title: Prognostic value of bone- and vascular-derived molecular biomarkers in hemodialysis and renal transplant patients: a systematic review and meta-analysis.
abstract: BACKGROUND
  Patients undergoing hemodialysis and kidney graft recipients are high-risk populations for cardiovascular and all-cause mortality. Fibroblast growth factor 23 (FGF23), osteoprotegerin (OPG), RANK ligand, osteopontin (OPN), Klotho protein and bone morphogenetic protein-7 (BMP-7) are bone- and vascular-derived molecular biomarkers that have been shown to be associated with cardiovascular surrogate end points; however, currently available data on the prognostic value of these biomarkers is inconsistent. The aim of the present study was to conduct a systematic review and meta-analysis in order to summarize the available evidence on the association of molecular biomarkers with mortality in individuals undergoing hemodialysis and renal transplant patients.
  
  
  METHODS
  Two databases (MEDLINE and Embase) were systematically searched. Studies were eligible if the association of biomarker and mortality was reported as time-to-event data [hazard Ratio (HR)] or as effect size with a fixed time of follow-up [odds Ratio (OR)]. Abstracted HRs were converted onto a standard scale of effect and combined using a random effects model.
  
  
  RESULTS
  From a total of 1170 studies identified in initial searches, 21 met the inclusion criteria. In hemodialysis patients, comparing the lower third with the upper third of baseline FGF23 distribution, pooled HRs (95% confidence intervals) were 1.94 (1.47, 2.56) for all-cause mortality and 2.4 (1.64, 3.51) for cardiovascular mortality. For the same comparison of baseline OPG distribution, pooled HRs were 1.8 (0.95, 3.39) for all-cause mortality and 2.53 (1.29, 4.94) for cardiovascular mortality. Reported risk estimates of RANK ligand, OPN, Klotho protein and BMP-7 were not suitable for pooling; however, only Klotho protein was significantly related to mortality. For kidney graft recipients, four studies that investigated the relationship of FGF23 and OPG with mortality were identified, all of which reported a significant association.
  
  
  CONCLUSIONS
  In hemodialysis patients, FGF23 is a predictor of all-cause and cardiovascular mortality, whereas the predictive value of OPG is restricted to cardiovascular mortality. Further studies are needed in order to gain insight into the prognostic value of these biomarkers in renal transplant recipients.
authors.affiliation: Area of Cardiometabolic and Renal Risk, Institute for Biomedical Research INCLIVA, Valencia, Spain.|Hypertension Unit, Department of Internal Medicine, University Hospital Clínico of Valencia, Valencia, Spain.|Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors.forename: Gernot
authors.initials: G
authors.lastname: Pichler
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Section for Clinical Biometrics, Medical University of Vienna, Vienna, Austria.|Department of Nephrology and Hypertension Diseases, Transplantation Medicine and Rheumatology, Krankenhaus Elisabethinen, Linz, Austria.|Methods Support Team European Renal Best Practice, Ghent University Hospital, Ghent, Belgium.
authors.forename: Maria C
authors.initials: MC
authors.lastname: Haller
authors.affiliation: Center for Medical Statistics, Informatics and Intelligent Systems (CeMSIIS), Section for Clinical Biometrics, Medical University of Vienna, Vienna, Austria.
authors.forename: Alexander
authors.initials: A
authors.lastname: Kainz
authors.affiliation: Division of Nephrology, Department of Medicine and Center for Translational Metabolism and Health, Institute for Public Health and Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
authors.forename: Myles
authors.initials: M
authors.lastname: Wolf
authors.affiliation: Area of Cardiometabolic and Renal Risk, Institute for Biomedical Research INCLIVA, Valencia, Spain.|CIBER Physiopathology of Obesity and Nutrition (CIBEROBN), Institute of Health Carlos III, Madrid, Spain.
authors.forename: Josep
authors.initials: J
authors.lastname: Redon
authors.affiliation: Department of Nephrology and Dialysis, Medical University of Vienna, Vienna, Austria.
authors.forename: Rainer
authors.initials: R
authors.lastname: Oberbauer
mesh_terms: D015415:Biomarkers / Q000378:metabolism*; D001847:Bone Diseases / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D002318:Cardiovascular Diseases / Q000175:diagnosis* / Q000209:etiology / Q000378:metabolism / Q000401:mortality; D000089703:Fibroblast Growth Factor-23; D006801:Humans; D007674:Kidney Diseases / Q000150:complications* / Q000628:therapy; D016030:Kidney Transplantation / Q000401:mortality*; D011379:Prognosis; D006435:Renal Dialysis / Q000401:mortality*; D015996:Survival Rate
chemical_list: D015415:Biomarkers; C000717427:FGF23 protein, human; D000089703:Fibroblast Growth Factor-23
keywords: ESRD; FGF23; biomarkers; meta-analysis; systematic review