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Combination of biomarkers of vascular calcification and sTWEAK to predict cardiovascular events in chronic kidney disease

  • Author Footnotes
    1 These authors contributed equally to this work.
    Milica Bozic
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Unit for Detection and Treatment of Atherothrombotic Diseases (UDETMA), Vascular and Renal Translational Research Group, IRBLLEIDA, Lleida, Spain

    Spanish Network for Renal Research (RedInRen), Spain
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  • Author Footnotes
    1 These authors contributed equally to this work.
    Nerea Méndez-Barbero
    Footnotes
    1 These authors contributed equally to this work.
    Affiliations
    Vascular Research Lab, FIIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain
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  • Carmen Gutiérrez-Muñoz
    Affiliations
    Vascular Research Lab, FIIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain
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  • Angels Betriu
    Affiliations
    Unit for Detection and Treatment of Atherothrombotic Diseases (UDETMA), Vascular and Renal Translational Research Group, IRBLLEIDA, Lleida, Spain

    Spanish Network for Renal Research (RedInRen), Spain
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  • Jesús Egido
    Affiliations
    Vascular Research Lab, FIIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain

    Spanish Biomedical Research Centre in Diabetes and Associated Metabolic Disorders (CIBERDEM), Spain
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  • Elvira Fernández
    Affiliations
    Unit for Detection and Treatment of Atherothrombotic Diseases (UDETMA), Vascular and Renal Translational Research Group, IRBLLEIDA, Lleida, Spain

    Spanish Network for Renal Research (RedInRen), Spain
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  • Jose L. Martín-Ventura
    Affiliations
    Vascular Research Lab, FIIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain

    Spanish Biomedical Research Centre in Cardiovascular Disease (CIBERCV), Spain
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  • Jose M. Valdivielso
    Correspondence
    Corresponding author. Unit for Detection and Treatment of Atherothrombotic Diseases (UDETMA), Vascular and Renal Translational Research Group, IRBLLEIDA, Lleida, Spain.
    Affiliations
    Unit for Detection and Treatment of Atherothrombotic Diseases (UDETMA), Vascular and Renal Translational Research Group, IRBLLEIDA, Lleida, Spain

    Spanish Network for Renal Research (RedInRen), Spain
    Search for articles by this author
  • Luis M. Blanco-Colio
    Correspondence
    Corresponding author. Vascular Research Lab, FIIS-Fundación Jiménez Díaz, Madrid, Spain.
    Affiliations
    Vascular Research Lab, FIIS-Fundación Jiménez Díaz, Autónoma University, Madrid, Spain

    Spanish Biomedical Research Centre in Cardiovascular Disease (CIBERCV), Spain
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  • investigators from the NEFRONA study
  • Author Footnotes
    1 These authors contributed equally to this work.

      Highlights

      • sTWEAK, OPG and OPN concentrations have been related with vascular calcification.
      • We evaluated the association between OPG, OPN and sTWEAK and their combination with cardiovascular outcomes in CKD patients.
      • OPG, OPN and sTWEAK concentrations were related to a higher prevalence of cardiovascular outcomes in CKD patients.
      • Combination of OPG, OPN and sTWEAK increased the predictability of cardiovascular outcomes.

      Abstract

      Background and aims

      Vascular calcification (VC) and atherosclerosis are associated with an increased cardiovascular morbimortality in chronic kidney disease (CKD). Osteoprotegerin (OPG) and osteopontin (OPN) are involved in both VC and CKD. Soluble tumor necrosis factor-like weak inducer of apoptosis (sTWEAK) has been related to cardiovascular disease. We hypothesized that OPG, OPN and sTWEAK levels may be associated with a higher prevalence of cardiovascular outcomes in patients with CKD.

      Methods

      The presence of calcified or non-calcified atherosclerotic plaques was assessed in 1043 stage 3 to 5D CKD patients from The NEFRONA Study. Biochemical measurements and OPG, OPN and sTWEAK serum levels were analyzed. Patients were followed for cardiovascular outcomes (41 ± 16 months).

      Results

      At recruitment, 26% of CKD patients had VC. The adjusted odds ratios for having VC were 2.22 (1.32–3.75); p=.003 for OPG, and 0.45 (0.24–0.84); p=.01 for sTWEAK concentrations. After follow-up, 95 CV events occurred. In a Cox model, patients with OPG or OPN above and sTWEAK below their optimal cut-off points had an adjusted higher risk of cardiovascular events [HR: 2.10 (1.49–3.90); p=.02; 1.65 (1.02–2.65); p=.04; 2.05 (1.28–3.29), p=.003; respectively]. When CKD patients were grouped according to the number of biomarkers above (OPG and OPN) or below (sTWEAK) their cut-off points, the combination of these biomarkers showed the highest risk for cardiovascular events [HR: 9.46 (3.80–23.5) p < .001]. A composite score of these three biomarkers increased the C-statistic and net reclassification index beyond conventional risk factors and VC.

      Conclusions

      The combination of OPG, OPN and sTWEAK increased the predictability of cardiovascular outcomes.

      Keywords

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      References

        • Foley R.N.
        • Parfrey P.S.
        • Sarnak M.J.
        Epidemiology of cardiovascular disease in chronic renal disease.
        J. Am. Soc. Nephrol. 1998; 9 (Am Soc Nephrol 1998;9 (12 Suppl):S16–23): S16-S23
        • Go A.S.
        • Chertow G.M.
        • Fan D.
        • McCulloch C.E.
        • Hsu C.Y.
        Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization.
        N. Engl. J. Med. 2004; 351: 1296-1305
        • Gluba-Brzozka A.
        • Michalska-Kasiczak M.
        • Franczyk-Skora B.
        • Nocun M.
        • Banach M.
        • Rysz J.
        Markers of increased cardiovascular risk in patients with chronic kidney disease.
        Lipids Health Dis. 2014; 13: 135
        • Hager M.R.
        • Narla A.D.
        • Tannock L.R.
        Dyslipidemia in patients with chronic kidney disease.
        Rev. Endocr. Metab. Disord. 2017; 18: 29-40
        • Liabeuf S.
        • Desjardins L.
        • Diouf M.
        • Temmar M.
        • Renard C.
        • Choukroun G.
        • Massy Z.A.
        The addition of vascular calcification scores to traditional risk factors improves cardiovascular risk assessment in patients with chronic kidney disease.
        PLoS One. 2015; 10e0131707
        • Bucay N.
        • Sarosi I.
        • Dunstan C.R.
        • Morony S.
        • Tarpley J.
        • Capparelli C.
        • Scully S.
        • Tan H.L.
        • Xu W.
        • Lacey D.L.
        • Boyle W.J.
        • Simonet W.S.
        Osteoprotegerin-deficient mice develop early onset osteoporosis and arterial calcification.
        Genes Dev. 1998; 12: 1260-1268
        • Giachelli C.M.
        • Bae N.
        • Almeida M.
        • Denhardt D.T.
        • Alpers C.E.
        • Schwartz S.M.
        Osteopontin is elevated during neointima formation in rat arteries and is a novel component of human atherosclerotic plaques.
        J. Clin. Invest. 1993; 92: 1686-1696
        • Simonet W.S.
        • Lacey D.L.
        • Dunstan C.R.
        • Kelley M.
        • Chang M.S.
        • Lüthy R.
        • Nguyen H.Q.
        • Wooden S.
        • Bennett L.
        • Boone T.
        • Shimamoto G.
        • DeRose M.
        • Elliot R.
        • Colombero A.
        • Tan H.L.
        • Trail G.
        • Sullivan J.
        • Davy E.
        • Bucay N.
        • Renshaw-Gegg L.
        • Hughes T.M.
        • Hill D.
        • Pattison W.
        • Campbell P.
        • Sander S.
        • Van G.
        • Tarpley J.
        • Derby P.
        • Lee R.
        • Boyle W.J.
        Osteoprotegerin: a novel secreted protein involved in the regulation of bone density.
        Cell. 1997; 89: 309-319
        • Boyle W.J.
        • Simonet W.S.
        • Lacey D.L.
        Osteoclast differentiation and activation.
        Nature. 2003; 423: 337-342
        • Sigrist M.K.
        • Levin A.
        • Er L.
        • McIntyre C.W.
        Elevated osteoprotegerin is associated with all-cause mortality in CKD stage 4 and 5 patients in addition to vascular calcification.
        Nephrol. Dial. Transplant. 2009; 24: 3157-3162
        • Lewis J.R.
        • Lim W.H.
        • Ueland T.
        • Wong G.
        • Zhu K.
        • Lim E.M.
        • Bollerslev J.
        • Prince R.L.
        Elevated circulating osteoprotegerin and renal dysfunction predict 15-year cardiovascular and all-cause mortality: a prospective study of elderly women.
        PLoS One. 2015; 10e0134266
        • De Fusco C.
        • Messina A.
        • Monda V.
        • Viggiano E.
        • Moscatelli F.
        • Valenzano A.
        • Esposito T.
        • Sergio C.
        • Cibelli G.
        • Monda M.
        • Messina G.
        Osteopontin: relation between adipose tissue and bone homeostasis.
        Stem Cells Int. 2017; 20174045238
        • Kothari A.N.
        • Arffa M.L.
        • Chang V.
        • Blackwell R.H.
        • Syn W.K.
        • Zhang J.
        • Mi Z.
        • Kuo P.C.
        Osteopontin-a master regulator of epithelial-mesenchymal transition.
        J. Clin. Med. 2016; 5 (pii: E39)
        • Barreto D.V.
        • Lenglet A.
        • Liabeuf S.
        • Kretschmer A.
        • Barreto F.C.
        • Nollet A.
        • Slama M.
        • Choukroun G.
        • Brazier M.
        • Massy Z.
        Prognostic implication of plasma osteopontin levels in patients with chronic kidney disease.
        Nephron Clin. Pract. 2011; 117: c363-c372
        • Sastre C.
        • Fernández-Laso V.
        • Madrigal-Matute J.
        • Muñoz-García B.
        • Moreno J.A.
        • Pastor-Vargas C.
        • Llamas-Granda P.
        • Burkly L.C.
        • Egido J.
        • Martín-Ventura J.L.
        • Blanco-Colio L.M.
        Genetic deletion or TWEAK blocking antibody administration reduce atherosclerosis and enhance plaque stability in mice.
        J. Cell Mol. Med. 2014; 18: 721-734
        • Schapira K.
        • Burkly L.C.
        • Zheng T.S.
        • Wu P.
        • Groeneweg M.
        • Rousch M.
        • Kockx M.M.
        • Daemen M.J.
        • Heeneman S.
        Fn14-Fc fusion proteína regulates atherosclerosis in ApoE-/- mice and inhibits macrophage lipid uptake in vitro.
        Arterioscler. Thromb. Vasc. Biol. 2009; 29: 2021-2027
        • Muñoz-García B.
        • Moreno J.A.
        • López-Franco O.
        • Sanz A.B.
        • Martín-Ventura J.L.
        • Blanco J.
        • Jakubowski A.
        • Burkly L.C.
        • Ortiz A.
        • Egido J.
        • Blanco-Colio L.M.
        Tumor necrosis factor-like weak inducer of apoptosis (TWEAK) enhances vascular and renal damage induced by hyperlipidemic diet in ApoE-knockout mice.
        Arterioscler. Thromb. Vasc. Biol. 2009; 29: 2061-2068
        • Hénaut L.
        • Sanz A.B.
        • Martin-Sanchez D.
        • Carrasco S.
        • Villa-Bellosta R.
        • Aldamiz-Echevarria G.
        • Massy Z.A.
        • Sanchez-Niño M.D.
        • Ortiz A.
        TWEAK favors phosphate-induced calcification of vascular smooth muscle cells through canonical and non-canonical activation of NFκB.
        Cell Death Dis. 2016; 7e2305
        • Fernández-Laso V.
        • Sastre C.
        • Valdivielso J.M.
        • Betriu A.
        • Fernández E.
        • Egido J.
        • Martín-Ventura J.L.
        • Blanco-Colio L.M.
        Soluble TWEAK and major adverse cardiovascular events in patients with CKD.
        Clin. J. Am. Soc. Nephrol. 2016; 11: 413-422
        • Yilmaz M.I.
        • Sonmez A.
        • Ortiz A.
        • Saglam M.
        • Kilic S.
        • Eyileten T.
        • Caglar K.
        • Oguz Y.
        • Vural A.
        • Cakar M.
        • Egido J.
        • Altun B.
        • Yenicesu M.
        • Blanco-Colio L.M.
        Soluble TWEAK and PTX3 in nondialysis CKD patients: impact on endothelial dysfunction and cardiovascular outcomes.
        Clin. J. Am. Soc. Nephrol. 2011; 6: 785-792
        • Junyent M.
        • Martínez M.
        • Borrás M.
        • Coll B.
        • Valdivielso J.M.
        • Vidal T.
        • Sarró F.
        • Roig J.
        • Craver L.
        • Fernández E.
        Predicting cardiovascular disease morbidity and mortality in chronic kidney disease in Spain. The rationale and design of NEFRONA. A prospective, multicenter, observational cohort study.
        BMC Nephrol. 2010; 11: 14
        • Junyent M.
        • Martínez M.
        • Borrás M.
        • Bertriu A.
        • Coll B.
        • Craver L.
        • Marco M.P.
        • Sarró F.
        • Valdivielso J.M.
        • Fernández E.
        Usefulness of imaging techniques and novel biomarkers in the prediction of cardiovascular risk in patients with chronic kidney disease in Spain: the NEFRONA project.
        Nefrologia. 2010; 30: 119-126
        • Anguiano L.
        • Riera M.
        • Pascual J.
        • Valdivielso J.M.
        • Barrios C.
        • Betriu A.
        • Clotet S.
        • Mojal S.
        • Fernández E.
        • Soler M.J.
        Circulating angiotensin converting enzyme 2 activity as a biomarker of silent atherosclerosis in patients with chronic kidney disease.
        Atherosclerosis. 2016; 253: 135-143
        • Stein J.H.
        • Korcarz C.E.
        • Hurst R.T.
        • Lonn E.
        • Kendall C.B.
        • Mohler E.R.
        • Najjar S.S.
        • Rembold C.M.
        • Post W.S.
        American society of echocardiography carotid intima-media thickness task force, use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the american society of echocardiography carotid intima-media thickness task force. Endorsed by the society for vascular medicine.
        J. Am. Soc. Echocardiogr. 2008; 21: 93-111
        • Touboul P.J.
        • Hennerici M.G.
        • Meairs S.
        • Adams H.
        • Amarenco P.
        • Desvarieux M.
        • Ebrahim S.
        • Fatar M.
        • Hernández-Hernández R.
        • Kownator S.
        • Prati P.
        • Rundek T.
        • Taylor A.
        • Bornstein N.
        • Csiba L.
        • Vicaut E.
        • Woo K.S.
        • Zannad F.
        Advisory board of the 3rd watching the risk symposium 2004, 13th european stroke conference: Mannheim intima-media thickness consensus.
        Cerebrovasc. Dis. 2004; 18: 346-349
        • DeLong E.R.
        • DeLong D.M.
        • Clarke-Pearson D.L.
        Comparing the areas under two or more correlated receiver operating characteristic curves: a nonparametric approach.
        Biometrics. 1988; 44: 837-845
        • Pencina M.J.
        • D'Agostino Sr., R.B.
        • D'Agostino Jr., R.B.
        • Vasan R.S.
        Evaluating the added predictive ability of a new marker: from area under the ROC curve to reclassification and beyond.
        Stat. Med. 2008; 27: 157-172
        • Reid P.
        • Holen I.
        Pathophysiological roles of osteoprotegerin (OPG).
        Eur. J. Cell Biol. 2009; 88: 1-17
        • Bennett B.J.
        • Scatena M.
        • Kirk E.A.
        • Rattazzi M.
        • Varon R.M.
        • Averill M.
        • Schwartz S.M.
        • Giachelli C.M.
        • Rosenfeld M.E.
        Osteoprotegerin inactivation accelerates advanced atherosclerotic lesion progression and calcification in older ApoE-/- mice.
        Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2117-2124
        • Ovchinnikova O.
        • Gylfe A.
        • Bailey L.
        • Nordström A.
        • Rudling M.
        • Jung C.
        • Bergström S.
        • Waldenström A.
        • Hansson G.K.
        • Nordström P.
        Osteoprotegerin promotes fibrous cap formation in atherosclerotic lesions of ApoE-deficient mice–brief report.
        Arterioscler. Thromb. Vasc. Biol. 2009; 29: 1478-1480
        • Moe S.M.
        • Reslerova M.
        • Ketteler M.
        • O'neill K.
        • Duan D.
        • Koczman J.
        • Westenfeld R.
        • Jahnen-Dechent W.
        • Chen N.X.
        Role of calcification inhibitors in the pathogenesis of vascular calcification in chronic kidney disease (CKD).
        Kidney Int. 2005; 67: 2295-2304
        • Panizo S.
        • Cardus A.
        • Encinas M.
        • Parisi E.
        • Valcheva P.
        • López-Ongil S.
        • Coll B.
        • Fernández E.
        • Valdivielso J.M.
        RANKL increases vascular smooth muscle cell calcification through a RANK-BMP4-dependent pathway.
        Circ. Res. 2009; 104: 1041-1048
        • Nishiura R.
        • Fujimoto S.
        • Sato Y.
        • Yamada K.
        • Hisanaga S.
        • Hara S.
        • Nakao H.
        • Kitamura K.
        Elevated osteoprotegerin levels predict cardiovascular events in new hemodialysis patients.
        Am. J. Nephrol. 2009; 29: 257-263
        • Matsui Y.
        • Rittling S.R.
        • Okamoto H.
        • Inobe M.
        • Jia N.
        • Shimuzi T.
        • Akino M.
        • Sugawara T.
        • Morimoto J.
        • Kimura C.
        • Kon S.
        • Denhardt D.
        • Kitabatake A.
        • Uede T.
        Osteopontin deficiency attenuates atherosclerosis in female apolipoprotein E-deficient mice.
        Arterioscler. Thromb. Vasc. Biol. 2003; 23: 1029-1034
        • Pei Z.
        • Okura T.
        • Nagao T.
        • Enomoto D.
        • Kukida M.
        • Tanino A.
        • Miyoshi K.
        • Kurata M.
        • Higaki J.
        Osteopontin deficiency reduces kidney damage from hypercholesterolemia in Apolipoprotein E-deficient mice.
        Sci. Rep. 2016; 28882
        • Lau W.L.
        • Pai A.
        • Moe S.M.
        • Giachelli C.M.
        Direct effects of phosphate on vascular cell function.
        Adv. Chron. Kidney Dic. 2011; 18: 105-112
        • O'Brien K.D.
        • Kuusisto J.
        • Reichenbach D.D.
        • Ferguson M.
        • Giachelli C.
        • Alpers C.E.
        • Otto C.M.
        Osteopontin is expressed in human aortic valvular lesions.
        Circulation. 1995; 92: 2163-2168
        • Chen J.J.
        • Zhang J.
        • Cai Y.
        • Zhou Y.B.
        • Wen G.B.
        • Tang C.S.
        • Qi Y.F.
        • Jiang Z.S.
        C-type natriuretic peptide inhibiting vascular calcification might involve decreasing bone morphogenic protein 2 and osteopontin levels.
        Mol. Cell. Biochem. 2014; 392: 65-76
        • Moe S.M.
        • Duan D.
        • Doehle B.P.
        • O'Neill K.D.
        • Chen N.X.
        Uremia induces the osteoblast differentiation factor Cbfa1 in human blood vessels.
        Kidney Int. 2003; 63: 1003-1011
        • Wada T.
        • McKee M.D.
        • Steitz S.
        • Giachelli C.M.
        Calcification of vascular smooth muscle cell cultures: inhibition by osteopontin.
        Circ. Res. 1998; 84: 166-178
        • Speer M.Y.
        • Chien Y.C.
        • Quan M.
        • Yang H.Y.
        • Vali H.
        • McKee M.D.
        • Giachelli C.M.
        Smooth muscle cells deficient in osteopontin have enhanced susceptibility to calcification in vitro.
        Cardiovasc. Res. 2005; 66: 324-333
        • Wolak T.
        Osteopontin - a multi-modal marker and mediator in atherosclerotic vascular disease.
        Atherosclerosis. 2014; 236: 327-337
        • Polek T.C.
        • Talpaz M.
        • Darnay B.G.
        • Spivak-Kroizman T.
        TWEAK mediates signal transduction and differentiation of RAW264.7 cells in the absence of Fn14/TweakR. Evidence for a second TWEAK receptor.
        J. Biol. Chem. 2003; 278: 32317-32323
        • Ammirati E.
        • Fogacci E.F.
        • Norata G.D.
        • Magnoni M.
        • Camici P.G.
        Markers of inflammation associated with plaque progression and instability in patients with carotid atherosclerosis.
        Mediat. Inflamm. 2015; 2015718329
        • Ammirati E.
        • Fogacci F.
        Clinical relevance of biomarkers for the identification of patients with carotid atherosclerotic plaque: potential role and limitations of cysteine protease legumain.
        Atherosclerosis. 2017; 257: 248-249