Cardiovascular Risk In Chronic Kidney Disease Research Articles

Clinical Acceptability of a Quality Improvement Program for Reducing Cardiovascular Disease Risk in People With Chronic Kidney Disease in Australian General Practice: Qualitative Study.

Future Health Today (FHT) is a technology program that integrates with general practice clinical software to provide point of care (PoC) clinical decision support and a quality improvement dashboard. This qualitative study looks at the use of FHT in the context of cardiovascular disease risk in chronic kidney disease (CKD). This study aims to explore factors influencing clinical implementation of the FHT module focusing on cardiovascular risk in CKD, from the perspectives of participating general practitioner staff. Practices in Victoria were recruited to participate in a pragmatic cluster randomized controlled trial using FHT, of which 19 practices were randomly assigned to use FHT's cardiovascular risk in CKD program. A total of 13 semistructured interviews were undertaken with a nominated general practitioner (n=7) or practice nurse (n=6) from 10 participating practices. Interview questions focused on the clinical usefulness of the tool and its place in clinical workflows. Qualitative data were coded by 2 researchers and analyzed using framework analysis and Clinical Performance Feedback Intervention Theory. All 13 interviewees had used the FHT PoC tool, and feedback was largely positive. Overall, clinicians described engaging with the tool as a "prompt" or "reminder" system. Themes reflected that the tool's goals and clinical content were aligned with clinician's existing priorities and knowledge, and the tool's design facilitated easy integration into existing workflows. The main barrier to implementation identified by 2 clinicians was notification fatigue. A total of 7 interviewees had used the FHT dashboard tool. The main barriers to use were its limited integration into clinical workflows, such that some participants did not know of its existence; clinicians' competing clinical priorities; and limited time to learn and use the tool. This study identified many facilitators for the successful use of the FHT PoC program, in the context of cardiovascular risk in CKD, and barriers to the use of the dashboard program. This work will be used to inform the wider implementation of FHT, as well as the development of future modules of FHT for other risk or disease states.

MCP1 Inverts the Correlation between FGF23 and Omega 6/3 Ratio: Is It Also True in Renal Transplantation?

During chronic kidney disease (CKD) progression, an increase in fibroblast growth factor (FGF23) is present. In stage 5, a positive correlation between FGF23 and omega-6 (n-6) polyunsaturated fatty acids (PUFAs) emerges. Hypothesizing that the rising positive correlation between monocyte chemoattractant protein 1 (MCP1) and n-6 in stage 4 could be the cause, we previously explored FGF23 and MCP1's roles in dyslipidemia and cardiovascular risk in CKD. In the present paper, we retraced the study evaluating 40 kidney transplant patients (KTx), a cohort where several factors might modify the previous relationships found. An ELISA and gas chromatography assessed the MCP1, FGF23, and PUFA levels. Despite the FGF23 increase (p < 0.0001), low MCP1 levels were found. A decrease in the n-6/n-3 ratio (p = 0.042 CKD stage 4 vs. 5) lowered by the increase in both n-3 αlinolenic (p = 0.012) and docosapentaenoic acid (p = 0.049) was observed. A negative correlation between FGF23 and the n-6/n-3 ratio in CKD stage 4 (r2 -0.3 p = 0.043) and none with MCP1 appeared. According to our findings, different mechanisms in the relationship between FGF23, PUFAs, and MCP1 in CKD and KTx patients might be present, which is possibly related to the immunosuppressive status of the last. Future research will further clarify our hypothesis.

#4457 IONIZED MAGNESIUM LEVELS IN PATIENTS WITH MODERATE-TO-ADVANCED CHRONIC KIDNEY DISEASE: RELATIONSHIP WITH TOTAL MAGNESIUM AND ASSOCIATED FACTORS

Abstract Background and Aims Magnesium (Mg) is involved in a multitude of essential physiological processes. In chronic kidney disease (CKD), the mechanisms compensating for the decrease in glomerular filtration rate (eGFR) become insufficient and Mg excretion tends to decrease, potentially resulting in hypermagnesemia. On the other hand, hypomagnesemia seems also to be common in CKD, due to changes in Mg intake through diet, reduced absorption and drug-induced hypomagnesemia. To date, a few studies have shown an association between increased cardiovascular risk in CKD and either low or high total Mg levels. However, the physiologically active fraction of extracellular Mg is ionized Mg (iMg), which is not routinely measured. In critical ill patients, the correlation between iMg and total Mg has been shown to be poor. Similar data on patients with CKD would be important to future studies aiming at clarifying the link between Mg and outcomes, and ultimately to determine the interest of iMg assay in routine practice. The objectives of this study are i) to study the correlation between total Mg and iMg and ii) to evaluate the relation between serum ionized magnesemia, estimated GFR (eGFR) and demographic and biologic parameters. Method CKD-REIN is a French, prospective, nationally representative cohort study of 3033 CKD patients under nephrology care not receiving maintenance dialysis (stage 3-5: eGFR&amp;lt;60 mL/min/1.73 m² based on 2009 CKD-EPI equation). Baseline iMg and total Mg serum concentrations were respectively centrally measured using the NOVA BIOMEDICAL Stat Profile PRIME ES analyser and with Atellica® CH SIEMENS analyser. Normal range of serum total Mg considered was 0.66 to 1.06 mmol/L (from Atellica®). Mean ± standard deviation (SD) ionized Mg level evaluated in a cohort of 457 healthy volunteers (age = 45 ± 17 years; eGFR = 72.3 ± 13 mL/min/1.73m²) was 0.49 ± 0.05 mmol/L (median [tertile 1 – tertile 3] = 0.49 [0.45-0.52] mmol/L). Correlation between iMg and total Mg was estimated overall. Multivariate linear regressions were performed to identify factors associated with iMg and total Mg levels. Results Among 1741 patients with iMg and total Mg at baseline, the median age was 68 years [59-76], 65% were men, and the mean eGFR was 35 ± 14 mL/min/1.73m². The mean baseline iMg level was 0.48 ± 0.1 mmol/L, 615 patients had an ionized Mg &amp;lt;0.45 mmol/L (Tertile 1), 599 had an iMg between 0.46 and 0.52 mmol/L (Tertile 2), and 527 had an iMg &amp;gt;0.52 mmol/L (Tertile 3). Compared to healthy volunteers, mean iMg levels were significantly lower in CKD patients. However, the difference was small (difference CKD-heatlhy = 0.01 mmol/L). Most of patients were within the total Mg normal range (n = 1522), 12% (n = 208) and 1% (n = 11) presented hypo- and hypermagnesemia, respectively. Correlation between iMg and total Mg was very high (r = 0.88; p&amp;lt;0.001). (Figure). Ionized Mg was weakly inversely correlated with eGFR (r = -0.22; p&amp;lt;0.001). Consequently, the mean iMg level differed according to CKD stages, being more elevated in the advanced stages (0.45 mmol/L in stages 2-3A; 0.47 mmol/L in stage 3B; 0.50 mmol/L in stages 4-5 (p&amp;lt;0.001)). In a fully adjusted linear regression model, iMg concentration was significantly associated with age, decline of eGFR, history of cardiovascular disease and the use of diuretics, and inversely associated with calcium and triglycerides levels, systolic blood pressure, diabetes, and the use of proton pump inhibitors and potassium chelators. The same factors were associated with total Mg. Conclusion Total Mg and iMg were strongly correlated. Decline of kidney function was associated to an increase of iMg in patients with moderate-to-advanced CKD. Additional studies need to compare the difference between total Mg and iMg as a biomarker to predict hard outcomes.

#3256 LONGITUDINAL ASSOCIATION BETWEEN IRON STORES BIOMARKERS AND MAJOR ADVERSE CARDIOVASCULAR EVENTS IN CHRONIC KIDNEY DISEASE

Abstract Background and Aims Iron deficiency is a frequent condition in moderate to severe chronic kidney disease (CKD), often left under-screened, and infrequently supplemented. Iron deficiency is a major contributor to anemia, which is known to negatively impact outcomes and quality of life in CKD. However, evidence of an anemia-independent effect of iron deficiency on cardiovascular morbidity and all-cause mortality has emerged. Current challenges of studying the association between iron deficiency and the risk of events in CKD are the definition of critical thresholds for these biomarkers, the potential interaction between them, and their evolution over time. Previous observational cohort studies have only focused on baseline values of transferrin saturation and ferritin, the two traditional biomarkers of iron deficiency. Our aim was to study the longitudinal association between iron stores biomarkers and cardiovascular risk in CKD by evaluating the total effect of these biomarkers on major adverse cardiovascular events (MACE). Method We used data from the CKD-REIN cohort, which included 3033 patients with moderate to severe CKD from 40 nationally representative nephrology clinics in France between 2013 and 2016. All patients with at least one measurement of TSAT and ferritin were included in the present study. Our primary endpoint was MACE, defined as the first event among cardiovascular death, myocardial infarction, stroke or hospitalization for acute heart failure. Repeated measures of TSAT and ferritin were included as time-dependent variables in cause-specific Cox proportional hazard models for risk of MACE, with initiation of kidney replacement therapy (KRT) and death as competitive events. Models were adjusted for time-varying estimated glomerular filtration rate (eGFR), white cells and baseline age, sex, iron supplementation, and erythropoietin stimulating agents. Analyses were not adjusted for hemoglobin level because the aim of the study was to investigate the total effect of iron deficiency on MACE. Non-linear effects of TSAT and ferritin and their interaction were modeled using natural splines functions. Results A total of 2670 patients were included in the analysis: 65% were men, median age was 68 years (interquartile range IQR 60-76). Median baseline eGFR was 34 ml/min/1.73 m2 (IQR 25-44), TSAT was 24% (IQR 18-30) and ferritin was 127 ng/ml (IQR 72-230). Over a median follow-up period of 4.4 years, participants had a median of 5 (IQR 2-8) and 4 (IQR 2-6) measurements of ferritin and TSAT, respectively; 396 MACE before KRT were recorded. The negative nonlinear association of iron deficiency with MACE was essentially captured by TSAT, and the interaction terms between TSAT and ferritin were not statistically significant (p = 0.94). Compared with patients with TSAT of 20% and ferritin of 100 ng/ml, those with TSAT values &amp;lt; 20% had a higher adjusted hazard of MACE independently of ferritin values (See Figure 1); for example, for TSAT = 10% and ferritin = 100 ng/ml, the hazard ratio (HR) was 1.96, 95% CI (1.60-2.39). Conclusion In CKD patients under nephrology care, current value of TSAT below 20% was associated with higher risk of MACE regardless of ferritin current value. Before investigating strategies of treatment in clinical trials as PIVOTAL in dialysis patients, further studies clarifying critical thresholds of TSAT and ferritin in non-dialysis CKD patients, in presence or absence of anemia and among specific CKD subpopulations are highly desirable.

#2889 CAROTID PLAQUE THICKNESS PREDICTS CARDIOVASCULAR EVENTS AND DEATH IN PATIENTS WITH CHRONIC KIDNEY DISEASE

Abstract Background and Aims Classical risk scoring systems highly underestimate the elevated risk of cardiovascular (CV) disease in chronic kidney disease (CKD) (1). Coronary artery calcification score (CACS) has improved prediction of CV events in patients with CKD (2). Recently, ultrasound examination of the carotid arteries with measurement of maximal carotid plaque thickness (cPTmax) has demonstrated similar predictive value as CACS in the general population (3). This is the first study to investigate whether cPTmax can predict CV events in patients with CKD. We also compared the predictive value of cPTmax and CACS. Method Two hundred patients with CKD stage 3 from the Copenhagen CKD Cohort underwent ultrasound scanning of the carotid arteries in 2016 to 2017. The assessment consisted of finding areas with plaque, if there were any, and measuring the thickest part of the plaque, cPTmax, defined as the radial distance from the media–adventitia interface to the intima–lumen interface towards the center of the arterial lumen. For the statistical analysis only the anatomical side with the highest cPTmax was used. The intra-observer coefficient of variation was 9%. Based on the distribution of cPTmax, the subjects were divided into 3 groups: No plaques, cPTmax 1.0-1.9 mm and cPTmax &amp;gt; 1.9 mm (the median cPTmax in the group was 1.9 mm). One hundred and seventy-five of the patients underwent a non-contrast CT scan of the coronary arteries, which was used to measure CACS. The patients were divided into the following categories: no calcification, CACS = 1-100, CACS = 101-400 and CACS &amp;gt; 400. The follow-up time was time elapsed from the ultrasound scan and until a predefined end-date or the time of first event, which was defined as a composite of major CV events or death of any cause (MACE). CV events included: myocardial infarction, percutaneous coronary intervention, coronary bypass surgery, ischemic stroke, carotid endarterectomy or stenting, non-traumatic lower limb amputation, lower limb artery bypass graft, percutaneous transluminal angioplasty of a lower limb. Results The average follow-up time was 5.4 years. Twenty patients (10%) experienced a CV event and 28 patients died (14%). In a crude absolute risk plot (Figure), patients with no plaque at baseline showed the lowest risk of MACE, whereas patients with cPTmax 1.0-1.9 mm showed an intermediate risk, and patients with cPTmax &amp;gt;1.9 mm the highest risk (log rank test, p&amp;lt;0.0001). When using the group of patients with no plaque as the reference in an unadjusted Cox-regression analysis, the hazard ratio (HR) of MACE was significantly increased in patients with cPTmax = 1.0-1.9 mm (HR = 3.8 (CI: 1.5 - 9.9), p&amp;lt;0.01) and in patients with cPTmax &amp;gt;1.9 mm (HR = 8.4 (CI: 3.4 – 20.8), p&amp;lt;0.0001). After adjustment for age, sex, diabetes, smoking, hypertension, and hypercholesterolemia, only patients with cPTmax &amp;gt;1.9 mm showed a significantly increased HR of MACE (HR 3.2, CI 1.1-9.3), p&amp;lt;0.05. We applied C-statistics to assess which imaging technique had the best predictive value of MACE in this cohort. The differences in C-statistics were similar for the two imaging methods: cPTmax (0.21, p &amp;lt; 0.0001) and CACS (0.21, p &amp;lt; 0.0001). Conclusion Our results indicate that measurement of cPTmax may be a useful method for prediction of MACE in CKD. In the present small study, cPTmax and CACS showed equal potential for predicting MACE Ultrasound imaging is more convenient, more widely available, and without radiation exposure. To further assess the value of cPTmax in predicting CV risk in CKD, a larger study of patients with all CKD stages is needed.

Resistin Contribution to Cardiovascular Risk in Chronic Kidney Disease Male Patients.

Resistin is a molecule that belongs to the Resistin-Like Molecules family (RELMs), the group of proteins taking part in inflammatory processes. Increased resistin concentrations are observed in cardiovascular complications. Resistin contributes to the onset of atherosclerosis and intensifies the atherosclerotic processes. The aim of this study was to investigate the relationship between resistin and cardiovascular (CV) risk in men with chronic kidney disease (CKD) not treated with dialysis. One hundred and forty-two men were included in the study: 99 men with eGFR lower than 60 mL/min/1.73 m2 and 43 men with eGFR ≥ 60 mL/min/1.73 m2. CV risk was assessed. Serum resistin, tumor necrosis factor-alpha (TNF-alpha) and plasminogen activator inhibitor-1 (PAI-1) were measured among other biochemical parameters. We observed that resistin concentrations were significantly higher in patients with CKD compared to individuals with eGFR ≥ 60 mL/min/1.73 m2 (p = 0.003). In CKD, after estimating the general linear model (GLM), we found that resistin is associated with CV risk (p = 0.026) and PAI-1 serum concentrations (0.012). The relationship of PAI-1 with resistin depends on the level of CV risk in CKD (p = 0.048). Resistin concentrations rise with the increase of CV risk in CKD patients and thus resistin may contribute to the progression of cardiovascular risk in this group of patients. The relationship between resistin and CV risk is modified by PAI-1 concentrations.

Platelet Activity and Cardiovascular Risk in CKD and Peripheral Artery Disease

IntroductionPlatelet dysfunction and cardiovascular risk are well-recognized features of chronic kidney disease (CKD). Platelets drive the development and progression of cardiovascular disease (CVD). The relationships between kidney function, platelet activity, and cardiovascular risk are poorly defined.MethodsWe compared platelet activity and incident cardiovascular events by CKD status (estimated glomerular filtration rate [eGFR] < 60 ml/min per 1.73 m2) using data from the Platelet Activity and Cardiovascular Events study, a prospective cohort study that enrolled adults with peripheral artery disease (PAD) undergoing lower extremity revascularization. Platelet activity was measured using light transmission aggregometry (LTA) in response to submaximal dose agonist stimulation, and the subjects were followed for incident adverse cardiovascular events for a median of 18 months.ResultsOverall, 113 of 285 (40%) subjects had CKD. Subjects with, versus without, CKD had higher platelet aggregation in response to stimulation with adenosine diphosphate (ADP), serotonin, epinephrine, and arachidonic acid (AA) + ex vivo aspirin (P < 0.05 for each). Following multivariable adjustment, subjects with CKD had elevated risk for myocardial infarction (MI) (adjusted hazard ratio 2.2, 95% confidence interval [1.02–4.9]) and major adverse cardiovascular events (MACE) (1.9 [1.2–3.3]) compared to those without CKD. Platelet aggregation in response to submaximal dose agonist stimulation mediated 7% to 26% of the excess risk for cardiovascular events associated with CKD.ConclusionAmong subjects with PAD undergoing lower extremity revascularization, CKD is associated with increased platelet activity that mediates, in part, elevated cardiovascular risk.

Impact of Uremic Toxins on Endothelial Dysfunction in Chronic Kidney Disease: A Systematic Review.

Patients with chronic kidney disease (CKD) are at a highly increased risk of cardiovascular complications, with increased vascular inflammation, accelerated atherogenesis and enhanced thrombotic risk. Considering the central role of the endothelium in protecting from atherogenesis and thrombosis, as well as its cardioprotective role in regulating vasorelaxation, this study aimed to systematically integrate literature on CKD-associated endothelial dysfunction, including the underlying molecular mechanisms, into a comprehensive overview. Therefore, we conducted a systematic review of literature describing uremic serum or uremic toxin-induced vascular dysfunction with a special focus on the endothelium. This revealed 39 studies analyzing the effects of uremic serum or the uremic toxins indoxyl sulfate, cyanate, modified LDL, the advanced glycation end products N-carboxymethyl-lysine and N-carboxyethyl-lysine, p-cresol and p-cresyl sulfate, phosphate, uric acid and asymmetric dimethylarginine. Most studies described an increase in inflammation, oxidative stress, leukocyte migration and adhesion, cell death and a thrombotic phenotype upon uremic conditions or uremic toxin treatment of endothelial cells. Cellular signaling pathways that were frequently activated included the ROS, MAPK/NF-κB, the Aryl-Hydrocarbon-Receptor and RAGE pathways. Overall, this review provides detailed insights into pathophysiological and molecular mechanisms underlying endothelial dysfunction in CKD. Targeting these pathways may provide new therapeutic strategies reducing increased the cardiovascular risk in CKD.

Dietary Lipids and Dyslipidemia in Chronic Kidney Disease.

The progression of chronic kidney disease (CKD) leads to altered lipid metabolism. CKD patients exhibit high blood triglyceride (TG) levels, reduced concentrations and functionality of high-density lipoproteins (HDL), and elevated levels of atherogenic small, dense, low-density lipoproteins (sdLDL). Disorders of lipid metabolism and other metabolic disturbances place CKD patients at high risk for cardiovascular disease (CVD). Extensive evidence supports the cardioprotective effects of unsaturated fatty acids, including their beneficial effect on serum cholesterol and TG levels. Dietary lipids might therefore be especially important in the nutritional management of CKD. We review current dietary recommendations for fat intake by CKD patients and suggest potential nutritional interventions by emphasizing dietary lipids that might improve the blood lipid profile and reduce cardiovascular risk in CKD.

The Role of Prognostic and Predictive Biomarkers for Assessing Cardiovascular Risk in Chronic Kidney Disease Patients.

Chronic kidney disease (CKD) is currently defined as the presence of proteinuria and/or an eGFR < 60 mL/min/1.73m2 on the basis of the renal diagnosis. The global dimension of CKD is relevant, since its prevalence and incidence have doubled in the past three decades worldwide. A major complication that occurs in CKD patients is the development of cardiovascular (CV) disease, being the incidence rate of fatal/nonfatal CV events similar to the rate of ESKD in CKD. Moreover, CKD is a multifactorial disease where multiple mechanisms contribute to the individual prognosis. The correct development of novel biomarkers of CV risk may help clinicians to ameliorate the management of CKD patients. Biomarkers of CV risk in CKD patients are classifiable as prognostic, which help to improve CV risk prediction regardless of treatment, and predictive, which allow the selection of individuals who are likely to respond to a specific treatment. Several prognostic (cystatin C, cardiac troponins, markers of inflammation, and fibrosis) and predictive (genes, metalloproteinases, and complex classifiers) biomarkers have been developed. Despite previous biomarkers providing information on the pathophysiological mechanisms of CV risk in CKD beyond proteinuria and eGFR, only a minority have been adopted in clinical use. This mainly depends on heterogeneous results and lack of validation of biomarkers. The purpose of this review is to present an update on the already assessed biomarkers of CV risk in CKD and examine the strategies for a correct development of biomarkers in clinical practice. Development of both predictive and prognostic biomarkers is an important task for nephrologists. Predictive biomarkers are useful for designing novel clinical trials (enrichment design) and for better understanding of the variability in response to the current available treatments for CV risk. Prognostic biomarkers could help to improve risk stratification and anticipate diagnosis of CV disease, such as heart failure and coronary heart disease.

The association of skin autofluorescence with cardiovascular events and all-cause mortality in persons with chronic kidney disease stage 3: A prospective cohort study.

Tissue advanced glycation end product (AGE) accumulation has been proposed as a marker of cumulative metabolic stress that can be assessed noninvasively by measurement of skin autofluorescence (SAF). In persons on haemodialysis, SAF is an independent risk factor for cardiovascular events (CVEs) and all-cause mortality (ACM), but data at earlier stages of chronic kidney disease (CKD) are inconclusive. We investigated SAF as a risk factor for CVEs and ACM in a prospective study of persons with CKD stage 3. Participants with estimated glomerular filtration rate (eGFR) 59 to 30 mL/min/1.73 m2 on two consecutive previous blood tests were recruited from 32 primary care practices across Derbyshire, United Kingdom between 2008 and 2010. SAF was measured in participants with CKD stage 3 at baseline, 1, and 5 years using an AGE reader (DiagnOptics). Data on hospital admissions with CVEs (based on international classification of diseases [ICD]-10 coding) and deaths were obtained from NHS Digital. Cox proportional hazards models were used to investigate baseline variables associated with CVEs and ACM. A total of 1,707 of 1,741 participants with SAF readings at baseline were included in this analysis: The mean (± SD) age was 72.9 ± 9.0 years; 1,036 (60.7%) were female, 1,681 (98.5%) were of white ethnicity, and mean (±SD) eGFR was 53.5 ± 11.9 mL/min/1.73 m2. We observed 319 deaths and 590 CVEs during a mean of 6.0 ± 1.5 and 5.1 ± 2.2 years of observation, respectively. Higher baseline SAF was an independent risk factor for CVEs (hazard ratio [HR] 1.12 per SD, 95% CI 1.03-1.22, p = 0.01) and ACM (HR 1.16, 95% CI 1.03-1.30, p = 0.01). Additionally, increase in SAF over 1 year was independently associated with subsequent CVEs (HR 1.11 per SD, 95% CI 1.00-1.22; p = 0.04) and ACM (HR 1.24, 95% CI 1.09-1.41, p = 0.001). We relied on ICD-10 codes to identify hospital admissions with CVEs, and there may therefore have been some misclassification. We have identified SAF as an independent risk factor for CVE and ACM in persons with early CKD. These findings suggest that interventions to reduce AGE accumulation, such as dietary AGE restriction, may reduce cardiovascular risk in CKD, but this requires testing in prospective randomised trials. Our findings may not be applicable to more ethnically diverse or younger populations.

MO062CHRONIC KIDNEY DISEASE, INFLAMMATION, AND HEART FAILURE WITH PRESERVED EJECTION FRACTION: A RENAL-CARDIO AXIS?

Abstract Background and Aims Inflammation contributes to progressive renal dysfunction and increases cardiovascular mortality of patients with chronic kidney disease (CKD). The association of CKD and heart failure with preserved ejection fraction (HFpEF) is observed in up to 50%, suggesting the possibility of a shared pathophysiology. CKD and HFpEF are commonly associated with inflammation. Using a novel swine model of CKD and HFpEF, we propose that a renal-cardio inflammatory axis drives diastolic dysfunction and HFpEF in CKD and that targeting renal inflammation will improve cardiac health and reduce cardiovascular risk. Methods We developed a biopolymer-fused peptide of nuclear-factor kappa (NFk)B (ELP-p50i) that we show it blocks its activity in vitro and in vivo. NFkB is a key pro-inflammatory transcription factor that is upregulated in CKD. To test our hypothesis, we induced CKD in 10 pigs via bilateral renovascular disease and dyslipidemia. Pigs were observed for 6 weeks, renal hemodynamics quantified (multi-detector CT), then randomized to single intra-renal ELP-p50i or placebo (n=5 each), and studies repeated 8 weeks later accompanied by echocardiographic assessment. Blood pressure was continuously measured (telemetry). Blood was collected to measure circulating TNF-α and biomarkers of HF (ANP, BNP). Furthermore, kidneys and hearts were used to quantify expression of factors involved in NFkB signaling. Results CKD led to a significant loss of renal function, accompanied by left ventricular hypertrophy and diastolic dysfunction with pEF, increased renal mRNA expression of TNF-α and canonical and non-canonical mediators of NFkB signaling, and elevated systemic TNF-α, ANP, and BNP, indicating renal and cardiac dysfunction. Most of these changes were improved after intra-renal ELP-p50i, although cardiac inflammatory signaling was unchanged (Figure) suggesting the kidney as a source of inflammation that can target the heart in CKD. Conclusion We show that a renal anti-inflammatory strategy via targeted inhibition of renal NFkB improves renal and cardiac function in CKD, suggesting an inflammatory renal-cardio axis. The translational pathological features of CKD and HFpEF combined with the predictive power of the model may contribute to advance the field towards new treatments targeting renal inflammation to reduce cardiovascular risk in CKD.

Renal Equations Using Cystatin C and Creatinine in Correlation to Lipids in Chronic Kidney Disease - A Cross-Sectional Study

Chronic kidney disease (CKD) is frequently complicated by the coexistence of cardiovascular (CV) events, making it essential to identify CV risk in CKD. Serum cystatin-C is an upcoming renal biomarker, which is used to measure estimated glomerular filtration rate (eGFR) by the CKD-EPI formula.

Apolipoproteins A and B and PCSK9: Nontraditional Cardiovascular Risk Factors in Chronic Kidney Disease and in End-Stage Renal Disease.

Purpose Nontraditional cardiovascular risk factors as apolipoprotein A (ApoA), apolipoprotein B (ApoB), and the proprotein convertase subtilisin/kexin type 9 (PCSK9) increase the prevalence of cardiovascular mortality in chronic kidney disease (CKD) or in end-stage renal disease (ESRD) through quantitative alterations. This review is aimed at establishing the biomarker (ApoA, ApoB, and PCSK9) level variations in uremic patients, to identify the studies showing the association between these biomarkers and the development of cardiovascular events and to depict the therapeutic options to reduce cardiovascular risk in CKD and ESRD patients. Methods We searched the electronic database of PubMed, Scopus, EBSCO, and Cochrane CENTRAL for studies evaluating apolipoproteins and PCSK9 in CKD and ESRD. Randomized controlled trials, observational studies (including case-control, prospective or retrospective cohort), and reviews/meta-analysis were included if reference was made to those keys and cardiovascular outcomes in CKD/ESRD. Results 18 studies met inclusion criteria. Serum ApoA-I has been significantly associated with the development of new cardiovascular event and with cardiovascular mortality in ESRD patients. ApoA-IV level was independently associated with maximum carotid intima-media thickness (cIMT) and was a predictor for sudden cardiac death. The ApoB/ApoA-I ratio represents a strong predictor for coronary artery calcifications, cardiovascular mortality, and myocardial infarction in CKD/ESRD. Plasma levels of PCSK9 were not associated with cardiovascular events in CKD patients. Conclusions Although the “dyslipidemic status” in CKD/ESRD is not clearly depicted, due to different research findings, ApoA-I, ApoA-IV, and ApoB/ApoA-I ratio could be predictors of cardiovascular risk. Serum PCSK9 levels were not associated with the cardiovascular events in patients with CKD/ESRD. Probably in the future, the treatment of dyslipidemia in CKD/ESRD will be aimed at discovering new effective therapies on the action of these biomarkers.

Prevalence and Disease Burden of Chronic Kidney Disease.

Chronic kidney disease (CKD) has been recognized as a leading public health problem worldwide. The global estimated prevalence of CKD is 13.4% (11.7-15.1%), and patients with end-stage kidney disease (ESKD) needing renal replacement therapy is estimated between 4.902 and 7.083 million. Through its effect on cardiovascular risk and ESKD, CKD directly affects the global burden of morbidity and mortality worldwide. The global increase in this disease is mainly driven by the increase in the prevalence of diabetes mellitus, hypertension, obesity, and aging. But in some regions, other causes such as infection, herbal and environmental toxins are still common. The large number of deaths for poor access to renal replacement therapy in developing countries, and also large increase of patients with ESKD in future, will produce substantial financial burden for even the most wealthy countries. Cost-effectiveness of preventive strategies to reduce the disease burden should be evaluated in relation to the local economic development and resource. Strategies reducing the cardiovascular risk in CKD still need further evaluation in large trials especially including patients with advanced kidney disease or end-stage kidney disease.

Coronary flow reserve is predictive of the risk of cardiovascular death regardless of chronic kidney disease stage

Microvascular rarefaction is found in experimental uremia, but data from patients with chronic kidney disease (CKD) are limited. We therefore quantified absolute myocardial blood flow and coronary flow reserve (the ratio of peak to resting flow) from myocardial perfusion positron emission tomography scans at a single institution. Individuals were classified into standard CKD categories based on the estimated glomerular filtration rate. Associations of coronary flow reserve with CKD stage and cardiovascular mortality were analyzed in models adjusted for cardiovascular risk factors. The coronary flow reserve was significantly associated with CKD stage, declining in early CKD, but it did not differ significantly among individuals with stage 4, 5, and dialysis-dependent CKD. Flow reserve with preserved kidney function was 2.01, 2.06 in stage 1 CKD, 1.91 in stage 2, 1.68 in stage 3, 1.54 in stage 4, 1.66 in stage 5, and 1.55 in dialysis-dependent CKD. Coronary flow reserve was significantly associated with cardiovascular mortality in adjusted models (hazard ratio 0.76, 95% confidence interval: 0.63-0.92 per tertile of coronary flow reserve) without evidence of effect modification by CKD. Thus, coronary flow reserve is strongly associated with cardiovascular risk regardless of CKD severity and is low in early stage CKD without further decrement in stage 5 or dialysis-dependent CKD. This suggests that CKD physiology rather than the effects of dialysis is the primary driver of microvascular disease. Our findings highlight the potential contribution of microvascular dysfunction to cardiovascular risk in CKD and the need to define mechanisms linking low coronary flow reserve to mortality.

Advanced chronic kidney disease populations have elevated trimethylamine N-oxide levels associated with increased cardiovascular events

Cardiovascular disease is more common in patients with chronic kidney disease (CKD), and traditional risk factors do not adequately predict those at risk for cardiovascular (CV) events. Recent evidence suggests elevated trimethylamine N-oxide (TMAO), created by gut microflora from dietary L-carnitine and choline, is associated with CV events. We investigated the relationship of TMAO levels in patients with stages 3b and 4 CKD to ischemic CV events using the CanPREDDICT cohort, a Canada-wide observational study with prospective 3-year follow-up of adjudicated CV events. Baseline samples were obtained for 2529 CKD patients. TMAO, choline, and L-carnitine levels were measured using tandem mass spectrometry. Baseline median TMAO level was high for the whole cohort (20.41 μM; interquartile range [IQR]: 12.82-32.70 μM). TMAO was independently associated with CV events (hazard ratio 1.23; 95% confidence interval: 1.06-1.42 / 1 SD lnTMAO) after adjusting for all potential CV risk factors. Those in the highest TMAO quartile had significantly higher risk of CV events (adjusted hazard ratio 1.59; 95% confidence interval: 1.04-2.43; P = 0.0351) in the analysis of recurring ischemic events. Among those with stage 3b CKD (hazard ratio 1.45; 95% confidence interval: 1.12-1.87 / 1 SD lnTMAO), independent of kidney function, TMAO levels identified those at highest risk for events. Our results suggest that TMAO may represent a new potentially modifiable CV risk factor for CKD patients. Further studies are needed to determine sources of variability and if lowering of TMAO reduces CV risk in CKD.

Cost-effectiveness of Simvastatin plus Ezetimibe for Cardiovascular Prevention in CKD: Results of the Study of Heart and Renal Protection (SHARP)

BackgroundSimvastatin, 20 mg, plus ezetimibe, 10 mg, daily (simvastatin plus ezetimibe) reduced major atherosclerotic events in patients with moderate to severe chronic kidney disease (CKD) in the Study of Heart and Renal Protection (SHARP), but its cost-effectiveness is unknown.Study DesignCost-effectiveness of simvastatin plus ezetimibe in SHARP, a randomized controlled trial.Setting & Population9,270 patients with CKD randomly assigned to simvastatin plus ezetimibe versus placebo; participants in categories by 5-year cardiovascular risk (low, <10%; medium, 10%-<20%; or high, ≥20%) and CKD stage (3, 4, 5 not on dialysis, or on dialysis therapy).Model, Perspective, & TimelineAssessment during SHARP follow-up from the UK perspective; long-term projections.InterventionSimvastatin plus ezetimibe (2015 UK £1.19 per day) during 4.9 years’ median follow-up in SHARP; scenario analyses with high-intensity statin regimens (2015 UK £0.05-£1.06 per day).OutcomesAdditional health care costs per major atherosclerotic event avoided and per quality-adjusted life-year (QALY) gained.ResultsIn SHARP, the proportional reductions per 1 mmol/L of low-density lipoprotein (LDL) cholesterol reduction with simvastatin plus ezetimibe in all major atherosclerotic events of 20% (95% CI, 6%-32%) and in the costs of vascular hospital episodes of 17% (95% CI, 4%-28%) were similar across participant categories by cardiovascular risk and CKD stage. The 5-year reduction in major atherosclerotic events per 1,000 participants ranged from 10 in low-risk to 58 in high-risk patients and from 28 in CKD stage 3 to 36 in patients on dialysis therapy. The net cost per major atherosclerotic event avoided with simvastatin plus ezetimibe compared to no LDL-lowering regimen ranged from £157,060 in patients at low risk to £15,230 in those at high risk (£30,500-£39,600 per QALY); and from £47,280 in CKD stage 3 to £28,180 in patients on dialysis therapy (£13,000-£43,300 per QALY). In scenario analyses, generic high-intensity statin regimens were estimated to yield similar benefits at substantially lower cost.LimitationsHigh-intensity statin-alone regimens were not studied in SHARP.ConclusionsSimvastatin plus ezetimibe prevented atherosclerotic events in SHARP, but other less costly statin regimens are likely to be more cost-effective for reducing cardiovascular risk in CKD.

Activation of Cardiac Fibroblast Growth Factor Receptor 4 Causes Left Ventricular Hypertrophy

Chronic kidney disease (CKD) is a worldwide public health threat that increases risk of death due to cardiovascular complications, including left ventricular hypertrophy (LVH). Novel therapeutic targets are needed to design treatments to alleviate the cardiovascular burden of CKD. Previously, we demonstrated that circulating concentrations of fibroblast growth factor (FGF) 23 rise progressively in CKD and induce LVH through an unknown FGF receptor(FGFR)-dependent mechanism. Here, we report that FGF23 exclusively activates FGFR4 on cardiac myocytes to stimulate phospholipase Cγ/calcineurin/nuclear factor of activated Tcell signaling. A specific FGFR4-blocking antibody inhibits FGF23-induced hypertrophy of isolated cardiac myocytes and attenuates LVH in rats with CKD. Mice lacking FGFR4 do not develop LVH in response to elevated FGF23, whereas knockin mice carrying an FGFR4 gain-of-function mutation spontaneously develop LVH. Thus, FGF23 promotes LVH by activating FGFR4, thereby establishing FGFR4 as a pharmacological target for reducing cardiovascular risk in CKD.

Insulin resistance and vascular dysfunction in chronic kidney disease: mechanisms and therapeutic interventions.

Insulin resistance (IR) is a novel cardiovascular risk factor that has been implicated in the pathogenesis of cardiovascular disease (CVD) in patients with chronic kidney disease (CKD). Beyond its metabolic effects, insulin can potentially mediate the increased risk for CVD through its vasoactive properties. This review examines key clinical data and potential mechanisms linking IR and cardiovascular risk in CKD. While lifestyle interventions and pharmacotherapies with known insulin-sensitizing properties are promising therapeutic targets to reduce the CVD burden in this population, clinical trial data on the effect of insulin sensitization on vascular function in CKD are either lacking or conflicting and are limited by small sample size and short duration of intervention. Affirming the role of IR in lowering CVD risk in CKD will require prospective randomized controlled studies with sufficient sample size and hard clinical outcomes. Future research efforts should be directed at assessing the efficacy, safety and mechanisms by which novel insulin sensitizers such as bile acid sequestrant, selective and dual peroxisome proliferator-activated receptor modulators and modulators of gut microbiota and uraemic toxins alter vascular function in patients with CKD.