scholarly journals RIP2 plays a role in cardiac Ca2+ mishandling prompted by chronic kidney disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
M Gil-Fernandez ◽  
J.A Navarro-Garcia ◽  
A Val-Blasco ◽  
L Gonzalez-Lafuente ◽  
J.C Martinez ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Cardiac Dysfunction ◽  
Fibroblast Growth Factor 23 ◽  
Funding Source ◽  
Mice Model ◽  
Health Institute ◽  
Major Player ◽  
Genetic Deletion ◽  
Carlos Iii

Abstract Background Chronic kidney disease (CKD) is a multifaceted disease that contributes to cardiac dysfunction. However, the mechanisms underlying the complex relationship between CKD and cardiac impairment remains almost completely unknown. Inflammation is a major player in both CKD and cardiovascular disease (CVD) and, in this context, nucleotide-binding oligomerization domain-containing protein 1 (NOD1) is a newly recognized innate immune receptor involved in both CKD and CVD independently. NOD1 activation is due to the recruitment of the receptor-interacting-serine/threonine-protein kinase 2 (RIP2), which induce NOD1 oligomerization and promotes the inflammatory response, being RIP2 a key partner in the NOD1 activation. Unpublished data from our group has demonstrated that genetic deletion of NOD1 prevents Ca2+ mishandling associated to CKD, next step will be to determine whether the absence of its specific adaptor; RIP2 can also mediate these effects. Purpose The main aim of this study was to determine whether NOD1-RIP2 axis impairs cardiac dysfunction and Ca2+ mishandling prompted by CKD induced by 5/6 nephrectomy (5/6Nx) in a mice model. Methods and results We have analysed intracellular Ca2+ handling in cardiomyocytes obtained from Wild type (Wt), Nod1−/− and Rip2−/− sham operated or nephrectomised mice. Compared with Wt-5/6Nx, cardiomyocytes obtained from Nod1−/−5/6Nx and Rip2−/−5/6Nx mice showed a significant improvement of Ca2+ mishandling, mainly by preventing: i) the reduction in [Ca2+]i transients amplitude; ii) the rise in their decay time; and iii) the lower cell contraction. The lack of NOD1 and RIP2 also prevents the reduced sarcoplasmic reticulum (SR) Ca2+ load and the augmented diastolic Ca2+ leak induced by 5/6Nx. Furthermore, the increased diastolic Ca2+ leak (Ca2+ sparks, spontaneous [Ca2+]i transients and waves) induced by 5/6Nx were also significantly prevented in absence of NOD1 and RIP2. Genetic deletion of NOD1 or RIP2 did not induces any improvement of several markers associated with renal dysfunction (urea, phosphate or fibroblast growth factor-23). Conclusions Our results confirmed that the absence of both NOD1 and RIP2 prevents the intracellular cardiac Ca2+ mishandling in experimental CKD. NOD1 and RIP2 emerge as novel targets for the development of innovative therapeutic strategies for the cardiac remodelling in CKD subjects. Funding Acknowledgement Type of funding source: Public grant(s) – National budget only. Main funding source(s): This work was supported by Spanish ISCIII (PI17/01093 and PI17/01344), Fondo Europeo de Desarrollo Regional (FEDER), FSE, and CIBER-CV, a network funded by ISCIII. MF-V is Miguel Servet II researcher of ISCIII (MSII16/00047 Carlos III Health Institute). GR-H is Miguel Servet I researcher of ISCIII (CP15/00129 Carlos III Health Institute). MT is a PhD student funded by the FPU program of the Spanish Ministry of Science, Innovation and Universities (FPU17/06135).

scholarly journals Lipocalin 2 stimulates bone fibroblast growth factor 23 production in chronic kidney disease

Bone Research ◽  
2021 ◽  
Vol 9 (1) ◽  
Author(s):  
Guillaume Courbon ◽  
Connor Francis ◽  
Claire Gerber ◽  
Samantha Neuburg ◽  
Xueyan Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Growth Factor ◽  
Kidney Disease ◽  
Iron Deficiency ◽  
Fibroblast Growth Factor ◽  
Kidney Function ◽  
Fibroblast Growth Factor 23 ◽  
Left Ventricular ◽  
Fibroblast Growth ◽  
Lipocalin 2

AbstractBone-produced fibroblast growth factor 23 (FGF23) increases in response to inflammation and iron deficiency and contributes to cardiovascular mortality in chronic kidney disease (CKD). Neutrophil gelatinase-associated lipocalin (NGAL or lipocalin 2; LCN2 the murine homolog) is a pro-inflammatory and iron-shuttling molecule that is secreted in response to kidney injury and may promote CKD progression. We investigated bone FGF23 regulation by circulating LCN2. At 23 weeks, Col4a3KO mice showed impaired kidney function, increased levels of kidney and serum LCN2, increased bone and serum FGF23, anemia, and left ventricular hypertrophy (LVH). Deletion of Lcn2 in CKD mice did not improve kidney function or anemia but prevented the development of LVH and improved survival in association with marked reductions in serum FGF23. Lcn2 deletion specifically prevented FGF23 elevations in response to inflammation, but not iron deficiency or phosphate, and administration of LCN2 increased serum FGF23 in healthy and CKD mice by stimulating Fgf23 transcription via activation of cAMP-mediated signaling in bone cells. These results show that kidney-produced LCN2 is an important mediator of increased FGF23 production by bone in response to inflammation and in CKD. LCN2 inhibition might represent a potential therapeutic approach to lower FGF23 and improve outcomes in CKD.

scholarly journals Impact of antithrombotic therapy in the prognosis of atrial fibrillation patients with advanced chronic kidney disease

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
J.M Andreu Cayuelas ◽  
S Raposeiras-Roubin ◽  
E Fortuny Frau ◽  
A Garcia Del Egido ◽  
J Seller-Moya ◽  
...  
Keyword(s):  
Atrial Fibrillation ◽  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Antithrombotic Therapy ◽  
Anticoagulation Therapy ◽  
Bleeding Event ◽  
Funding Source ◽  
Newly Diagnosed ◽  
Bleeding Events ◽  
Cox Regression Analysis

Abstract Introduction Chronic kidney disease (CKD) is associated with an elevated thromboembolic and bleeding risk in atrial fibrillation (AF) patients, so the decision of antithrombotic therapy is a challenge. Purpose To analyze mortality, embolic and bleeding events in patients with advanced CKD and AF. Methods Multicentric retrospective registry on patients with AF and advanced CKD (CKD-EPI <30 mL/min/1.73 m2). For death, multivariable Cox regression analysis was developed. For embolic and bleeding events, competing-risks regression based on Fine and Gray's proportional subhazards model was performed, being death the competing event Results We analysed 405 patients with advanced CKD and newly diagnosed AF. 57 patients were not treated with antithrombotic therapy (14.1%), 80 only with antiplatelet/s (19.8%), 211 only with anticoagulation (52.1%), and 57 with anticoagulant plus antiplatelet/s (14.1%). During a follow-up of 4.6±2.5 years, 205 died (50.6%), 34 had embolic events (8.4%) and 85 had bleeding outcomes (21.0%). Bleeding event rate was significantly lower in patients without antithrombotic therapy (Figure). After multivariate analysis, anticoagulant treatment was associated with higher bleeding rates, without differences in mortality or embolic events (Table). Conclusion Anticoagulation therapy was associated with a significant increase in bleeding events in patients with advanced CKD and newly diagnosed AF. None of the antithrombotic therapy regimens resulted in lower embolic events rate neither benefit in mortality. Funding Acknowledgement Type of funding source: Private grant(s) and/or Sponsorship. Main funding source(s): This study was supported by an unconditional grant from BMS-Pfizer

scholarly journals The Copenhagen chronic kidney disease echo study (COInCYDE)

2020 ◽  
Vol 41 (Supplement_2) ◽  
Author(s):  
N Landler ◽  
S Bro ◽  
B Feldt-Rasmussen ◽  
D Hansen ◽  
A.L Kamper ◽  
...  
Keyword(s):  
Blood Pressure ◽  
Chronic Kidney Disease ◽  
Cohort Study ◽  
Kidney Disease ◽  
Cardiac Function ◽  
Left Ventricular ◽  
Funding Source ◽  
Ckd Stage ◽  
Significant Difference ◽  
Stage 1

Abstract Background The cardiovascular mortality of patients with chronic kidney disease (CKD) is 2–10 times higher than in the average population. Purpose To estimate the prevalence of abnormal cardiac function or structure across the stages CKD 1 to 5nonD. Method Prospective cohort study. Patients with CKD stage 1 to 5 not on dialysis, aged 30 to 75 (n=875) and age-/sex-matched controls (n=173) were enrolled consecutively. All participants underwent a health questionnaire, ECG, morphometric and blood pressure measurements. Blood and urine were analyzed. Echocardiography was performed. Left ventricle (LV) hypertrophy, dilatation, diastolic and systolic dysfunction were defined according to current ESC guidelines. Results 63% of participants were men. Mean age was 58 years (SD 12.6 years). Mean eGFR was 46.7 mL/min/1,73 m (SD 25.8) for patients and 82.3 mL/min/1,73 m (SD 13.4) for controls. The prevalence of elevated blood pressure at physical exam was 89% in patients vs. 53% in controls. Patients were more often smokers and obese. Left ventricular mass index (LVMI) was slightly, albeit insignificantly elevated at CKD stages 1 & 2 vs. in kontrols: 3.1 g/m2, CI: −0.4 to 6.75, p-value 0.08. There was no significant difference in LV-dilatation between patients and controls. Decreasing diastolic and systolic function was observed at CKD stage 3a and later: LVEF decreased 0.95% (CI: −1.5 to −0.2), GLS increased 0.5 (CI: 0.3 to 0.8), and OR for diastolic dysfunction increased 3.2 (CI 1.4 to 7.3) pr. increment CKD stage group. Conclusion In accordance to previous studies, we observe in the CPHCKD cohort study signs of early increase of LVMI in patients with CKD stage 1 & 2. Significant decline in systolic and diastolic cardiac function is apparent already at stage 3 CKD. Figure 1. Estimated GFR vs. GLS & histogram of GLS Funding Acknowledgement Type of funding source: Public hospital(s). Main funding source(s): The Capital Region of Denmark

scholarly journals A phosphate and calcium-enriched diet promotes progression of 5/6-nephrectomy-induced chronic kidney disease in C57BL/6 mice

2021 ◽  
Vol 11 (1) ◽  
Author(s):  
J. Radloff ◽  
N. Latic ◽  
U. Pfeiffenberger ◽  
C. Schüler ◽  
S. Tangermann ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Calcium Phosphate ◽  
Kidney Disease ◽  
Renal Fibrosis ◽  
Time Course ◽  
Bone Mineralization ◽  
Fibroblast Growth Factor 23 ◽  
Functional Decline ◽  
Left Ventricular ◽  
Normal Diet

AbstractC57BL/6 mice are known to be rather resistant to the induction of experimental chronic kidney disease (CKD) by 5/6-nephrectomy (5/6-Nx). Here, we sought to characterize the development of CKD and its cardiac and skeletal sequelae during the first three months after 5/6-Nx in C57BL/6 mice fed a calcium- and phosphate enriched diet (CPD) with a balanced calcium/phosphate ratio. 5/6-NX mice on CPD showed increased renal fibrosis and a more pronounced decrease in glomerular filtration rate when compared to 5/6-Nx mice on normal diet (ND). Interestingly, despite comparable levels of serum calcium, phosphate, and parathyroid hormone (PTH), circulating intact fibroblast growth factor-23 (FGF23) was 5 times higher in 5/6-Nx mice on CPD, relative to 5/6-Nx mice on ND. A time course experiment revealed that 5/6-Nx mice on CPD developed progressive renal functional decline, renal fibrosis, cortical bone loss, impaired bone mineralization as well as hypertension, but not left ventricular hypertrophy. Collectively, our data show that the resistance of C57BL/6 mice to 5/6-Nx can be partially overcome by feeding the CPD, and that the CPD induces a profound, PTH-independent increase in FGF23 in 5/6-Nx mice, making it an interesting tool to assess the pathophysiological significance of FGF23 in CKD.

scholarly journals FGF-23 and Phosphate in Children with Chronic Kidney Disease: A Cross-Sectional Study in Kazakhstan

Medicina ◽  
2020 ◽  
Vol 57 (1) ◽  
pp. 15
Author(s):  
Altynay Balmukhanova ◽  
Kairat Kabulbayev ◽  
Harika Alpay ◽  
Assiya Kanatbayeva ◽  
Aigul Balmukhanova
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Fibroblast Growth Factor 23 ◽  
Cross Sectional Study ◽  
Sectional Study ◽  
Cross Sectional ◽  
Ckd Stage ◽  
Advanced Stages ◽  
Fgf 23 ◽  
Stage 1

Background and objectives: Chronic kidney disease (CKD) in children is a complex medical and social issue around the world. One of the serious complications is mineral-bone disorder (CKD-MBD) which might determine the prognosis of patients and their quality of life. Fibroblast growth factor 23 (FGF-23) is a phosphaturic hormone which is involved in the pathogenesis of CKD-MBD. The purpose of the study was to determine what comes first in children with CKD: FGF-23 or phosphate. Materials and Methods: This cross-sectional study included 73 children aged 2–18 years with CKD stages 1–5. We measured FGF-23 and other bone markers in blood samples and studied their associations. Results: Early elevations of FGF-23 were identified in children with CKD stage 2 compared with stage 1 (1.6 (1.5–1.8) pmol/L versus 0.65 (0.22–1.08), p = 0.029). There were significant differences between the advanced stages of the disease. FGF-23 correlated with PTH (r = 0.807, p = 0.000) and phosphate (r = 0.473, p = 0.000). Our study revealed that the elevated level of FGF-23 went ahead hyperphosphatemia and elevated PTH. Thus, more than 50% of children with CKD stage 2 had the elevating level of serum FGF-23, and that index became increasing with the disease progression and it achieved 100% at the dialysis stage. The serum phosphate increased more slowly and only 70.6% of children with CKD stage 5 had the increased values. The PTH increase was more dynamic. Conclusions: FGF-23 is an essential biomarker, elevates long before other markers of bone metabolism (phosphate), and might represent a clinical course of disease.

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