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Introduction: AMPK (AMP-activated protein kinase) is an enzyme that acts as a metabolic sensor and regulates multiple pathways via phosphorylating proteins in metabolic and proliferative pathways. The aim of this work was to study the activated cellular AMPK (phosphorylated-AMPK at Thr172, pAMPK) levels in pituitary tumor samples from patients with sporadic and familial acromegaly, as well as in samples from normal human pituitary gland., Methods: We studied pituitary adenoma tissue from patients with sporadic somatotroph adenomas, familial acromegaly with heterozygote germline variants in the aryl hydrocarbon receptor interacting protein (AIP) gene (p.Q164*, p.R304* and p.F269&#95;H275dup) and autopsy from normal pituitary glands without structural alterations., Results: Cellular levels of pAMPK were significantly higher in patients with sporadic acromegaly compared to normal pituitary glands (p < 0.0001). Tissues samples from patients with germline AIP mutations also showed higher cellular levels of pAMPK compared to normal pituitary glands. We did not observe a significant difference in cellular levels of pAMPK according to the cytokeratin (CAM5.2) pattern (sparsely or densely granulated) for tumor samples of sporadic acromegaly., Conclusion: Our data show, for the first time in human cells, an increase of cellular levels of pAMPK in sporadic somatotropinomas, regardless of cytokeratin pattern, as well as in GH-secreting adenomas from patients with germline AIP mutations., Competing Interests: Declaration of competing Interest The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. MFB and AROJr are current full-time employees at Ipsen in Brazil and USA, respectively. AROJr has stock shares from Ipsen., (Copyright © 2024. Published by Elsevier B.V.)

African Americans have a significantly higher risk of developing chronic kidney disease, especially focal segmental glomerulosclerosis -, than European Americans. Two coding variants (G1 and G2) in the APOL1 gene play a major role in this disparity. While 13% of African Americans carry the high-risk recessive genotypes, only a fraction of these individuals develops FSGS or kidney failure, indicating the involvement of additional disease modifiers. Here, we show that the presence of the APOL1 p.N264K missense variant, when co-inherited with the G2 APOL1 risk allele, substantially reduces the penetrance of the G1G2 and G2G2 high-risk genotypes by rendering these genotypes low-risk. These results align with prior functional evidence showing that the p.N264K variant reduces the toxicity of the APOL1 high-risk alleles. These findings have important implications for our understanding of the mechanisms of APOL1-associated nephropathy, as well as for the clinical management of individuals with high-risk genotypes that include the G2 allele., (© 2023. The Author(s).)

Liver test abnormalities are frequently observed in patients with coronavirus disease 2019 (COVID-19) and are associated with worse prognosis. However, information is limited about pathological changes in the liver in this infection, so the mechanism of liver injury is unclear. Here we describe liver histopathology and clinical correlates of 27 patients who died of COVID-19 in Manaus, Brazil. There was a high prevalence of liver injury (elevated alanine aminotransferase and aspartate aminotransferase in 44% and 48% of patients, respectively) in these patients. Histological analysis showed sinusoidal congestion and ischemic necrosis in more than 85% of the cases, but these appeared to be secondary to systemic rather than intrahepatic thrombotic events, as only 14% and 22% of samples were positive for CD61 (marker of platelet activation) and C4d (activated complement factor), respectively. Furthermore, the extent of these vascular findings did not correlate with the extent of transaminase elevations. Steatosis was present in 63% of patients, and portal inflammation was present in 52%. In most cases, hepatocytes expressed angiotensin-converting enzyme 2 (ACE2), which is responsible for binding and entry of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), even though this ectoenzyme was minimally expressed on hepatocytes in normal controls. However, SARS-CoV-2 staining was not observed. Most hepatocytes also expressed inositol 1,4,5-triphosphate receptor 3 (ITPR3), a calcium channel that becomes expressed in acute liver injury. Conclusion: The hepatocellular injury that commonly occurs in patients with severe COVID-19 is not due to the vascular events that contribute to pulmonary or cardiac damage. However, new expression of ACE2 and ITPR3 with concomitant inflammation and steatosis suggests that liver injury may result from inflammation, metabolic abnormalities, and perhaps direct viral injury., (© 2021 The Authors. Hepatology Communications published by Wiley Periodicals LLC on behalf of American Association for the Study of Liver Diseases.)

Background and Aim: Idiopathic nephrotic syndrome (INS) is classified according to the response to drug therapy in steroid-sensitive (SS), steroid-dependent (SD), and steroid-resistant (SR) categories. Previous studies showed changes in inflammatory activity of subpopulations of lymphocytes in INS. This study aimed to compare SS and SR patients in regard to subpopulations of leukocytes, profile of regulatory lymphocytes, and migratory activity of lymphocyte subpopulations. Results obtained in INS patients were also compared to age and sex-matched healthy controls. Methods: This is a cross-sectional study including SS patients ( n = 30), SR patients ( n = 14), and controls ( n = 10). Peripheral blood samples were withdrawn for ex-vivo leukocyte flow cytometry analysis. Results: Percentage of B-lymphocytes and natural killer (NK) cells were significantly reduced in SR patients when compared to controls, while the percentage of NKT cells were decreased in SS patients in comparison to controls. Percentages of CD4 + expressing FoxP3 and CTLA4 were significantly higher in SS patients in comparison to SR patients and controls. The expression of integrin CD18 on the surface of T lymphocytes (CD3 + ) was reduced in SS patients if compared to controls. Conclusion: This study found that SS INS patients have higher levels of regulatory T-lymphocytes and lower expression of adhesion molecules than SR patients.

Involvement of the kidneys by lupus nephritis (LN) is one of the most severe clinical manifestations seen in individuals with systemic lupus erythematosus (SLE). LN is more frequent and severe in pediatric patients and has been associated with higher morbidity and mortality rates. This narrative review aimed to describe the general aspects of LN and its particularities when affecting children and adolescents, while focusing on the disease's etiopathogenesis, clinical manifestations, renal tissue alterations, and treatment options.

Introduction: Renin angiotensin system (RAS) plays a role in idiopathic nephrotic syndrome (INS). Most studies investigated only the classical RAS axis. Therefore, the aims of the present study were to evaluate urinary levels of RAS molecules related to classical and to counter-regulatory axes in pediatric patients with INS, to compare the measurements with levels in healthy controls and to search for associations with inflammatory molecules, proteinuria and disease treatment. Subjects and methods: This cross-sectional study included 31 patients with INS and 19 healthy controls, matched for age and sex. Patients and controls were submitted to urine collection for measurement of RAS molecules [Ang II, Ang-(1-7), ACE and ACE2] by enzyme immunoassay and cytokines by Cytometric Bead Array. Findings in INS patients were compared according to proteinuria: absent (<150 mg/dl, n = 15) and present (≥150 mg/dl, n = 16). Results: In comparison to controls, INS patients had increased Ang II, Ang-(1-7) and ACE, levels while ACE2 was reduced. INS patients with proteinuria had lower levels of ACE2 than those without proteinuria. ACE2 levels were negatively correlated with 24-h-proteinuria. Urinary concentrations of MCP-1/CCL2 were significantly higher in INS patients, positively correlated with Ang II and negatively with Ang-(1-7). ACE2 concentrations were negatively correlated with IP-10/CXCL-10 levels, which, in turn, were positively correlated with 24-h-proteinuria. Conclusion: INS patients exhibited changes in RAS molecules and in chemokines. Proteinuria was associated with low levels of ACE2 and high levels of inflammatory molecules., (© 2019 The Author(s).)

Type 4 phosphodiesterases (PDE4s) of the large PDE enzyme superfamily have unique specificity for cAMP and may, therefore, be relevant for somatotroph tumorigenesis. Somatotroph adenomas typically overexpress PDEs probably as part of a compensatory mechanism to reduce cAMP levels. The rat PDE4A5 isoform (human homolog PDE4A4) interacts with the AIP protein, coded by a tumour suppressor gene mutated in a subgroup of familial isolated pituitary adenomas (FIPAs). PDE4A8 is the closest related isoform of PDE4A4. We aimed to evaluate the expression of both PDE4A4 and PDE4A8 in GH cells of AIP-mutated adenomas and compare their expression with that in GH cells from sporadic AIP-mutation negative GH-secreting adenomas, where we had shown previously that both PDE4A4 and PDE4A8 isoforms had been over-expressed. Confocal immunofluorescence analysis showed that both PDE4A8 and PDE4A4 had lower expression in AIP-mutated somatotropinoma samples compared to sporadic GH-secreting tumours (P < 0.0001 for both). Based on the association of low PDE4A4 and PDE4A8 expression with germline AIP-mutations positive samples we suggest that lack of AIP hinders the upregulation of PDE4A8 and PDE4A4 protein seen in sporadic somatotrophinomas. These data point to a unique disturbance of the cAMP-PDE pathway in AIP-mutation positive adenomas, which may help to explain their well-described poor response to somatostatin analogues., (Crown Copyright © 2018. Published by Elsevier B.V. All rights reserved.)

Losartan (Los), a non-peptidic orally active agent, reduces arterial pressure through specific and selective blockade of angiotensin II receptor AT1. However, this widely used AT1 antagonist presents low bioavailability and needs once or twice a day dosage. In order to improve its bioavailability, we used the host: guest strategy based on β-cyclodextrin (βCD). The results suggest that Los included in βCD showed a typical pulsatile release pattern after oral administration to rats, with increasing the levels of plasma of Los. In addition, the inclusion compound presented oral efficacy for 72 h, in contrast to Los alone, which shows antagonist effect for only 6 h. In transgenic (mREN2)L27 rats, the Los/βCD complex reduced blood pressure for about 6 d, whereas Los alone reduced blood pressure for only 2 d. More importantly, using this host: guest strategy, sustained release of Los for over a week via the oral route can be achieved without the need for encapsulation in a polymeric carrier. The proposed preformulation increased the efficacy reducing the dose or spacing between each dose intake.

Objective: There is evidence of an important role of immune system changes in the triggering and maintenance of idiopathic nephrotic syndrome (INS). The aim of this study was to investigate the expression of cytokines in lymphocyte populations of patients with INS in comparison to healthy individuals, according to proteinuria., Methods: This cross-sectional study included 44 patients with INS and eight healthy children, matched for age and sex (controls). Patients were subdivided according to proteinuria: persistent proteinuria or partial remission (PP≥300mg/24h, n=17) and low proteinuria or complete remission (LP<300mg/24h, n=27). Ex vivo analysis of peripheral blood leukocytes by flow cytometry was performed using surface markers for T-lymphocytes, TCD4, TCD8, natural killer (NK) cells, NKT, and B-lymphocytes. Frequencies of intracellular cytokines were analyzed in these cells., Results: The frequencies of B-lymphocytes, NK cells, and NKT cells were lower in INS than in controls, whereas INS patients had a higher frequency of CD4 + tumor necrosis factor (TNF)-α + cells than controls. Cytotoxic-T-lymphocytes expressing IFN-γ were lower in INS than in controls. Patients with PP showed higher frequencies of CD4-T-lymphocytes expressing IFN-γ and TNF-α than controls. CD8-lymphocytes expressing TNF-α were increased in PP group when compared with LP and controls, while CD8 + interferon (IFN)-γ + cells were lower than in LP and in controls., Conclusion: Regardless the level of proteinuria, INS patients had increased expression of TNF-α in CD4-lymphocytes and reduced expression of IFN-γ in CD8-lymphocytes. Persistence of proteinuria was associated with higher levels of inflammatory markers., (Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Background: The search for risk factors for chronic kidney disease in children with focal segmental glomerulosclerosis (FSGS) is important in defining prognosis and individualized treatment. This study preliminarily investigated whether CD44 immunostaining in glomerular parietal epithelial cells (PECs) is a prognostic marker in pediatric FSGS., Methods: In this retrospective study, 26 patients with FSGS, biopsied from 1985 to 2010, were evaluated. Immunohistochemistry for CD44 was performed in all cases. For analysis purposes, patients were grouped according to whether or not they were positive for CD44 in PECs. The primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) of 50% or more., Results: Median follow-up was 6.9 years. Median renal survival was 14.5 years and probability of a 50% decline of eGRF was 30% in 10 years. Nine children exhibited the primary outcome and 7 developed end-stage renal disease (ESRD). In comparison with PEC CD44-negative patients (n = 18), PEC CD44-positive patients (n = 8) presented lower baseline eGFR (99 ± 41 versus 141 ± 44 ml/min/1.73 m 2 , p = 0.035) and a significant decline in eGFR (-38.6 ± 39.5 versus -5.6 ± 25.3 ml/min/1.73 m 2 /year, p = 0.018). No difference was observed in FSGS subtypes or other glomerular features. Presence of CD44 staining in PECs was significantly associated with the decline in baseline eGFR of 50% or more. Renal survival was significantly reduced in PEC CD44-positive patients (3.8 vs 14.6 years in C4d-negative, p < 0.05)., Conclusion: Our preliminary findings indicate, for the first time, that positivity for CD44 in PECs seems to be a pathological marker of renal function deterioration in pediatric patients with FSGS.

Background: Data on the risk factors for chronic kidney disease in children with immunoglobulin A nephropathy (IgAN) are scarce. This study was aimed at investigating whether glomerular C4d immunostaining is a prognostic marker in pediatric IgAN., Methods: In this retrospective cohort study, 47 patients with IgAN biopsied from 1982 to 2010 were evaluated. Immunohistochemistry for C4d was performed in all cases. For analysis, patients were grouped according to positivity or not for C4d in the mesangial area. Primary outcome was a decline in baseline estimated glomerular filtration rate (eGFR) by 50% or more., Results: Median follow-up was 8.3 years. Median renal survival was 13.7 years and the probability of a 50% decline in eGFR was 13% over 10 years. Nine children exhibited the primary outcome and 4 developed end-stage renal disease (ESRD). Compared with C4d-negative patients (n = 37), C4d-positive patients (n = 10) presented higher baseline proteinuria (1.66 ± 0.68 vs 0.47 ± 0.19 g/day/1.73 m2, p < 0.001), a progressive decline in eGFR (−10.04 ± 19.38 vs 1.70 ± 18.51 ml/min/1.73 m2/year; p = 0.045), and more frequently achieved the primary outcome (50.0 vs 10.8%, p = 0.013), and ESRD (30.0 vs 2.7%, p = 0.026). No difference was observed in Oxford classification variables. Baseline proteinuria, endocapillary hypercellularity and mesangial C4d deposition were associated with primary outcome in univariate analysis. Proteinuria and mesangial C4d deposition at baseline independently predicted the decline in eGFR. Renal survival was significantly reduced in C4d-positive patients (8.6 vs 15.1 years in C4d-negative patients, p < 0.001)., Conclusions: In this exclusively pediatric cohort, positivity for C4d in the mesangial area was an independent predictor of renal function deterioration in IgAN.

Objective: The Oxford Classification for Immunoglobulin A nephropathy (IgAN) identifies pathological variables that may predict the decline of renal function. This study aimed to evaluate the Oxford Classification variables as predictors of renal dysfunction in a cohort of Brazilian children and adolescents with IgAN., Methods: A total of 54 patients with IgAN biopsied from 1982 to 2010 were assessed. Biopsies were re-evaluated and classified according to the Oxford Classification. Multivariate analysis of laboratory and pathological data was performed. The primary outcomes were decline of baseline estimated glomerular filtration rate (eGFR) greater than or equal to 50%., Results: Mean follow-up was 7.6±5.0 years. Mean renal survival was 13.5±0.8 years and probability of decline ≥50% in baseline eGFR was 8% at five years of follow-up and 15% at ten years. Ten children (18.5%) had a decline of baseline eGFR≥50% and five (9.3%) evolved to end-stage renal disease. Kaplan-Meier analysis showed that baseline proteinuria, proteinuria during follow-up, endocapillary proliferation, and tubular atrophy/interstitial fibrosis were associated with the primary outcome. Multivariate Cox analysis showed that only baseline proteinuria (HR, 1.73; 95% CI, 1.20-2.50, p=0.003) and endocapillary hypercellularity (HR, 37.18; 95% CI, 3.85-358.94, p=0.002) were independent predictors of renal dysfunction. No other pathological variable was associated with eGFR decline in the multivariate analysis., Conclusion: This is the first cohort study that evaluated the predictive role of the Oxford Classification in pediatric patients with IgAN from South America. Endocapillary proliferation was the unique pathological feature that independently predicted renal outcome., (Copyright © 2017 Sociedade Brasileira de Pediatria. Published by Elsevier Editora Ltda. All rights reserved.)

Purpose:: To evaluate the effects of chronic consumption of green tea on body weight and distribution of visceral fat by Computed tomography in female Wistar rats., Methods:: Wistar rats were divided into control group (n = 5), which received water and feed ad libitum, and green tea group (n = 8), in which water has been replaced by green tea. The animals were weighed weekly and Computed Tomography was used at the beginning (1st week) and end (18th week) of the experiment for evaluating the distribution of visceral fat. The animals were followed for 18 weeks., Results:: There was no significant difference in body weight between the groups. However, there was significant difference in visceral fat area. The green tea group had less visceral fat area at the end of the experiment, 3.67 ± 1.2 cm2, while the control group showed an area of 6.25 ± 2.2 cm (p = 0.00)., Conclusions:: Chronic consumption of green tea leads to decreased visceral adipose tissue area.

Nitric oxide (NO) is widely recognized for its role in regulating renal function and blood pressure. However, the precise mechanisms by which NO affects renal epithelial cells remain understudied. Our previous research has shown that NO signaling in glomerular podocytes can be initiated by Angiotensin II (ANG II) but not by ATP. This study aims to elucidate the crucial interplay between the renin-angiotensin system (RAS) and NO production in podocytes. To conduct our research, we used cultured human podocytes and freshly isolated rat glomeruli. A variety of RAS peptides were used, alongside confocal microscopy, to detect NO production and NO/Ca2+ cross talk. Dynamic changes in the podocyte cytoskeleton, mediated by RAS-NO intracellular signaling, were observed using fluorescent labeling for F-actin and scanning probe microscopy. The experiments demonstrated that ANG II and ANG III generated high levels of NO by activating the angiotensin II type 2 receptor (AT2R). We did not detect functional MAS receptor presence in podocytes, and the moderate NO response to ANG 1–7 was also mediated through AT2R. Furthermore, NO production impacted intracellular Ca2+ signaling and correlated with an increase in podocyte volume and growth. Scanning probe experiments revealed that AT2R activation and the corresponding NO generation are responsible for the protrusion of podocyte lamellipodia. Taken together, our data indicate that AT2R activation enhances NO production in podocytes and subsequently mediates changes in Ca2+ signaling and podocyte volume dynamics. These mechanisms may play a significant role in both physiological and pathophysiological interactions between the RAS and podocytes. NEW & NOTEWORTHY: The renin-angiotensin system plays a crucial role in the production of intracellular nitric oxide within podocytes. This mechanism operates through the activation of the angiotensin II type 2 receptor, leading to dynamic modifications in intracellular calcium levels and the actin filament network. This intricate process is vital for linking the activity of angiotensin receptors to podocyte function. [ABSTRACT FROM AUTHOR]

Angiotensin-(1-7), an active fragment of both angiotensins I and II, generally opposes the vascular and proliferative actions of angiotensin II. Here we evaluated effects of the angiotensin-(1-7) receptor Mas on renal physiology and morphology using Mas-knockout mice. Compared to the wild-type animals, Mas knockout mice had significant reductions in urine volume and fractional sodium excretion without any significant change in free-water clearance. A significantly higher inulin clearance and microalbuminuria concomitant with a reduced renal blood flow suggest that glomerular hyperfiltration occurs in the knockout mice. Histological analysis found reduced glomerular tuft diameter and increased expression of collagen IV and fibronectin in the both the mesangium and interstitium, along with increased collagen III in the interstitium. These fibrogenic changes and the renal dysfunction of the knockout mice were associated with an upregulation of angiotensin II AT1 receptor and transforming growth factor-beta mRNA. Our study suggests that Mas acts as a critical regulator of renal fibrogenesis by controlling effects transduced through angiotensin II AT1 receptors in the kidney.

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Copyright of Journal of Medical Biochemistry is the property of Society of Medical Biochemists of Serbia and its content may not be copied or emailed to multiple sites or posted to a listserv without the copyright holder's express written permission. However, users may print, download, or email articles for individual use. This abstract may be abridged. No warranty is given about the accuracy of the copy. Users should refer to the original published version of the material for the full abstract. (Copyright applies to all Abstracts.)

C4d, a split product of C4 activation in classical and lectin pathways of the complement system activation, has been regarded as a footprint of tissue damage in antibody-mediated rejection in transplantology. The introduction of C4d staining into daily clinical practice aroused an ever-increasing interest in the role of antibody-mediated mechanisms in kidney allograft rejection. However, this marker of complement activation is also important in other various kidney glomerular pathologies such as immunoglobulin A nephropathy, membranoproliferative glomerulonephritis, lupus nephritis, and others. In routine histopathological practice, C4d staining can be done by two his tological methods, specifically by immunofluorescence on frozen tissue using monoclonal antibody to C4d (with the downside of unsteady availability of frozen tissue) or by immunohistochemistry using C4d antibodies on formalin-fixed and paraffin-embedded renal tissue. The aim of this narrative review is to summarize recent knowled ge about the complement fragment C4d and its significance in differe nt kidney pathologies, focusing on its immunohistochemical detection in renal tissue biopsies. We have supplemented this review with our experience with our proprietary methodology of preparation and practical use of antibodies such as anti-C4d, on a small national level. Immunohistochemical staining for C4d has revolutionized the field of renal histopathology. Despite being a simple diagnostic test, its utility can be of utmost importance, especially in a resource-poor setting where immunofluorescence and frozen tissue may not be available [ABSTRACT FROM AUTHOR]

Depression is a mood disorder characterized by abnormal thoughts. The pathophysiology of depression is related to the deficiency of serotonin (5HT), which is derived from tryptophan (Trp). Mitochondrial dysfunction, oxidative stress, and neuroinflammation are involved in the pathogenesis of depression. Notably, the renin–angiotensin system (RAS) is involved in the pathogenesis of depression, and different findings revealed that angiotensin‐converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) may be effective in depression. However, the underlying mechanism for the role of dysregulated brain RAS‐induced depression remains speculative. Therefore, this review aimed to revise the conceivable role of ACEIs and ARBs and how these agents ameliorate the pathophysiology of depression. Dysregulation of brain RAS triggers the development and progression of depression through the reduction of brain 5HT and expression of brain‐derived neurotrophic factor (BDNF) and the induction of mitochondrial dysfunction, oxidative stress, and neuroinflammation. Therefore, inhibition of central classical RAS by ARBS and ACEIs and activation of non‐classical RAS prevent the development of depression by regulating 5HT, BDNF, mitochondrial dysfunction, oxidative stress, and neuroinflammation. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE) is a chronic, multisystem autoimmune disorder. When SLE occurs in individuals under the age of 18, it is referred to as childhood-onset SLE (cSLE). Currently, there is a dearth of bibliometric research pertaining to cSLE. Method: Relevant studies in the field of cSLE from 2000 to 2022 were screened from the Web of Science Core Collection (WoSCC). CiteSpace and VOSviewer software were used to visualize the annual publications, countries, institutions, authors, journals, keywords, and references, after which the authors conducted the scientific analysis. Results: A total of 2857 articles were included in this study, and the number of articles published in the past 20 years showed an overall upwards trend. The most prolific countries are the United States, China, and Brazil; however, the United States, Canada, and the United Kingdom are clearly superior in terms of literary influence, and there is more cooperation between them and their institutions. LUPUS (n = 389) contributed the most to the variance. Brunner, HI's contribution in the field of cSLE is outstanding. The words related to 'lupus nephritis' and 'antibodies' are important words reflected in the keyword network diagram. The keywords included 'evidence-based recommendation', 'validation', 'diagnosis' and 'adult' from 2019, and 'continuous bursts' to the present. Conclusion: This study examined the research status of cSLE patients, discussed and analysed the research hotspots and trends in this field, and provided a reference for further research in this field to promote the development of cSLE research. [ABSTRACT FROM AUTHOR]

Glomerular diseases are a leading cause of chronic kidney disease worldwide. Both acquired and hereditary glomerulopathies frequently share a common final disease mechanism: disruption of the glomerular filtration barrier, podocyte injury, and ultimately podocyte death and detachment. Over 70 monogenic causes of proteinuric kidney disease have been identified, and most of these genes are highly expressed in podocytes, regulating key processes such as maintenance of the slit diaphragm, regulation of actin cytoskeleton remodeling, and modulation of downstream transcriptional pathways. Collectively, these are increasingly being referred to as hereditary "podocytopathies," in which podocyte injury is the central feature driving proteinuria and kidney dysfunction. In this review, we provide an overview of the monogenic podocytopathies and discuss the molecular mechanisms by which single-gene defects lead to podocyte injury and ultimately glomerulosclerosis. We review how advances in genomic technology and a better understanding of the cell biological basis of disease have led to the development of more targeted and personalized therapeutic strategies, including an overview of small molecule and gene therapy approaches., (© 2024. The Author(s), under exclusive licence to International Pediatric Nephrology Association.)

Introduction: The review discusses the pathophysiological mechanisms of SARS-CoV-2, the modes of transmission, and the long-term health consequences of COVID-19, emphasizing the importance of research and successful public health initiatives., Content: COVID-19 taxonomy, pathophysiology, symptomatology, and epidemiological importance are the key objects of this research paper. This review explains how COVID-19 affects different systems of the body, including respiratory, cardiovascular, and reproductive systems of the human body. It describes the modes of entry of the virus into the cell; more precisely, ACE2 and TMPRSS2 in viral entry. In addition, the present study analyzes the situation of COVID-19 in India regarding vaccine development and the transmission rate related to socioeconomic factors., Summary: The manifestation of COVID-19 presents a lot of symptoms and post-acute problems, issues which are seriously impacting mental health and physical health as well. The present review summarizes current research into pathogenicity and the mode of virus transmission, together with immunological responses. Coupled with strong vaccination programs, public health initiatives should hold the key to fighting this pandemic., Outlook: Long-term effects and the development of treatment methods will need further study, as ambiguities on COVID-19 remain. Multidisciplinary collaboration across healthcare sectors in this respect is of paramount importance for the prevention of further spread and protection of public health., (© 2024 Walter de Gruyter GmbH, Berlin/Boston.)

Spike surface glycoprotein and small envelope matrix-nucleocapsid proteins, is from the Coronaviridae family and binds to host receptors via spike surface proteins. Although it shows its symptoms especially on the respiratory tract, various studies have been carried out considering that it also affects other systems in the body. For the virus to enter the host cell, it must bind to ACE2 (angiotensin converting enzyme 2). ACE2 is a key protein involved in balancing Ang I and Ang II levels. With receptors such as TMPRSS2 (transmembrane serine protease 2), the effects of the virus on the human reproductive system are much better understood. Since human germ cells and early embryos express ACE2, there is a potential risk of the Coronavirus associated with germ cells. Studies show that the coronavirus changes the amount and density of hormones in the human reproductive system. The fact that most of the partners of 35 female patients who had SARS-CoV-2 in the studies were infected individuals suggests that sexual transmission may be possible. It was determined that TMPRSS4, Cathepsin B and L, FURIN, MX1 and BSG gene expressions were high in the menstrual cycle, while ACE 2 and TMPRSS2 were moderately expressed. It has been shown that the ACE2 enzyme is most intensely expressed is the testes. Studies have shown that sperm DNA (deoxyribonucleic acid) fragmentation, changes in hormone levels and the formation of anti-sperm antibodies are an important cause of male infertility. Infected men have been found to have an impaired spermatogenesis. This rewiew; it aims to draw attention to the possible effects of the corona virus on the human reproductive system and to reveal new mechanisms for new research to be done. [ABSTRACT FROM AUTHOR]

The pathogenetic mechanisms underlying the onset and the post-transplant recurrence of primary focal segmental glomerulosclerosis (FSGS) are complex and remain yet to be fully elucidated. However, a growing body of evidence emphasizes the pivotal role of the immune system in both initiating and perpetuating the disease. Extensive investigations, encompassing both experimental models and patient studies, have implicated T cells, B cells, and complement as crucial actors in the pathogenesis of primary FSGS, with various molecules being proposed as potential "circulating factors" contributing to the disease and its recurrence post kidney-transplantation. In this review, we critically assessed the existing literature to identify essential pathways for a comprehensive characterization of the pathogenesis of FSGS. Recent discoveries have shed further light on the intricate interplay between these mechanisms. We present an overview of the current understanding of the engagement of distinct molecules and immune cells in FSGS pathogenesis while highlighting critical knowledge gaps that require attention. A thorough characterization of these intricate immune mechanisms holds the potential to identify noninvasive biomarkers that can accurately identify patients at high risk of post-transplant recurrence. Such knowledge can pave the way for the development of targeted and personalized therapeutic approaches in the management of FSGS. [ABSTRACT FROM AUTHOR]

Acute leukemias (ALs) are the most common cancers in pediatric population. There are two types of ALs: acute lymphoblastic leukemia (ALL) and acute myeloid leukemia (AML). Some studies suggest that the Renin Angiotensin System (RAS) has a role in ALs. RAS signaling modulates, directly and indirectly, cellular activity in different cancers, affecting tumor cells and angiogenesis. Our review aimed to summarize the role of RAS in ALs and to explore future perspectives for the treatment of these hematological malignancies by modulating RAS molecules. The database including Pubmed, Scopus, Cochrane Library, and Scielo were searched to find articles about RAS molecules in ALL and in pediatric patients. The search terms were "RAS", "Acute Leukemia", "ALL", "Angiotensin-(1-7)", "Pediatric", "Cancer", "Angiotensin II", "AML". In the bone marrow, RAS has been found to play a key role in blood cell formation, affecting several processes including apoptosis, cell proliferation, mobilization, intracellular signaling, angiogenesis, fibrosis, and inflammation. Local tissue RAS modulates tumor growth and metastasis through autocrine and paracrine actions. RAS mainly acts via two molecules, Angiotensin II (Ang II) and Angiotensin (1-7) [Ang-(1-7)]. While Ang II promotes tumor cell growth and stimulates angiogenesis, Ang-(1-7) inhibits the proliferation of neoplastic cells and the angiogenesis, suggesting a potential therapeutic role of this molecule in ALL. The interaction between ALs and RAS reveals a complex network of molecules that can affect the hematopoiesis and the development of hematological cancers. Understanding these interactions could pave the way for innovative therapeutic approaches targeting RAS components., (© 2024. The Author(s), under exclusive licence to Springer Nature B.V.)

Since the Corona Virus Disease 2019 (COVID-19) pandemic, there has been increasing evidence that severe acute respiratory syndrome coronavirus 2 (SARSCoV- 2) infection is associated with acute cerebrovascular events such as cerebral infarction, cerebral hemorrhage, and cerebral venous thrombosis. Although the mechanism of cerebrovascular complications among COVID-19 patients has not been adequately elucidated, the hypercoagulable state, excessive inflammation and ACE-2-associated alterations in the renin-angiotensin-aldosterone system after SARS-CoV-2 infection probably play an essential role. In this overview, we discuss the possible mechanisms underlying the SARS-CoV-2 infection leading to acute cerebrovascular events and review the characteristics of COVID- 19-related acute cerebrovascular events cases and treatment options available worldwide. [ABSTRACT FROM AUTHOR]

IgA nephropathy (IgAN) is observed in subjects of any age, however perspective and management of this disease are different between adult and pediatrician Nephrologists. Most children with IgAN present with gross hematuria rapidly vanishing or persistent mild microscopic hematuria, which rarely progresses to end stage renal disease (ESRD) over the pediatric observation. The perspective of IgAN in adults is of a slowly progressive glomerular disease with 30-40% probabilities to reach ESRD. However, mild cases of IgAN in children might be missed with manifestation of irreversible damage only decades after the true onset, as 50% of subjects with IgAN enter renal replacement treatment before the age of 50 years. In both adults and children the assessment of risk profile is crucial to avoid overtreatment in benign cases or institute a prompt and valid therapy in potentially progressive cases. In case of common risk factors, new therapeutic opportunities tested in adults might be applied to children with the expectation of similar results. If IgAN is the same disease in spite of different clinical profiles in children and adults, an early intervention may be the correct way to prevent progression decades later. On the contrary, if we are dealing with different clinical entities, the treatment in pediatric and in adult settings must be kept apart. This review addresses to report similarities and differences of IgAN across the life periods in order to reason on the application of newly offered treatments over the entire spectrum of this disease or in focused age indications.

Background: C4d may be used as a marker to evaluate the condition and prognosis of adults with IgA nephropathy, but there have been few studies of children with IgA nephropathy. Methods: C4d immunohistochemical staining was performed on samples from children with IgA nephropathy with C1q-negative immunofluorescence. The clinical and pathological treatment and prognostic characteristics of children in the C4d-positive and -negative groups were compared. Results: A total of sixty-five children with IgA nephropathy were included in the study and were followed up for an average of 37 months. C4d was mainly deposited along the capillary loops. The urinary protein-to-creatinine ratio (UPCR) in the C4d-positive group was significantly higher than that in the C4d-negative group (3.97 vs. 0.81, P < 0.001), and the average integrated optical density value of each child was positively correlated with the UPCR (r = 0.441, P < 0.001). There was a significant difference in the proportions of children with mesangial hypercellularity (M1) (68.97% vs. 44.44%, P = 0.048) and segmental glomerulosclerosis (S1) (65.52% vs. 33.33%, P = 0.010) between the C4d-positive group and the C4d-negative group. The proportion of children who received immunosuppressants in the C4d-positive group was higher than that in the C4d-negative group (86.21% vs. 36.11%, P < 0.001). There was no significant difference in the proportion of children developing kidney failure between the two groups. Conclusion: C4d was found to be associated with proteinuria, segmental lesions, and immunosuppressant treatment. Activation of the lectin pathway may reflect the severity of clinical and pathological manifestations of IgA nephropathy in children. [ABSTRACT FROM AUTHOR]

Childhood-onset systemic lupus erythematosus (SLE) is characterized by increased rates of kidney involvement, termed lupus nephritis. Despite the significant morbidity and mortality associated with this disease, lupus nephritis trials have been plagued by repeated failures to meet clinical endpoints. However, improvements in trial design and the development of targeted approaches have begun to yield promising results, including two new FDA-approved lupus nephritis treatments since 2020. These include belimumab, a monoclonal antibody targeting the B cell survival cytokine BAFF (B cell activating factor), and voclosporin, a cyclosporin analog with improved pharmacokinetic characteristics. In this review, we will summarize the data supporting regulatory approval for these agents in lupus nephritis and highlight ongoing clinical trials targeting the diverse immunologic drivers of renal inflammation in SLE. While pediatric patients remain underrepresented in lupus clinical trials, given the increased severity of childhood-onset SLE and need for long-term protection from kidney damage, we anticipate the need for off-label use of these targeted therapies in the pediatric population. Future studies are needed to define optimal patient selection, drug combinations, and treatment duration in pediatric lupus nephritis. [ABSTRACT FROM AUTHOR]

Background: Recent studies suggest that angiotensin-converting enzyme 2 (ACE2) and angiotensin-(1–7) [Ang-(1–7)] might have beneficial effects on the cardiovascular system. We investigated the effects of olmesartan on the changes in serum ACE2 and Ang-(1–7) levels as well as kidney and vascular function in patients with type 2 diabetes and hypertension. Methods: This was a prospective, randomized, active comparator-controlled trial. Eighty participants with type 2 diabetes and hypertension were randomized to receive 20 mg of olmesartan (N = 40) or 5 mg of amlodipine (N = 40) once daily. The primary endpoint was changes of serum Ang-(1–7) from baseline to week 24. Results: Both olmesartan and amlodipine treatment for 24 weeks decreased systolic and diastolic blood pressures significantly by > 18 mmHg and > 8 mmHg, respectively. Serum Ang-(1–7) levels were more significantly increased by olmesartan treatment (25.8 ± 34.5 pg/mL → 46.2 ± 59.4 pg/mL) than by amlodipine treatment (29.2 ± 38.9 pg/mL → 31.7 ± 26.0 pg/mL), resulting in significant between-group differences (P = 0.01). Serum ACE2 levels showed a similar pattern (6.31 ± 0.42 ng/mL → 6.74 ± 0.39 ng/mL by olmesartan treatment vs. 6.43 ± 0.23 ng/mL → 6.61 ± 0.42 ng/mL by amlodipine treatment; P < 0.05). The reduction in albuminuria was significantly associated with the increases in ACE2 and Ang-(1–7) levels (r = − 0.252 and r = − 0.299, respectively). The change in Ang-(1–7) levels was positively associated with improved microvascular function (r = 0.241, P < 0.05). Multivariate regression analyses showed that increases in serum Ang-(1–7) levels were an independent predictor of a reduction in albuminuria. Conclusions: These findings suggest that the beneficial effects of olmesartan on albuminuria may be mediated by increased ACE2 and Ang-(1–7) levels. These novel biomarkers may be therapeutic targets for the prevention and treatment of diabetic kidney disease. Trial registration: ClinicalTrials.gov NCT05189015. [ABSTRACT FROM AUTHOR]

Introduction: Immune dysfunction contributes to the progression of idiopathic nephrotic syndrome (INS), but the details of the pathogenesis of progression remain unknown. This study of children with INS investigated the relationship of activation of the mechanistic target of rapamycin (mTOR) pathway (PI3K/AKT/mTOR/p70S6K) with the levels of T helper 2/regulatory T (Th2/Treg) cells. Materials and Methods: Twenty children with active INS (before steroid treatment), 20 children with remitting INS (INS-R, after steroid treatment), and 20 healthy control children (Ctrl) were enrolled. The levels of Th2/Treg cells in their peripheral circulatory systems were measured using flow cytometry, and the concentration of interleukin (IL)-4 was determined using a cytometric bead array (CBA). The levels of PI3K, AKT, mTOR, p70S6K, and transcription factors associated with Th2/Treg cells were measured using real-time polymerase chain reaction. Results: The INS group had a greater proportion of circulating Th2 cells; level of IL-4 protein; and levels of GATA, PI3K, AKT, mTOR, and p70S6K mRNAs than the Ctrl group (all P < 0.05), but a lower proportion of circulating Tregs and expression of Foxp3 (both P < 0.05). Patients in the INS-R group had normalization of these markers (all P < 0.05). Patients in the INS group had negative correlation in the percentage of Treg cells with Th2 cells and with IL-4 level and a negative correlation in the levels of GATA3 and Foxp3 mRNAs. Conclusions: Patients with active INS had an imbalance of Th2/ Treg cells, which might result from the aberrant signaling of the mTOR pathway (PI3K/AKT/mTOR/ p70S6K). [ABSTRACT FROM AUTHOR]

Objectives: To evaluate the impact of genetic deletion of receptors of the counterregulatory arms of the renin–angiotensin system in depressive-like behaviours. Methods: 8–12 weeks-old male mice wild type (WT, C57BL/6J) and mice with genetic deletion of MrgD (MrgD KO) or Mas receptors (Mas KO) were subjected to the Forced Swim Test (FST) and the Tail Suspension Test (TST). Brain-derived neurotrophic factor (BDNF) levels were measured by enzyme-linked immunosorbent assay (ELISA). Blockade of Mas was performed by acute intracerebroventricular (icv) injection of its selective antagonist, A779. Results: No statistical difference in immobility time was observed between MrgD KO and WT male animals subjected to FST and TST. However, acute icv injection of A779 significantly increased the immobility time of MrgD KO male mice subjected to FST and TST, suggesting the involvement of Mas in preventing depressive-like behaviour. Indeed, Mas KO male animals showed increased immobility time in FST and TST, evidencing a depressive-like behaviour in these animals, in addition to a reduction in BDNF levels in the prefrontal cortex and hippocampus. No changes in BDNF levels were observed in MrgD KO male animals. Conclusion: Our data showed that Mas plays an important role in the neurobiology of depression probably by modulating BDNF expression. On the contrary, lack of MrgD did not alter depressive-like behaviour, which was supported by the lack of alterations in BDNF levels. [ABSTRACT FROM AUTHOR]

Background: Both IgA nephropathy (IgAN) and Henoch-Schönlein purpura nephropathy (HSPN) are characterized by glomerular mesangial IgA deposition. Several large studies on adults have suggested that glomerular C4d deposition has prognostic value in IgAN. However, there are few relevant studies on the clinical value of C4d deposition in children with IgAN or HSPN. Methods: We performed a retrospective cohort study in pediatric patients with IgAN or HSPN. Clinicopathological data were collected at the time of kidney biopsy. Kidney C4d deposition was analyzed by immunohistochemistry. The end point was defined as a ≥ 20% decrease in estimated glomerular filtration from baseline. Results: We enrolled 75 children, including 36 children with IgAN and 39 with HSPN. The prevalence of C4d deposition was 36% (27/75). C4d deposition was more abundant in children with proteinuria ≥ 50 mg/kg/day (51.9% versus 20.8%, P = 0.006) or nephrotic syndrome (37.0% versus 10.4%, P = 0.006). Mesangial hypercellularity (hazard ratio [HR], 5.745, 95% confidence interval [CI], 1.670–19.761, P = 0.006) and IgM deposition (HR, 4.522, 95% CI, 1.321–15.478, P = 0.016) were associated with C4d deposition. After a median follow-up of 22 months, seven (19.4%) IgAN patients and one (2.6%) HSPN patient had decreased kidney function. In children with IgAN, positive C4d was associated with decreased kidney function (P = 0.047). Conclusion: Glomerular C4d deposition was associated with mesangial hypercellularity and glomerular IgM deposition in IgAN and HSPN. Glomerular C4d deposition may be a risk factor for eGFR decline in children with IgAN. A higher resolution version of the Graphical abstract is available as Supplementary information. [ABSTRACT FROM AUTHOR]

Background: Nephrotic syndrome (NS) in children is widely believed to be associated with severe changes in the immune system. Based on lymphocyte subset analysis, we examined the pathogenesis of immune deficiencies in children with NS with varying steroid sensitivity. Methods: Our study utilized flow cytometry to retrospectively analyze the ratios of lymphocyte subsets in 204 children with nephrotic syndrome and 19 healthy children. Results: Compared with healthy children, the ratio of CD4 + /CD8 + in onset and remission was decreased in SRNS group (p < 0.05), and CD19 + B lymphocytes were increased in onset (p < 0.05). Compared with onset, the proportion of CD19 + B lymphocytes decreased in SRNS, while the proportion of CD19 + B lymphocytes increased in SDNS, p < (0.01). The ratio of CD8 + T/CD19 + B in onset in SDNS group was significantly higher than that in SSNS and SRNS groups (p < 0.01) and healthy control group (p < 0.05). Compared with onset, the ratio of CD8 + T/CD19 + B in SDNS group decreased significantly (p < 0.01), while the ratio of CD8 + T/CD19 + B in SRNS group increased significantly (p < 0.01). The proportion of CD56 + CD16 + NK cells was significantly reduced in children with INS (p < 0.01). Conclusion: CD8 + T lymphocytes may be involved in the mechanism of lymphocyte subsets disorder during onset of SDNS, while CD19 + B lymphocytes may be involved in the mechanism of lymphocyte subsets disorder during relapse of SDNS. The CD8 + T/CD19 + B ratio may predict the degree of frequent recurrence. There is a certain degree of lymphoid subsets disorder in children with NS. [ABSTRACT FROM AUTHOR]

Background: Lupus nephritis (LN) is a serious manifestation of systemic lupus erythematosus (SLE). The aim of this study was to identify serum insulin‐like growth factor binding protein‐2 (IGFBP‐2) as a novel non‐invasive biomarker for clinical disease and renal pathology in pediatric LN. Methods: A cross‐sectional study on 93 newly diagnosed LN children who were biopsy‐proven, 35 SLE children with no renal involvement as disease controls, and 30 healthy controls (HC) with age and gender‐matched. All children were ELISA tested for serum IGFBP‐2 levels. Clinical, laboratory, histopathological features of LN patients were collected. Results: Compared to SLE or HC, serum IGFBP‐2 levels were significantly elevated in LN patients. Serum IGFBP‐2 could distinguish LN patients from two others (AUC = 0.937, p < 0.001 for LN vs. HC; 0.897, p < 0.0001 for LN vs. SLE). In ROC analysis, IGFBP‐2 had a higher ability to differentiate between LN and SLE than anti‐dsDNA with AUC values of 0.895 and 0.643, respectively. LN children with systemic lupus erythematosus disease activity index (SLEDAI) in high activity had significantly higher IGFBP‐2 concentration than the others with SLEDAI in moderate activity. Serum IGFBP‐2 correlated with albuminemia levels (r = 0.415, p < 0.001), urine protein‐to‐creatinine levels (r = 0.316, p = 0.002), estimated glomerular filtration rate (r = 0.438, p < 0.001), complement C3 (r = 0.333, p = 0.001). More importantly, serum IGFBP‐2 correlated with the activity index of renal pathology (r = 0.312, p = 0.007, n = 75). Conclusions: Serum IGFBP‐2 is a promising biomarker for pediatric lupus nephritis, reflective of disease activity and activity index in renal patients. [ABSTRACT FROM AUTHOR]

Long COVID or post-acute Coronavirus disease 2019 (COVID-19), a malady defined by the persistence of COVID-19 symptoms for weeks or even months, is expected to affect the lives of millions of individuals worldwide significantly. Cardiopulmonary symptoms such as chest discomfort, shortness of breath, fatigue, and autonomic manifestations such as postural orthostatic tachycardia syndrome, and arrhythmias are prevalent and widely recognized. A variety of cardiovascular problems, including myocardial inflammation, myocardial infarction, ventricular dysfunction, and endothelial dysfunction, have been described in individuals following the initial acute phase. With over 10,000 published publications on COVID-19 and the cardiovascular system, presenting an unbiased thorough analysis of how SARSCoV-2 affects the system is essentially challenging. This review will provide an overview of frequent cardiovascular manifestations, emphasizing consequences, proposed pathophysiology, and clinical diagnostic manifestation strategy. [ABSTRACT FROM AUTHOR]

Purpose: COVID-19, a novel infection, presented with several complications, including socioeconomical and reproductive health challenges such as erectile dysfunction (ED). The present review summarizes the available shreds of evidence on the impact of COVID-19 on ED. Materials and methods: All published peer-reviewed articles from the onset of the COVID-19 outbreak to date, relating to ED, were reviewed. Results: Available pieces of evidence that ED is a consequence of COVID-19 are convincing. COVID-19 and ED share common risk factors such as disruption of vascular integrity, cardiovascular disease (CVD), cytokine storm, diabetes, obesity, and chronic kidney disease (CKD). COVID-19 also induces impaired pulmonary haemodynamics, increased ang II, testicular damage and low serum testosterone, and reduced arginine-dependent NO bioavailability that promotes reactive oxygen species (ROS) generation and endothelial dysfunction, resulting in ED. In addition, COVID-19 triggers psychological/mental stress and suppresses testosterone-dependent dopamine concentration, which contributes to incident ED. Conclusions: In conclusion, COVID-19 exerts a detrimental effect on male reproductive function, including erectile function. This involves a cascade of events from multiple pathways. As the pandemic dwindles, identifying the long-term effects of COVID-19-induced ED, and proffering adequate and effective measures in militating against COVID-19-induced ED remains pertinent. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complicated autoimmune disease with female susceptibility. It is characterized by over-activation of the immune system and deposit of autoimmune complex in multiple organs. High heterogeneity, unpredictable disease course of SLE as well as the lack of specific and sensitive biomarkers posed diagnostic challenges to clinicians. Despite the complicated clinical presentation and pathogenesis of SLE, research regarding this disease has made many significant breakthroughs over the past decades. Some new learning can potentially be translated into clinical practice. In addition, new classification criteria to increase diagnostic accuracy were defined in 2019 by the European League Against Rheumatism/American College of Rheumatology (EULAR/ACR). Real-world studies have accumulated evidence for the adoption of this new classification criteria. Abundant classification criteria, improved recognition of organ-specific manifestations, and updated knowledge about lupus autoantibodies enable earlier diagnosis and more personalized medicine. Thus, it is important to update our knowledge about the latest clinical practices for lupus diagnosis. This review provides new insight into the diagnosis of SLE by summarizing recent advances in epidemiology, etiology, classification criteria, clinical manifestations, and study of autoantibodies. [ABSTRACT FROM AUTHOR]

Monoclonal antibodies targeting the SARS‐CoV‐2 spike (S) neutralize infection and are efficacious for the treatment of COVID‐19. However, SARS‐CoV‐2 variants, notably sublineages of B.1.1.529/omicron, have emerged that escape antibodies in clinical use. As an alternative, soluble decoy receptors based on the host entry receptor ACE2 broadly bind and block S from SARS‐CoV‐2 variants and related betacoronaviruses. The high‐affinity and catalytically active decoy sACE22.v2.4‐IgG1 was previously shown to be effective against SARS‐CoV‐2 variants when administered intravenously. Here, inhalation of aerosolized sACE22.v2.4‐IgG1 increased survival and ameliorated lung injury in K18‐hACE2 mice inoculated with P.1/gamma virus. Loss of catalytic activity reduced the decoy's therapeutic efficacy, which was further confirmed by intravenous administration, supporting dual mechanisms of action: direct blocking of S and turnover of ACE2 substrates associated with lung injury and inflammation. Furthermore, sACE22.v2.4‐IgG1 tightly binds and neutralizes BA.1, BA.2, and BA.4/BA.5 omicron and protects K18‐hACE2 mice inoculated with a high dose of BA.1 omicron virus. Overall, the therapeutic potential of sACE22.v2.4‐IgG1 is demonstrated by the inhalation route and broad neutralization potency persists against highly divergent SARS‐CoV‐2 variants. Synopsis: SARS‐CoV‐2 infects cells via interactions between the viral Spike and ACE2 on host cells. A soluble derivative of ACE2 that is engineered for tight Spike affinity is effective against newly circulating SARS‐CoV‐2 variants and is efficacious through multiple mechanisms and routes of administration. An engineered decoy receptor, sACE22.v2.4‐IgG1, binds tightly to Spike proteins and blocks replication in vitro and in vivo of SARS‐CoV‐2 omicron variants.Proteolytic activity of the decoy receptor contributes to its therapeutic efficacy to increase survival of SARS‐CoV‐2 infected K18‐hACE2 transgenic mice.The decoy receptor is therapeutically effective via intravenous infusion and inhalation routes. [ABSTRACT FROM AUTHOR]

Objective(s): Chronic kidney disease (CKD), accompanied by renal dysfunction, fibrosis, and apoptosis, is highly prevalent in postmenopausal women. We tested the hypothesis that isoflavone daidzein may ameliorate renal dysfunction and fibrosis through angiotensin II type 1 (AT1R) and angiotensin 1-7 (MasR) receptors in association with microRNAs 33a and 27a. Materials and Methods: Two weeks before the initiation of the experiments, rats (n=84) underwent ovariectomy (OVX). Then, unilateral ureteral obstruction (UUO) was performed in OVX rats, and animals were allocated to the following groups (n=21): sham vehicle (dimethyl sulfoxide; DMSO 1%), UUO vehicle, UUO+17β-estradiol (E2), and UUO+daidzein. Each group encompassed three subgroups (n=7) treated with saline, A779 (MasR antagonist), or losartan (AT1R antagonist) for 15 days. The fractional urine excretion of sodium (FENa+) and potassium (FEK+), renal failure index (RFI), renal interstitial fibrosis (RIF index), glomerulosclerosis, miR-33a, and miR-27a expressions and their target genes were analyzed. Apoptosis was measured via cleaved caspase-3 immunohistochemistry. Results: UUO increased kidney weight, FENa+, FEK+, urine calcium, RFI, RIF index, glomerulosclerosis, and cleaved caspase-3. Moreover, expression of renal miR-33a and miR-27a, collagen3A1 mRNA, and protein were up-regulated post-UUO. Daidzein treatment alleviated the harmful effects of UUO especially in co-treatment with losartan. They also masked the anticipated worsening effects of A779 on UUO. Conclusion: Compared with E2, daidzein efficiently ameliorated renal dysfunction, fibrosis, and apoptosis through modulation of miR-33a and miR-27a expression and their crosstalk with AT1R and MasR. Therefore, daidzein might be a promising candidate for treating CKD in postmenopausal and older women. [ABSTRACT FROM AUTHOR]

Background: Glomerular diseases are important causes of morbidity and mortality among children in developing countries. Renal biopsy is the gold standard for determining histological diagnosis, prognosis, and therapy options. This study aimed to investigate the clinical, histopathological, and direct immunofluorescence findings of renal biopsy results in Nepalese children under 18 years old. Methods: In this retrospective cross-sectional study, the available data from children who had undergone kidney biopsy between 2016 and the end of 2020 were evaluated. Demographic data, indications of biopsy, histopathologic findings, and direct immunofluorescence findings were collected and presented. Results: The mean age of the patients was 12.14 ± 4.07 years. Male/female ratio was 1:1. The majority of biopsy cases were aged between 11–15 years of age. The most common indication for biopsy in children was nephrotic syndrome (68.25%). Lupus nephritis with 28 cases (22.22%) had the highest frequency in overall renal biopsies. Minimal change disease (MCD) with 22 cases (17.46%) followed by Ig A nephropathy with 16 cases (12.69%) were the most frequent primary glomerulonephritis. Lupus nephritis showed full house positivity, and MCD showed full house negativity in all Direct immunofluorescence (DIF) parameters, whereas immunoglobulin A nephropathy showed 100% positivity in Ig A in DIF. Conclusions: Nephrotic syndrome was the most common indication for renal biopsy. The most common primary glomerulonephritis was MCD, while secondary glomerulonephritis was lupus nephritis. Clinical data, light microscopy, and direct DIF played an integral role in the overall final diagnosis. [ABSTRACT FROM AUTHOR]

Background: Lupus nephritis (LN) increases mortality and morbidity in systemic lupus erythematosus (SLE) patients. Clinical and laboratory presentations for LN differ, and patients most commonly present in a state of acute kidney failure. One of the indicators of kidney involvement in SLE patients is proteinuria. Neutrophils and lymphocytes play an important role in the pathogenesis of LN. Neutrophil-to-lymphocyte ratio (NLR) is one of the known biomarkers for measuring the degree of LN disease activity, as measured by a simple blood test, and easily obtained in a cost-effective manner. Objective: The aim of this study was to investigate the correlation between the degree of proteinuria and NLR in paediatric SLE patients. Method: This study was conducted retrospectively, using a cross-sectional research method. Data were extracted from the medical records of 62 patients with paediatric SLE at the time of diagnosis. Patients were divided into two groups according to infection status. All patients had urine dipstick measurements for proteinuria. NLR was calculated by comparing the absolute neutrophil count with absolute lymphocyte number obtained from a patient's peripheral blood sample. Result: There was an increase in NLR according to the positivity rate of proteinuria, but this was not statistically significant (P >0.05). There was no correlation between NLR and the degree of proteinuria in patients who were diagnosed with early SLE (P >0.05). Conclusion: There was no significant correlation between NLR and the degree of proteinuria in paediatric patients with an early diagnosis of SLE. [ABSTRACT FROM AUTHOR]

Background: Complement activation has an important role in the pathogenesis of IgA nephropathy. Objective: To determine the correlation between IgAC3 ratio (IgA/C3) and total Oxford score and predictive value of IgA/C3 in IgA nephropathy. Methods Forty-three patients diagnosed with IgA nephropathy with > 10 glomerular + 1 arteries in biopsy were included in the study. Hematological and biochemical variables of the blood sample taken before the biopsy and total Oxford score were recorded. The study group was divided into two groups as proteinuria ≥ 1 g (PU ≥ 1) and proteinuria < 1 g (PU < 1). Statistics were carried out with SPSS 22.0 program. p <.05 considered as significant. Results: The mean age of 43 patients was 40.4 (± 11.9) years; 51.2% of them were women. Proteinuria as 1 g or more was in 27 of 43 patients, and less than 1 g in 16 patients. The serum C3 level was lower in the group with PU ≥ 1 and showed a significant positive correlation with the IgA/C3 total Oxford score. Conclusion: A significant correlation was found between serum IgA/C3 and total Oxford score. [ABSTRACT FROM AUTHOR]

Background: Endocapillary hypercellularity (ECHC) is commonly seen in class IV lupus nephritis (LN), the most common and severe LN in children. Factors influencing early complete remission (CR) in pediatric class IV LN have been poorly described. We investigated the relationship between ECHC levels and early CR in pediatric class IV LN. Methods: Patients with newly, simultaneously diagnosed systemic lupus erythematosus (SLE) and class IV LN by renal biopsy from 2012 to 2021 were studied. In this retrospective study, two pathologists who were blind to clinical information reviewed all pathological data retrospectively and classified glomerular lesions according to the revised criteria of the International Society of Nephrology and the Renal Pathology Society (ISN/RPS). The demographics, baseline clinical characteristics, laboratory parameters, renal histopathological findings, treatment regimen and CR at 6 months after immunosuppressive therapy were analyzed. ECHC was categorized as: > 50% (group A), 25–50% (group B) and < 25% (group C). CR was defined as absence of clinical symptoms, 24-hour urinary protein < 0.15 g, and normal levels of serum creatinine and albumin. Results: Sixty-four patients were identified: 23, 15 and 26 in groups A, B and C, respectively. Group A had significantly higher levels of D-dimer, urine protein, and SLE disease activity index (SLEDAI) than groups B and C. Group C had a markedly higher estimated glomerular filtration rate (eGFR) than groups A and B. A substantially greater proportion of patients in group A had glomerular microthrombi and basement membrane thickening than in groups B and C. At 6 months post treatment, CR was achieved in 19 (82.6%), 5 (33.3%) and 11 (42.3%) in groups A, B and C, respectively (p < 0.05, group A vs groups B and C). Multiple logistic regression analysis revealed that ECHC and urine protein levels were significantly associated with CR. Conclusion: ECHC and urine protein levels may be valuable biomarkers for predicting early CR in pediatric class IV LN. [ABSTRACT FROM AUTHOR]