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Background: Chronic kidney disease (CKD) affects more women than men worldwide, however, men comprise the majority of patients who receive kidney replacement therapy. We aimed to describe the perspectives of patients and their caregivers regarding gender disparities in CKD., Methods: Semi-structured interviews were conducted with 45 patients with CKD (20 women) and 14 caregivers (12 women) from seven clinics in Austria. The interviews were analyzed thematically., Results: Five themes were identified in this study. Participants perceived that women were "disadvantaged and vulnerable" (silent and intimidated, single mother predicament, impeded access to care and support due to socioeconomic disadvantage, had to fend for themselves); "fulfilling gender roles and norms" (primarily responsible for childcare, pressure to perform well as homemakers, put others' needs before their own, encouraging husband's treatment adherence), and "protecting their own health" (self-disciplined, vigilant, confronted health challenges, advocated for their needs). Men were seen to "place the onus of care on others" (expected help from family, relied on others for decisions). Both men and women experienced a "disease-related identity crisis and distress" (women: impaired body image, mental distress; men: denial and self-destruction, emasculated by sickness)., Conclusions: Women with CKD felt vulnerable and were inclined to fulfill gender norms and responsibilities as caregivers but were also vigilant about protecting their own health. Men tended to be reluctant to accept CKD and appeared to depend on others for disease management. Better awareness and addressing these concerns can inform strategies to minimize gender disparities in access to care and outcomes in CKD., (Copyright © 2024 The Author(s). Published by Wolters Kluwer Health, Inc. on behalf of the American Society of Nephrology.)

Background: Adverse pregnancy outcomes (APO), such as preeclampsia (PE) and gestational diabetes (GDM) are substantial risk factors for cardiovascular disease (CVD) later in life. Identifying these high-risk female individuals during pregnancy offers the possibility of preventing long-term CVD and chronic kidney disease via a structured therapeutic and surveillance plan. We aimed to evaluate the current practice of postpartum care in women after APO and the impact on the women's awareness about their future risk for CVD., Methods: Women diagnosed with PE and GDM at the University Hospital of St. Poelten/Lilienfeld between 2015-2020 were identified and participated in a structured telephone interview about postpartum medical care and knowledge about the impact of APOs on long-term cardiovascular health., Results: Of 161 out of the 750 women contacted, 29% (n = 46) were diagnosed with PE and 71% (n = 115) with GDM. One third of all women and up to 44% of women diagnosed with PE, were unaware that APOs are related to CVD. Women diagnosed with PE were less likely to receive postpartum care information than those with GDM (30.4% vs. 49.6%, p = 0.027), and only one third of all women after APOs were counselled by a physician or healthcare professional. Of the women 50% received recommendations regarding lifestyle changes after delivery; significantly more women with GDM than women with PE (54% vs. 37%, p = 0.05). Only 14% had at least one long-term follow-up., Conclusion: This study identified a significant deficit of structured postpartum care and a lack of awareness among women after APO and their healthcare providers about the increased risk of long-term CVD., (© 2023. The Author(s).)

Introduction: Chronic kidney disease (CKD) in stages 3-5 without albuminuria occurs more often in women than in men; however, most patients initiating and receiving kidney replacement therapy are men. Sex-determined biological factors and gender-related aspects both likely account for this discrepancy. Patient opinions on gender-related discrepancies in kidney care have not been investigated., Methods: Building upon the findings of semi-structured interviews previously conducted with CKD patients and their caregivers, two questionnaires were developed to investigate patient behavior and opinions relating to gender and CKD. These questionnaires containing 39 items were distributed to eight outpatient clinics in Austria. Responses were descriptively analyzed and compared between genders, as well as between age-groups and CKD stages., Results: Questionnaires from 783 patients and 98 caregivers were included in the analysis and covered health awareness and self-management of disease, the impact of gender roles and gender equality, and patient autonomy and trust in the health-care system. A total of 56.1% of men patients and 63.1% of women patients found that women were better at looking after their health compared to men (41.1%/34.3% no difference, 2.8%/2.6% men better). A total of 95.4% of men patients, 95.0% of women patients, 100% of men caregivers, and 95.5% of women caregivers stated that all patients with kidney disease were treated completely equally, irrespective of gender., Conclusion: Neither the patients nor the caregivers stated gender-determined treatment decisions in CKD care. Both men and women however agreed that women are better at maintaining their own health and excel in disease self-management., (© 2024 The Author(s). Published by S. Karger AG, Basel.)

Background: A discrepancy between sex-specific treatment of kidney failure by dialysis (higher in men) and the prevalence of chronic kidney disease in the general population (higher in women) has been reported internationally, but the prevalence by sex has not been described for Austria. Sex disparity among nephrology outpatients has not been studied., Methods: We employed two formulae (2009 CKD-EPI suppressing the race factor, and race-free 2021 CKD-EPI) to estimate the sex distribution of CKD in Austrian primary care, based on creatinine measurements recorded in a medical sample of 39,800 patients from general practitioners' offices (1989-2008). Further, we collected information from all clinic appointments scheduled at nephrology departments of 6 Austrian hospitals (Wien, Linz, Wels, St. Pölten, Villach, Innsbruck) during 2019 and calculated visit frequencies by sex., Results: Using the 2009 CKD-EPI formula, the prevalence of CKD in stages G3-G5 (estimated glomerular filtration rate < 60 mL/min/1.73 m 2 ) was 16.4% among women and 8.5% among men aged > 18 years who had attended general practitioners' offices in Austria between 1989 and 2008 and had at least one creatinine measurement performed. Using the 2021 CKD-EPI formula, the respective CKD prevalence was 12.3% among women and 6.1% among men. In 2019, 45% of all outpatients at 6 participating nephrology departments were women. The median of nephrology clinic visits in 2019 was two (per year) for both sexes., Conclusion: CKD is more prevalent among Austrian women than men. Men are more prevalent in nephrology outpatient services. Research into causes of this sex disparity is urgently needed., (© 2022. The Author(s).)

Co-stimulation is a prerequisite for pathogenic activity in T cell-mediated diseases and has been demonstrated to achieve tolerance in organ-specific autoimmunity as a therapeutic target. Here, we evaluated the involvement of the tumor necrosis factor family members CD30 and OX40 in immune-complex mediated kidney disease. In vitro stimulation and proliferation studies were performed with CD4 + cells from wild type and CD30/OX40 double knock-out (CD30OX40 -/- ) mice. In vivo studies were performed by induction of nephrotoxic serum nephritis in wild type, CD30OX40 - /- , CD30 -/- , OX40 -/- , reconstituted Rag1 -/- and C57Bl/6J mice treated with αCD30L αOX40L antibodies. CD30, OX40 and their ligands were upregulated on various leukocytes in nephrotoxic serum nephritis. CD30OX40 -/- mice, but not CD30 -/- or OX40 -/- mice were protected from nephrotoxic serum nephritis. Similar protection was found in Rag1 -/- mice injected with CD4 + T cells from CD30OX40 -/- mice compared to Rag1 -/- mice injected with CD4 + T cells from wild type mice. Furthermore, CD4 + T cells deficient in CD30OX40 -/- displayed decreased expression of CCR6 in vivo. CD30OX40 -/- cells were fully capable of differentiating into disease mediating T helper cell subsets, but showed significantly decreased levels of proliferation in vivo and in vitro compared to wild type cells. Blocking antibodies against CD30L and OX40L ameliorated nephrotoxic serum nephritis without affecting pan-effector or memory T cell populations. Thus, our results indicate disease promotion via CD30 and OX40 signaling due to facilitation of exaggerated T cell proliferation and migration of T helper 17 cells in nephrotoxic serum nephritis. Hence, co-stimulation blockade targeting the CD30 and OX40 signaling pathways may provide a novel therapeutic strategy in autoimmune kidney disease., (Copyright © 2021 International Society of Nephrology. All rights reserved.)

Selectively targeting the E-type prostanoid receptor 4 (EP4) might be a new therapeutic option in the treatment of glomerulonephritis (GN), since the EP4 receptor is expressed on different immune cells, resident kidney cells, and endothelial cells, which are all involved in the pathogenesis of immune-complex GN. This study aimed to evaluate the therapeutic potential and to understand the mode of action of EP4 agonist in immune-complex GN using the murine model of nephrotoxic serum nephritis (NTS). In vivo, NTS mice were treated two times daily with two different doses of an EP4 agonist ONO AE1-329 or vehicle for 14 days total. The effect of PGE2 and EP4 agonism and antagonism was tested on murine distal convoluted tubular epithelial cells (DCT) in vitro. In vivo, the higher dose of the EP4 agonist led to an improved NTS phenotype, including a reduced tubular injury score and reduced neutrophil gelatinase-associated lipocalin (NGAL) and blood urea nitrogen (BUN) levels. EP4 agonist treatment caused decreased CD4 + T cell infiltration into the kidney and increased proliferative capacity of tubular cells. Injection of the EP4 agonist resulted in dose-dependent vasodilation and hypotensive episodes. The low-dose EP4 agonist treatment resulted in less pronounced episodes of hypotension. In vitro, EP4 agonism resulted in cAMP production and increased distal convoluted tubular (DCT) proliferation. Taken together, EP4 agonism improved the NTS phenotype by various mechanisms, including reduced blood pressure, decreased CD4 + T cell infiltration, and a direct effect on tubular cells leading to increased proliferation probably by increasing cAMP levels.

Glucagon-like peptide (GLP)-1 analogs such as liraglutide improved albuminuria in patients with type 2 diabetes in large randomized controlled trials. One of the suspected mechanisms is the anti-inflammatory potential of GLP-1 receptor (Glp1r) agonism. Thus, the anti-inflammatory action of Glp1r agonism was tested in a nondiabetic, T-cell-mediated murine model of nephrotoxic serum nephritis (NTS). The role of Glp1r in NTS was evaluated by using Glp1r -/- mice or C57BL/6 mice treated with liraglutide. In vitro, murine T cells were stimulated in the presence of liraglutide or vehicle. Glp1r -/- mice displayed increased renal infiltration of neutrophils and T cells after induction of NTS. Splenocyte proliferation and TH1 cytokine transcription were increased in spleen and lymph nodes of Glp1r -/- mice. Liraglutide treatment significantly improved the renal outcome of NTS in C57BL/6 mice by decreasing renal infiltration and proliferation of T cells, which resulted in decreased macrophage infiltration. In vitro, T cells stimulated in the presence of liraglutide showed decreased proliferation of TH1 and TH17 cells. Liraglutide blocked glycolysis in T cells and decreased their Glut1 mRNA expression. Together, Glp1r agonism protects mice from a T-cell-dependent glomerulonephritis model by inhibition of T-cell proliferation, possibly by interacting with their metabolic program. This mechanism may explain in part the renoprotective effects of Glp1r agonism in diabetic nephropathy., (Copyright © 2020 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Background and Aims: Chronic kidney disease (CKD) is strongly associated with a high burden of cardiovascular morbidity and mortality. Therefore, we aimed to characterize the putative role of microRNAs (miR)s in uremic vascular remodelling and endothelial dysfunction., Methods: We investigated the expression pattern of miRs in two independent end-stage renal disease (ESRD) cohorts and in the animal model of uremic DBA/2 mice via quantitative RT-PCR. Moreover, DBA/2 mice were treated with intravenous injections of synthetic miR-142-3p mimic and were analysed for functional and morphological vascular changes by mass spectrometry and wire myography., Results: The expression pattern of miRs was regulated in ESRD patients and was reversible after kidney transplantation. Out of tested miRs, only blood miR-142-3p was negatively associated with carotid-femoral pulse-wave velocity in CKD 5D patients. We validated these findings in a murine uremic model and found similar suppression of miR-142-3p as well as decreased acetylcholine-mediated vascular relaxation of the aorta. Therefore, we designed experiments to restore bioavailability of aortic miR-142-3p in vivo via intravenous injection of synthetic miR-142-3p mimic. This intervention restored acetylcholine-mediated vascular relaxation., Conclusions: Taken together, we provide compelling evidence, both in humans and in mice, that miR-142-3p constitutes a potential pharmacological agent to prevent endothelial dysfunction and increased arterial stiffness in ESRD., (Copyright © 2018 The Authors. Published by Elsevier B.V. All rights reserved.)

Prostaglandin E 2 (PGE 2 ) signaling is known to modulate inflammation and vascular resistance. Receptors of PGE 2 [E-type prostanoid receptors (EP)] might be an attractive pharmacological target in immune-mediated diseases such as glomerulonephritis. We hypothesized that selective EP4 antagonism improves nephrotoxic serum nephritis (NTS) by its anti-inflammatory properties. Mice were subjected to NTS and treated with the EP4 antagonist ONO AE3-208 (10 mg·kg body wt -1 ·day -1 ] or vehicle starting from disease initiation. In one set of experiments, treatment was started 4 days after NTS induction. Tubular epithelial cells were evaluated in vitro under starving conditions. EP4 antagonist treatment significantly improved the NTS phenotype without affecting blood pressure levels. Remarkably, the improved NTS phenotype was also observed when treatment was started 4 days after NTS induction. EP4 antagonism decreased tubular chemokine (C-X-C motif) ligand ( Cxcl) 1 and Cxcl-5 expression and thereby subsequently reduced interstitial neutrophil infiltration into the kidney. In vitro, tubular epithelial cells increasingly expressed Cxcl-5 mRNA and Cxcl-5 protein when treated with PGE 2 or an EP4 agonist under starving conditions, which was blunted by EP4 antagonist treatment. Together, EP4 antagonism improves the NTS phenotype, probably by decreasing mainly Cxcl-5 production in tubular cells, thereby reducing renal neutrophil infiltration.

The role of innate and adaptive immune cells in the experimental model of nephrotoxic serum nephritis (NTS) has been rigorously studied in recent years. The model is dependent on kidney-infiltrating T helper (TH) 17 and TH1 cells, which recruit neutrophils and macrophages, respectively, and cause sustained kidney inflammation. In a later phase of disease, regulatory T cells (Tregs) infiltrate the kidney in an attempt to limit disease activity. In the early stage of NTS, lymph node drainage plays an important role in disease initiation since dendritic cells present the antigen to T cells in the T cell zones of the draining lymph nodes. This results in the differentiation and proliferation of TH17 and TH1 cells. In this setting, immune regulatory cells (Tregs), namely, CCR7-expressing Tregs and mast cells (MCs), which are recruited by Tregs via the production of interleukin-9, exert their immunosuppressive capacity. Together, these two cell populations inhibit T cell differentiation and proliferation, thereby limiting disease activity by as yet unknown mechanisms. In contrast, the spleen plays no role in immune activation in NTS, but constitutes a place of extramedullary haematopoiesis. The complex interactions of immune cells in NTS are still under investigation and might ultimately lead to targeted therapies in glomerulonephritis.

Chronic kidney disease (CKD) is associated with mineral and bone disorder (MBD), which is the main cause of the extensively increased cardiovascular mortality in the CKD population. We now aimed to establish a new murine experimental CKD-MBD model. Dilute brown non-Agouti (DBA/2) mice were fed with high-phosphate diet for 4 (HPD4) or 7 (HPD7) days, then with standard chow diet (SCD) and subsequently followed until day 84. They were compared to DBA/2 mice maintained on SCD during the whole study period. Both 4 and 7 days HPD-fed mice developed phosphate nephropathy with tubular atrophy, interstitial fibrosis, decreased glomerular filtration rate, and increased serum urea levels. The abdominal aorta of HPD-treated mice showed signs of media calcification. Histomorphometric analysis of HPD-treated mice showed decreased bone volume/tissue volume, low mineral apposition rate, and low bone formation rate as compared to SCD-fed mice, despite increased parathyroid hormone levels. Overall, the observed phenotype was more pronounced in the HPD7 group. In summary, we established a new, noninvasive, and therefore easy to perform reproducible CKD-MBD model, which showed media calcification, secondary hyperparathyroidism, and low-turnover bone disease.

Background: Prostaglandin (PG) D2 is an early-phase mediator in inflammation, but its action and the roles of the 2 D-type prostanoid receptors (DPs) DP1 and DP2 (also called chemoattractant receptor-homologous molecule expressed on T(H)2 cells) in regulating macrophages have not been elucidated to date., Objective: We investigated the role of PGD2 receptors on primary human macrophages, as well as primary murine lung macrophages, and their ability to influence neutrophil action in vitro and in vivo., Methods: In vitro studies, including migration, Ca(2+) flux, and cytokine secretion, were conducted with primary human monocyte-derived macrophages and neutrophils and freshly isolated murine alveolar and pulmonary interstitial macrophages. In vivo pulmonary inflammation was assessed in male BALB/c mice., Results: Activation of DP1, DP2, or both receptors on human macrophages induced strong intracellular Ca(2+) flux, cytokine release, and migration of macrophages. In a murine model of LPS-induced pulmonary inflammation, activation of each PGD2 receptor resulted in aggravated airway neutrophilia, tissue myeloperoxidase activity, cytokine contents, and decreased lung compliance. Selective depletion of alveolar macrophages abolished the PGD2-enhanced inflammatory response. Activation of PGD2 receptors on human macrophages enhanced the migratory capacity and prolonged the survival of neutrophils in vitro. In human lung tissue specimens both DP1 and DP2 receptors were located on alveolar macrophages along with hematopoietic PGD synthase, the rate-limiting enzyme of PGD2 synthesis., Conclusion: For the first time, our results show that PGD2 markedly augments disease activity through its ability to enhance the proinflammatory actions of macrophages and subsequent neutrophil activation., (Copyright © 2015 The Authors. Published by Elsevier Inc. All rights reserved.)

Background and Purpose: Pulmonary vascular dysfunction is a key event in acute lung injury. We recently demonstrated that PGE 2 , via activation of E-prostanoid (EP) 4 receptors, strongly enhances microvascular barrier function in vitro. The aim of this study was to investigate the beneficial effects of concomitant EP 4 receptor activation in murine models of acute pulmonary inflammation., Experimental Approach: Pulmonary inflammation in male BALB/c mice was induced by LPS (20 μg per mouse intranasally) or oleic acid (0.15 μL·g -1 , i.v . ). In-vitro, endothelial barrier function was determined by measuring electrical impedance., Key Results: PGE 2 activation of EP 4 receptors reduced neutrophil infiltration, pulmonary vascular leakage and TNF-α concentration in bronchoalveolar lavage fluid from LPS-induced pulmonary inflammation. Similarly, pulmonary vascular hyperpermeability induced by oleic acid was counteracted by EP 4 receptor activation. In lung function assays, the EP 4 agonist ONO AE1-329 restored the increased resistance and reduced compliance upon methacholine challenge in mice treated with LPS or oleic acid. In agreement with these findings, EP 4 receptor activation increased the in vitro vascular barrier function of human and mouse pulmonary microvascular endothelial cells and diminished the barrier disruption induced by LPS. The EP 2 agonist ONO AE1-259 likewise reversed LPS-induced lung dysfunction without enhancing vascular barrier function., Conclusion and Implications: Our results show that activation of the EP 4 receptor strengthens the microvascular barrier function and thereby ameliorates the pathology of acute lung inflammation, including neutrophil infiltration, vascular oedema formation and airway dysfunction. This suggests a potential benefit for EP 4 agonists in acute pulmonary inflammation., (© 2015 The British Pharmacological Society.)

Background: The spleen has been implicated in the pathogenesis of immune-complex glomerulonephritis by initiating and resolving adaptive immune responses. Thus, we aimed to evaluate the role of the spleen in experimental nephrotoxic serum nephritis (NTS)., Methods: In order to accelerate the disease, animals were subjected to NTS by preimmunizing male C57BL/6J mice with rabbit IgG three days before injecting the rabbit anti-glomerular basement antiserum, or were immunized only. A group underwent splenectomy before NTS induction., Results: We observed enlargement of the spleen with a maximum at 14 days after NTS induction or immunization only. Splenectomized mice were found to develop albuminuria and renal histological changes comparable to sham-operated controls. Nevertheless, anaemia was aggravated in mice after splenectomy. During the course of NTS, we detected CD41+ megakaryocytes and Ter119+ erythroid precursor cells in the spleen of mice with NTS and of immunized mice. Ter119+Cxcr4+ cells and the binding partner Cxcl12 increased in the spleen, and decreased in the bone marrow. This was accompanied by a significant systemic increase of interferon-gamma in the serum., Conclusions: In summary, splenectomy does not influence the course of NTS per se, but is involved in concomitant anaemia. Extramedullary haematopoiesis in the spleen is probably facilitated through the migration of Cxcr4+ erythroid precursor cells from the bone marrow to the spleen via a Cxcl12 gradient and likely arises from the suppressive capacity of chronic inflammation on the bone marrow.