scholarly journals Association of a single nucleotide polymorphism combination pattern of the Klotho gene with non-cardiovascular death in patients with chronic kidney disease

2020 ◽  
Vol 13 (6) ◽  
pp. 1017-1024 ◽  
Author(s):  
Serafi Cambray ◽  
Marcelino Bermudez-Lopez ◽  
Milica Bozic ◽  
Jose M Valdivielso ◽  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Rare Allele ◽  
Cardiovascular Death ◽  
Adverse Outcomes ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide ◽  
Klotho Gene

Abstract Background Chronic kidney disease (CKD) is associated with an elevated risk of all-cause mortality, with cardiovascular death being extensively investigated. However, non-cardiovascular mortality represents the biggest percentage, showing an evident increase in recent years. Klotho is a gene highly expressed in the kidney, with a clear influence on lifespan. Low levels of Klotho have been linked to CKD progression and adverse outcomes. Single nucleotide polymorphisms (SNPs) of the Klotho gene have been associated with several diseases, but studies investigating the association of Klotho SNPs with non-cardiovascular death in CKD populations are lacking. Methods The main aim of this study was to assess whether 11 Klotho SNPs were associated with non-cardiovascular death in a subpopulation of the National Observatory of Atherosclerosis in Nephrology (NEFRONA) study (n = 2185 CKD patients). Results After 48 months of follow-up, 62 cardiovascular deaths and 108 non-cardiovascular deaths were recorded. We identified a high non-cardiovascular death risk combination of SNPs corresponding to individuals carrying the most frequent allele (G) at rs562020, the rare allele (C) at rs2283368 and homozygotes for the rare allele (G) at rs2320762 (rs562020 GG/AG + rs2283368 CC/CT + rs2320762 GG). Among the patients with the three SNPs genotyped (n = 1016), 75 (7.4%) showed this combination. Furthermore, 95 (9.3%) patients showed a low-risk combination carrying all the opposite genotypes (rs562020 AA + rs2283368 TT + rs2320762 GT/TT). All the other combinations [n = 846 (83.3%)] were considered as normal risk. Using competing risk regression analysis, we confirmed that the proposed combinations are independently associated with a higher {hazard ratio [HR] 3.28 [confidence interval (CI) 1.51–7.12]} and lower [HR 6 × 10−6 (95% CI 3.3 × 10−7–1.1 × 10−5)] risk of suffering a non-cardiovascular death in the CKD population of the NEFRONA cohort compared with patients with the normal-risk combination. Conclusions Determination of three SNPs of the Klotho gene could help in the prediction of non-cardiovascular death in CKD.

Causal associations of obesity with chronic kidney disease and arterial stiffness: a Mendelian randomization study

2021 ◽  
Author(s):  
Chaojie Ye ◽  
Lijie Kong ◽  
Zhiyun Zhao ◽  
Mian Li ◽  
Shuangyuan Wang ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Standard Deviation ◽  
Kidney Disease ◽  
Single Nucleotide Polymorphisms ◽  
Arterial Stiffness ◽  
Genetic Risk ◽  
Mendelian Randomization ◽  
Genetic Risk Score ◽  
Nucleotide Polymorphisms ◽  
Single Nucleotide

Abstract Purpose Observational studies have associated obesity with chronic kidney disease (CKD) and arterial stiffness, but the causality remains unclear. We aimed to investigate the causality of obesity with CKD and arterial stiffness using Mendelian randomization (MR) analysis. Methods We genotyped 14 body mass index (BMI)-associated variants validated in East Asians in 11384 Chinese adults. A genetic risk score based on the 14 variants and the 14 individual single nucleotide polymorphisms were respectively used as instrumental variables (IVs). CKD was defined as estimated glomerular filtration rate <60 mL/min/1.73 m 2. Arterial stiffness was defined as brachial-ankle pulse wave velocity >1550 cm/s. Results Using the genetic risk score as the IV, we demonstrated causal relations of each 1-standard deviation increment in BMI with CKD (odds ratio [OR]: 2.36; 95% confidence interval [CI]: 1.11-5.00) and arterial stiffness (OR: 1.71; 95% CI: 1.22-2.39). Using the 14 single nucleotide polymorphisms individually as IVs, each 1-standard deviation increment in BMI casually associated with CKD (OR: 2.58; 95% CI: 1.39-4.79) and arterial stiffness (OR: 1.87; 95% CI: 1.24-2.81) in the inverse-variance weighted analysis, and MR-Egger regression revealed no evidence of horizontal pleiotropy (Both P for intercept≥0.34). The causality between obesity and CKD was validated in two-sample MR analysis among Europeans (681275 of Genetic Investigation of ANthropometric Traits and 133413 of CKD Genetics). Conclusions This study provided novel insights into causality of obesity with CKD and arterial stiffness, highlighting the importance of weight management for primary prevention and control of subclinical vascular diseases.

scholarly journals Machine learning analysis of serum biomarkers for cardiovascular risk assessment in chronic kidney disease

2019 ◽  
Author(s):  
Carles Forné ◽  
Serafi Cambray ◽  
Marcelino Bermudez-Lopez ◽  
Elvira Fernandez ◽  
Milica Bozic ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Cardiovascular Risk ◽  
High Risk ◽  
Kidney Disease ◽  
Cardiovascular Death ◽  
Lipid Lowering ◽  
Cardiovascular Risk Prediction ◽  
Competing Events ◽  
Endothelial Growth Factor

Abstract Background Chronic kidney disease (CKD) patients show an increased burden of atherosclerosis and high risk of cardiovascular events (CVEs). There are several biomarkers described as being associated with CVEs, but their combined effectiveness in cardiovascular risk stratification in CKD has not been tested. The objective of this work is to analyse the combined ability of 19 biomarkers associated with atheromatous disease in predicting CVEs after 4 years of follow-up in a subcohort of the NEFRONA study in individuals with different stages of CKD without previous CVEs. Methods Nineteen putative biomarkers were quantified in 1366 patients (73 CVEs) and their ability to predict CVEs was ranked by random survival forest (RSF) analysis. The factors associated with CVEs were tested in Fine and Gray (FG) regression models, with non-cardiovascular death and kidney transplant as competing events. Results RSF analysis detected several biomarkers as relevant for predicting CVEs. Inclusion of those biomarkers in an FG model showed that high levels of osteopontin, osteoprotegerin, matrix metalloproteinase-9 and vascular endothelial growth factor increased the risk for CVEs, but only marginally improved the discrimination obtained with classical clinical parameters: concordance index 0.744 (95% confidence interval 0.609–0.878) versus 0.723 (0.592–0.854), respectively. However, in individuals with diabetes treated with antihypertensives and lipid-lowering drugs, the determination of these biomarkers could help to improve cardiovascular risk estimates. Conclusions We conclude that the determination of four biomarkers in the serum of CKD patients could improve cardiovascular risk prediction in high-risk individuals.

scholarly journals Effects of Dapagliflozin in Stage 4 Chronic Kidney Disease

2021 ◽  
pp. ASN.2021020167
Author(s):  
Glenn Chertow ◽  
Priya Vart ◽  
Niels Jongs ◽  
Robert Toto ◽  
Jose Luis Gorriz ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Adverse Events ◽  
Controlled Trial ◽  
Composite Endpoint ◽  
Cardiovascular Death ◽  
Adverse Outcomes ◽  
Serious Adverse Events ◽  
Stage 4 ◽  
Cardiovascular Endpoint

Background In the Dapagliflozin And Prevention of Adverse Outcomes in Chronic Kidney Disease (DAPA-CKD) randomized placebo-controlled trial, the sodium-glucose cotransporter 2 inhibitor dapagliflozin significantly reduced risk of kidney failure and prolonged survival in CKD patients with or without type 2 diabetes. Methods In this prespecified analysis of dapagliflozin's effects in patients with stage 4 CKD (eGFR<30 mL/min per 1.73m2) at baseline, we randomized adults with eGFR of 25-75 mL/min per 1.73m2 and urinary albumin-to-creatinine ratio of 200-5000 mg/g to receive dapagliflozin 10 mg/day or placebo. The primary outcome was a composite of time to ≥50% sustained decline in eGFR, end-stage kidney disease, or kidney or cardiovascular death. Secondary outcomes were a kidney composite (same as the primary endpoint but without cardiovascular death), a composite of cardiovascular death or heart failure hospitalization, and all-cause death. Results A total of 293 participants received dapagliflozin and 331 received placebo. Relative to placebo, dapagliflozin was associated with reductions in the primary composite endpoint (hazard ratio [HR], 0.73; 95% confidence interval [95% CI], 0.53 to 1.0), the kidney endpoint (HR, 0.71; 95% CI, 0.49 to 1.02), the cardiovascular endpoint (HR, 0.83; 95% CI, 0.45 to 1.53), and the mortality endpoint (HR, 0.68; 95% CI, 0.39 to 1.21). The eGFR slope declined by 2.15 and 3.38 mL/min per 1.73m2 per year in the dapagliflozin and placebo groups, respectively (P=0.005). Patients treated with dapagliflozin or placebo had similar rates of serious adverse events and adverse events of interest. Conclusions Among patients with stage 4 CKD and albuminuria, dapagliflozin's benefits were consistent with those observed in the DAPA-CKD trial overall, with no evidence of increased risks.

scholarly journals MO159CHA2DS2-VASC SCORE AS A PREDICTOR OF CARDIOVASCULAR MORTALITY IN CHRONIC KIDNEY DISEASE PATIENTS

2021 ◽  
Vol 36 (Supplement_1) ◽  
Author(s):  
Nina Vodošek Hojs ◽  
Robert Ekart ◽  
Sebastjan Bevc ◽  
Nejc Piko ◽  
Radovan Hojs
Keyword(s):  
Chronic Kidney Disease ◽  
Regression Analysis ◽  
Cardiovascular Risk ◽  
Kidney Disease ◽  
Cardiovascular Mortality ◽  
Cox Regression ◽  
High Sensitivity ◽  
Cardiovascular Death ◽  
Cox Regression Analysis

Abstract Background and Aims Cardiovascular mortality is high in chronic kidney disease (CKD) patients. Recognizing patients with higher cardiovascular risk might help in their treatment. CHA2DS2-VASc score was originally used to predict cerebral infarction in patients with atrial fibrillation (AF). However, it is also useful in predicting outcome in different cardiovascular conditions, independent of the presence of AF. Therefore, the aim of our research was to assess the role of CHA2DS2-VASc score in cardiovascular mortality in CKD patients. Method Eighty-seven non-dialysis CKD patients from our outpatient clinic were included. At the time of inclusion, medical history data and standard blood results were collected and CHA2DS2-VASc score was calculated. Patients were followed for assigned time or until their death. Mean follow-up time was 1696.45±564.60 days. Results Descriptive statistics of our patients are presented in table 1. During follow-up 11 patients suffered from cardiovascular death. Univariate Cox regression analysis showed that CHA2DS2-VASc score is a significant predictor of cardiovascular mortality (HR: 2.19, CI: 1.42-3.37, p=0.001). In multivariate Cox regression analysis in which CHA2DS2-VASc score, serum creatinine, urinary albumin/creatinine, haemoglobin, high sensitivity CRP and intact PTH were included, CHA2DS2-VASc score was an independent predictor of cardiovascular mortality (HR: 2.04, CI: 1.20-3.45, p=0.008) (table 2). Conclusion CHA2DS2-VASc score is a simple and quick way to identify cardiovascular risk in CKD patients.

scholarly journals Genetic Variants Associated with Chronic Kidney Disease in a Spanish Population

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Zuray Corredor ◽  
Miguel Inácio da Silva Filho ◽  
Lara Rodríguez-Ribera ◽  
Antonia Velázquez ◽  
Alba Hernández ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Resistance Index ◽  
Nucleotide Polymorphisms ◽  
C Reactive Protein ◽  
Single Nucleotide ◽  
Reactive Protein ◽  
Tnf Α ◽  
Physiological Pathways ◽  
Comprehensive Study

AbstractChronic kidney disease (CKD) patients have many affected physiological pathways. Variations in the genes regulating these pathways might affect the incidence and predisposition to this disease. A total of 722 Spanish adults, including 548 patients and 174 controls, were genotyped to better understand the effects of genetic risk loci on the susceptibility to CKD. We analyzed 38 single nucleotide polymorphisms (SNPs) in candidate genes associated with the inflammatory response (interleukins IL-1A, IL-4, IL-6, IL-10, TNF-α, ICAM-1), fibrogenesis (TGFB1), homocysteine synthesis (MTHFR), DNA repair (OGG1, MUTYH, XRCC1, ERCC2, ERCC4), renin-angiotensin-aldosterone system (CYP11B2, AGT), phase-II metabolism (GSTP1, GSTO1, GSTO2), antioxidant capacity (SOD1, SOD2, CAT, GPX1, GPX3, GPX4), and some other genes previously reported to be associated with CKD (GLO1, SLC7A9, SHROOM3, UMOD, VEGFA, MGP, KL). The results showed associations of GPX1, GSTO1, GSTO2, UMOD, and MGP with CKD. Additionally, associations with CKD related pathologies, such as hypertension (GPX4, CYP11B2, ERCC4), cardiovascular disease, diabetes and cancer predisposition (ERCC2) were also observed. Different genes showed association with biochemical parameters characteristic for CKD, such as creatinine (GPX1, GSTO1, GSTO2, KL, MGP), glomerular filtration rate (GPX1, GSTO1, KL, ICAM-1, MGP), hemoglobin (ERCC2, SHROOM3), resistance index erythropoietin (SOD2, VEGFA, MTHFR, KL), albumin (SOD1, GSTO2, ERCC2, SOD2), phosphorus (IL-4, ERCC4 SOD1, GPX4, GPX1), parathyroid hormone (IL-1A, IL-6, SHROOM3, UMOD, ICAM-1), C-reactive protein (SOD2, TGFB1,GSTP1, XRCC1), and ferritin (SOD2, GSTP1, SLC7A9, GPX4). To our knowledge, this is the second comprehensive study carried out in Spanish patients linking genetic polymorphisms and CKD.

scholarly journals Effects of dapagliflozin on mortality in patients with chronic kidney disease: a pre-specified analysis from the DAPA-CKD randomized controlled trial

2021 ◽  
Vol 42 (13) ◽  
pp. 1216-1227
Author(s):  
Hiddo J L Heerspink ◽  
C David Sjöström ◽  
Niels Jongs ◽  
Glenn M Chertow ◽  
Mikhail Kosiborod ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Relative Risk ◽  
Kidney Disease ◽  
Risk Reduction ◽  
Relative Risk Reduction ◽  
Controlled Trial ◽  
Cardiovascular Death ◽  
All Cause Mortality ◽  
The Mean

Abstract Aims  Mortality rates from chronic kidney disease (CKD) have increased in the last decade. In this pre-specified analysis of the DAPA-CKD trial, we determined the effects of dapagliflozin on cardiovascular and non-cardiovascular causes of death. Methods and results  DAPA-CKD was an international, randomized, placebo-controlled trial with a median of 2.4 years of follow-up. Eligible participants were adult patients with CKD, defined as a urinary albumin-to-creatinine ratio (UACR) 200–5000 mg/g and an estimated glomerular filtration rate (eGFR) 25–75 mL/min/1.73 m2. All-cause mortality was a key secondary endpoint. Cardiovascular and non-cardiovascular death was adjudicated by an independent clinical events committee. The DAPA-CKD trial randomized participants to dapagliflozin 10 mg/day (n = 2152) or placebo (n = 2152). The mean age was 62 years, 33% were women, the mean eGFR was 43.1 mL/min/1.73 m2, and the median UACR was 949 mg/g. During follow-up, 247 (5.7%) patients died, of whom 91 (36.8%) died due to cardiovascular causes, 102 (41.3%) due to non-cardiovascular causes, and in 54 (21.9%) patients, the cause of death was undetermined. The relative risk reduction for all-cause mortality with dapagliflozin (31%, hazard ratio [HR] [95% confidence interval (CI)] 0.69 [0.53, 0.88]; P = 0.003) was consistent across pre-specified subgroups. The effect on all-cause mortality was driven largely by a 46% relative risk reduction of non-cardiovascular death (HR [95% CI] 0.54 [0.36, 0.82]). Deaths due to infections and malignancies were the most frequently occurring causes of non-cardiovascular deaths and were reduced with dapagliflozin vs. placebo. Conclusion  In patients with CKD, dapagliflozin prolonged survival irrespective of baseline patient characteristics. The benefits were driven largely by reductions in non-cardiovascular death.

scholarly journals P0795OUTCOME COMPARISON STUDY ACCORDING TO THE CAUSE OF CHRONIC KIDNEY DISEASE: RESULTS FROM KNOW-CKD STUDY

2020 ◽  
Vol 35 (Supplement_3) ◽  
Author(s):  
Hyunjin Ryu ◽  
Yeji Hong ◽  
Jayoun Kim ◽  
Curie Ahn ◽  
Yun Kyu Oh ◽  
...  
Keyword(s):  
Chronic Kidney Disease ◽  
Kidney Disease ◽  
Mixed Model ◽  
Linear Mixed Model ◽  
Adverse Outcomes ◽  
Hypertensive Nephropathy ◽  
Linear Pattern ◽  
Hazard Ratios ◽  
Egfr Slope

Abstract Background and Aims The cause of chronic kidney disease (CKD) is one of important factors for predicting the outcome. However, relative risks for the adverse outcomes according to the specific causes of CKD is unknown. Method Using the longitudinal data of prospective cohort of Korean predialysis CKD, KNOW-CKD cohort, the relative risk of end-stage renal disease (ESRD), composite of ESRD development or creatinine doubling, and composite of cardiovascular disease (CVD) and all-cause mortality according to the cause of CKD were compared. The patients were subgrouped in to four categories at the study entry according to the cause of CKD: glomerulonephritis (GN), diabetic nephropathy (DN), hypertensive nephropathy (HTN), and polycystic kidney disease (PKD). Since the baseline characteristics differed according to the causes of CKD, the inverse probability of treatment weighting (IPTW) methods was used to exclude the effects of other variables on the outcomes. The estimated glomerular filtration rate (eGFR) slope during follow-up was calculated for each cause of CKD using linear mixed model Results During the median follow-up of 4.1 years (interquartile range 1.12-7.12 years) total 441 (21.5%) of ESRD, 556 (27.1%) of composite of ESRD or creatinine doubling and 190 (9.3%) composite of CVD and all cause death occurred. In the IPTW adjusted cohorts, DN and PKD showed significantly increased hazard ratios of 1.85 and 5.57 for ESRD development and 1.74 and 4.57 for composite of ESRD developement or creatinine doubling, respectively, compared to GN in the fully adjusted model. Regarding compsite of CVD and all-cause death, also DN and PKD showed significantly increased hazard ratios of 1.93 and 2.16 compared to GN. The adjusted eGFR slope for DN, HTN and PKD was -2.32, -0.90, and -2.41 mL/min/1.73m2 per year, respectively, and all differ statistically significantly compared to GN (eGFR slope of -1.49 mL/min/1.73m2 per year). During the follow-up, GN and DN showed linear declining pattern however, HTN and PKD showed convex linear pattern. Conclusion The DN and PKD showed relatively higher risks for renal progression and composite of CVD and death compared to GN.

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