Chronic kidney disease (CKD) is a strong risk factor for cardiovascular mortality and morbidity. We hypothesized that a senescent phenotype instigated by uremic toxins could account for early vascular aging (EVA) and vascular dysfunctions of microvasculature in end stage kidney disease (ESKD) patients which ultimately lead to increased cardiovascular complication. To test this hypothesis, we utilized both in vivo, and ex vivo approaches to study endothelial and smooth muscle function and structure, and characterized markers related to EVA in 82 ESKD patients (eGFR <15 ml/min) and 70 non-CKD controls. In vivo measurement revealed no major difference in endothelial function between ESKD and control group, aside from higher stiffness detected in the microcirculation of ESKD participants. In contrast, ex vivo measurements revealed a notable change in the contribution of endothelium-derived factors and increased stiffness in ESKD patients vs. controls. In support, we demonstrated that ex vivo exposure of arteries to uremic toxins such as Trimethylamine N-oxide, Phenylacetylglutamine, or extracellular vesicles from CKD patients impaired endothelial function via diminishing the contribution of endothelium-derived relaxing factors such as nitric oxide and endothelium derived hyperpolarizing factor. Uremic arteries displayed elevated expression of senescence markers (p21CIP1, p16INK4a, and SA-β-gal), calcification marker (RUNX2), and reduced expression of Ki67, sirtuin1, Nrf2, and MHY11 markers, indicating the accumulation of senescent cells and EVA phenotype. Correspondingly, treating uremic vessel rings ex vivo with senolytic agents (Dasatinib + Quercetin) effectively reduced the senescence-associated secretory phenotype and changed the origin of extracellular vesicles. Notably, sex differences exist for certain abnormalities suggesting the importance of biological sex in the pathogenesis of vascular complications. In conclusion, the uremic microvasculature is characterized by a "senescence signature", which may contribute to EVA and cardiovascular complications in ESKD patients and could be alleviated by treatment with senolytic agents.

In today's industrialized society food consumption has changed immensely toward heightened red meat intake and use of artificial sweeteners instead of grains and vegetables or sugar, respectively. These dietary changes affect public health in general through an increased incidence of metabolic diseases like diabetes and obesity, with a further elevated risk for cardiorenal complications. Research shows that high red meat intake and artificial sweeteners ingestion can alter the microbial composition and further intestinal wall barrier permeability allowing increased transmission of uremic toxins like p-cresyl sulfate, indoxyl sulfate, trimethylamine n-oxide and phenylacetylglutamine into the blood stream causing an array of pathophysiological effects especially as a strain on the kidneys, since they are responsible for clearing out the toxins. In this review, we address how the burden of the Western diet affects the gut microbiome in altering the microbial composition and increasing the gut permeability for uremic toxins and the detrimental effects thereof on early vascular aging, the kidney per se and the blood-brain barrier, in addition to the potential implications for dietary changes/interventions to preserve the health issues related to chronic diseases in future.

Abstract Background and Aims Chronic kidney disease (CKD) is an irreversible decline in renal function where kidney transplantation (KT) is the optimal therapeutic intervention. We aim to investigate the role and activation of the uremic toxin receptor aryl hydrocarbon receptor (AhR) in the microvasculature, particularly its implication in the blood-brain barrier impairment. We will also explore the potential role of growth hormone-releasing hormone (GHRH) as a biomarker reflecting the resolution of uremia-induced inflammation, early vascular ageing (EVA) phenotype, and potential enhancement in central nervous system (CNS) function post-KT. Method Resistance arteries from KT patients and non-CKD controls were isolated and expression of AhR was analysed by immunohistochemistry. The study used plasma samples from 60 KT patients, and levels of GHRH were measured at baseline and two years after transplantation using ELISA. Results Following KT, our initial findings indicate a decrease in levels of DBP, Lp(a), creatinine, homocysteine, phosphate, and troponin T among KT patients. Conversely, there was an increase in albumin, HBA1c, calcium and NfL post-transplantation. The expression of AhR in the resistance arteries of KT patients (2.6%) was notably lower compared to non-CKD controls (9.7%). Plasma concentrations of GHRH were significantly higher (p < 0.0001) in CKD-5 patients two years post-KT (2.94 ng/mL, IQR 2.60-3.43) compared to baseline (2.32 mg/L, IQR 1.84-3.24). This elevated trend in GHRH levels post-KT was observed in both sexes, with males (p < 0.0001) and females (p 0.0084) showing higher levels—males (3.0 ng/mL, IQR 2.6-3.5) and females (2.8 ng/mL, IQR 2.4-3.5)—compared to baseline level of males (2.4 ng/mL, IQR 1.8-3.2) and females (2.2 ng/mL, 1.9-3.3). No significant difference in GHRH levels was observed when assessing extreme EVA phenotypes based on the presence or absence of calcification or fibrosis. Conclusion Contrary to our initial expectation, the preliminary results indicate a downregulation in AhR expression within resistance vessels of CKD patients, implying modifications in AhR signaling within the uremic environment. The observed alteration in GHRH levels presents a promising avenue for further investigation focusing on its possible application as a biomarker for assessing CNS status in CKD patients undergoing KT. Prospective clinical application could involve the administration of GHRH agonists as a protective measure against cognitive impairment, considering its deficiency in CKD. Such supplementation holds promise to prevent further cognitive morbidity. The modulation in the levels of this hormone has the potential to significantly influence the treatment trajectory of CKD patients and enhance clinical outcomes.

( Acta Obstet Gynecol Scand . 2023;102(11):1459–1468. doi: 10.1111/aogs.14659) Many studies have shown that socioeconomic factors have large impacts on many areas of life including education, unemployment, housing security, nutrition, and reduced access to health care. In addition, low-socioeconomic indicators have been linked to pregnancy complications for both mother and neonate and have persisted even in areas with universal health care systems. However, other studies have shown an absence of association with socioeconomic status for outcomes such as low birthweight and preterm birth. Previous literature has suggested that assessing individual-level socioeconomic factors and their association with pregnancy outcomes may provide better understanding than area-based analysis. This study was designed to evaluate associations of individual-level socioeconomic factors (education, employment, relationship status, and income) with adverse pregnancy and neonatal outcomes (gestational hypertension, preeclampsia, gestational diabetes, emergency cesarean delivery, preterm birth, post-term delivery, small for gestational age, and Apgar score).

The pathophysiology of vascular disease is linked to accelerated biological aging and a combination of genetic, lifestyle, biological, and environmental risk factors. Within the scenario of uncontrolled artery wall aging processes, CKD (chronic kidney disease) stands out as a valid model for detailed structural, functional, and molecular studies of this process. The cardiorenal syndrome relates to the detrimental bidirectional interplay between the kidney and the cardiovascular system. In addition to established risk factors, this group of patients is subjected to a plethora of other emerging vascular risk factors, such as inflammation, oxidative stress, mitochondrial dysfunction, vitamin K deficiency, cellular senescence, somatic mutations, epigenetic modifications, and increased apoptosis. A better understanding of the molecular mechanisms through which the uremic milieu triggers and maintains early vascular aging processes, has provided important new clues on inflammatory pathways and emerging risk factors alike, and to the altered behavior of cells in the arterial wall. Advances in the understanding of the biology of uremic early vascular aging opens avenues to novel pharmacological and nutritional therapeutic interventions. Such strategies hold promise to improve future prevention and treatment of early vascular aging not only in CKD but also in the elderly general population.

Background Chronic kidney disease (CKD) is linked to an increased cardiovascular disease (CVD) burden. Albeit underappreciated, sex differences are evident in CKD with females being more prone to CKD development, but males progressing more rapidly to kidney failure (KF). Cardiovascular remodelling is a hallmark of CKD with increased arterial and valvular calcification contributing to CKD. However, little is known regarding sex differences in calcific cardiovascular remodelling in KF patients. Thus, we hypothesise that sex differences are present in coronary artery calcification (CAC) and aortic valve calcification (AVC) in patients with KF. Methods KF patients, males (n = 214) and females (n = 107), that had undergone computer tomography (CT) assessment for CAC and AVC were selected from three CKD cohorts. All patients underwent non-contrast multi-detector cardiac CT scanning, with CAC and AVC scoring based on the Agatston method. Baseline biochemical measurements were retrieved from cohort databases, including plasma analyses for inflammation markers (IL-6, TNF, hsCRP) and oxidative stress by skin autofluorescence measuring advanced glycation end-products (AGE), amongst other variables. Results Sex-disaggregated analyses revealed that CAC score was associated with age in both males and females (both p < 0.001). Age-adjusted analyses revealed that in males CAC was associated with diabetes mellitus (DM) (p = 0.018) and CVD (p = 0.011). Additionally, for females CAC associated with IL-6 (p = 0.005) and TNF (p = 0.004). In both females and males CAC associated with AGE (p = 0.042 and p = 0.05, respectively). CAC was associated with mortality for females (p = 0.015) independent of age. AVC in females was not reviewed due to low AVC-positive samples (n = 14). In males, in multivariable regression AVC was associated with age (p < 0.001) and inflammation, as measured by IL-6 (p = 0.010). Conclusions In female KF patients inflammatory burden and oxidative stress were associated with CAC. Whereas in male KF patients oxidative stress and inflammation were associated with CAC and AVC, respectively. Our findings suggest a sex-specific biomarker signature for cardiovascular calcification that may affect the development of cardiovascular complications in males and females with KF.

Circulating cell-free DNA (cfDNA) has diverse applications in oncological, prenatal, toxicological, cardiovascular, and autoimmune diseases, diagnostics, and organ transplantation. In particular, mitochondrial cfDNA (mt-cfDNA) is associated with inflammation and linked to early vascular ageing (EVA) in end-stage kidney failure (ESKF), which could be a noninvasive marker for graft rejection and organ damage. Plasma samples from 44 ESKF patients, of whom half (n = 22) underwent either conservative therapy (non-HD) or hemodialysis (HD) before kidney transplantation (KT). These samples were analyzed at baseline and two years after KT. cfDNA was extracted from plasma and quantified using the fluorometric method. qPCR was used to quantify and differentiate the fractions of mt-cfDNA and nuclear cfDNA (nc-cfDNA). mt-cfDNA levels in KT patients decreased significantly from baseline to two years post-KT (p < 0.0268), while levels of total cfDNA and nc-cfDNA did not differ. Depending on therapy modality (HD vs. non-HD) before KT, total cfDNA levels were higher in HD patients at both baseline (p = 0.0133) and two years post-KT (p = 0.0421), while nc-cfDNA levels were higher in HD only at baseline (p = 0.0079). Males showed a nonsignificant trend of higher cfDNA levels. Patients with assessed vascular fibrosis (p = 0.0068), either alone or in combination with calcification plus fibrosis, showed reduced mt-cfDNA post-KT (p = 0.0195). Changes in mt-cfDNA levels suggests the impact of KT on the inflammatory state of ESKF, as evidenced via its correlation with high sensitivity C-reactive protein after KT. Further studies are warranted to assess if cfDNA could serve as a noninvasive method for monitoring the response to organ transplantation and even for amelioration of EVA status per se.

Kidney transplantation (KT) may improve the neurological status of chronic kidney disease (CKD) patients, reflected by the altered levels of circulating BBB-specific biomarkers. This study compares the levels of neuron specific enolase (NSE), brain-derived neurotrophic factor (BDNF), neurofilament light chain (NfL), and circulating plasma extracellular vesicles (EVs) in kidney-failure patients before KT and at a two-year follow up. Using ELISA, NSE, BDNF, and NfL levels were measured in the plasma of 74 living-donor KT patients. Plasma EVs were isolated with ultracentrifugation, and characterized for concentration/size and surface protein expression using flow cytometry from a subset of 25 patients. Lower NSE levels, and higher BDNF and NfL were observed at the two-year follow-up compared to the baseline (p < 0.05). Male patients had significantly higher BDNF levels compared to those of females. BBB biomarkers correlated with the baseline lipid profile and with glucose, vitamin D, and inflammation markers after KT. BBB surrogate marker changes in the microcirculation of early vascular aging phenotype patients with calcification and/or fibrosis were observed only in NSE and BDNF. CD31+ microparticles from endothelial cells expressing inflammatory markers such as CD40 and integrins were significantly reduced after KT. KT may, thus, improve the neurological status of CKD patients, as reflected by changes in BBB-specific biomarkers.

Introduction: Previous evidence examining the association between socioeconomic status and pregnancy complications are conflicted and often limited to using area-based measures of socioeconomic status. In this study, we aimed to examine the association between individual-level socioeconomic factors and a wide range of adverse pregnancy and neonatal outcomes using data from the IMPROvED birth cohort conducted in Sweden, the Netherlands and Republic of Ireland. Material and methods: The study cohort consisted of women who participated in the IMPROvED birth cohort between 2013 and 2017. Data on socioeconomic factors were self-reported and obtained at 15 weeks' gestation, and included level of education, employment status, relationship status, and income. Data on pregnancy and neonatal outcomes included gestational hypertension, pre-eclampsia, gestational diabetes mellitus, emergency cesarean section, preterm birth, post term delivery, small for gestational age and Apgar score at 1 min. These data were obtained within 72 h following delivery and confirmed using medical records. Multivariable logistic regression examined the association between each socioeconomic variable and each outcome separately adjusting for maternal age, maternal body mass index, maternal smoking, maternal alcohol consumption and cohort center. We also examined the effect of exposure to any >= 2 risk factors compared to none. Results: A total of 2879 participants were included. Adjusted results suggested that those with less than third level of education had an increased odds of gestational hypertension (OR: 1.74, 95% CI: 1.23-2.46), while those on a middle level of income had a reduced odds of emergency cesarean section (OR: 0.59, 95% CI: 0.42-0.84). No significant associations were observed between socioeconomic variables and neonatal outcomes. Exposure to any >= 2 socioeconomic risk factors was associated with an increased risk of preterm birth (OR: 1.75, 95% CI: 1.06-2.89). Conclusions: We did not find strong evidence of associations between individual-level socioeconomic factors and pregnancy and neonatal outcomes in high-income settings overall, with only few significant associations observed among pregnancy outcomes.

Kidney transplantation (KTx) is the preferred form of renal replacement therapy in chronic kidney disease (CKD) patients, owing to increased quality of life and reduced mortality when compared to chronic dialysis. Risk of cardiovascular disease is reduced after KTx; however, it is still a leading cause of death in this patient population. Thus, we aimed to investigate whether functional properties of the vasculature differed two years post-KTx (postKTx) compared to baseline (time of KTx). Using the EndoPAT device in 27 CKD patients undergoing living-donor KTx, we found that vessel stiffness significantly improved while endothelial function worsened postKTx vs. baseline. Furthermore, baseline serum indoxyl sulphate (IS), but not p-cresyl sulphate, was independently negatively associated with reactive hyperemia index, a marker of endothelial function, and independently positively associated with P-selectin postKTx. Finally, to better understand the functional effects of IS in vessels, we incubated human resistance arteries with IS overnight and performed wire myography experiments ex vivo. IS-incubated arteries showed reduced bradykinin-mediated endothelium-dependent relaxation compared to controls via reduced nitric oxide (NO) contribution. Endothelium-independent relaxation in response to NO donor sodium nitroprusside was similar between IS and control groups. Together, our data suggest that IS promotes worsened endothelial dysfunction postKTx, which may contribute to the sustained CVD risk.

BACKGROUND:Individuals with chronic kidney disease are affected by acute respiratory syndrome coronavirus 2 (SARS-CoV-2) due to multiple comorbidities and altered immune system. The first step of the infection process is the binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE2) receptor, followed by its priming by transmembrane protease serine 2 (TMPRSS2). We hypothesized that circulating soluble ACE2 levels, as well as the expressions of ACE2 and TMPRSS2 in the microvasculature, are increased in patients with end-stage kidney disease (ESKD). METHODS:A total of 210 participants were enrolled, representing 80 ESKD patients and 73 non-CKD controls for soluble ACE2, and 31 ESKD and 26 non-CKD controls for vasculature and fat tissue bioassays. We have assessed ACE2 expression in blood using ELISA and in tissue using immunofluorescence. RESULTS:Soluble ACE2 levels were higher in ESKD patients compared to controls; however, there is no sex difference observed. In ESKD and controls, soluble ACE2 positively correlated with Interleukin 6 (IL-6) and C-reactive protein (CRP), respectively. Similarly, ACE2 tissue expression in the vasculature was higher in ESKD patients; moreover, this higher ACE2 expression was observed only in male ESKD patients. In addition, TMPRSS2 expression was observed in vessels from males and females but showed no sex difference. The expression of ACE2 receptor was higher in ESKD patients on ACE-inhibitor/angiotensin blocker treatment. CONCLUSION:ESKD is associated with increased ACE2 levels in the circulation and pronounced in male vasculature; however, further studies are warranted to assess possible sex differences on specific treatment regime(s) for different comorbidities present in ESKD.

Cardio-pulmonary diseases, which were once regarded as a man's illness, have been one of the leading causes of morbidity and mortality for both men and women in many countries in recent years. Both gender and sex influence the functional and structural changes in the human body and therefore play an important role in disease clinical manifestation, treatment choice, and/or response to treatment and prognosis of health outcomes. The gender dimension integrates sex and gender analysis in health sciences and medical research, however, it is still relatively overlooked suggesting the need for empowerment in the medical research community. Latest advances in the field of cardiovascular research have provided supportive evidence that the application of biological variables of sex has led to the understanding that heart disease in females may have different pathophysiology compared to males, particularly in younger adults. It has also resulted in new diagnostic techniques and a better understanding of symptomatology, while gender analysis has informed more appropriate risk stratification and prevention strategies. The existing knowledge in the pulmonary field shows the higher prevalence of pulmonary disorders among females, however, the role of gender as a socio-cultural construct has yet to be explored for the implementation of targeted interventions. The purpose of this review is to introduce the concept of gender dimension and its importance for the cardiopulmonary continuum with a focus on shared pathophysiology and disease presentation in addition to interrelation with chronic kidney disease. The review presents basic knowledge of what gender dimension means, and the application of sex and gender aspects in cardiovascular medicine with a specific focus on early pulmonary development, pulmonary hypertension, and chronic obstructive pulmonary disease (COPD). Early vascular aging and inflammation have been presented as a potential pathophysiological link, with further interactions between the cardiopulmonary continuum and chronic kidney disease. Finally, implications for potential future research have been provided to increase the impact of gender dimension on research excellence that would add value to everybody, foster toward precision medicine and ultimately improve human health.

Kidney failure and associated uraemia have implications for the cardiovascular system, brain, and blood–brain barrier (BBB). We aim to examine BBB disruption, by assessing brain-derived neurotropic factor (BDNF), neuron-specific enolase (NSE) levels, and gut-blood barrier (GBB) disruption by trimethylamine N-oxide (TMAO), in chronic kidney disease (CKD) patients. Additionally, endothelial tight-junction protein expressions and modulation via TMAO were assessed. Serum from chronic kidney disease (CKD) female and male haemodialysis (HD) patients, and controls, were used to measure BDNF and NSE by enzyme-linked immunosorbent assays, and TMAO by mass spectrometry. Immunofluorescent staining of subcutaneous fat biopsies from kidney transplant recipients, and controls, were used to measure microvascular expression of tight-junction proteins (claudin-5, occludin, JAM-1), and control microvasculature for TMAO effects. HD patients versus controls, had significantly lower and higher serum levels of BDNF and NSE, respectively. In CKD biopsies versus controls, reduced expression of claudin-5, occludin, and JAM-1 were observed. Incubation with TMAO significantly decreased expression of all tight-junction proteins in the microvasculature. Uraemia affects BBB and GBB resulting in altered levels of circulating NSE, BDNF and TMAO, respectively, and it also reduces expression of tight-junction proteins that confer BBB maintenance. TMAO serves as a potential candidate to alter BBB integrity in CKD.

Abstract Background and Aims Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has led to dramatic loss of lives due to COVID-19. Individuals with chronic conditions, including patients with kidney failure and/or kidney transplants, are affected more substantially due to multiple comorbidities and altered immune system. The first step of this infection process is the binding of SARS-CoV-2 with angiotensin-converting enzyme 2 (ACE-2) receptor, followed by its priming by transmembrane protease serine 2 (TMPRSS2). We hypothesized that the expressions of ACE-2 and TMPRSS2 are increased in microvasculature, in addition to increased circulating soluble ACE-2 levels in patients with end stage kidney disease (ESKD); i.e. prerequisites to explain to why ESKD patients are susceptible to SARS-CoV-2 infection. Therefore, we assessed if there is a difference in the expression of ACE-2 and TMPRSS2 receptors in the resistance artery and subcutaneous adipose tissue, alongside circulating soluble ACE-2 levels in ESKD patients versus controls. Method A total of 210 participants were enrolled, representing 80 ESKD and 73 healthy controls for soluble ACE-2 analysis, and 31 ESKD and 26 healthy controls for isolated subcutaneous vasculature bioassay. Immunofluorescence techniques were performed for the detection and evaluation of ACE-2 and TMPRSS2 in isolated subcutaneous resistance artery (200-300 µm of internal âCE€) and adipose tissue. Soluble ACE-2 protein concentration was detected using commercially available ELISA kits. Results Soluble ACE-2 levels were significantly higher in ESKD (3.8 ng/mL, IQR 2.4-5.5, n=80) vs control groups (2.7 ng/mL, IQR 2.1-3.7 ng/mL, n=73). There was no difference in soluble ACE-2 between females and males in either group. Soluble ACE-2 was positively correlated with IL-6 (rho=0.257, p=0.02, n=80), while it was negatively correlated with cholesterol (rho= -0.248, p=0.02, n=78) in ESKD patients. The expression of ACE-2 receptor was observed both on endothelium and vascular smooth muscle cells (VSMCs) in arteries from both groups. The expression was higher in ESKD patients (19.1%, n=23) vs controls (15.4%, n=15). Patients with ESKD on ACE-inhibitor/angiotensin receptor blocker treatment showed higher expression of ACE-2 vs. non-treatment group (treatment: 20.2%, n=12 vs non-treatment: 12.8%, n=11) in resistance artery. In subcutaneous adipose tissue the ACE-2 staining was not statistically different among the groups (ESKD: 2.9%, n=10 vs controls: 3.6%, n=10). In addition, TMPRSS2 was expressed both on endothelium and VSMCs in resistance artery, however there was no difference in the expression (ESKD: 8.4%, n=23 vs controls: 10.2%, n=15) between the groups. Conclusion Soluble ACE-2 levels and ACE-2 receptor expression in the vasculature were higher in patients with ESKD as compared to controls. The ACE-2 receptor is present both in the endothelium and VSMCs from arteries in peripheral microcirculation. This supports the suggestion that the uremic milieu induces an optimal environment for SARS-CoV-2 entrance in microcirculation with following consequence on the vasculature during the COVID-19. Similarly, TMPRSS2 expression was observed in vessels from both groups, while increased expression of ACE-2 receptor was observed in those ESKD patients receiving ACE-inhibitor/angiotensin receptor blocker treatment. Further studies are warranted to assess possible sex differences in the target receptor expressions with further elaboration on specific treatment regime(s) for different comorbidities present in patients with ESKD.

Abstract Background and Aims This study was performed on behalf of the GOING-FWD Consortium. The importance of sex difference in the development of cardiovascular complications is well appreciated, however, further studies are warranted to assess if sex specific pathophysiological changes occur under uremic environment. Little is known about the relationship between the uremic phenotype and novel cardiovascular biomarkers like growth differentiation factor 15 (GDF-15), cartilage glycoprotein 39 (YKL-40), and matrix metalloproteinase 9 (MMP9), and if they have a sex specific effects in relation to inflammation, vascular remodelling, cardiovascular outcomes and all-cause mortality. Therefore, we hypothesise that there is a sex specific relationship between GDF-15, YKL-40, MMP9 and vascular outcomes defined as athero-/arteriosclerosis and vascular calcification. Method ESKD patients (n = 231), males (n = 152) and females (n = 79), not receiving renal replacement therapy were selected from two ongoing prospective CKD cohorts from the Division of Renal Medicine, Karolinska University Hospital, Sweden. Three putative CVD biomarkers, GDF-15, YKL-40 and MMP9 were analysed using enzyme-linked immunosorbent assay (ELISA) kits. Biomarker level/activity was analysed in the context of gut microbiota derived TMAO, vascular calcification (determined as CAC score on CT scans, aortic valve calcification (AVC) and medial calcification on epigastric artery biopsies), inflammatory response, oxidative stress and all-cause mortality. Results The levels of investigated biomarkers have not differed between female and male patients with ESKD. However, GDF-15 correlated with TMAO in females from more severe cohort that are not receiving renal replacement therapy yet, whereas in males increased GDF-15 level was associated with higher Agatston score on CT-scans, inflammatory biomarker (IL-6) and oxidative stress biomarker 8-OHdG. None of biomarkers was related to intimal medial calcification assessed in epigastric artery biopsies. Comorbidity analysis revealed elevated GDF-15 levels in both females and males, while increased MMP-9 levels were observed only in females with diabetes mellitus, but not with CVD. When assessing death of any cause in our cohorts, both deceased males and females had higher GDF-15 concentration (p = 0.01 and p < 0.001, respectively), meanwhile only YKL-40 level was increased in deceased males (p = 0.02). Conclusion In summary, here we report that in males GDF-15 and YKL-40 were related to vascular calcification, inflammageing and oxidative stress, while in females the relationship of GDF-15 with TMAO was observed. Higher MMP-9 level was seen in males without diabetes and in females with confirmed diabetes mellitus. YKL-40 increase in males and GDF-15 in both males and females were associated with all-cause mortality. Our findings suggest that sex specific associations exist and those could have a potential to affect development of cardiovascular complications in patients with ESKD.

BACKGROUND AND AIMS: Chronic kidney disease (CKD) is a progressive systemic disease that affect the microvascular permeability of the blood-brain barrier (BBB) and intestinal barrier leading to increased morbidity, mortality and central nervous system symptoms. In this study we examined the relationship of blood brain and intestinal barrier dysfunction in relation to uraemic environment and increased risk of developing neurologic complications and mortality. In addition, potential proteins conferring the junctional communications were assessed. METHOD: The study included s erum samples from 216 prevalent haemodialysis (HD), 80 peritoneal dialysis (PD) and 80 healthysubjects. Permeability of the BBB was evaluated by measuring serum concentrations for brain-specific biomarkers S100B, NSE (neuron specific enolase), BDNF (brain-derived neurotrophic factor), GFAP (glial fibrillary acidic protein) using ELISA. TMAO (trimethylamine-N-Oxide) as a surrogate of gut generated uraemic toxins was analysed by mass spectrophotometry. Subcutaneous fat tissues with identified microvessels from 10 kidney transplant recipients and 11 donors were examined for expression of tight junction proteins claudin-5, occludin and JAM-1 (junction adhesion molecule-1) by immunohistochemical staining. RESULTS: HD and PD groups showed elevated cholesterol, triglyceride, creatinine, hsCRP and lower BMI, and P-albumin compared to healthy controls. BDNF participants an early (E) to early diastolic mitral annular (e’) (E/e’) of (cid:2) 8 measured with echocardiography) Routine echocardiography and laboratory at the outpatient were for all participants. An expert panel decided on presence or absence of heart failure with preserved ejection fraction (HFpEF), and left ventricular diastolic dysfunction (LVDD), guided by available international guidelines. The between renal function, in terms of estimated glomerular filtration rate (eGFR) categories, and diagnosis of HFpEF and LVDD was assessed with multivariable logistic regression analyses, adjusted for cardiovascular and lifestyle risk factors. The association between renal function, in terms of creatinine and cystatin C levels, and echocardiographic parameters, including E/e’ ratio, LAVI (Left atrial volume index), LVMI (left ventricular mass index), and E/A (early (E) to late (A) ventricular filling ratio, was assessed with multivariable linear regression analyses, adjusted for age, sex, cardiovascular and lifestyle risk factors. Adjusted odds ratios (OR) were reported and the corresponding 95% confidence interval (95%CI). RESULTS: 777 participants were included, mean age 62.9 (SD: 9.3) years, 67.3% were female. Hundred and fifty-six (20.1%) participants had mild renal dysfunction (eGFR: 60-89 ml/min/1.73 m2), and 24 (3.1%) moderate renal dysfunction (eGFR: 30-59 ml/ min/1.73 m2). HFpEF and LVDD was more common in participants with moderate renal dysfunction (13% and 33%, respectively) than in those with normal renal function (6% and 16%, respectively). In the multivariable regression model. participants with both mild and moderate renal dysfunction had a higher likelihood of being diagnosed with HFpEF (OR: 2.82, 95%CI: 1.32 to 5.91; and OR: 5.37, 95%CI: 1.11 to 19.88, respectively), LVDD (OR: 2.08, 95%CI: 1.28 to 3.36; and OR: 2.92, 95%CI: 1.04 to 7.55, respectively), compared with participants with a normal renal function. However, no significant association between creatinine or cystatin C with E/e’, LAVI, LVMI, and E/A ratio was found after adjustment for age, sex, and cardiovascular risk and lifestyle factors. CONCLUSION: Mild renal dysfunction is related to both LVDD and HFpEF, however, this might be partly explained by a higher age in patients with renal dysfunction. Further studies are warranted to determine if preventive cardiac treatment in patients with early renal dysfunction will benefit clinical outcomes. BACKGROUND AND AIMS: Mammalian Protein Arginine Methyltransferase 3 (PRMT3) catalyzes the monomethylation and dimethylation of the Arginine residues of proteins. The role of PRMT3 in renal fibrosis is currently unknown. We aimed to study the role of PRMT3 in renal fibrosis and explored its underlining mechanisms. METHOD: Sham or Unilateral Ureter Obstruction (UUO) operation was performed in Prmt3 wild-type (WT), heterozygous (Het) and homozygous (Homo) mutant mice, which were sacrificed at day 14. A single dose of aristolochic acid (5mg/kg) was injected in WT or HE mice, which was sacrificed at day 42. RESULTS: A stronginterstitial fibrosis was observed in WT UUO mice as shown by Masson staining, and heterozygous or homozygous deletion of Prmt3 gene further enhanced interstitial fibrosis in mouse kidneys. The expression of collagen-I in mouse kidneys were analyzed by Western blotting. UUO operation increased the expression of collagen-I in WT mouse kidneys, which were further increased by genetic deletion of Prmt3 gene in a dose-dependent manner. A mild renal interstitial fibrosis was observed in AAN mice, which was enhanced by heterozygous deletion of Prmt3 gene. Western blot analysis showed that aristolochic acid increased the expression of collagen-I in WT mice, which was further increased in Prmt3 Het mutant mice. Mechanismly, asymmetric dimethylarginine levels were elevated in UUO or AAN mouse kidneys as compared with its controls as shown by immnohistochemistry staining or ELISA. Renal ADMA levels were not elevated in Prmt3 mutant UUO or AAN mice. Moreover, renal injection of ADMA in UUO kidneys blocked the enhanced renal interstitial fibrosis in Prmt3 Het mutant mice as shown by Masson staining and Western blot analysis of collagen-I. CONCLUSION: Prmt3 inhibits renal interstitial fibrosis through enhancing renal ADMA levels. The is controlled at the post- transcriptional level by the action of small non-coding RNAs known as microRNAs (miRNAs), short, single-stranded molecules that control mRNA stability or translational repression via base pairing with regions in the 3’ untranslated region of their target mRNAs. considerable has to elucidate the roles of miRNAs in vascular pathogenesis and develop the use of miRNAs as biomarkers, and innovative We demonstrated during the last decade that miRNAs miR-126 and miR-223 are implicated in the course of chronic kidney disease (CKD) and cardiovascular damage. miR-223 expression is enhanced in vascular smooth muscle cells (VSMCs) subjected to an uremic toxin and also in aortas of a murine model of CKD.