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      Cystatin C as a Candidate Biomarker of Cardiovascular Outcomes: Too Near, but too Far from Reality

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          Abstract

          While the development of novel risk factors for cardiovascular risk assessment is necessary to improve risk stratification, proving its clinical value on top of traditional risk factors is routinely challenging. 1-3 Besides all the innovative and straightforward biomarker research published in the last decades, only very few markers of cardiovascular risk have shown clinical significance. 4,5 Among many of them, cystatin C has emerged some years ago as a candidate for improving cardiovascular risk stratification. In the Cardiovascular Health Study (CHS), 6 a community-based and longitudinal study with over 4,600 elderly individuals, cystatin C has shown to predict cardiovascular outcomes. As compared with the lowest quintile, the highest quintile of cystatin C was associated with a significantly increased risk of death from cardiovascular causes (hazard ratio [HR] 2.27 [1.73 to 2.97]), myocardial infarction (HR 1.48 [1.08 to 2.02]), and stroke (HR 1.47 [1.09 to 1.96]) after multivariate adjustment. However, cystatin C is typically known as a marker of renal function, being roughly correlated with glomerular filtration rate in early stages of kidney diseases. 7,8 Reasonably, since glomerular function is a strong surrogate marker of cardiovascular disease, it suggests an obvious association between cystatin C and cardiovascular outcomes. A mechanism to avoid the impact of this inexorable bias was to study only individuals with normal kidney function. Yet, additional studies have shown inconsistent magnitudes of effect between cystatin C and cardiovascular outcomes. In that context, Einwoegerer and Domingueti 9 in this issue of the Brazilian Archives of Cardiology investigated the role of plasma cystatin C levels on the risk of all-cause mortality and other softer endpoints by pooling studies of individuals with normal renal function. Unfortunately, only two studies compared quartiles of cystatin C with multivariate regression analysis, hence providing a sample size that is not too far from the original Ludwigshafen Risk and Cardiovascular Health (LURIC) study. 10 The meta-analysis suggested a robust association between high levels of cystatin C and the risk of all-cause mortality in individuals with normal renal function (HR 2.28 [1.70 - 3.05], p < 0.001). Heterogeneity among studies was substantial (I2 > 50%) and no sensitivity analysis was provided. Besides the critical limitations in meta-analysis data, authors also provided substantial elements in a systematic review of studies on the same topic. Although a first step for a candidate biomarker is to show strong association with a clinical outcome, this is not sufficient to prove its complementary clinically usefulness beyond traditional cardiovascular risk factors, such as age, gender, smoking, hypertension, diabetes, hyperlipidemia, obesity and aortic stenosis. A next fundamental step is to show whether cystatin C could improve risk prediction of cardiovascular outcomes in Receiver operating characteristic (ROC) curves models, net reclassification index (NRI) and integrated discrimination index (IDI) compared-to or added-to the Framinghan Heart Risk, ASCVD risk score, or any validated cardiovascular risk scores/engines. 11,12 Besides the potential mechanistic link between cystatin C and atherosclerotic disease, this association is unlikely to be causal. By using a Mendelian randomization approach, which takes into account both the genetic association with cystatin C and CVD to triangulate the causal effect, and combining a set of cohorts of over 250,000 individuals with 63,000 cases of cardiovascular events from the Cystatin C Mendelian Randomization Consortium no association could be found. 13 This finding in no way suggests that we should abandon the use of cystatin C for risk stratification purposes in kidney diseases, but there are two key messages in it: (i) it alerts against the chase of therapeutic strategies that target at lowering plasma cystatin C levels; (ii) it also indicates a low likelihood of association between cystatin C as a surrogate cardiovascular marker on top of classical risk factors. However, the last word in favor or against the use of cystatin C in clinical practice for cardiovascular risk stratification of individuals with normal renal function should be based on studies evaluating detrimental effects of this marker on established risk scores/engines.

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          Most cited references10

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          General cardiovascular risk profile for use in primary care: the Framingham Heart Study.

          Separate multivariable risk algorithms are commonly used to assess risk of specific atherosclerotic cardiovascular disease (CVD) events, ie, coronary heart disease, cerebrovascular disease, peripheral vascular disease, and heart failure. The present report presents a single multivariable risk function that predicts risk of developing all CVD and of its constituents. We used Cox proportional-hazards regression to evaluate the risk of developing a first CVD event in 8491 Framingham study participants (mean age, 49 years; 4522 women) who attended a routine examination between 30 and 74 years of age and were free of CVD. Sex-specific multivariable risk functions ("general CVD" algorithms) were derived that incorporated age, total and high-density lipoprotein cholesterol, systolic blood pressure, treatment for hypertension, smoking, and diabetes status. We assessed the performance of the general CVD algorithms for predicting individual CVD events (coronary heart disease, stroke, peripheral artery disease, or heart failure). Over 12 years of follow-up, 1174 participants (456 women) developed a first CVD event. All traditional risk factors evaluated predicted CVD risk (multivariable-adjusted P<0.0001). The general CVD algorithm demonstrated good discrimination (C statistic, 0.763 [men] and 0.793 [women]) and calibration. Simple adjustments to the general CVD risk algorithms allowed estimation of the risks of each CVD component. Two simple risk scores are presented, 1 based on all traditional risk factors and the other based on non-laboratory-based predictors. A sex-specific multivariable risk factor algorithm can be conveniently used to assess general CVD risk and risk of individual CVD events (coronary, cerebrovascular, and peripheral arterial disease and heart failure). The estimated absolute CVD event rates can be used to quantify risk and to guide preventive care.
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            Cystatin C and Cardiovascular Disease

            BACKGROUND Epidemiological studies show that high circulating cystatin C is associated with risk of cardiovascular disease (CVD), independent of creatinine-based renal function measurements. It is unclear whether this relationship is causal, arises from residual confounding, and/or is a consequence of reverse causation. OBJECTIVES The aim of this study was to use Mendelian randomization to investigate whether cystatin C is causally related to CVD in the general population. METHODS We incorporated participant data from 16 prospective cohorts (n = 76,481) with 37,126 measures of cystatin C and added genetic data from 43 studies (n = 252,216) with 63,292 CVD events. We used the common variant rs911119 in CST3 as an instrumental variable to investigate the causal role of cystatin C in CVD, including coronary heart disease, ischemic stroke, and heart failure. RESULTS Cystatin C concentrations were associated with CVD risk after adjusting for age, sex, and traditional risk factors (relative risk: 1.82 per doubling of cystatin C; 95% confidence interval [CI]: 1.56 to 2.13; p = 2.12 × 10−14). The minor allele of rs911119 was associated with decreased serum cystatin C (6.13% per allele; 95% CI: 5.75 to 6.50; p = 5.95 × 10−211), explaining 2.8% of the observed variation in cystatin C. Mendelian randomization analysis did not provide evidence for a causal role of cystatin C, with a causal relative risk for CVD of 1.00 per doubling cystatin C (95% CI: 0.82 to 1.22; p = 0.994), which was statistically different from the observational estimate (p = 1.6 × 10−5). A causal effect of cystatin C was not detected for any individual component of CVD. CONCLUSIONS Mendelian randomization analyses did not support a causal role of cystatin C in the etiology of CVD. As such, therapeutics targeted at lowering circulating cystatin C are unlikely to be effective in preventing CVD.
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              Cystatin C and contrast-induced acute kidney injury.

              Cystatin C (CyC) is more sensitive than serum creatinine (sCr) to rapidly detect acute changes in renal function. We measured CyC together with sCr in 410 consecutive patients with chronic kidney disease undergoing either coronary and/or peripheral angiography and/or angioplasty. sCr was assessed at baseline and 24 and 48 hours after contrast media exposure. CyC was assessed at baseline and at 24 hours. Major adverse events (including death of any cause and dialysis) at 12 months were assessed. At 48 hours after contrast media exposure, contrast-induced acute kidney injury (defined as a sCr increase > or =0.3 mg/dL) occurred in 34 patients (8.2%). A CyC increase concentration > or =10% at 24 hours after contrast media exposure was detected in 87 patients (21.2%). This was the best CyC cutoff for the early identification of patients at risk for contrast-induced acute kidney injury (negative predictive value=100%; positive predictive value=39.1%). According to the defined cutoffs (that is, increase in CyC > or =10% and sCr > or =0.3 mg/dL), major adverse events occurred in 16 of 297 patients (5.4%) without any cutoffs satisfied (group 1), in 9 of 49 patients (18.4%) with only a CyC increase > or =10% (group 2), and in 9 of 31 patients (29%) with both cutoffs satisfied (group 3). By logistic regression analysis, the independent predictors of major adverse events at 1 year were group 2 (odds ratio=2.52; 95% confidence interval, 1.17 to 5.41; P=0.02), group 3 (odds ratio=4.45; 95% confidence interval, 1.72 to 11.54; P=0.002), and baseline glomerular filtration rate (odds ratio=0.91; 95% confidence interval, 0.88 to 0.95; P<0.001). In patients with chronic kidney disease, CyC seems to be a reliable marker for the early diagnosis and prognosis of contrast-induced acute kidney injury.
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                Author and article information

                Journal
                Arq Bras Cardiol
                Arq. Bras. Cardiol
                abc
                Arquivos Brasileiros de Cardiologia
                Sociedade Brasileira de Cardiologia - SBC
                0066-782X
                1678-4170
                December 2018
                December 2018
                : 111
                : 6
                : 808-809
                Affiliations
                [1 ] Disciplina de Cardiologia - Departamento de Medicina Interna - Universidade Estadual de Campinas (UNICAMP), Campinas, SP - Brazil
                [2 ] Escola Superior de Ciências da Saúde, Brasília, DF - Brazil
                Author notes
                Mailing Address: Otavio Rizzi Coelho-Filho Disciplina de Cardiologia - Departamento de Medicina Interna - Hospital das Clínicas - Universidade Estadual de Campinas (UNICAMP) - Rua Vital Brasil, 251 - Cidade Universitária "Zeferino Vaz". Postal Code 13083-888, Campinas, SP - Brasil Email: orcfilho@ 123456unicamp.br or tavicocoelho@ 123456gmail.com
                Article
                10.5935/abc.20180226
                6263453
                30517376
                1d33e582-9d9b-4162-b8f6-6315ec66dae9

                This is an Open Access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

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                cardiovascular diseases,cystatin c,biomarkers,atherosclerosis,glomerular filtration rate

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