Survey
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
* Your assessment is very important for improving the workof artificial intelligence, which forms the content of this project
Intensive care conference: --Clinical usefulness of novel prognostic biomarkers in patients on hemodialysis 報告人: R2 王俊偉 Review article Alberto Ortiz, Ziad A. Massy, Danilo Fliser, Bengt Lindholm, Andrzej Wiecek, Alberto Martínez-Castelao, Adrian Covic, David Goldsmith, Gültekin Süleymanlar, Gérard M. London & Carmine Zoccali Nature Reviews Nephrology 8, 141-150 (March 2012) Introduction - Prognosis and risk stratification are fundamental elements in the decision making process, ex: Framingham Risk Score. - Risk estimates based on traditional risk factors and simple clinical information remain fairly imprecise =>intensive research on biomarkers as risk scores. Introduction -Patients on hemodialysis represent a highly selected population: 1. eldly multiple comorbidities 2. survived long enough to develop ESRD. Specific risk stratification methods such as the Khan Index have been proposed but remain imperfect Biomarkers - Definition: a characteristic that is objectively measured and evaluated as an indicator of normal biologic processes, pathogenic processes, or pharmacologic responses to a therapeutic intervention”.-U.S. NIH -Prognosis -Disease monitoring -Objective measures of the effect of treatments on targeted pathophysiological phenomena Biomarkers The predictive power of single biomarkers can be improved by combining these with other factors. Four criteria of prognostic biomarkers: accuracy, simplicity, cost, relevance Biomarkers accuracy 1.Discrimination: identify individuals who go on to develop the outcome of interest from those who do not 2. Calibration: correctly estimates the probability of the same outcome at an individual level 3. Reclassification: increases the proportion of individuals correctly classified as having, or not having, the outcome of interest Biomarkers in patients on hemodialysis -Cardiovascular risk prediction -Monitoring treatment 1.Biomarkers related to the CKD-related mineral and bone disorder (CKD–MBD) 2.Biomarkers of protein–energy wasting and inflammation 3. Biomarkers of myocardial injury and dysfunction 4. Undefined or mixed biomarkers. CKD–MBD - Only a few studies link individual biomarkers in this category to death - Fibroblast growth factor 23 (FGF23) and alkaline phosphatase are the only biomarkers whose prognostic potential for death has been confirmed in at least two different study populations CKD–MBD FGF23 is a phosphaturic hormone synthesized in bone cells that inhibits renal production of 1,25dihydroxyvitamin D.25,26 Increased FGF23 levels are independently associated with mortality in patients on hemodialysis. Reducing phosphate intake can lower FGF23 levels, the measurement of this biomarker may be useful to set individual phosphate targets in patients with ESRD accuracy? CKD–MBD Serum alkaline phosphatase is an established marker of bone turnover Alkaline phosphatase concentration had a dose-response relationship with mortality that was independent of other CKD–MBD biomarkers Cost, simplicity ok, but accuracy? Protein–energy wasting and inflammation CRP High CRP levels were found to predict all-cause and cardiovascular mortality in 57% and 38% of studies, respectively; a meta-analysis of these studies showed a weak but significant association of CRP with allcause mortality but not with cardiovascular mortality. Protein–energy wasting and inflammation In a study involving 3 European centers, CRP as a strong predictor of death in males but not in females with ESRD In the Netherlands Cooperative Study on the Adequacy of Dialysis-2 (NECOSAD-2), the risk of death associated with high CRP levels was particularly strong in patients with malnutrition and past cardiovascular events. Protein–energy wasting and inflammation In the Mapping of Inflammatory Markers in Chronic Kidney Disease (MIMICK) Study, serial measurements of CRP levels in patients on hemodialysis provided additional information compared with a single measurement. Accuracy? AURORA rosuvastatin study: CRP levels may not help nephrologists decide whether to prescribe this drug or not Protein–energy wasting and inflammation Interleukin (IL)-6 is a stronger marker of risk of death than is CRP in patients with ESRD. Tumor necrosis factor (TNF) is a weaker predictor of mortality than is IL-6. Accuracy? Expensive! Fetuin A is an inverse marker of inflammation (low levels denote inflammation) and allcause and cardiovascular mortality Accuracy? Myocardial injury or dysfunction The prevalence of left ventricular hypertrophy is very high (about 75%) in patients on hemodialysis and about 30–40% of these patients have clinical evidence of heart failure and/or coronary artery disease BNP, NT-proBNP and TnT predict decreased survival and cardiovascular events. Myocardial injury or dysfunction For a biomarker to be recommended in clinical practice, formal proof is needed that its systematic use leads to improved clinical outcomes, such proof has been provided for BNP in one study of non-uremic patients with heart failure. Accuracy? Other biomarkers Plasma free triiodothyronine (fT3) is an inverse acute-phase reactant, which predicts risk of mortality in patients on hemodialysis. In a subsequent study in patients with predialysis stage 5 CKD, initiating renal replacement therapy, low T3 levels had a stronger link with mortality than did fT3 levels; Other biomarkers fT3 reflects thyroid function better than the bound form and differences between assays and alterations in protein binding in patients with ESRD. fT3 levels can be normalized by correction of acidosis in ESRD Other biomarkers Asymmetric dimethylarginine (ADMA) is an endogenous inhibitor of nitric oxide synthase. High plasma levels of ADMA are indicative of endothelial dysfunction and atherosclerosis, and predict mortality in the general population and in patients with various diseases, including heart failure, coronary artery disease, diabetes mellitus, liver disease and predialysis CKD. Accuracy? Expensive! A multimarker approach Thus, evidence accumulated so far indicates that, although combined use of novel biomarkers may refine prognosis, the gain in accuracy is only modest. A multimarker approach the gain in prognostic power of the multivariate model including these cytokines was only marginally higher than that provided by a model in which only IL-6 was used (9.1% versus 6.1%, respectively; P = 0.06). Conclusions Novel biomarkers have the potential to refine risk stratification based on standard risk scores and to guide therapy in patients on hemodialysis Biomarkers of chronic kidney disease-related mineral and bone disorders, protein–energy wasting, inflammation and myocardial injury or dysfunction have been linked with decreased survival Conclusions To date, no biomarker has had sufficient fullscale testing to qualify as a useful addition to standard prognostic factors or to guide therapy in patients on hemodialysis A multimarker approach holds potential for refining prognosis in patients on hemodialysis, but this concept still needs to be properly evaluated in large cohorts and in clinical trials Conclusions Biomarkers can be applied to improve the design of clinical trials and to target specific subpopulations among patients on hemodialysis The end Thanks for listening