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Vol. 35, No. 3, 2012
Issue release date: April 2012
Section title: Original Paper
Kidney Blood Press Res 2012;35:192–201
(DOI:10.1159/000332086)

Pregnancy-Associated Plasma Protein A as an Independent Mortality Predictor in Long-Term Hemodialysis Patients

Kalousová M.a · Benáková H.a · Kuběna A.A.a · Dusilová-Sulková S.c · Tesař V.b · Zima T.a
aInstitute of Clinical Biochemistry and Laboratory Diagnostics and bDepartment of Nephrology, First Faculty of Medicine, Charles University and General University Hospital, and cDepartment of Nephrology, Institute of Clinical and Experimental Medicine, Prague, Czech Republic
email Corresponding Author

Abstract

Background/Aims: Pregnancy-associated plasma protein A (PAPP-A) is a biomarker related to vascular damage. The aim of the study was to focus on PAPP-A and related parameters and their relationship to the prognosis of long-term hemodialysis (HD) patients. Methods: This is a prospective observational cohort study which included 261 long-term HD patients followed up for 5 years and 66 healthy subjects. PAPP-A, placental growth factor (PlGF), matrix metalloproteinase 2 and 9 (MMP-2, MMP-9), insulin-like growth factor 1 (IGF-1), insulin-like growth factor binding protein-4 (IGFBP-4), and cardiac, nutritional and inflammatory parameters were measured at the beginning of the study and tested as predictors of mortality. Results: PAPP-A, PlGF, IGF-1, IGFBP-4 and MMP-2 were significantly increased in HD patients compared to controls (PAPP-A 27.6 ± 15.5 mIU/l in HD vs. 9.4 ± 2.5 mIU/l in controls, p < 0.001). Increased PAPP-A was a significant independent predictor of overall mortality and mortality due to infection in the multivariate Cox analysis [HR (95% CI): 1.237 (1.060–1.444), p = 0.007, and 1.416 (1.115–1.798), p = 0.004, per standard deviation, respectively]. PAPP-A was not related to cardiovascular mortality. Conclusion: Increased PAPP-A is a significant independent predictor of overall mortality and mortality due to infection but it was not related to cardiovascular mortality in this study.

© 2011 S. Karger AG, Basel


  

Key Words

  • Cardiovascular mortality
  • Hemodialysis
  • Infection
  • Mortality
  • Pregnancy-associated plasma protein A

References

  1. Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32:S112–S119.
  2. Bayes-Genis A, Conover CA, Overgaard MT, et al: Pregnancy-associated plasma protein A as marker of acute coronary syndromes. N Engl J Med 2001;345:1057–1059.
  3. Wald NJ, Kennard A, Hackshaw AK: First trimester serum screening for Down’s syndrome. Prenat Diagn 1995;15:1227–1240.
  4. Bonno M, Oxvig C, Kephart GM, et al: Localization of pregnancy-associated plasma protein-A and colocalization of pregnancy-associated protein-A messenger ribonucleic acid and eosinophil granule major basic protein messenger ribonucleic acid in placenta. Lab Invest 1994;71:560–566.
  5. Overgaard MT, Oxvig C, Christiansen M, et al: Messenger ribonucleic acid levels of pregnancy-associated plasma protein-A and the proform of eosinophil major basic protein: expression in human reproductive and nonreproductive tissues. Biol Reprod 1999;61:1083–1089.
  6. Lawrence JB, Oxvig C, Overgaard MT, et al: The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts in pregnancy-associated plasma protein-A. Proc Natl Acad Sci USA 1999;96:3149–3153.
  7. Laursen LS, Overgaard MT, Søe R, et al: Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS Lett 2001;504:36–40.
  8. Monget P, Mazerbourg S, Delpuech T, et al: Pregnancy-associated plasma protein-A is involved in insulin-like growth factor binding protein-2 (IGFBP-2) proteolytic degradation in bovine and porcine preovulatory follicles: identification of cleavage site and characterization of IGFBP-2 degradation. Biol Reprod 2003;68:77–86.
  9. Jones JI, Prevette T, Gockerman A, Clemmons DR: Ligand occupancy of the αVβ3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor. Proc Natl Acad Sci USA 1996;93:2482–2487.
  10. Renier G, Clement I, Desfaits AC, Lambert A: Direct stimulatory effect of insulin-like growth factor-I on monocyte and macrophage tumor necrosis factor-α production. Endocrinology 1996;137:4611–4618.
  11. Conti E, Andreotti F, Zuppi C: Pregnancy-associated plasma protein a as predictor of outcome in patients with suspected acute coronary syndromes. Circulation 2004;109: e211–e212.
  12. Lund J, Ruin QP, Ilva T, et al: Circulating pregnancy-associated plasma protein A predicts outcome in patients with acute coronary syndrome but not troponin I elevation. Circulation 2003;108:1924–1926.
  13. Kalousová M, Sulková S, Fialová L, et al: Glycoxidation and inflammation in chronic hemodialysis patients. Nephrol Dial Transplant 2003;18:2577–2581.
  14. Fialová L, Kalousová M, Soukupová J, et al: Relationship of pregnancy-associated plasma protein A to renal function and dialysis modalities. Kidney Blood Press Res 2004;27:88–95.
  15. Kalousová M, Bartošová K, Zima T, Skibová J, Teplan V, Viklický O: Pregnancy-associated plasma protein A and soluble receptor for advanced glycation end products after kidney transplantation. Kidney Blood Press Res 2007;30:31–37.
  16. Kalousová M, Hořejší M, Fialová L, et al: Increased levels of pregnancy-associated plasma protein A are associated with mortality of haemodialysis patients: preliminary results. Blood Purif 2004;22:298–300.
  17. Etter C, Straub Y, Hersberger M, et al: Pregnancy-associated plasma protein A is an independent short-time predictor of mortality in patients on maintenance haemodialysis. Eur Heart J 2010;31:354–359.
  18. Lauzurica R, Pastor C, Bayes B, Hernandez JM, Romero M: Pretransplant pregnancy-associated plasma protein-A as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events. Transplantation 2005;80:1441–1446.
  19. Apple FS, Wu AH, Mair J, et al: Committee on Standardization of Markers of Cardiac Damage of the IFCC. Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome. Clin Chem 2005;51:810–824.
  20. Kalousová M, Kuběna AA, Koštířová M, et al: Lower retinol as an independent predictor of mortality in long-term hemodialysis patients: a prospective observational cohort study. Am J Kidney Dis 2010;6:513–521.

    External Resources

  21. Heeschen C, Dimmeler S, Hamm CW, Fichtischerer S, Simoons ML, Zeiher AM, CAPTURE Study Investigators: Pregnancy-associated plasma protein A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. J Am Coll Cardiol 2005;45:229–237.
  22. Elesber AA, Conover CA, Denktas AE, et al: Prognostic value of circulating pregnancy-associated plasma protein levels in patients with chronic stable angina pectoris. Eur Heart J 2006;27:1678–1684.
  23. Mueller T, Dieplinger B, Forstner T, Poelz W, Haltmayer M: Pregnancy-associated plasma protein A as a marker for long-term mortality in patients with peripheral atherosclerosis: inconclusive findings from the Linz Peripheral Arterial Disease (LIPAD) study. Clin Chem Lab Med 2010;48:537–542.
  24. Astrup AS, Tarnow L, Christiansen M, Hansen PR, Parving HH, Rossing P: Pregnancy-associated plasma protein A in a large cohort of Type 1 diabetic patients with and without diabetic nephropathy – a prospective follow-up study. Diabet Med 2007;24:1381–1385.
  25. Lauzuriza R, Pastor MC, Bayes B, et al: Pretransplant inflammation: a risk factor for delayed graft function? J Nephrol 2008;21:221–228.
  26. Resch ZT, Chen BK, Bale LK, Oxvig C, Overgaard MT, Conover CA: Pregnancy-associated plasma protein a gene expression as a target of inflammatory cytokines. Endocrinology 2004;145:1124–1129.
  27. Conover CA, Harrington SC, Bale LK: Differential regulation of pregnancy-associated plasma protein A in human coronary artery endothelial cells and smooth muscle cells. Growth Horm IGF Res 2008;18:213–220.
  28. Conover CA, Bale LK, Harrington SC, Resch ZT, Overgaard MT, Oxvig C: Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells: inhibition by resveratrol. Am J Physiol Cell Physiol 2006;290: C183–C188.
  29. Crea F, Andreotti F: Pregnancy-associated plasma protein-A and coronary atherosclerosis: marker, friend or foe? Eur Heart J 2005;26:2075–2076.
  30. Conti E, Carrozza C, Capoluongo E, et al: Insulin-like growth factor-1 as vascular protective factor. Circulation 2004;110:2260–2265.
  31. Watanabe S, Tamura T, Ono K, et al: Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: association with adiponectin. Eur J Heart Fail 2010;12:1214–1222.
  32. Andreassen M, Kistorp C, Raymond I, et al: Plasma insulin-like growth factor I as predictor of progression and all-cause mortality in chronic heart failure. Growth Horm IGF Res 2009;19:486–490.
  33. Kumar A, Mohan S, Newton J, et al: Pregnancy-associated plasma protein A regulates myoblast proliferation and differentiation through an insulin-like growth factor-dependent mechanism. J Biol Chem 2005;280:37782–37789.
  34. Conover CA, Mason MA, Bale LK, et al: Transgenic overexpression of pregnancy-associated plasma protein A in murine arterial smooth muscle accelerates atherosclerotic lesion development. Am J Physiol Heart Circ Physiol 2010;299:H284–H291.
  35. Lenderink T, Heeschen C, Fichtlscherer S, et al: CAPTURE Investigators: Elevated placental growth factor levels are associated with adverse outcomes at four-year follow-up in patients with acute coronary syndromes. J Am Coll Cardiol 2006;47:307–311.
  36. Dhillon OS, Khan SQ, Narayan HK, et al: Matrix metalloproteinase-2 predicts mortality in patients with acute coronary syndrome. Clin Sci (Lond) 2009;118:249–257.
  37. Ye YX, Leu HB, Wu TC, Lin SJ, Chen JW: Baseline serum matrix metalloproteinase-9 level predicts long-term prognosis after coronary revascularizations in stable coronary artery disease. Clin Biochem 2008;41:292–298.

  

Author Contacts

Prof. Marta Kalousova, MD, PhD
Institute of Clinical Biochemistry and Laboratory Diagnostics
First Faculty of Medicine, Charles University and General University Hospital
Na Bojišti 3, CZ–121 08 Prague 2 (Czech Republic)
Tel. +420 224 964 212, E-Mail marta.kalousova@seznam.cz

  

Article Information

Received: March 18, 2011
Accepted: August 23, 2011
Published online: November 25, 2011
Number of Print Pages : 10
Number of Figures : 3, Number of Tables : 3, Number of References : 37

  

Publication Details

Kidney and Blood Pressure Research

Vol. 35, No. 3, Year 2012 (Cover Date: April 2012)

Journal Editor: Tesar V. (Prague)
ISSN: 1420-4096 (Print), eISSN: 1423-0143 (Online)

For additional information: http://www.karger.com/KBR


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References

  1. Foley RN, Parfrey PS, Sarnak MJ: Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 1998;32:S112–S119.
  2. Bayes-Genis A, Conover CA, Overgaard MT, et al: Pregnancy-associated plasma protein A as marker of acute coronary syndromes. N Engl J Med 2001;345:1057–1059.
  3. Wald NJ, Kennard A, Hackshaw AK: First trimester serum screening for Down’s syndrome. Prenat Diagn 1995;15:1227–1240.
  4. Bonno M, Oxvig C, Kephart GM, et al: Localization of pregnancy-associated plasma protein-A and colocalization of pregnancy-associated protein-A messenger ribonucleic acid and eosinophil granule major basic protein messenger ribonucleic acid in placenta. Lab Invest 1994;71:560–566.
  5. Overgaard MT, Oxvig C, Christiansen M, et al: Messenger ribonucleic acid levels of pregnancy-associated plasma protein-A and the proform of eosinophil major basic protein: expression in human reproductive and nonreproductive tissues. Biol Reprod 1999;61:1083–1089.
  6. Lawrence JB, Oxvig C, Overgaard MT, et al: The insulin-like growth factor (IGF)-dependent IGF binding protein-4 protease secreted by human fibroblasts in pregnancy-associated plasma protein-A. Proc Natl Acad Sci USA 1999;96:3149–3153.
  7. Laursen LS, Overgaard MT, Søe R, et al: Pregnancy-associated plasma protein-A (PAPP-A) cleaves insulin-like growth factor binding protein (IGFBP)-5 independent of IGF: implications for the mechanism of IGFBP-4 proteolysis by PAPP-A. FEBS Lett 2001;504:36–40.
  8. Monget P, Mazerbourg S, Delpuech T, et al: Pregnancy-associated plasma protein-A is involved in insulin-like growth factor binding protein-2 (IGFBP-2) proteolytic degradation in bovine and porcine preovulatory follicles: identification of cleavage site and characterization of IGFBP-2 degradation. Biol Reprod 2003;68:77–86.
  9. Jones JI, Prevette T, Gockerman A, Clemmons DR: Ligand occupancy of the αVβ3 integrin is necessary for smooth muscle cells to migrate in response to insulin-like growth factor. Proc Natl Acad Sci USA 1996;93:2482–2487.
  10. Renier G, Clement I, Desfaits AC, Lambert A: Direct stimulatory effect of insulin-like growth factor-I on monocyte and macrophage tumor necrosis factor-α production. Endocrinology 1996;137:4611–4618.
  11. Conti E, Andreotti F, Zuppi C: Pregnancy-associated plasma protein a as predictor of outcome in patients with suspected acute coronary syndromes. Circulation 2004;109: e211–e212.
  12. Lund J, Ruin QP, Ilva T, et al: Circulating pregnancy-associated plasma protein A predicts outcome in patients with acute coronary syndrome but not troponin I elevation. Circulation 2003;108:1924–1926.
  13. Kalousová M, Sulková S, Fialová L, et al: Glycoxidation and inflammation in chronic hemodialysis patients. Nephrol Dial Transplant 2003;18:2577–2581.
  14. Fialová L, Kalousová M, Soukupová J, et al: Relationship of pregnancy-associated plasma protein A to renal function and dialysis modalities. Kidney Blood Press Res 2004;27:88–95.
  15. Kalousová M, Bartošová K, Zima T, Skibová J, Teplan V, Viklický O: Pregnancy-associated plasma protein A and soluble receptor for advanced glycation end products after kidney transplantation. Kidney Blood Press Res 2007;30:31–37.
  16. Kalousová M, Hořejší M, Fialová L, et al: Increased levels of pregnancy-associated plasma protein A are associated with mortality of haemodialysis patients: preliminary results. Blood Purif 2004;22:298–300.
  17. Etter C, Straub Y, Hersberger M, et al: Pregnancy-associated plasma protein A is an independent short-time predictor of mortality in patients on maintenance haemodialysis. Eur Heart J 2010;31:354–359.
  18. Lauzurica R, Pastor C, Bayes B, Hernandez JM, Romero M: Pretransplant pregnancy-associated plasma protein-A as a predictor of chronic allograft nephropathy and posttransplant cardiovascular events. Transplantation 2005;80:1441–1446.
  19. Apple FS, Wu AH, Mair J, et al: Committee on Standardization of Markers of Cardiac Damage of the IFCC. Future biomarkers for detection of ischemia and risk stratification in acute coronary syndrome. Clin Chem 2005;51:810–824.
  20. Kalousová M, Kuběna AA, Koštířová M, et al: Lower retinol as an independent predictor of mortality in long-term hemodialysis patients: a prospective observational cohort study. Am J Kidney Dis 2010;6:513–521.

    External Resources

  21. Heeschen C, Dimmeler S, Hamm CW, Fichtischerer S, Simoons ML, Zeiher AM, CAPTURE Study Investigators: Pregnancy-associated plasma protein A levels in patients with acute coronary syndromes: comparison with markers of systemic inflammation, platelet activation, and myocardial necrosis. J Am Coll Cardiol 2005;45:229–237.
  22. Elesber AA, Conover CA, Denktas AE, et al: Prognostic value of circulating pregnancy-associated plasma protein levels in patients with chronic stable angina pectoris. Eur Heart J 2006;27:1678–1684.
  23. Mueller T, Dieplinger B, Forstner T, Poelz W, Haltmayer M: Pregnancy-associated plasma protein A as a marker for long-term mortality in patients with peripheral atherosclerosis: inconclusive findings from the Linz Peripheral Arterial Disease (LIPAD) study. Clin Chem Lab Med 2010;48:537–542.
  24. Astrup AS, Tarnow L, Christiansen M, Hansen PR, Parving HH, Rossing P: Pregnancy-associated plasma protein A in a large cohort of Type 1 diabetic patients with and without diabetic nephropathy – a prospective follow-up study. Diabet Med 2007;24:1381–1385.
  25. Lauzuriza R, Pastor MC, Bayes B, et al: Pretransplant inflammation: a risk factor for delayed graft function? J Nephrol 2008;21:221–228.
  26. Resch ZT, Chen BK, Bale LK, Oxvig C, Overgaard MT, Conover CA: Pregnancy-associated plasma protein a gene expression as a target of inflammatory cytokines. Endocrinology 2004;145:1124–1129.
  27. Conover CA, Harrington SC, Bale LK: Differential regulation of pregnancy-associated plasma protein A in human coronary artery endothelial cells and smooth muscle cells. Growth Horm IGF Res 2008;18:213–220.
  28. Conover CA, Bale LK, Harrington SC, Resch ZT, Overgaard MT, Oxvig C: Cytokine stimulation of pregnancy-associated plasma protein A expression in human coronary artery smooth muscle cells: inhibition by resveratrol. Am J Physiol Cell Physiol 2006;290: C183–C188.
  29. Crea F, Andreotti F: Pregnancy-associated plasma protein-A and coronary atherosclerosis: marker, friend or foe? Eur Heart J 2005;26:2075–2076.
  30. Conti E, Carrozza C, Capoluongo E, et al: Insulin-like growth factor-1 as vascular protective factor. Circulation 2004;110:2260–2265.
  31. Watanabe S, Tamura T, Ono K, et al: Insulin-like growth factor axis (insulin-like growth factor-I/insulin-like growth factor-binding protein-3) as a prognostic predictor of heart failure: association with adiponectin. Eur J Heart Fail 2010;12:1214–1222.
  32. Andreassen M, Kistorp C, Raymond I, et al: Plasma insulin-like growth factor I as predictor of progression and all-cause mortality in chronic heart failure. Growth Horm IGF Res 2009;19:486–490.
  33. Kumar A, Mohan S, Newton J, et al: Pregnancy-associated plasma protein A regulates myoblast proliferation and differentiation through an insulin-like growth factor-dependent mechanism. J Biol Chem 2005;280:37782–37789.
  34. Conover CA, Mason MA, Bale LK, et al: Transgenic overexpression of pregnancy-associated plasma protein A in murine arterial smooth muscle accelerates atherosclerotic lesion development. Am J Physiol Heart Circ Physiol 2010;299:H284–H291.
  35. Lenderink T, Heeschen C, Fichtlscherer S, et al: CAPTURE Investigators: Elevated placental growth factor levels are associated with adverse outcomes at four-year follow-up in patients with acute coronary syndromes. J Am Coll Cardiol 2006;47:307–311.
  36. Dhillon OS, Khan SQ, Narayan HK, et al: Matrix metalloproteinase-2 predicts mortality in patients with acute coronary syndrome. Clin Sci (Lond) 2009;118:249–257.
  37. Ye YX, Leu HB, Wu TC, Lin SJ, Chen JW: Baseline serum matrix metalloproteinase-9 level predicts long-term prognosis after coronary revascularizations in stable coronary artery disease. Clin Biochem 2008;41:292–298.