11.52 ng/dL and 0.61 mmol/L respectively (P<0.001), whereas the reduction in cortisol level was not apparent. Moreover, AAE is a relatively safe procedure which only causes some minor complications such as back pain and fever. Conclusions: This meta-analysis indicated that AAE could effectively and safely treat PA. It is a good choice for patients that are not suitable for adrenalectomy or drug therapy.

Comparing ARR Versus Suppressed PRA as Screening Tests for Primary Aldosteronism.

BACKGROUND: In many practices, the screening for primary aldosteronism relies on a single-blood draw for plasma aldosterone concentration (PAC) and plasma renin activity (PRA) to establish an aldosterone-to-renin ratio (ARR). ARR levels vary between expert centers and repeated assays in the same individual, emphasizing the potential variability of this screening approach. A suppressed PRA to <1 ng/mL per h has been proposed as an alternative test to the ARR. METHODS: We compared 2 potential screening approaches to identify probable primary aldosteronism (ARR≥30 or ARR≥20 versus PRA suppressed below 1 ng/mL per h) in a cohort of 94 829 paired PRA and PAC samples submitted by clinicians to evaluate the presence of primary aldosteronism. RESULTS: Of 94 829 patients, 20.3% tested positive based on ARR≥20 (95% CI, 20.0%-20.5%), 13.9% based on ARR≥30 (95% CI, 13.6%-14.1%), versus 45.9% based on suppressed PRA (<1 ng/mL per minute [95% CI, 45.5%-46.2%]). In the PRA group, a range of aldosterone levels was observed: 5.5% had PAC >15 ng/dL, 25.2% had PAC 5 to 15 ng/dL, and 15.2% had PAC <5 ng/dL, compared with 6%, 12.7%, and 1.6% in the ARR≥20 group and 4.7%, 8.5%, and 0.7% in the ARR≥30 group. CONCLUSIONS: In this cohort of individuals being screened for primary aldosteronism, substantially more individuals were identified using criteria focused on suppression of renin activity compared with using the aldosterone renin ratio as a screening tool.