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Purpose: To study the effect of SARS-CoV-2 infection on pregnancy rates in frozen embryo transfer (FET) cycles. Methods: A retrospective cohort study including women under the age of 42 with documented SARS-CoV-2 infection up to 1 year prior to treatment, undergoing FET cycles in the first half of 2021, with transfer of embryos generated prior to the infection. Controls were SARS-CoV-2 non-diagnosed, non-vaccinated women matched by age, number, and day of embryo transfer. Demographic and cycle characteristics and outcomes were compared. Results: Forty-one recovered women and 41 controls were included. Pregnancy rates were 29% and 49% respectively (p = 0.070). Stratification by time from SARS-CoV-2 infection to transfer into ≤ 60 and > 60 days revealed a difference in pregnancy rates, with women in the COVID group having lower pregnancy rates if infected in proximity to the transfer (21% vs. 55%; p = 0.006). In a logistic regression model, infection was a significant variable (p = 0.05, OR 0.325, 95% CI 0.106–0.998). Logistic regression applied on the subgroup of women infected in proximity to the transfer further strengthened the univariate results, with COVID-19 remaining a significant parameter (p = 0.005, OR 0.072, 95% CI 0.012–0.450). Conclusions: In FET cycles of patients with past SARS-CoV-2 infection, in which oocytes were retrieved prior to infection, decreased pregnancy rates were observed, specifically in patients who recovered less than 60 days prior to embryo transfer. Pending further studies, in cases of FET cycles with limited number of embryos, postponing embryo transfer for at least 60 days following recovery from COVID-19 might be considered when feasible. [ABSTRACT FROM AUTHOR]

Study Question: Does prior severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2) infection in women undergoing fertility treatments affect the outcomes of fresh ART cycles?Summary Answer: SARS-CoV-2 infection does not affect fresh ART treatment outcomes, except for a possible long-term negative effect on oocyte yield (>180 days postinfection).What Is Known Already: A single previous study suggested no evidence that a history of asymptomatic or mild SARS-CoV-2 infection in females caused impairment of fresh ART treatment outcomes.Study Design, Size, Duration: Retrospective cohort study, including all SARS-CoV-2 infected women who underwent fresh ART cycles within a year from infection (the first cycle postinfection), between October 2020 and June 2021, matched to non-diagnosed controls.Participants/materials, Setting, Methods: Patients from two large IVF units in Israel who were infected with SARS-CoV-2 and later underwent fresh ART cycles were matched by age to non-diagnosed, non-vaccinated controls. Demographics, cycle characteristics and cycle outcomes, including oocyte yield, maturation rate, fertilization rate, number of frozen embryos per cycle and clinical pregnancy rates, were compared between groups.Main Results and the Role Of Chance: One hundred and twenty-one infected patients and 121 controls who underwent fresh ART cycles were included. Oocyte yield (12.50 versus 11.29; P = 0.169) and mature oocyte rate (78% versus 82%; P = 0.144) in all fresh cycles were similar between groups, as were fertilization rates, number of frozen embryos per cycle and clinical pregnancy rates (43% versus 40%; P = 0.737) in fresh cycles with an embryo transfer. In a logistic regression model, SARS-CoV-2 infection more than 180 days prior to retrieval had a negative effect on oocyte yield (P = 0.018, Slope = -4.08, 95% CI -7.41 to -0.75), although the sample size was small.Limitations, Reasons For Caution: A retrospective study with data that was not uniformly generated under a study protocol, no antibody testing for the control group.Wider Implications Of the Findings: The study findings suggest that SARS-CoV-2 infection does not affect treatment outcomes, including oocyte yield, fertilization and maturation rate, number of good quality embryos and clinical pregnancy rates, in fresh ART cycles, except for a possible long-term negative effect on oocyte yield when retrieval occurs >180 days post-SARS-CoV-2 infection. Further studies are warranted to support these findings.Study Funding/competing Interest(s): None.Trial Registration Number: 0010-21-HMC, 0094-21-ASF. [ABSTRACT FROM AUTHOR]

Glomerulonephritis is the third most common cause of end-stage kidney disease. The presentation, clinical course, and outcome of glomerular diseases are highly variable. A kidney biopsy is always needed to clarify the diagnosis; however, performing a kidney biopsy is limited by several factors such as bleeding disorders, obesity, and other comorbid conditions. There is a need for less invasive, simple, and reproducible tests, especially by using blood and urine samples, which could replace kidney biopsy. Our review focuses on the novel clinical, histopathological, blood, and urine biomarkers to make an accurate diagnosis and predict the prognosis of primary glomerular diseases including immunoglobulin A nephropathy, membranous nephropathy, focal segmental glomerulosclerosis, and membranoproliferative glomerulonephritis. Overall, although there are promising biomarkers for glomerulonephritis, long-term evaluation of these biomarkers is still needed. [ABSTRACT FROM AUTHOR]

SARS-CoV-2, the virus responsible for COVID-19, uses angiotensin converting enzyme 2 (ACE2) as its primary cell-surface receptor. ACE2 is a key enzyme in the counter-regulatory pathway of the broader renin-angiotensin system (RAS) that has been implicated in a broad array of human pathology. The RAS is composed of two competing pathways that work in opposition to each other: the "conventional" arm involving angiotensin converting enzyme (ACE) generating angiotensin-2 and the more recently identified ACE2 pathway that generates angiotensin (1–7). Following the original SARS pandemic, additional studies suggested that coronaviral binding to ACE2 resulted in downregulation of the membrane-bound enzyme. Given the similarities between the two viruses, many have posited a similar process with SARS-CoV-2. Proponents of this ACE2 deficiency model argue that downregulation of ACE2 limits its enzymatic function, thereby skewing the delicate balance between the two competing arms of the RAS. In this review we critically examine this model. The available data remain incomplete but are consistent with the possibility that the broad multisystem dysfunction of COVID-19 is due in large part to functional ACE2 deficiency leading to angiotensin imbalance with consequent immune dysregulation and endothelial cell dysfunction. [ABSTRACT FROM AUTHOR]

Immunoglobulin A nephropathy is the main cause of glomerulonephritis globally and an important aetiology of end‐stage renal disease in children. It has been considered an autoimmune disease that can lead to the production of autoantibodies against abnormal IgA1 and formation of immune complexes. These autoantibodies and immune complexes deposit in the glomeruli, resulting in renal injury. At the beginning of IgA nephropathy course, most patients are asymptomatic and the first clinical manifestations in children are macroscopic hematuria and proteinuria. The diagnosis is defined by the detection of IgA mesangial deposits in kidney biopsy using immunofluorescence techniques. The Oxford MEST‐C score is the most used classification to associate histological findings and clinical outcomes, being validated for application in children. Recommended treatment options are antihypertensive and antiproteinuric therapy, corticosteroids, immunosuppressive agents, and other non‐pharmacological approaches. There is no ideal prognosis indicator but new perspectives are in science's scope to find possible biomarkers of the disease through OMICS's research. This review aims to summarize and to up‐to‐date the scientific literature on paediatric IgA nephropathy, focusing on pathophysiology, clinical findings, histopathology, current treatment, prognosis, and future perspectives. SUMMARY AT A GLANCE: This review provides an update on IgA nephropathy in paediatric patients ranging from diagnosis using the Oxford MEST‐C score validated for children to recommended treatment options including antihypertensive and antiproteinuric therapy, corticosteroids, immunosuppressive agents, and other non‐pharmacological approaches. [ABSTRACT FROM AUTHOR]

Aneurysmal subarachnoid hemorrhage (SAH) is a substantial cause of mortality and morbidity worldwide. Moreover, survivors after the initial bleeding are often subject to secondary brain injuries and delayed cerebral ischemia, further increasing the risk of a poor outcome. In recent years, the renin–angiotensin system (RAS) has been proposed as a target pathway for therapeutic interventions after brain injury. The RAS is a complex system of biochemical reactions critical for several systemic functions, namely, inflammation, vascular tone, endothelial activation, water balance, fibrosis, and apoptosis. The RAS system is classically divided into a pro-inflammatory axis, mediated by angiotensin (Ang)-II and its specific receptor AT1R, and a counterbalancing system, presented in humans as Ang-(1–7) and its receptor, MasR. Experimental data suggest that upregulation of the Ang-(1–7)/MasR axis might be neuroprotective in numerous pathological conditions, namely, ischemic stroke, cognitive disorders, Parkinson's disease, and depression. In the presence of SAH, Ang-(1–7)/MasR neuroprotective and modulating properties could help reduce brain damage by acting on neuroinflammation, and through direct vascular and anti-thrombotic effects. Here we review the role of RAS in brain ischemia, with specific focus on SAH and the therapeutic potential of Ang-(1–7). [ABSTRACT FROM AUTHOR]

Background The reason why mesangial C4d deposits are detected in only certain biopsies of immunoglobulin A nephropathy (IGAN) remains unclear. We analyse the association between IgA glycosylation patterns, mesangial C4 deposition and clinical phenotypes in IgAN. Methods This cross-sectional study included 145 patients with idiopathic IgAN. We measured the serum levels of three different IgA1 lectin-binding specificities using enzyme-linked immunosorbent assays with and without treatment with neuraminidase and we analysed the relationship between these glycoforms, C4d mesangial deposits and clinical phenotypes. Results C4d-positive versus Cd4-negative patients had higher proteinuria [median 3.1 g/g (0.9–4.2) versus 1.8 (1–2.2); P = 0.000], haematuria [223 cells/µL (32–278) versus 99 (25–186); P = 0.000] and higher levels of IgA binding to neuraminidase untreated Helix aspersa (HA IgA1 neu−; 150.6 ± 52 U versus 96.2 ± 64.1; P = 0.000), neuraminidase untreated Helix pomatia (HPA IgA1 neu−; 0.34 ± 0.15 U versus 0.27 ± 0.13; P = 0.04), Triticum vulgaris (TV IgA1; 85.1 ± 31.7 U versus 42.2 ± 26.9; P = 0.000) and Canavalia ensiformis (ConA IgA1; 32.5 ± 18 U versus 16.7 ± 9.38; P = 0.000). The levels of HA IgA1 neu−, HPA IgA1 neu−, TV IgA1 and ConA IgA1 were all associated with the mesangial deposition of C4d, extracapillary proliferation and acute kidney injury. In receiver operating characteristics curves, HA IgA1 neu−, HPA IgA1 neu−, TV IgA1 and ConA IgA1 significantly discriminated between C4d-positive ad C4d-negative biopsies. In logistics models, TV IgA1 and ConA IgA1 were the only independent predictors of mesangial C4d deposits. Conclusions In IgAN, the severity of the disease is associated with the level of IgA exposing N -acetyl- d -galactosamine, N -acetyl- d -glucosamine or mannose, whereas C4d deposits are only associated with elevated levels of IgA1 glycoforms exhibiting glycan residues with specificity for mannose and N -acetyl- d -glucosamine binding lectins. [ABSTRACT FROM AUTHOR]

Identification of a new axis of angiotensin-converting enzyme 2 (ACE2)/angiotensin (1–7)/Mas receptor, in the renin-angiotensin system (RAS), has opened a new insight regarding the role of RAS and angiotensin in higher brain functions. ACE2 catabolizes angiotensin II and produces angiotensin (1–7), an agonist of Mas receptor. Mice lacking the Mas receptor (angiotensin 1–7 receptor) exhibit anxiety-like behaviours. The present study was conducted to test the hypothesis of the involvement of ACE2 genetic variant (G8790A) on response to selective serotonin reuptake inhibitors (SSRIs). In a randomised control trial, 200 newly diagnosed Iranian patients with major depressive disorder completed 6 weeks of fluoxetine or sertraline treatment. Patients with a reduction of 50% or more in the Hamilton Rating Scale for Depression score were considered responsive to treatment. G8790A polymorphism was determined in extracted DNAs using restriction fragment length polymerase chain reaction method. Our results show that the A allele and AA and GA genotypes were significantly associated with better response to SSRIs (p = 0.008; OR = 3.4; 95% CI = 1.4–8.5 and p = 0.027; OR = 3.3, 95% CI = 1.2–9.2, respectively). Moreover, patients with GA and AA genotypes responded significantly better to sertraline (p = 0.0002; OR = 9.1; 95% CI = 2.4–33.7). The A allele was significantly associated with better response to sertraline (p = 0.0001; OR = 7.6; 95% CI = 2.5–23.3). In conclusion, our results confirm the role of G8790A in response to some SSRIs. [ABSTRACT FROM AUTHOR]

Background: ACE2, a component of the non-classic renin-angiotensin system (RAS), acts as a functional receptor for severe acute respiratory syndrome coronavirus 2 (SARS-CoV 2) spike protein, which enables the entry of the virus into the host cells. Non-classical ACE2 is one of two types of ACE2 that has a protective effect on vascular and respiratory cells. RAS modulators like angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) are among the first-line treatment for hypertensive patients. An upregulation in ACE2 levels with RAS modulators was observed in few preclinical studies, which raised concerns regarding possible increased infectivity among patients treated with RAS modulators. Method: For shortlisting the outcome effects, open-ended, English-restricted databases, published literature, and various clinical studies performed utilizing RAS modulators in COVID 19 patients were considered. Conclusion: Current evidence reveals no increased risk of COVID‐19 infection among hypertensive patients on ACEIs/ARBs compared to other antihypertensive medications. Several studies have demonstrated no detrimental effects of RAS modulators on clinical severity, hospital/intensive care unit stay, ventilation and mortality. Hence, we can conclude that neither ARBs nor ACEIs treatment will cause any side effects or undesirable interactions in COVID-19 infected hypertensive patients. [ABSTRACT FROM AUTHOR]

Background: Understanding Alzheimer's disease (AD) in terms of its various pathophysiological pathways is essential to unravel the complex nature of the disease process and identify potential therapeutic targets. The renin-angiotensin system (RAS) has been implicated in several brain diseases, including traumatic brain injury, ischemic stroke, and AD.Objective: This study was designed to evaluate the protein expression levels of RAS components in postmortem cortical and hippocampal brain samples obtained from AD versus non-AD individuals.Methods: We analyzed RAS components in the cortex and hippocampus of postmortem human brain samples by western blotting and immunohistochemical techniques in comparison with age-matched non-demented controls.Results: The expression of AT1R increased in the hippocampus, whereas AT2R expression remained almost unchanged in the cortical and hippocampal regions of AD compared to non-AD brains. The Mas receptor was downregulated in the hippocampus. We also detected slight reductions in ACE-1 protein levels in both the cortex and hippocampus of AD brains, with minor elevations in ACE-2 in the cortex. We did not find remarkable differences in the protein levels of angiotensinogen and Ang II in either the cortex or hippocampus of AD brains, whereas we observed a considerable increase in the expression of brain-derived neurotrophic factor in the hippocampus.Conclusion: The current findings support the significant contribution of RAS components in AD pathogenesis, further suggesting that strategies focusing on the AT1R and AT2R pathways may lead to novel therapies for the management of AD. [ABSTRACT FROM AUTHOR]

This study investigated the impact of intrarenal angiotensin 1–7 (Ang [1–7]) infusion on renal excretory function in a rat model of hypertension. Eleven‐week‐old spontaneously hypertensive rats (SHRs, n = 7) and Han Wistar controls (NCR, n = 7) were anaesthetised with sodium pentobarbital (60 mg/kg i.p.) and prepared for the measurement of mean arterial pressure (MAP) and left renal function during renal interstitial infusion of Ang (1–7) (50 ng/min). The kidneys were harvested, the renal cortex and medulla separated, prepared for measurement of Ang II and Ang (1–7) and Western blot determination of AT1 and Mas receptor protein expression. MAP, glomerular filtration rate (GFR), urine flow (UF) and absolute sodium excretion (UNaV) were 109 ± 16 mmHg, 4.4 ± 1.0 mL/min/kg, 102 ± 16 µL/min/kg and 16 ± 3 µmol/min/kg, respectively in the NCR and 172 ± 24 mmHg, 3.4 ± 0.7 mL/min/kg, 58 ± 30 μL/min/kg and 8.6 ± 4.8 μmol/min/kg respectively in the SHR. Ang (1–7) increased UF (31%), UNaV (50%) and fractional sodium excretion (FENa+) (22%) in the NCR group (all p < 0.05) but had no effect on GFR in either group. The magnitudes of the Ang (1–7)‐induced increases in UF and UNaV were significantly blunted in the SHR group (model × drug p < 0.05). The renal cortical AT1: Mas receptor expression ratio was significantly higher in the SHR group (p < 0.05) but renal Ang II and Ang (1–7) levels were not statistically different between groups. The Ang (1–7)‐induced increases in sodium and water excretion were impaired in the SHR group in the context of an unstimulated RAS. The decrease in responsiveness of the SHR kidney to Ang (1–7) appears to be associated with higher levels of AT1 receptor expression in the renal cortex. [ABSTRACT FROM AUTHOR]

Glomerular diseases are often chronic or recurring and thus associated with a tremendous physical, psychological, and economic burden. Their etiologies are often unknown, and their pathogeneses are frequently poorly understood. The diagnoses and management of these diseases are therefore based on clinical features, traditional laboratory markers, and, often, kidney pathology. However, the clinical presentation can be highly variable, the kidney pathology may not establish a definitive diagnosis, and the therapeutic responses and resulting clinical outcomes are often unpredictable. To try to address these challenges, significant research efforts have been made over the last decade to identify potential biomarkers that can help clinicians optimize the diagnosis and prognosis at clinical presentation, as well as help predict long-term outcomes. Unfortunately, these efforts have to date only identified a single biomarker for glomerular disease that has been fully validated and developed for widespread clinical use (anti-PLA2R antibodies to diagnose membranous nephropathy). In this manuscript, we review the definitions and development of biomarkers, as well as the current knowledge on both historical and novel candidate biomarkers of glomerular disease, with an emphasis on those associated with idiopathic nephrotic syndrome. [ABSTRACT FROM AUTHOR]

The clinical features of the kidney involvement in immunoglobulin A (IgA) vasculitis (IgAVN) differ in children and adults for both clinical presentation and progression. IgAVN in children has mostly a self-limiting course and favorable resolution, while in adults the kidney involvement is frequently severe with unfavorable outcome. However, a subset of children is at risk of progression within the pediatric age or decades later in adulthood, particularly when the diagnosis and a prompt intervention are delayed. Factors predicting progression and outcome in the whole spectrum of age have been investigated in recent research, as well as the relationship between IgAVN and primary IgAN, which share the same pathology features, in the light of peculiar clinical differences and progression tendencies, and hence need for selective treatments. The search for a personalized treatment in children with IgAV and in different ages of life should rely on the identification of different risks for progression. This review will focus on recent studies which contribute to improve our knowledge in this still largely unclear area. [ABSTRACT FROM AUTHOR]

Crescentic glomerulonephritis represents a group of kidney diseases characterized by rapid loss of kidney function and the formation of glomerular crescents. While the role of the immune system has been extensively studied in relation to the development of crescents, recent findings show that parietal epithelial cells play a key role in the pathophysiology of crescent formation, even in the absence of immune modulation. This review highlights our current understanding of parietal epithelial cell biology and the reported physiological and pathological roles that these cells play in glomerular lesion formation, especially in the context of crescentic glomerulonephritis. [ABSTRACT FROM AUTHOR]

Hepatorenal syndrome (HRS) occurs in patients with cirrhosis or fulminant hepatic failure and is a kind of pre-renal failure due to intense reduction of kidney perfusion induced by severe hepatic injury. While other causes of pre-renal acute kidney injury (AKI) respond to fluid infusion, HRS does not. HRS incidence is 5% in children with chronic liver conditions before liver transplantation. Type 1 HRS is an acute and rapidly progressive form that often develops after a precipitating factor, including gastrointestinal bleeding or spontaneous bacterial peritonitis, while type 2 is considered a slowly progressive form of kidney failure that often occurs spontaneously in chronic ascites settings. HRS pathogenesis is multifactorial. Cirrhosis causes portal hypertension; therefore, stasis and release of vasodilator substances occur in the hepatic vascular bed, leading to vasodilatation of splanchnic arteries and systemic hypotension. Many mechanisms seem to work together to cause this imbalance: splanchnic vasodilatation; vasoactive mediators; hyperdynamic circulation states and subsequent cardiac dysfunction; neuro-hormonal mechanisms; changes in sympathetic nervous system, renin-angiotensin system, and vasopressin. In patients with AKI and cirrhosis, fluid expansion therapy needs to be initiated as soon as possible and nephrotoxic drugs discontinued. Once HRS is diagnosed, pharmacological treatment with vasoconstrictors, mainly terlipressin plus albumin, should be initiated. If there is no response, other options can include surgical venous shunts and kidney replacement therapy. In this regard, extracorporeal liver support can be a bridge for liver transplantation, which remains as the ideal treatment. Further studies are necessary to investigate early biomarkers and alternative treatments for HRS. [ABSTRACT FROM AUTHOR]

Mesangial C4d deposits have been associated with worse outcomes in Western patients with IgA nephropathy (IgAN), but there is limited data in Asians. Previously, a high proportion of stained glomeruli was often required for the classification of C4d positive (C4d+ve). Positive staining in lower proportion of staining would be classified as C4d-ve. This retrospective study evaluated the prognostic value of C4d+ve using a less stringent definition (one C4d+ve glomerulus) in Thai patients with IgAN (n = 120). Baseline findings and outcomes were compared between those with more extensive C4d staining patterns and those with more restricted staining. Clinico-pathologic parameters and risk for kidney outcomes (kidney failure or decline GFR50%) were compared between C4d+ve versus C4d-ve, and between different patterns: Focal (< 50%) versus Diffuse (≥ 50% of glomeruli); or Global (≥ 50) versus Segmental (< 50% of mesangial area). The hazard ratios were estimated using Cox proportional hazard models for Model 1 (Oxford score+ C4d) and Model 2 (Model 1+ clinical factors). C4d+ve (n = 81) had lower eGFR, more global sclerosis, and interstitial fibrosis than C4d-ve at baseline. The 5-year kidney survival for C4d+ve was lower (53.7%) than C4d-ve (89.7%); P = 0.0255. By univariate analysis, T1, T2, C4d+ve, eGFR<60, proteinuria were predictors of kidney outcome. By multivariate analysis, proteinuria, T1, T2 and C4d+ve were independent predictors (Model 2 HR (95% CI) C4d+ve: 3.24 (1.09–9.58), p = 0.034). Segmental had lower eGFR, higher tubulointerstitial fibrosis, and segmental sclerosis compared to Global pattern. Clinicopathological parameters were not different between Focal and Diffuse patterns. Outcomes were similar between staining patterns. In conclusion, C4d staining may be a valuable marker of poor prognosis in Asian patients with IgAN. Less stringent criteria for C4d+ve should be considered as no differences in outcomes were observed between more extensive staining with less extensive patterns. More studies are needed to identify the optimum criteria for C4d+ve. [ABSTRACT FROM AUTHOR]

The last decade was crucial for our understanding of the renin–angiotensin–aldosterone system (RAAS) as a two-axis, counter-regulatory system, divided into the classical axis, formed by angiotensin-converting enzyme (ACE), angiotensin II (Ang II), and the angiotensin type 1 receptor (AT1R), and the alternative axis comprising angiotensin-converting enzyme 2 (ACE2), angiotensin-(1-7) (Ang-(1-7)), and the Mas receptor. Breakthrough discoveries also took place, with other RAAS endopeptides being described, including alamandine and angiotensin A. In this review, we characterize the two RAAS axes and the role of their components in pediatric kidney diseases, including childhood hypertension (HTN), pediatric glomerular diseases, congenital abnormalities of the kidney and urinary tract (CAKUT), and chronic kidney disease (CKD). We also present recent findings on potential interactions between the novel coronavirus, SARS-CoV-2, and components of the RAAS, as well as potential implications of coronavirus disease 2019 (COVID-19) for pediatric kidney diseases. [ABSTRACT FROM AUTHOR]

Objective: No information exists in the literature regarding the effect of mRNA SARS-CoV-2 vaccine on subsequent IVF cycle attempt. We therefore aim to assess the influence of mRNA SARS-CoV-2 vaccine on IVF treatments. Design: An observational study. Setting: A tertiary, university-affiliated medical center. Patients and Methods: All couples undergoing consecutive ovarian stimulation cycles for IVF before and after receiving mRNA SARS-CoV-2 vaccine, and reached the ovum pick-up (OPU) stage. The stimulation characteristics and embryological variables of couples undergoing IVF treatments after receiving mRNA SARS-CoV-2 vaccine were assessed and compared to their IVF cycles prior to vaccination. Main outcome measures: Stimulation characteristics and embryological variables. Results: Thirty-six couples resumed IVF treatment 7–85 days after receiving mRNA SARS-CoV-2 vaccine. No in-between cycles differences were observed in ovarian stimulation and embryological variables before and after receiving mRNA SARS-CoV-2 vaccination. Conclusions: mRNA SARS-CoV-2 vaccine did not affect patients' performance or ovarian reserve in their immediate subsequent IVF cycle. Future larger studies with longer follow-up will be needed to validate our observations. [ABSTRACT FROM AUTHOR]

Introduction: IgA nephropathy (IgAN) is the most common primary glomerulonephritis (GN) in western countries and Henoch-Schönlein purpura nephritis (HSPN) is the most common form of vasculitis in childhood. Renal biopsy findings in both nephropathies are often similar and are characterized by mesangioproliferative GN with mesangial or mesangiocapillary IgA and C3c deposits. Objectives: The aim of this study was to investigate the significance of glomerular C4d-deposition as a discriminating factor between pediatric HSPN and IgAN. Patients and Methods: We retrospectively analyzed patient records and renal biopsies from 53 pediatric patients from one single center with a median age of 10.5 years (range 2.3-18 years). Twenty-two patients suffered from IgAN and 31 from HSPN. Work-up of all renal biopsies was performed using standard protocols including immunohistochemistry for C4d. Results: Pediatric IgAN patients presented significantly more often with gross hematuria, higher serum creatinine, lower glomerular filtration rate, lower serum C3 and proteinuria and on histology less endocapillary hypercellularity compared to HSPN patients. However, the rate of glomerular C4d-positivity was not different between IgAN (36%) and HSPN (42%). Comparing all cases with positive versus negative glomerular C4d-staining, pediatric patients with glomerular C4d-positivity showed significantly lesser gross hematuria and received significantly more often cyclophosphamide. This was in line with a tendency towards more proteinuria, hypertension and renal insufficiency at last follow-up in C4d-positive compared to C4d-negative patients. Conclusion: In conclusion, in our monocentric study glomerular C4d does not differ between pediatric HSPN and IgAN, but was associated with a tendency to a more severe course of the disease that needs to be confirmed in larger multicentric studies. [ABSTRACT FROM AUTHOR]

In the early months of the coronavirus disease 2019 (COVID-19) pandemic, a hypothesis emerged suggesting that pharmacologic inhibitors of the renin–angiotensin system (RAS) may increase COVID-19 severity. This hypothesis was based on the role of angiotensin-converting enzyme 2 (ACE2), a counterregulatory component of the RAS, as the binding site for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), allowing viral entry into host cells. Extrapolations from prior evidence led to speculation that upregulation of ACE2 by RAS blockade may increase the risk of adverse outcomes from COVID-19. However, counterarguments pointed to evidence of potential protective effects of ACE2 and RAS blockade with regard to acute lung injury, as well as substantial risks from discontinuing these commonly used and important medications. Here we provide an overview of classic RAS physiology and the crucial role of ACE2 in systemic pathways affected by COVID-19. Additionally, we critically review the physiologic and epidemiologic evidence surrounding the interactions between RAS blockade and COVID-19. We review recently published trial evidence and propose important future directions to improve upon our understanding of these relationships. [ABSTRACT FROM AUTHOR]

A diagnostic of hypertension increases the risk of erectile dysfunction (ED); likewise, ED can be an early sign of hypertension. In both cases, there is evidence that endothelial dysfunction is a common link between the 2 conditions. During hypertension, the sustained and widespread release of procontractile factors (e.g. angiotensin II, endothelin 1, and aldosterone) impairs the balance between vasoconstrictors and vasodilators and, in turn, detrimentally impacts vascular and erectile structures. This prohypertensive state associates with an enhancement in the generation of reactive oxygen species, which is not compensated by internal antioxidant mechanisms. Recently, the innate immune system, mainly via Toll-like receptor 4, has also been shown to actively contribute to the pathophysiology of hypertension and ED not only by inducing oxidative stress but also by sustaining a low-grade inflammatory state. Furthermore, some drugs used to treat hypertension can cause ED and, consequently, reduce compliance with the prescribed pharmacotherapy. To break down these challenges, in this review, we focus on discussing the well-established as well as the emerging mechanisms linking hypertension and ED with an emphasis on the signaling network of the vasculature and corpora cavernosa, the vascular-like structure of the penis. [ABSTRACT FROM AUTHOR]

Pituitary adenomas (PAs) can be classified as non-secreting adenomas, somatotroph adenomas, corticotroph adenomas, lactotroph adenomas, and thyrotroph adenomas. Substantial advances have been made in our knowledge of the pathobiology of PAs. To obtain a comprehensive understanding of the molecular biological characteristics of different types of PAs, we reviewed the important advances that have been made involving genetic and epigenetic variation, comprising genetic mutations, chromosome number variations, DNA methylation, microRNA regulation, and transcription factor regulation. Classical tumor predisposition syndromes include multiple endocrine neoplasia type 1 (MEN1) and type 4 (MEN4) syndromes, Carney complex, and X-LAG syndromes. PAs have also been described in association with succinate dehydrogenase-related familial PA, neurofibromatosis type 1, and von Hippel–Lindau, DICER1, and Lynch syndromes. Patients with aryl hydrocarbon receptor-interacting protein (AIP) mutations often present with pituitary gigantism, either in familial or sporadic adenomas. In contrast, guanine nucleotide-binding protein G(s) subunit alpha (GNAS) and G protein-coupled receptor 101 (GPR101) mutations can lead to excess growth hormone. Moreover, the deubiquitinase gene USP8 , USP48 , and BRAF mutations are associated with adrenocorticotropic hormone production. In this review, we describe the genetic and epigenetic landscape of PAs and summarize novel insights into the regulation of pituitary tumorigenesis. [ABSTRACT FROM AUTHOR]

Objectives: The present study aimed to examine the expression of CD44 and claudin-1 markers using immunohistochemical methods to differentiate patients with minimal change disease (MCD) from those afflicted with focal segmental glomerulosclerosis (FSGS). Materials and Methods: In this descriptive-analytical study, twenty patients with definite FSGS, twenty patients with FSGS/MCD spectrum, and seven patients with definite MCD were randomly chosen from Imam Reza hospital affiliated with Tabriz University of Medical Sciences. All patients underwent renal biopsy, and then the presence of the immune complex was examined in the obtained samples using immunofluorescence staining. Some renal specimens were paraffin-embedded for the evaluation of the expression levels of CD44 and claudin-1 utilizing the immunohistochemistry method. Results: Among the twenty samples obtained from patients with definite FSGS, 13 samples (65%) were double-positive for CD44 and claudin-1, 3 specimens (15%) were positive only for claudin-1, and 4 samples (20%) were double-negative for CD44 and claudin-1. The percentages of renal specimens expressing claudin-1 in patients with definite FSGS, FSGS/MCD, and MCD were 80%, 85%, and 0%, respectively. Finally, the percentages of renal samples expressing CD44 in patients with definite FSGS, FSGS/MCD, and MCD were 65%, 10%, and 0%, respectively. Conclusions: The results of the present research indicated that the rate of CD44-positive specimens was higher in patients with FSGS while the percentage of claudin-1-positive samples was more frequent in MCD patients compared with FSGS patients. [ABSTRACT FROM AUTHOR]

Background: Platelets as immune cells have been shown to play several roles in inflammation. Increasing of anti-double stranded DNA (anti-dsDNA) autoantibody levels are commonly used to assess the high disease activity of Systemic Lupus Erythematosus (SLE). Platelet count is a cost effective indicator that can easily be detected as inflammatory marker. Objective: This study aimed to see the correlation between platelet count and anti-dsDNA antibody levels. Methods: This study was a cross-sectional study using data from medical records involving 41 newly-diagnosed pediatric SLE (pSLE) patients (aged ≤18 years) was conducted at Department of Child Health in our hospital between January 1st 2018 and June 30th 2019. Platelet count was measured using Sysmex XN analyzer. Anti-dsDNA antibody levels were measured by Standard Enzyme Linked Immunosorbent Assay (ELISA). Spearman's rank correlation and Pearson's chi squared test were performed to analyze the data (p<0.05 is considered significant). Results: Forty-one pSLE patients were included in this study, consisting of 38 female (92.7%) and 3 male (7.3%) patients with median age of 15 (IQR=13-17). The median value of platelet count was 238000/mm3 (IQR = 152000-355000/mm3). The median value of anti-dsDNA antibody levels was 153.8 IU/ml (IQR = 30.5-416.2). Platelet count was inversely correlated with anti-dsDNA antibody levels (Spearman correlation Rho=-0.433, p=0.005). Thrombocytopenia was correlated with rash (p=0.001), fever (p=0.0002), and arthritis (p=0.001). Conclusion: Decreasing of platelet count can be considered as new parameter in predicting SLE with highly active disease course. [ABSTRACT FROM AUTHOR]

Objectives: To compare serum levels of RAS components in women with RA versus healthy females and to investigate the association between these molecules and subclinical atherosclerosis. Methods: A cross-sectional study involving female RA patients without ischemic CVD. Disease activity was assessed using the DAS28 and the CDAI. IMT of the common carotid artery was evaluated by ultrasonography. Serum levels of Ang II, Ang-(1-7), ACE and ACE2 were determined by enzyme immunoassay. Results: Fifty women with RA, mean 48.2 (7.3) years, were compared to 30 healthy women, paired by age. RA patients had higher plasma levels of Ang II (p<.01), Ang-(1-7) (p<.01), and ACE (p<.01) than controls. The ratios of ACE to ACE2 were higher in RA patients, whereas Ang II/Ang-(1-7) ratios were lower in RA patients. The presence of hypertension and the treatment with ACE inhibitors did not significantly modify serum levels of Ang II, Ang-(1-7), ACE and ACE2 in patients with RA. Seven RA patients had altered IMT, and eight patients exhibited atherosclerotic plaque. There was a negative correlation between ACE2 levels and IMT (p=.041). IMT positively correlated with age (p=.022), disease duration (p=.012) and overall Framingham risk score (p¼.008). Ang II concentrations positively correlated with DAS28 (p=.034) and CDAI (p=.040). Conclusion: Patients with RA had an activation of the RAS, suggesting an association with disease activity and cardiovascular risk. [ABSTRACT FROM AUTHOR]

The complement system comprises the frontline of the innate immune system. Triggered by pathogenic surface patterns in different pathways, the cascade concludes with the formation of a membrane attack complex (MAC; complement components C5b to C9) and C5a, a potent anaphylatoxin that elicits various inflammatory signals through binding to C5a receptor 1 (C5aR1). Despite its important role in pathogen elimination, priming and recruitment of myeloid cells from the immune system, as well as crosstalk with other physiological systems, inadvertent activation of the complement system can result in self-attack and overreaction in autoinflammatory diseases. Consequently, it constitutes an interesting target for specialized therapies. The paradigm of safe and efficacious terminal complement pathway inhibition has been demonstrated by the approval of eculizumab in paroxysmal nocturnal hematuria. In addition, complement contribution in rare kidney diseases, such as lupus nephritis, IgA nephropathy, atypical hemolytic uremic syndrome, C3 glomerulopathy, or antineutrophil cytoplasmic antibody-associated vasculitis has been demonstrated. This review summarizes the involvement of the terminal effector agents of the complement system in these diseases and provides an overview of inhibitors for complement components C5, C5a, C5aR1, and MAC that are currently in clinical development. Furthermore, a link between increased complement activity and lung damage in severe COVID-19 patients is discussed and the potential for use of complement inhibitors in COVID-19 is presented. [ABSTRACT FROM AUTHOR]

Substantial advances have been made recently in the pathobiology of pituitary tumors. Similar to many other endocrine tumors, over the last few years we have recognized the role of germline and somatic mutations in a number of syndromic or nonsyndromic conditions with pituitary tumor predisposition. These include the identification of novel germline variants in patients with familial or simplex pituitary tumors and establishment of novel somatic variants identified through next generation sequencing. Advanced techniques have allowed the exploration of epigenetic mechanisms mediated through DNA methylation, histone modifications and noncoding RNAs, such as microRNA, long noncoding RNAs and circular RNAs. These mechanisms can influence tumor formation, growth, and invasion. While genetic and epigenetic mechanisms often disrupt similar pathways, such as cell cycle regulation, in pituitary tumors there is little overlap between genes altered by germline, somatic, and epigenetic mechanisms. The interplay between these complex mechanisms driving tumorigenesis are best studied in the emerging multiomics studies. Here, we summarize insights from the recent developments in the regulation of pituitary tumorigenesis. [ABSTRACT FROM AUTHOR]

Background COVID-19 is typically a primary respiratory illness with multisystem involvement. The prevalence and clinical significance of cardiovascular and multisystem involvement in COVID-19 remain unclear. Methods This is a prospective, observational, multicentre, longitudinal, cohort study with minimal selection criteria and a near-consecutive approach to screening. Patients who have received hospital care for COVID-19 will be enrolled within 28 days of discharge. Myocardial injury will be diagnosed according to the peak troponin I in relation to the upper reference limit (URL, 99th centile) (Abbott Architect troponin I assay; sex-specific URL, male: >34 ng/L; female: >16 ng/L). Multisystem, multimodality imaging will be undertaken during the convalescent phase at 28 days post-discharge (Visit 2). Imaging of the heart, lung, and kidneys will include multiparametric, stress perfusion, cardiovascular magnetic resonance imaging, and computed tomography coronary angiography. Health and well-being will be assessed in the longer term. The primary outcome is the proportion of patients with a diagnosis of myocardial inflammation. Conclusion CISCO-19 will provide detailed insights into cardiovascular and multisystem involvement of COVID-19. Our study will inform the rationale and design of novel therapeutic and management strategies for affected patients. Clinical trial registration ClinicalTrials.gov identifier NCT04403607. [ABSTRACT FROM AUTHOR]

Severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2) that causes COVID-19 infections penetrates body cells by binding to angiotensin-converting enzyme-2 (ACE2) receptors. Evidence shows that SARS-CoV-2 can also affect the urogenital tract. Hence, it should be given serious attention when treating COVID-19-infected male patients of reproductive age group. Other viruses like HIV, mumps, papilloma and Epstein–Barr can induce viral orchitis, germ cell apoptosis, inflammation and germ cell destruction with attending infertility and tumors. The blood-testis barrier (BTB) and blood-epididymis barrier (BEB) are essential physical barricades in the male reproductive tract located between the blood vessel and seminiferous tubules in the testes. Despite the significant role of these barriers in male reproductive function, studies have shown that a wide range of viruses can still penetrate the barriers and induce testicular dysfunctions. Therefore, this mini-review highlights the role of ACE2 receptors in promoting SARS-CoV-2-induced blood-testis/epididymal barrier infiltration and testicular dysfunction. [ABSTRACT FROM AUTHOR]

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The pathogenesis of Coronavirus disease 2019 (COVID-19) is gradually being comprehended. A high number of thrombotic episodes are reported, along with the mortality benefits of heparin. COVID-19 can be viewed as a prothrombotic disease. We overviewed the available evidence to explore this possibility. We identified various histopathology reports and clinical case series reporting thromboses in COVID-19. Also, multiple coagulation markers support this. COVID-19 can be regarded as a risk factor for thrombosis. Applying the principles of Virchow's triad, we described abnormalities in the vascular endothelium, altered blood flow, and platelet function abnormalities that lead to venous and arterial thromboses in COVID-19. Endothelial dysfunction, activation of the renin-angiotensin-aldosterone system (RAAS) with the release of procoagulant plasminogen activator inhibitor (PAI-1), and hyperimmune response with activated platelets seem to be significant contributors to thrombogenesis in COVID-19. Stratifying risk of COVID-19 thromboses should be based on age, presence of comorbidities, D-dimer, CT scoring, and various blood cell ratios. Isolated heparin therapy may not be sufficient to combat thrombosis in this disease. There is an urgent need to explore newer avenues like activated protein C, PAI-1 antagonists, and tissue plasminogen activators (tPA). These should be augmented with therapies targeting RAAS, antiplatelet drugs, repurposed antiinflammatory, and antirheumatic drugs. Key Points • Venous and arterial thromboses in COVID-19 can be viewed through the prism of Virchow's triad. • Endothelial dysfunction, platelet activation, hyperviscosity, and blood flow abnormalities due to hypoxia, immune reactions, and hypercoagulability lead to thrombogenesis in COVID-19. • There is an urgent need to stratify COVID-19 patients at risk for thrombosis using age, comorbidities, D-dimer, and CT scoring. • Patients with COVID-19 at high risk for thrombosis should be put on high dose heparin therapy. [ABSTRACT FROM AUTHOR]

Evidence has shown that the ACE2/Ang (1–7)/Mas axis plays an important role in the control of hypertension. Thus, we hypothesized that chemical renal denervation (RDN) could reduce blood pressure by regulating the ACE2/Ang (1–7)/Mas axis in spontaneously hypertensive rats. Twelve rats were randomly divided into sham group and chemical RDN group. All the rats were sacrificed 4 weeks later. Plasma samples were collected to measure the renin-angiotensin system (RAS) activities and reactive oxygen species levels by radioimmunoassay, chromatometry and ELISA. Paraventricular nucleus (PVN) tissues were collected to examine the expression of the components of the ACE2/Ang (1–7)/Mas axis by western bolt and immunofluorescence. The systolic blood pressure (169.33 ± 7.50 vs 182.67 ± 7.00 mmHg, p <.05) and the diastolic blood pressure (97.50 ± 4.68 vs 109.33 ± 4.41 mmHg, p <.05) in the RDN group were obviously lower than the baseline levels, whereas the opposite results were observed in the sham group. The RDN group exhibited a significant reduction in the plasma ROS (91.59 ± 13.12 vs 72.34 ± 11.76 U/ml, p <.05) and NADPH oxidase (171.86 ± 1.14 vs 175.75 ± 1.74 nmol/ml, p <.001) compared with the sham group, while the plasma eNOS (3.47 ± 0.42 vs 2.49 ± 0.51 U/ml, p <.05) and NO (55.92 ± 8.10 vs 43.53 ± 4.58 μmol/L, p <.05) were increased. The expression of the components of the ACE2/Ang (1–7)/Mas axis was upregulated while the expression of the components of the ACE/Ang II/AT1 R axis was downregulated in the plasma and PVN in the RDN group. Our findings suggested that the reduction in blood pressure was regulated by chemical RDN-induced upregulation of the components of the ACE2/Ang (1–7)/Mas axis. [ABSTRACT FROM AUTHOR]

Familial isolated pituitary adenoma (FIPA) is one of the most f requent conditions associated with an inherited presentation of pituitary tumors. FIPA can present with pituitary adenomas of any secretory/non-secretory type. Mutations in the gene for the aryl-hydrocarbon receptor interacting protein (AIP) have been identified in approximately 20% of FIPA families and are the most frequent cause (29%) of p ituitary gigantism. Pituitary tumors in FIPA are larger, occur at a younger age and display more aggressive characteristics and evolution than sporadic adenomas. This aggressiveness is especially marked in FIPA kindreds with AIP mutations. Special attention should be paid to young patients with pituitary gigantism and/or macroadenomas, as AIP mutations are prevalent in these groups. Duplications on chromosome Xq26.3 involving the gene GPR101 lead to X-linked acrogigantism (X-LAG), a syndrome of pituitary gigantism beginning in early childhood; three kindreds with X-LAG have presented in the setting of FIPA. Management of pituitary adenomas in the setting of FIPA, AIP mutations and GPR101 duplications is often more complex than in sporadic disease due to early onset disease, aggressive tumor growth and resistance to medical therapy. [ABSTRACT FROM AUTHOR]

Background: Proteinuria, a marker of kidney injury, may be related to skeletal muscle loss. Whether the severity of proteinuria is associated with physical performance is unclear.Methods: We examined the association of proteinuria severity with physical performance cross-sectionally in 3357 military young males, free of chronic kidney disease, from the cardiorespiratory fitness and hospitalization events in armed Forces (CHIEF) study in Taiwan. The grades of proteinuria were classified according to one dipstick urinalysis which were collected at morning after an 8-h fast as unremarkable (0, +/-, and 1+), moderate (2+) and severe (3+ and 4+). Aerobic physical performance was evaluated by time for a 3000-m run and anaerobic physical performance was evaluated by numbers of 2-min sit-ups and 2-min push-ups, separately. Multiple linear regressions were used to determine the relationship.Results: As compared with unremarkable proteinuria, moderate and severe proteinuria were dose-dependently correlated with 3000-m running time (β: 4.74 (95% confidence intervals (CI): - 0.55, 10.02) and 7.63 (95% CI: 3.21, 12.05), respectively), and inversely with numbers of 2-min push-ups (β = - 1.13 (- 1.97, - 0.29), and - 1.00 (- 1.71, - 0.28), respectively) with adjustments for age, service specialty, body mass index, blood pressure, alcohol intake, smoking, fasting plasma glucose, blood urea nitrogen, serum creatinine and physical activity. However, there was no association between proteinuria severity and 2-min sit-ups.Conclusions: Our findings show a relationship of dipstick proteinuria with aerobic physical performance and parts of anaerobic physical performance in military healthy males. This mechanism is not fully understood and requires further investigations. [ABSTRACT FROM AUTHOR]

Background: Childhood-onset systemic lupus erythematosus (cSLE) is an autoimmune and multifactorial disease that can affect the renal system. Exposure to air pollution can trigger systemic inflammation in cSLE patients and increase risk of disease activity. We evaluated effects of individual real-time exposure to air pollutants on renal activity in cSLE patients using the Systemic Lupus Erythematosus Disease Activity Index 2000. Methods: Longitudinal panel study of 108 repetitive measures from 9 pediatric lupus patients. Over three consecutive weeks, daily individual levels of fine particulate matter (PM2.5) and nitrogen dioxide (NO2) were measured, as well as weekly clinical evaluation and laboratory tests. This was repeated every 10 weeks over a 1-year period. Specific generalized estimating equation models were used to evaluate the impact of these pollutants on risk of nephritis and anti-dsDNA > 20 UI/mL and on 24-h urine protein and serum complement (C3) levels. Results: An interquartile range (IQR) increase of 18.12 μg/m3 in PM2.5 daily concentration was associated with increased risk of nephritis and positive results for anti-dsDNA. Moreover, increase in 24-h urine protein and decrease in C3 serum levels also associated with exposure to pollutants. An IQR increase in PM2.57-day moving average was associated with increased risks of leukocyturia (3.4; 95% CI 2.6:4.3), positive anti-dsDNA (3.1; 95% CI 2.1:4.0), and 36.3-mg increase (95% IC 20.2:52.3) in 24-h urine protein. An IQR increase (63.1 μg/m3) in 7-day cumulative NO2 levels was associated with decreased serum C3 levels. Conclusions: This prospective study suggests exposure to air pollution can trigger renal activity in cSLE patients. [ABSTRACT FROM AUTHOR]

Introduction: Mental health problems, such as anxiety, depression, and ineffective family coping, in children with lupus nephritis (LN) can increase the severity and affect the management of the disease, thus affecting the quality of life (QoL) of patients. Objective: Analyzing the association between levels of depression, anxiety, coping, disease activity on the QoL of pediatric patients with LN. Patients and Methods: There were 62 pediatric LN participants (16 participants in the induction phase and 46 participants in the maintenance phase). Participants were measured for anxiety, depression, coping, disease activity (systemic lupus erythematosus disease activity index/SLEDAI), and QoL. The measurement results were compared between induction and maintenance groups. Analysis of the association between anxiety, depression, coping, and disease activity with the QoL of children with LN used a multiple logistic regression test with p < 0.05. Results:: The measurement results obtained anxiety (induction = 69.06± 3.92 and maintenance = 45.24± 10.33; p < 0.001), depression (induction = 69.88± 3.34 and maintenance = 42.20± 9.12; p < 0.001), coping (induction = 99.88± 12.93 and maintenance = 115.67± 7.34; p < 0.001), SLEDAI (induction = 15.81± 12.58 and maintenance = 0.43± 1.26; p < 0.001), and QoL (induction = 49.92± 12.44 and maintenance = 88.15± 8.06; p < 0.001).. Anxiety level in the induction group (p = 0.043) and maintenance group (p < 0.001; p = 0.032; p = 0.008; p = 0.009). Depression level in the induction group (p = 0.031) and maintenance group (p = 0.024; p = 0.042; p = 0.003). SLEDAI score in the maintenance group (p = 0.003; p = 0.003). Coping in induction group (p = 0.016; p = 0.016) and maintenance group (p = 0.005). Conclusion: Mental health disorders reduce the QoL of LN children, and the level of QoL in induction phase is lower than maintenance phase. [ABSTRACT FROM AUTHOR]

Background/Aims: The beneficial effect of aerobic exercise training (ET) on cardiac remodeling caused by supravalvar aortic stenosis (AS) has been demonstrated in experimental studies; however, the mechanisms responsible for improving cardiac function are not entirely under-stood. We evaluated whether ET-generated cardioprotection in pressure-overloaded rats is dependent on cardiomyocyte proliferation, increased angiotensin-(1-7) (Ang-1-7) levels, and its receptor in the myocardium. Methods: Eighteen weeks after ascending AS surgery, Wistar rats were randomly assigned to four groups: sedentary control (C-Sed), exercised control (C-Ex), sedentary aortic stenosis (AS-Sed) and exercised aortic stenosis (AS-Ex) groups. The moderate treadmill exercise protocol was performed for ten weeks. The functional capacity was assessed by treadmill exercise testing. Cardiac structure and function were evaluated by echocardiogram. Cardiomyocyte proliferation was evaluated by flow cytometry. Expression of cell cycle regulatory genes as CCND2, AURKB, CDK1, and MEIS1 was verified by RT-qPCR. Cardiac and plasma angiotensin I (Ang I), angiotensin II (Ang II), and Ang-(1-7) levels were analyzed by high-performance liquid chromatography (HPLC). The angiotensin-converting enzyme (ACE) activity was assessed by the fluorometric method and protein expression of AT1 and Mas re-ceptors by Western blot. Results: The AS-Ex group showed reduced left ventricular wall rela-tive thickness and improved ejection fraction; also, it showed decreased gene expression of myocyte cell cycle regulators, ACE, Ang I, Ang II and Ang II/Ang-(1-7) ratio levels compared to AS-Sed group. However, ET did not induce alterations in Ang-(1-7) and cardiac Mas receptor expression and myocyte proliferation. Conclusion: Aerobic exercise training improves systolic function regardless of myocyte proliferation and Ang-(1-7)/Mas receptor levels. However, the ET negatively modulates the vasoconstrictor/hypertrophic axis (ACE/Ang II) and decreases the expression of negative regulatory genes of the cell cycle in cardiomyocytes of rats with supravalvular aortic stenosis. [ABSTRACT FROM AUTHOR]

Rennin-angiotensin system (RAS) has been involved in sperm function, even so, little is known about the implication of one of the RAS axis formed by Ang-(1-7) (angiotensin-(1-7)) and MAS receptor. Hence, in the present work, we focused on elucidating the function of the MAS receptor in human spermatozoa. We analyzed the expression and localization of MAS receptor in human spermatozoa and we observed if its activation is able to modulate the sperm motility of normal motility and/or asthenozoospermic patients, as well as, the acrosome reaction of the spermatozoa. MAS receptor is present in human mature spermatozoa, not only at the mRNA level but also at protein level. MAS is localized at the acrosome region, as well as, in the tail of spermatozoa. The sperm incubation with MAS agonist Ang-(1-7) activates at dose-dependent manner the PI3K/AKT pathway (P < 0.01 vs control) and improves the motility of asthenozoospermic patients (P < 0.01 vs control), which is blocked by the specific antagonist (A779) (P < 0.01), but it do not modulate the acrosome reaction. These findings suggest that the ACE2/Ang-(1-7)/Mas axis may be a useful biochemical tool for the treatment of male infertility related to sperm mobility. [ABSTRACT FROM AUTHOR]

Purpose: To study the retinal and choroidal microvascular parameters in children with nephrotic syndrome (NS). Methods: This is a cross-sectional study. Optical coherence tomography angiography was used to evaluate the changes of retinal and choroidal microvessels in patients with NS. Thirty NS children and 20 normal controls were included in this study. The macular vessel density (VD) of the superficial capillary plexus (SCP), deep capillary plexus (DCP), choroid capillary plexus (CCP), and foveal avascular zone (FAZ) area of the SCP and DCP was quantitatively calculated. Clinical data including serum protein, blood lipid, uric acid, urea, serum creatinine, urinary protein concentration, urinary creatinine, 24-h urine volume, 24-h urinary total protein, 24-h creatinine clearance rate, and urinary albumin to creatinine ratio were collected. Results: The VDs of the DCP and CCP in children with NS were significantly lower than those in controls (59.35 ± 2.45 vs. 61.15 ± 1.53, p = 0.002, 66.34 ± 1.43 vs. 67.16 ± 1.23, p = 0.042, respectively). The VD of the SCP in children with NS had a tendency to decrease compared with that in controls, but there were no significant differences. There were also no significant differences in FAZ area between the two groups. The VD of the SCP was positively correlated with serum total protein (ρ = 0.446, p = 0.014), serum albumin (ρ = 0.431, p = 0.017), and 24-h urine volume (ρ = 0.389, p = 0.034) but negatively correlated with triglyceride (ρ = − 0.450, p = 0.013), low-density lipoprotein cholesterol (ρ = −0.432, p = 0.017), urinary protein concentration (ρ = − 0.606, p < 0.001), and 24-h urinary total protein (ρ = − 0.517, p = 0.004). The VDs of the SCP, DCP, and CCP were negatively correlated with the urinary albumin to creatinine ratio (ρ = − 0.473, p = 0.008, ρ = − 0.438, p = 0.015, ρ = −0.467, p = 0.009, respectively). Conclusions: Retinal and choroidal VDs were decreased in children with NS and paralleled the severity of kidney disease. Optical coherence tomography angiography can be used as a noninvasive method for evaluating renal injury in patients with NS. [ABSTRACT FROM AUTHOR]

Neprilysin (NEP) is an endogenously induced peptidase for modulating production and degradation of various peptides in humans. It is most abundantly present in kidney and regulates the intrinsic renal homeostatic mechanism. Recently, drugs inhibiting NEP have been approved for the use in heart failure. In the context of increased prevalence of ischemia associated renal failure, NEP could be an attractive target for treating kidney failure. In the kidney, targeting NEP may possess potential benefits as well as adverse consequences. The unfavorable outcomes of NEP are mainly attributed to the degradation of the natriuretic peptides (NPs). NPs are involved in the inhibition of the renin–angiotensin–aldosterone system (RAAS) and activation of the sympathetic system contributing to the tubular and glomerular injury. In contrary, NEP exerts the beneficial effect by converting angiotensin-1 (Ang I) to angiotensin-(1–7) (Ang-(1–7)), thus activating MAS-related G-protein coupled receptor. MAS receptor antagonizes angiotensin type I receptor (AT-1R), reduces reactive oxygen species (ROS) and inflammation, thus ameliorating renal injury. However, the association of NEP with complex cascades of renal ischemia remains vague. Therefore, there is a need to evaluate the putative mechanism of NEP and its overlap with other signaling cascades in conditions of renal ischemia. [ABSTRACT FROM AUTHOR]

Despite decades of research and numerous treatment approaches, hypertension and cardiovascular disease remain leading global public health problems. A major contributor to regulation of blood pressure, and the development of hypertension, is the renin-angiotensin system. Of particular concern, uncontrolled activation of angiotensin II contributes to hypertension and associated cardiovascular risk, with antihypertensive therapies currently available to block the formation and deleterious actions of this hormone. More recently, angiotensin-(1–7) has emerged as a biologically active intermediate of the vasodilatory arm of the renin-angiotensin system. This hormone antagonizes angiotensin II actions as well as offers antihypertensive, antihypertrophic, antiatherogenic, antiarrhythmogenic, antifibrotic and antithrombotic properties. Angiotensin-(1–7) elicits beneficial cardiovascular actions through mas G protein-coupled receptors, which are found in numerous tissues pivotal to control of blood pressure including the brain, heart, kidneys, and vasculature. Despite accumulating evidence for favorable effects of angiotensin-(1–7) in animal models, there is a paucity of clinical studies and pharmacokinetic limitations, thus limiting the development of therapeutic agents to better understand cardiovascular actions of this vasodilatory peptide hormone in humans. This review highlights current knowledge on the role of angiotensin-(1–7) in cardiovascular control, with an emphasis on significant animal, human, and therapeutic research efforts. [ABSTRACT FROM AUTHOR]

Background: FSGS is the final common pathway to nephron loss in most forms of severe or progressive glomerular injury. Although podocyte injury initiates FSGS, parietal epithelial cells (PECs) are the main effectors. Because PDGF takes part in fibrotic processes, we hypothesized that the ligand PDGF-B and its receptor PDGFR- β participate in the origin and progression of FSGS., Methods: We challenged Thy1.1 transgenic mice, which express Thy1.1 in the podocytes, with anti-Thy1.1 antibody to study the progression of FSGS. We investigated the role of PDGF in FSGS using challenged Thy1.1 mice, 5/6 nephrectomized mice, Col4 -/- (Alport) mice, patient kidney biopsies, and primary murine PECs, and challenged Thy1.1 mice treated with neutralizing anti-PDGF-B antibody therapy., Results: The unchallenged Thy1.1 mice developed only mild spontaneous FSGS, whereas challenged mice developed progressive FSGS accompanied by a decline in kidney function. PEC activation, proliferation, and profibrotic phenotypic switch drove the FSGS. During disease, PDGF-B was upregulated in podocytes, whereas PDGFR- β was upregulated in PECs from both mice and patients with FSGS. Short- and long-term treatment with PDGF-B neutralizing antibody improved kidney function and reduced FSGS, PEC proliferation, and profibrotic activation. In vitro , stimulation of primary murine PECs with PDGF-B recapitulated in vivo findings with PEC activation and proliferation, which was inhibited by PDGF-B antibody or imatinib., Conclusion: PDGF-B-PDGFR- β molecular crosstalk between podocytes and PECs drives glomerulosclerosis and the progression of FSGS., Podcast: This article contains a podcast at., (Copyright © 2022 by the American Society of Nephrology.)

Background: Immunoglobulin A nephropathy (IgAN) is a major cause of end‐stage renal disease. Complement activation via the lectin pathway influences outcomes in IgAN. We examined the association of glomerular C4d deposition with clinicopathological severity at diagnosis and the disappearance of proteinuria in Japanese pediatric IgAN patients. Methods: We retrospectively analyzed 25 children newly diagnosed with IgAN at Hokkaido University Hospital. We evaluated glomerular C4d immunofluorescent staining at diagnosis. We compared clinical findings, pathological findings (based on Oxford classification), and the disappearance of proteinuria within 24 months after renal biopsy between C4d‐positive and C4d‐negative patients. Results: Glomerular C4d staining was observed in 14 patients (56.0%). C4d‐positive patients had significantly higher proteinuria at diagnosis than C4d‐negative patients (2.03 g/gCr vs 0.78 g/gCr; P = 0.005). The number of glomeruli with segmental glomerulosclerosis or adhesion (8.0% vs 0.0%; P = 0.046) and the extent of tubular atrophy/interstitial fibrosis (9.46% vs 2.86%; P = 0.031) were significantly increased in C4d‐positive patients compared with C4d‐negative patients. Further, the proportion of patients with modified T1 (>10%) was significantly higher in the C4d‐positive group than the C4d‐negative group. There was no significant difference, however, in the disappearance rate of proteinuria at 24 months after renal biopsy between groups (64% vs 82%; P = 0.149). Conclusions: Glomerular C4d deposition was associated with clinicopathological severity at diagnosis in Japanese pediatric patients with IgAN. Glomerular C4d deposition, however, was not a predictor of the disappearance of proteinuria within 24 months after diagnosis in Japanese pediatric patients with IgAN. [ABSTRACT FROM AUTHOR]

Focal segmental glomerulosclerosis (FSGS) presents with scar in parts of some glomeruli and often progresses to global and diffuse glomerulosclerosis. Podocyte injury is the initial target in primary FSGS, induced by a circulating factor. Several gene variants, for example, APOL1, are associated with increased susceptibility to FSGS. Primary FSGS may be due to genetic mutation in key podocyte genes. Increased work stress after loss of nephrons, epigenetic mechanisms, and various profibrotic pathways can contribute to progressive sclerosis, regardless of the initial injury. The progression of FSGS lesions also involves crosstalk between podocytes and other kidney cells, such as parietal epithelial cells, glomerular endothelial cells, and even tubular epithelial cells. New insights related to these mechanisms could potentially lead to new therapeutic strategies to prevent progression of FSGS. [ABSTRACT FROM AUTHOR]