Renin-angiotensin-aldosterone System Activation Research Articles

Hypokalemia and the renin-angiotensinaldosterone system activity in COVID-19 patients

Background. Hypokalemia is a common electrolyte complication among hospitalized patients with pneumonia caused by a new coronavirus SARS-CoV-2. Hyperactivation of the renin-angiotensin-aldosterone system (RAAS) is suggested as a possible cause of hypokalemia in patients with COVID-19.Objective. To investigate the RAAS activity in COVID-19 patients with and without hypokalemia and its possible association with treatment outcomes.Design and methods. The cross-sectional cohort study included 172 patients with COVID-19 pneumonia. Potassium, aldosterone and venous renin were measured in 77 patients. The differences in the levels of acute phase proteins, the degree of lung damage and the severity of COVID-19 were compared between patients with and without hypokalemia.Results. Hypokalemia was found in 19 of 77 patients (25%): the median potassium level in hypokalemia and eukalemia group was 3,1 [2,8–3,3] and 4,1 [3,9–4,5] mmol/L, respectively (p = 0,001). Plasma aldosterone and renin levels in patients with and without hypokalemia did not differ significantly: aldosterone 76,0 [57,7–121,5] and 70,9 [26,3–113,8] pg/ml (p = 0,23), renin 17,0 [8,5–47,2] and 11,0 [6,5–38,1] pg/ml (p = 0,35), respectively. Differences in the degree of lung tissue damage, acute phase proteins, severity of COVID-19, length of hospitalization and mortality in patients with and without identified electrolyte disturbances were also not significant.Conclusions. Our results showed that there were no laboratory signs of RAAS hyperactivation in COVID-19 patients with registered hypokalemia. Identification of the cause and clinical significance of hypokalemia among patients with COVID-19 needs to be specified.

Determinants and Mechanisms of the Renin-Aldosterone Stress Response.

The renin-angiotensin-aldosterone system (RAAS) plays a relevant role in regulating blood pressure and thus maintaining cardiovascular homeostasis. Although it was recently shown that RAAS parameters are responsive to acute psychosocial stress, the psychobiological determinants of the acute stress-induced RAAS activation have not yet been investigated. In a randomized placebo-controlled design, we investigated potential psychological and physiological determinants of the RAAS response and underlying mechanisms. Fifty-seven young healthy male participants underwent either an acute standardized psychosocial stress test or a nonstress placebo task. We measured aldosterone in plasma and saliva, as well as renin, and the stress-reactive endocrine measures adrenocorticotropic hormone (ACTH), epinephrine, and norepinephrine in plasma at rest, immediately after the task and several times up to 3 hours thereafter. Moreover, we assessed stress-reactive psychological (anticipatory cognitive stress appraisal, mood, physical discomfort) and basal demographic-physiological measures (age, body mass index, blood pressure). Acute psychosocial stress elicited changes in all assessed endocrine (p values ≤ .028, ηp2 values ≥ 0.07) and stress-reactive psychological measures (p values ≤ .003, ηp2 values ≥ 0.15). The basal parameter body mass index, the stress-reactive endocrine parameters ACTH and norepinephrine, and the psychological parameter anticipatory stress appraisal were identified as determinants of higher RAAS parameter reactivity to acute psychosocial stress. The association between anticipatory cognitive stress appraisal and plasma RAAS measures was fully mediated by ACTH increases (p values ≤ .044, ηp2 values ≥ 0.05). Cognitive stress appraisal processes seem to modulate RAAS stress reactivity. This points to potential clinical implications for psychoeducative therapeutical interventions targeting stress appraisal processes to reduce endocrine stress reactivity.

Screening of QTc interval and global autonomic activity in autosomal dominant polycystic kidney disease and atherosclerotic renal artery stenosis hypertensive patients.

Arterial hypertension (AH) represents a major risk factor for cardiovascular disease and is associated to several complications, such as prolonged corrected QT (QTc) interval and impaired heart rate variability (HRV). Secondary causes of AH include autosomal dominant polycystic kidney disease (ADPKD) and atherosclerotic renal artery stenosis (ARAS), both known to be related to arrhythmic risk and autonomic imbalance. The aim of the study is to evaluate whether global autonomic activity and QTc interval differently affect ADPKD and ARAS hypertensive patients. An observational study was performed on 59 patients: 16 ADPKD patients and 19 diagnosed with ARAS, compared to 24 healthy controls (HC). All patients underwent clinical evaluation, biochemical lab tests, 24-hour electrocardiogram (ECG) and renal Doppler ultrasound. HRV was assessed through the analysis of 24-hour ECG to detect standard deviation of normal-to-normal RR intervals (SDNN). QTc interval was defined as prolonged when > 440 msec. SDNN was significantly lower in ADPKD and ARAS patients than HC (p < 0.0001) and no significant differences were found between ADPKD and ARAS patients (p > 0.05). QTc was found significantly higher in ARAS patients than HC (p = 0.001) and in ARAS patients than ADPKD patients (p = 0.004). The pathogenesis of hypertension in ADPKD and ARAS patients is related to the activation of the renin angiotensin aldosterone system (RAAS). In ADPKD, cyst enlargement leads to kidney ischemia and renin release, associated to endothelial dysfunction, low nitric oxide and sympathetic tone activation. Differently, reduction in renal perfusion pressure activates RAAS and renal adrenergic nerves in ARAS patients. We can speculate that prolonged QTc interval is more present in ARAS vs. ADPKD hypertensive patients due to a greater activation of RAAS. We suggest adding 24-hour HRV evaluation in association with traditional risk factors in course of ADPKD and ARAS hypertension to better stratify cardiovascular risk in these groups of patients.

Hyperuricemia and Progression of Chronic Kidney Disease: A Review from Physiology and Pathogenesis to the Role of Urate-Lowering Therapy.

The relationship between hyperuricemia, gout, and renal disease has been investigated for several years. From the beginning, kidney disease has been considered a complication of gout; however, the viewpoints changed, claiming that hypertension and elevated uric acid (UA) levels are caused by decreased urate excretion in patients with renal impairment. To date, several examples of evidence support the role of hyperuricemia in cardiovascular or renal diseases. Several mechanisms have been identified that explain the relationship between hyperuricemia and chronic kidney disease, including the crystal effect, renin–angiotensin–aldosterone system activation, nitric oxide synthesis inhibition, and intracellular oxidative stress stimulation, and urate-lowering therapy (ULT) has been proven to reduce renal disease progression in the past few years. In this comprehensive review, the source and physiology of UA are introduced, and the mechanisms that explain the reciprocal relationship between hyperuricemia and kidney disease are reviewed. Lastly, current evidence supporting the use of ULT to postpone renal disease progression in patients with hyperuricemia and gout are summarized.

Angiotensin Receptor-Neprilysin Inhibitor (ARNI) and Cardiac Arrhythmias.

The renin-angiotensin-aldosterone system (RAAS) plays a major role in cardiovascular health and disease. Short-term RAAS activation controls water and salt retention and causes vasoconstriction, which are beneficial for maintaining cardiac output in low blood pressure and early stage heart failure. However, prolonged RAAS activation is detrimental, leading to structural remodeling and cardiac dysfunction. Natriuretic peptides (NPs) are activated to counterbalance the effect of RAAS and sympathetic nervous system by facilitating water and salt excretion and causing vasodilation. Neprilysin is a major NP-degrading enzyme that degrades multiple vaso-modulatory substances. Although the inhibition of neprilysin alone is not sufficient to counterbalance RAAS activation in cardiovascular diseases (e.g., hypertension and heart failure), a combination of angiotensin receptor blocker and neprilysin inhibitor (ARNI) was highly effective in several clinical trials and may modulate the risk of atrial and ventricular arrhythmias. This review summarizes the possible link between ARNI and cardiac arrhythmias and discusses potential underlying mechanisms, providing novel insights about the therapeutic role and safety profile of ARNI in the cardiovascular system.

Effect of Mineralocorticoid Receptor Antagonism and ACE Inhibition on Angiotensin Profiles in Diabetic Kidney Disease: An Exploratory Study.

BackgroundRenin–angiotensin–aldosterone system (RAAS) blockade with angiotensin-converting enzyme inhibitors (ACEi) or angiotensin receptor blockers (ARB) is the cornerstone of antihypertensive treatment in patients with chronic kidney disease (CKD) and diabetes mellitus. Mineralocorticoid receptor antagonists (MRA) on top of conventional RAAS blockade confer cardio- and renoprotective effects. Yet, the detailed effects of this therapeutic approach on key RAAS effectors have not been elucidated to date.MethodsIn this exploratory placebo-controlled study, 15 patients with CKD stages 2–3 and albuminuria due to diabetic kidney disease (DKD) were randomized to receive the MRA eplerenone or placebo in addition to ACEi therapy. Employing mass-spectrometry, we quantified plasma angiotensin levels [Ang I, Ang II, Ang-(1–7), Ang-(1–5), Ang III, Ang IV], renin and aldosterone in patients before and after 8 weeks of MRA treatment.ResultsWhile blood pressure and kidney function were similar in the placebo and eplerenone treatment group during the study period, distinct differences in RAAS regulation occurred: eplerenone treatment resulted in an increase in plasma renin activity, Ang I and aldosterone concentrations, indicating global RAAS activation. In addition, eplerenone on top of ACEi profoundly upregulated the alternative RAAS effector Ang-(1–7).ConclusionsCombined eplerenone and ACEi therapy increases Ang-(1–7) levels in patients with CKD indicating a unique nephroprotective RAAS pattern with considerable therapeutic implications.Supplementary InformationThe online version contains supplementary material available at 10.1007/s13300-021-01118-7.

Xin-Ji-Er-Kang protects myocardial and renal injury in hypertensive heart failure in mice

BackgroundXin-Ji-Er-Kang (XJEK) as a herbal formula of traditional Chinese medicine (TCM) has shown the protective effects on myocardial function as well as renal function in mouse models of myocardial infarction. Hypothesis/PurposeWe investigated the effects of XJEK on cardiovascular- and renal-function in a heart failure mouse model induced by high salt (HS) and the associated mechanisms. Study designFor the purpose of assessing the effects of XJEK on a hypertensive heart failure model, mice were fed with 8% high salt diet. XJEK was administered by oral gavage for 8 weeks. Cardiovascular function parameters, renal function associated biomarkers and XJEK's impact on renin-angiotensin–aldosterone system (RAAS) activation were assessed. To determine the underlying mechanism, the calpain1/junctophilin-2 (JP2)/sarcoplasmic reticulum Ca2+ ATPase (SERCA2a) pathway was further studied in AC16 cells after angiotensin II-challenge or after calpastatin small interfering RNA (siRNA) transfection. ResultsMice on HS-diet exhibited hypertensive heart failure along with progressive kidney injury. Similar to fosinopril, XJEK ameliorated hypertension, cardiovascular-and renal- dysfunction in mice of HS-diet group. XJEK inhibited HS-induced activation of RAAS and reversed the abnormal expression pattern of calpain1and JP2 protein in heart tissues. XJEK significantly improved cell viability of angiotensin II-challenged AC16 cells. Moreover, XJEK's impact on calpain1/JP2 pathway was partly diminished in AC16 cells transfected with calpastatin siRNA. ConclusionXJEK was found to exert cardiovascular- and renal protection in HS-diet induced heart failure mouse model. XJEK inhibited HS-diet induced RAAS activation by inhibiting the activity and expression of calpain1 and protected the junctional membrane complex (JMC) in cardiomyocytes.

New Pandemic: Obesity and Associated Nephropathy.

Incidence of obesity related renal disorders have increased 10-folds in recent years. One of the consequences of obesity is an increased glomerular filtration rate (GFR) that leads to the enlargement of the renal glomerulus, i.e., glomerulomegaly. This heightened hyper-filtration in the setting of type 2 diabetes irreparably damages the kidney and leads to progression of end stage renal disease (ESRD). The patients suffering from type 2 diabetes have progressive proteinuria, and eventually one third of them develop chronic kidney disease (CKD) and ESRD. For ameliorating the progression of CKD, inhibitors of renin angiotensin aldosterone system (RAAS) seemed to be effective, but on a short-term basis only. Long term and stable treatment strategies like weight loss via restricted or hypo-caloric diet or bariatric surgery have yielded better promising results in terms of amelioration of proteinuria and maintenance of normal GFR. Body mass index (BMI) is considered as a traditional marker for the onset of obesity, but apparently, it is not a reliable indicator, and thus there is a need for more precise evaluation of regional fat distribution and amount of muscle mass. With respect to the pathogenesis, recent investigations have suggested perturbation in fatty acid and cholesterol metabolism as the critical mediators in ectopic renal lipid accumulation associated with inflammation, increased generation of ROS, RAAS activation and consequential tubulo-interstitial injury. This review summarizes the renewed approaches for the obesity assessment and evaluation of the pathogenesis of CKD, altered renal hemodynamics and potential therapeutic targets.

Non-dipping nocturnal blood pressure correlates with obstructive sleep apnoea severity in normotensive subjects and may reverse with therapy.

BackgroundObstructive sleep apnoea (OSA) is strongly associated with systemic hypertension, but there are limited data on the relationship with blood pressure (BP) in normotensive subjects. Here, we examined the relationship of OSA with nocturnal BP in a documented diurnal normotensive cohort, explored potential intermediate pathways and assessed the effects on BP of continuous positive airways pressure (CPAP) therapy.Methods65 males referred for assessment of possible OSA and normotensive on 24-hour BP monitoring underwent overnight inpatient polysomnography (age 41±7 years, body mass index (BMI) 34±6 kg·m−2, apnoea–hypopnoea index (AHI) 14 (interquartile range 5–26)). Urine and serum were assessed for markers of sympathetic activation, renin–angiotensin–aldosterone system activity, oxidative stress, endothelial function and systemic inflammation. In a subset of patients, 24-hour BP monitoring was repeated after CPAP therapy.ResultsWithin this normotensive cohort, night-time systolic and diastolic BP and nocturnal BP dip were highest in the fourth OSA severity quartile (p<0.05). Nocturnal BP dip correlated with AHI (r=−0.327, p<0.05) and oxygen desaturation index (ODI) (r=−0.371, p<0.05), but only ODI was an independent predictor of BP dip (B=–0.351, p<0.01) and non-dipping status (B=0.046, p<0.05). Overnight urinary norepinephrine correlated with nocturnal systolic BP (r=0.387, p<0.01) with a trend towards correlation with systolic dipping (p=0.087). In 20 CPAP-treated patients, night-time systolic BP decreased (p<0.05) and mean nocturnal BP dip increased (p≤0.05).ConclusionIn this normotensive cohort, OSA severity was associated with higher nocturnal BP, which improved following CPAP therapy, and intermittent hypoxia was the most important OSA-related variable in this relationship.

Aldosterone and angiotensin II profiles in young black and white women using different hormonal contraceptives: the African-PREDICT study.

Exogenous estrogens and progestins may affect the components of the renin-angiotensin-aldosterone system (RAAS). Changes in ventricular blood volume are associated with increased secretion of N-terminal pro-hormone B-type natriuretic peptide (NT-proBNP), which may also be affected by hormonal contraceptives. In this study, we aimed to compare components of the RAAS and NT-proBNP between groups using different hormonal contraceptives, including the combination pill, the injection or implant, and controls (no contraception) in black and white women of fertile age (20 - 30 years). Secondly, we determined whether blood pressure and NT-proBNP are associated with the RAAS components. We included 397 black and white women not using contraceptives, 120 using the combination pill, and 103 receiving an injection/implant. RAAS Triple-A analysis was carried out with LC-MS/MS quantification, and blood pressure measurements (ABPM) taken over 24 h. We found that serum aldosterone was higher (475.7 vs. 249.2 pmol/L; p < 0.001) in the combination pill group than in the no contraception group of white women. The aldosterone-angiotensin II ratio (AA2) was higher (5.4 vs. 2.5; p < 0.001) in the combination pill group than in the no contraception group. In the black women using the combination pill, we found a borderline-positive and borderline-negative association between 24-h systolic blood pressure and NT-proBNP with equilibrium (eq) Ang II, respectively. In white women using the combination pill, only CRP contributed positively and independently to NT-proBNP. To conclude, activation of RAAS by different hormonal contraceptives may increase future risk for the development of hypertension in young black and white women.

Angiotensin II augments renal vascular smooth muscle soluble GC expression via an AT1 receptor-forkhead box subclass O transcription factor signalling axis.

Reduced renal blood flow triggers activation of the renin-angiotensin-aldosterone system (RAAS) leading to renovascular hypertension. Renal vascular smooth muscle expression of the NO receptor, soluble GC (sGC), modulates the vasodilator response needed to control renal vascular tone and blood flow. Here, we tested if angiotensin II (Ang II) affects sGC expression via an AT1 receptor-forkhead box subclass O (FoxO) transcription factor dependent mechanism. Using a murine two-kidney-one-clip (2K1C) renovascular hypertension model, we measured renal artery vasodilatory function and sGC expression. Additionally, we conducted cell culture studies using rat renal pre-glomerular smooth muscle cells (RPGSMCs) to test the in vitro mechanistic effects of Ang II treatment on sGC expression and downstream function. Contralateral, unclipped renal arteries in 2K1C mice showed increased NO-dependent vasorelaxation compared to sham control mice. Immunofluorescence studies revealed increased sGC protein expression in 2K1C contralateral renal arteries over sham controls. RPGSMCs treated with Ang II caused a significant up-regulation of sGC mRNA and protein expression as well as downstream sGC-dependent signalling. Ang II signalling effects on sGC expression occurred through an AT1 receptor and FoxO transcription factor-dependent mechanism at both the mRNA and protein expression levels. Renal artery smooth muscle, in vivo and in vitro, up-regulates expression of sGC following RAAS activity. In both cases, up-regulation of sGC leads to increased downstream cGMP signalling, suggesting a previously unrecognized protective mechanism to improve renal blood flow in the uninjured contralateral renal artery. This article is part of a themed issue on cGMP Signalling in Cell Growth and Survival. To view the other articles in this section visit http://onlinelibrary.wiley.com/doi/10.1111/bph.v179.11/issuetoc.

The Acute Effects of Different Spironolactone Doses on Oxidative Stress in Streptozotocin-Induced Diabetic Rats

Abstract Cardiovascular diseases are the leading cause of morbidity and mortality in patients with diabetes mellitus. Increased bioavailability of reactive oxygen species is defined as oxidative stress and is noticed in type 2 DM and reduced antioxidant enzymes expression/activity. Aldosterone, an adrenal hormone, is secreted due to renin-angiotensin-aldosterone system activation, representing one of the fundamental physiological reactions in CVD. Spironolactone, a mineralocorticoid receptor antagonist, uses enhanced coronary microvascular function, suggesting a beneficial role of aldosterone in preventing diabetic cardiovascular complications in patients with type 2 DM. In this study, we evaluated the influence of spironolactone's acute administration on oxidative stress in rats with diabetes mellitus induced by streptozotocin. The present study was carried out on 40 adult male Wistar albino rats (8 weeks old). Rats were randomly divided into 4 groups (10 animals per group): healthy rats treated with 0.1 μM of spironolactone, diabetic rats treated with 0.1 μM of spironolactone, healthy rats treated with 3 μM of spironolactone, and diabetic rats treated with 3 μM of spironolactone. Spironolactone achieved different effects on oxidative stress parameters when given acutely in different doses in diabetic and healthy rats. In lower doses, spironolactone's acute administration reached lowered parameters of oxidative stress in healthy rats better than higher doses of spironolactone. In contrast, in the diabetic group, acute effects of higher doses of spironolactone lowered oxidative stress parameters better than lower spironolactone doses.

Review and Analysis of Two Gitelman Syndrome Pedigrees Complicated with Proteinuria or Hashimoto's Thyroiditis Caused by Compound Heterozygous SLC12A3 Mutations.

Gitelman syndrome (GS) is an autosomal recessive inherited salt-losing renal tubular disease, which is caused by a pathogenic mutation of SLC12A3 encoding thiazide-sensitive Na-Cl cotransporter, which leads to disturbance of sodium and chlorine reabsorption in renal distal convoluted tubules, resulting in phenotypes such as hypovolemia, renin angiotensin aldosterone system (RAAS) activation, hypokalemia, and metabolic alkalosis. In this study, two GS families with proteinuria or Hashimoto's thyroiditis were analyzed for genetic-phenotypic association. Sanger sequencing revealed that two probands carried SLC12A3 compound heterozygous mutations, and proband A carried two pathogenic mutations: missense mutation Arg83Gln, splicing mutation, or frameshift mutation NC_000016.10:g.56872655_56872667 (gcggacatttttg>accgaaaatttt) in exon 8. Proband B carries two missense mutations: novel Asp839Val and Arg904Gln. Both probands manifested hypokalemia, hypomagnesemia, hypocalcinuria, metabolic alkalosis, and RAAS activation; in addition, the proband A exhibited decreased urinary chloride, phosphorus, and increased magnesium ions excretion, complicated with Hashimoto's Thyroiditis, while the proband B exhibited enhanced urine sodium excretion and proteinuria. The older sister of proband B with GS also had Hashimoto's thyroiditis. Electron microscopy revealed swelling and vacuolar degeneration of glomerular epithelial cells, diffuse proliferation of mesangial cells and matrix, accompanied by a small amount of low-density electron-dense deposition, and segmental fusion of epithelial cell foot processes in proband B. Light microscopy showed mild mesangial hyperplasia in the focal segment of the glomerulus, hyperplasia, and hypertrophy of juxtaglomerular apparatus cells, mild renal tubulointerstitial lesions, and one glomerular sclerosis. So, long-term hypokalemia of GS can cause kidney damage and may also be susceptible to thyroid disease.

Aortic stiffness is sympathetically mediated in fructose‐induced salt‐sensitive hypertension

Introduction Hypertension is one of the leading risk factors for major adverse cardiovascular events (MACE). Likewise, suboptimal dietary habits, including high fructose and sodium intake, are major leading causes of mortality. High dietary fructose alone predisposes to salt-sensitivity of blood pressure, which is an independent, significant cardiovascular risk factor. Aortic stiffness is now recognized as the most robust predictor of MACE and renal failure. Sympathoexcitation also imparts increased cardiovascular risk. Emerging data show that sympathetic inputs strongly impact aortic stiffness, and renal sympathetic denervation improves aortic distensibility. Recently published studies from our laboratory showed that with even short-term fructose in combination with high salt intake renal sympathetic nerve activity (RSNA) is significantly elevated prior to any increase in blood pressure and is responsible for activation of the renin-angiotensin-aldosterone system (RAS). Most recently, we also reported increased aortic stiffness in the fructose-induced salt-sensitive hypertension rat model. The present investigation was designed to assess the impact of acute blockade of RAS and/or sympathetic nervous activity on cardiovascular function in a rat model of fructose- induced salt-sensitive hypertension. Methods Sprague-Dawley rats were placed on a diet containing either 20% fructose or 20% glucose in their drinking water while consuming normal sodium. After one week, the fructose group was switched to a 4% sodium chow (FHS) and the rats were maintained on their respective diets for two additional weeks. At the beginning of week three, arterial and venous catheters were implanted and rats allowed to recover for one day. The following day, aortic pulsed wave velocity was measured using Vevo3100 ultrasound at two time points: 1) at baseline and 2) after intravenous injection of either sympatholytic agent clonidine, RAS inhibitor enalapril or diuretic hydrochlorothiazide (HCTZ). Blood pressure and heart rate were monitored throughout the entire experiment. Results Intravenous administration of clonidine, a central sympatholytic agent, reduced MAP and PWV in FHS rats significantly (by 23 ± 3 mmHg and by 212 ± 39 mm/s, respectively). A similar decline in blood pressure occurred in control rats (27 mmHg) but PWV did not change. The dose of enalapril used to inhibit RAS was chosen to provide a similar decline in MAP as clonidine. The reduction in MAP was slightly less profound (17 ± 4 mmHg); nonetheless, only a minimal change was observed in PWV in FHS (10 ± 6 mm/s) and no change in control rats. The diuretic HCTZ given acutely did not change either MAP or PWV. Conclusion Increase in aortic stiffness after two weeks of fructose and high salt diet appears to be sympathetically driven, since the abrogation of the sympathetic activity with clonidine decreased PWV in FHS rats. The effects of the RAS blockade may require a longer period of treatment to permit vascular remodeling and other cellular mechanisms and, thus, may not have been observable in an acute setting. Likewise, the intravascular volume changes due to the diuretic may also require longer exposure.

Comparison between ultrafiltration and loop diuretics to neurohormonal and kidney parameters in cardiorenal syndrome type 1: a meta-analysis of randomized controlled trials

Abstract Funding Acknowledgements Type of funding sources: None. Introduction Acute heart failure can affect the kidney, which is known as cardiorenal syndrome (CRS) type 1 that may worsen renal function and increase mortality. Ultrafiltration (UF) and loop diuretics are CRS type 1 treatment modalities mainly in improving congestion. Renin-angiotensin-aldosterone system (RAAS) is one of the key role mechanisms in type-1 CRS patients. Previous studies showed inconclusive neurohormonal and kidney parameters outcome comparisons between UF and loop diuretics in type-1 CRS patients. Purpose This study has the purpose to compare the effect of UF and loop diuretics to neurohormonal and renal parameters in type-1 CRS patients. Methods We did comprehensive searching using predefined keywords in online databases of Pubmed, ScienceDirect, EMBASE, and The Cochrane Library to screen all relevant literature until November 2020. We included all randomized controlled trials (RCTs) that compared the neurohormonal and renal parameters between UF and loop diuretics in type-1 CRS patients, not on chronic dialysis therapy and have serum creatinine (SCr) below 3 mg/dL. The neurohormonal parameters analysed in this study are changes of N-terminal pro-brain natriuretic peptide (NT-proBNP), plasma renin activity (PRA), and serum aldosterone, while the renal parameters analysed are changes of SCr, Cystatin-C, and dialysis dependency. We used Cochrane Risk-of-bias tools for accessing bias risk. We performed analysis to provide standard mean difference (SMD) for laboratory parameters and risk ratio (RR) for dialysis dependency with 95% confidence interval (CI) using fixed-effect heterogeneity test. Results We included 11 RCTs met our inclusion criteria. The UF groups showed more NT-proBNP decline compared with the diuretics groups although not statistically significant (SMD = -0.02, 95% CI -0.22 to 0.17, p = 0.80, I²=0%). The UF group showed RAAS activity increment, which are significantly difference in PRA (SMD = 0.38, 95% CI 0.12 to 0.63, p = 0.004, I²=54%) but no significance in aldosterone change (SMD = 0.09, 95% CI -0.17 to 0.34, p = 0.50, I²=0%). Surprisingly, the UF group tends to have incremental dialysis dependency risk although not statistically significant (pooled RR = 1.28, 95% CI 0.73 to 2.26, p = 0.39, I²=0%). The diuretics group shows more significant SCr improvement (SMD = 0.23, 95% CI 0.08 to 0.38, p = 0.003, I²=41%), yet no significance Cystatin-C improvement (SMD = 0.21, 95% CI -0.02 to 0.43, p = 0.07, I²=0%). Conclusions There is no significant difference between ultrafiltration and loop diuretics to neurohormonal and kidney parameters change in type-1 CRS patients although loop diuretics administration shows more benefits. However, further trials are needed to establish the comparison.

POS-294 COX-2 INHIBITION AND KIDNEY HEMODYNAMICS: THE EFFECT OF SEX

Animal studies suggest that kidney vasculature in males may be more dependent on vasodilatory prostaglandins than females, though the role of prostaglandins in kidney hemodynamics in healthy humans is unknown. We sought to determine the effect of cyclooxygenase-2 (COX-2) inhibition and resultant inhibition of prostaglandin synthesis on kidney hemodynamics and renin angiotensin aldosterone system (RAAS) activity, and to explore whether differences in COX-2 effects exist between sexes.

Dipeptidyl peptidase 3, a marker of the antagonist pathway of the renin-angiotensin-aldosterone system in patients with heart failure.

AimsRecently, dipeptidyl peptidase 3 (DPP3) has been discovered as the peptidase responsible for cleavage of angiotensin (1–7) [Ang (1–7)]. Ang (1–7) is part of the angiotensin‐converting enzyme–Ang (1–7)–Mas pathway which is considered to antagonize the renin–angiotensin–aldosterone system (RAAS). Since DPP3 inhibits the counteracting pathway of the RAAS, we hypothesize that DPP3 might be deleterious in the setting of heart failure. However, no data are available on DPP3 in chronic heart failure. We therefore investigated the clinical characteristics and outcome related to elevated DPP3 concentrations in patients with worsening heart failure.Methods and resultsDipeptidyl peptidase 3 was measured in 2156 serum samples of patients with worsening heart failure using luminometric immunoassay (DPP3‐LIA) by 4TEEN4 Pharmaceuticals GmbH, Hennigsdorf, Germany. Predictors of DPP3 levels were selected using multiple linear regression with stepwise backward selection. Median DPP3 concentration was 11.45 ng/mL with a range from 2.8 to 84.9 ng/mL. Patients with higher DPP3 concentrations had higher renin [78.3 (interquartile range, IQR 26.3–227.7) vs. 120.7 IU/mL (IQR 34.74–338.9), P < 0.001, for Q1–3 vs. Q4] and aldosterone [88 (IQR 44–179) vs. 116 IU/mL (IQR 46–241), P < 0.001, for Q1–3 vs. Q4] concentrations. The strongest independent predictors for higher concentration of DPP3 were log‐alanine aminotransferase, log‐total bilirubin, the absence of diabetes, higher osteopontin, fibroblast growth factor‐23 and N‐terminal pro‐B‐type natriuretic peptide concentrations (all P < 0.001). In univariable survival analysis, DPP3 was associated with mortality and the combined endpoint of death or heart failure hospitalization (P < 0.001 for both). After adjustment for confounders, this association was no longer significant.ConclusionsIn patients with worsening heart failure, DPP3 is a marker of more severe disease with higher RAAS activity. It may be deleterious in heart failure by counteracting the Mas receptor pathway. Procizumab, a specific antibody against DPP3, might be a potential future treatment option for patients with heart failure.

An Outline of Renal Artery Stenosis Pathophysiology-A Narrative Review.

Renal artery stenosis (RAS) is conditioned mainly by two disturbances: fibromuscular dysplasia or atherosclerosis of the renal artery. RAS is an example of renovascular disease, with complex pathophysiology and consequences. There are multiple pathophysiological mechanisms triggered in response to significant renal artery stenosis, including disturbances within endothelin, kinin–kallikrein and sympathetic nervous systems, with angiotensin II and the renin–angiotensin-aldosterone system (RAAS) playing a central and key role in the pathogenesis of RAS. The increased oxidative stress and the release of pro-inflammatory mediators contributing to pathological tissue remodelling and renal fibrosis are also important pathogenetic elements of RAS. This review briefly summarises these pathophysiological issues, focusing on renovascular hypertension and ischemic nephropathy as major clinical manifestations of RAS. The activation of RAAS and its haemodynamic consequences is the primary and key element in the pathophysiological cascade triggered in response to renal artery stenosis. However, the pathomechanism of RAS is more complex and also includes other disturbances that ultimately contribute to the development of the diseases mentioned above. To sum up, RAS is characterised by different clinical pictures, including asymptomatic disorders diagnosed in kidney imaging, renovascular hypertension, usually characterised by severe course, and chronic ischemic nephropathy, described by pathological remodelling of kidney tissue, ultimately leading to kidney injury and chronic kidney disease.

Metabolic Disorder Perturb Renal Homeostasis

Obesity related nephropathy disorders have increased ten-folds in recent years. One of the consequences of obesity is an increased Glomerular Filtration Rate (GFR) that leads to an enlargement of the renal glomerulus, i.e., glomerulomegaly. This heightened hyper-filtration in the setting of type 2 diabetes irreparably damages the kidney and leads to the progression of an End Stage Renal Disease (ESRD). Patients suffering from type 2 diabetes have progressive proteinuria, and eventually one third of them develop Chronic Kidney Disease (CKD) and ESRD. For ameliorating the progression of CKD inhibitors of Renin Angiotensin Aldosterone System (RAAS) seemed to be effective, but for short-term basis only. Long term and stable treatment strategies like weight loss via restricted or hypo-caloric diet or bariatric surgery have yielded more promising results in terms of proteinuria and maintenance of GFR. Body Mass Index (BMI) is considered as a traditional marker for obesity onset, but apparently, it is not a reliable indicator, and thus there is a need for more precise evaluation of regional fat distribution and amount of muscle mass. With respect to the pathogenesis, recent investigations have suggested perturbation in fatty acid and cholesterol metabolism as the critical mediators in ectopic renal lipid accumulation, inflammation, increased generation of ROS, RAAS activation and consequential tubulo-interstitial fibrosis. This review summarizes the renewed approaches for obesity assessment and evaluation of the pathogenesis of CKD, altered renal hemodynamics and potential therapeutic targets.

Possibilities of predicting the risk of cardiorenal syndrome in patients with chronic kidney disease on the background of congenital malformations of the urinary system

BACKGROUND. Currently, there is no doubt that there is a close relationship between the condition of the kidneys and the cardiovascular system. Neurohormonal systems various parts long-term hyperactivation is important in the development of pathological processes. Natriuretic peptides provide cardio and renoprotective effects, inhibit the activity of the renin-angiotensin-aldosterone system (RAAS). AIM. To establish the prognostic significance of determining the concentration of natriuretic peptides in comparison with the activity of RAAS in children with congenital malformations of the urinary system to assess the risk of cardiovascular complications.PATIENTS AND METHODS. 76 patients with congenital malformations OUS aged 3 to 18 years were examined: – 40 children with congenital vesicoureteral reflux, – 18 children with hydronephrosis, 18 children with other forms of OUS dysembryogenesis ( 10 patients with renal agenesis, 8-with hypoplasia). The control group consisted of 10 clinically healthy children of the appropriate age. The following parameters were determined in the blood by the enzyme immunoassay: renin, aldosterone, n-terminal propeptide of natriuretic hormone (NТ-рroВNР).RESULTS. Hyperproduction of NТ-рroВNР was observed in 61.8 % of patients, stimulation of renin and/or aldosterone production in 39.5 % of cases. Elevated levels of natriuretic peptides were found in 32.8 % of cases in 25 children with congenital OUS defects without signs of arterial hypertension (AH) and left ventricular hypertrophy (LVH). Significantly higher concentrations of (NТ-рroВNР), renin, and aldosterone are recorded in patients with AH and LVH.CONCLUSION. The increased level of natriuretic peptides is noted earlier than the clinical and instrumental signs of heart dysfunction are noticeable, it is important in identifying early stages of cardiovascular complications, evaluating the prognosis, and in justifying renoprotective treatment in pediatric Nephrology practice.