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Inflammation and the bone-vascular axis in end-stage renal disease

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Abstract

Summary

Bone loss and vascular calcification coincide in patients with end-stage renal disease, similar as to what is observed in the general population. In the present bone biopsy study, we provide further evidence that (micro-)inflammation may represent a common soil for both diseases.

Introduction

Vascular calcification is a common complication of end-stage renal disease (ESRD) and is predictive of subsequent cardiovascular disease and mortality. Mounting evidence linking bone disorders with vascular calcification has contributed to the development of the concept of the bone-vascular axis. Inflammation is involved in the pathogenesis of both disorders. The aim of the present study was to evaluate the relationship between aortic calcification, inflammation, and bone histomorphometry in patients with ESRD.

Methods

Parameters of inflammation and mineral metabolism were assessed in 81 ESRD patients (55 ± 13 year, 68 % male) referred for renal transplantation. Static bone histomorphometry parameters were determined on transiliac bone biopsies performed during the transplant procedure. Aortic calcification was quantified on lateral lumbar X-rays using the Kauppila method.

Results

Aortic calcification, low bone turnover, and low bone area were observed in 53, 37, and 21 % of patients respectively. Inflammatory markers were found to be independently associated with aortic calcification (hsIL-6) and low bone area (TNF-α). Low bone area associated with aortic calcification, independent of age, diabetes, and inflammation.

Conclusions

Low bone area and inflammation associates with aortic calcification, independent of each other and traditional risk factors. Our data emphasize the role of (micro-)inflammation in the bone-vascular axis in CKD.

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References

  1. Cunningham J, Sprague SM, Cannata-Andia J, Coco M, Cohen-Solal M, Fitzpatrick L, Goltzmann D, Lafage-Proust MH, Leonard M, Ott S, Rodriguez M, Stehman-Breen C, Stern P, Weisinger J (2004) Osteoporosis in chronic kidney disease. Am J Kidney Dis 43:566–571

    Article  PubMed  Google Scholar 

  2. Budoff MJ, Rader DJ, Reilly MP, Mohler ER III, Lash J, Yang W, Rosen L, Glenn M, Teal V, Feldman HI (2011) Relationship of estimated GFR and coronary artery calcification in the CRIC (Chronic Renal Insufficiency Cohort) Study. Am J Kidney Dis 58:519–526

    Article  PubMed Central  PubMed  Google Scholar 

  3. Ball AM, Gillen DL, Sherrard D, Weiss NS, Emerson SS, Seliger SL, Kestenbaum BR, Stehman-Breen C (2002) Risk of hip fracture among dialysis and renal transplant recipients. JAMA 288:3014–3018

    Article  PubMed  Google Scholar 

  4. Tanko LB, Christiansen C, Cox DA, Geiger MJ, McNabb MA, Cummings SR (2005) Relationship between osteoporosis and cardiovascular disease in postmenopausal women. J Bone Miner Res 20:1912–1920

    Article  PubMed  Google Scholar 

  5. Thompson B, Towler DA (2012) Arterial calcification and bone physiology: role of the bone-vascular axis. Nat Rev Endocrinol 8:529–543

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. London GM (2009) Bone-vascular axis in chronic kidney disease: a reality? Clin J Am Soc Nephrol 4:254–257

    Article  PubMed  Google Scholar 

  7. Schulz E, Arfai K, Liu X, Sayre J, Gilsanz V (2004) Aortic calcification and the risk of osteoporosis and fractures. J Clin Endocrinol Metab 89:4246–4253

    Article  CAS  PubMed  Google Scholar 

  8. Naves M, Rodriguez-Garcia M, Diaz-Lopez JB, Gomez-Alonso C, Cannata-Andia JB (2008) Progression of vascular calcifications is associated with greater bone loss and increased bone fractures. Osteoporos Int 19:1161–1166

    Article  CAS  PubMed  Google Scholar 

  9. Hyder JA, Allison MA, Wong N, Papa A, Lang TF, Sirlin C, Gapstur SM, Ouyang P, Carr JJ, Criqui MH (2009) Association of coronary artery and aortic calcium with lumbar bone density: the MESA Abdominal Aortic Calcium Study. Am J Epidemiol 169:186–194

    Article  PubMed Central  PubMed  Google Scholar 

  10. London GM, Marty C, Marchais SJ, Guerin AP, Metivier F, de Vernejoul MC (2004) Arterial calcifications and bone histomorphometry in end-stage renal disease. J Am Soc Nephrol 15:1943–1951

    Article  PubMed  Google Scholar 

  11. Adragao T, Herberth J, Monier-Faugere MC, Branscum AJ, Ferreira A, Frazao JM, Dias CJ, Malluche HH (2009) Low bone volume—a risk factor for coronary calcifications in hemodialysis patients. Clin J Am Soc Nephrol 4:450–455

    Article  PubMed Central  PubMed  Google Scholar 

  12. Rodriguez-Garcia M, Gomez-Alonso C, Naves-Diaz M, Diaz-Lopez JB, Diaz-Corte C, Cannata-Andia JB (2009) Vascular calcifications, vertebral fractures and mortality in haemodialysis patients. Nephrol Dial Transplant 24:239–246

    Article  PubMed Central  PubMed  Google Scholar 

  13. Barreto DV, Barreto FC, Carvalho AB, Cuppari L, Cendoroglo M, Draibe SA, Moyses RM, Neves KR, Jorgetti V, Blair A, Guiberteau R, Fernandes Canziani ME (2005) Coronary calcification in hemodialysis patients: the contribution of traditional and uremia-related risk factors. Kidney Int 67:1576–1582

    Article  PubMed  Google Scholar 

  14. Neven E, De Schutter TM, De Broe ME, D'Haese PC (2011) Cell biological and physicochemical aspects of arterial calcification. Kidney Int 79:1166–1177

    Article  CAS  PubMed  Google Scholar 

  15. Oh J, Wunsch R, Turzer M, Bahner M, Raggi P, Querfeld U, Mehls O, Schaefer F (2002) Advanced coronary and carotid arteriopathy in young adults with childhood-onset chronic renal failure. Circulation 106:100–105

    Article  PubMed  Google Scholar 

  16. Guerin AP, London GM, Marchais SJ, Metivier F (2000) Arterial stiffening and vascular calcifications in end-stage renal disease. Nephrol Dial Transplant 15:1014–1021

    Article  CAS  PubMed  Google Scholar 

  17. Barreto FC, Barreto DV, Moyses RM, Neves CL, Jorgetti V, Draibe SA, Canziani ME, Carvalho AB (2006) Osteoporosis in hemodialysis patients revisited by bone histomorphometry: a new insight into an old problem. Kidney Int 69:1852–1857

    Article  CAS  PubMed  Google Scholar 

  18. Barreto DV, Barreto FC, Carvalho AB, Cuppari L, Draibe SA, Dalboni MA, Moyses RM, Neves KR, Jorgetti V, Miname M, Santos RD, Canziani ME (2008) Association of changes in bone remodeling and coronary calcification in hemodialysis patients: a prospective study. Am J Kidney Dis 52:1139–1150

    Article  CAS  PubMed  Google Scholar 

  19. Tomiyama C, Carvalho AB, Higa A, Jorgetti V, Draibe SA, Canziani ME (2010) Coronary calcification is associated with lower bone formation rate in CKD patients not yet in dialysis treatment. J Bone Miner Res 25:499–504

    Article  CAS  PubMed  Google Scholar 

  20. London GM, Marchais SJ, Guerin AP, Boutouyrie P, Metivier F, de Vernejoul MC (2008) Association of Bone Activity, Calcium Load, Aortic Stiffness, and Calcifications in ESRD. J Am Soc Nephrol 19:1827–1835

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  21. Bouillon R, Coopmans W, Degroote DE, Radoux D, Eliard PH (1990) Immunoradiometric assay of parathyrin with polyclonal and monoclonal region-specific antibodies. Clin Chem 36:271–276

    CAS  PubMed  Google Scholar 

  22. Spasovski GB, Bervoets ARJ, Behets GJS, Ivanovski N, Sikole A, Dams G, Couttenye MM, De Broe ME, D'Haese PC (2003) Spectrum of renal bone disease in end-stage renal failure patients not yet on dialysis. Nephrol Dial Transplant 18:1159–1166

    Article  CAS  PubMed  Google Scholar 

  23. Dempster DW, Compston JE, Drezner MK, Glorieux FH, KANIS JA, Malluche H, Meunier PJ, Ott SM, Recker RR, Parfitt AM (2013) Standardized nomenclature, symbols, and units for bone histomorphometry: a 2012 update of the report of the ASBMR Histomorphometry Nomenclature Committee. J Bone Miner Res 28:2–17

    Article  PubMed Central  PubMed  Google Scholar 

  24. Kauppila LI, Polak JF, Cupples LA, Hannan MT, Kiel DP, Wilson PW (1997) New indices to classify location, severity and progression of calcific lesions in the abdominal aorta: a 25-year follow-up study. Atherosclerosis 132:245–250

    Article  CAS  PubMed  Google Scholar 

  25. Moe S, Drueke T, Cunningham J, Goodman W, Martin K, Olgaard K, Ott S, Sprague S, Lameire N, Eknoyan G (2006) Definition, evaluation, and classification of renal osteodystrophy: a position statement from Kidney Disease: improving Global Outcomes (KDIGO). Kidney Int 69:1945–1953

    Article  CAS  PubMed  Google Scholar 

  26. Cannata-Andia JB, Rodriguez-Garcia M, Carrillo-Lopez N, Naves-Diaz M, Diaz-Lopez B (2006) Vascular calcifications: pathogenesis, management, and impact on clinical outcomes. J Am Soc Nephrol 17:S267–S273

    Article  PubMed  Google Scholar 

  27. Meneghini M, Regalia A, Alfieri C, Barretta F, Croci D, Gandolfo MT, Vettoretti S, Rastaldi MP, Messa P (2013) Calcium and osteoprotegerin levels predict the progression of the abdominal aortic calcifications after kidney transplantation. Transplantation 96:42–48

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  28. Coen G, Mazzaferro S, Ballanti P, Sardella D, Chicca S, Manni M, Bonucci E, Taggi F (1996) Renal bone disease in 76 patients with varying degrees of predialysis chronic renal failure: a cross-sectional study. Nephrol Dial Transplant 11:813–819

    Article  CAS  PubMed  Google Scholar 

  29. Malluche HH, Mawad HW, Monier-Faugere MC (2011) Renal osteodystrophy in the first decade of the new millennium: analysis of 630 bone biopsies in black and white patients. J Bone Miner Res 26:1368–1376

    Article  PubMed Central  PubMed  Google Scholar 

  30. von der RP, Hansen MA, Hassager C (1999) The association between low bone mass at the menopause and cardiovascular mortality. Am J Med 106:273–278

    Article  Google Scholar 

  31. Braun J, Oldendorf M, Moshage W, Heidler R, Zeitler E, Luft FC (1996) Electron beam computed tomography in the evaluation of cardiac calcification in chronic dialysis patients. Am J Kidney Dis 27:394–401

    Article  CAS  PubMed  Google Scholar 

  32. Toussaint ND, Lau KK, Strauss BJ, Polkinghorne KR, Kerr PG (2008) Associations between vascular calcification, arterial stiffness and bone mineral density in chronic kidney disease. Nephrol Dial Transplant 23:586–593

    Article  PubMed  Google Scholar 

  33. Asmus HG, Braun J, Krause R, Brunkhorst R, Holzer H, Schulz W, Neumayer HH, Raggi P, Bommer J (2005) Two year comparison of sevelamer and calcium carbonate effects on cardiovascular calcification and bone density. Nephrol Dial Transplant 20:1653–1661

    Article  CAS  PubMed  Google Scholar 

  34. Khosla S (2011) The bone and beyond: a shift in calcium. Nat Med 17:430–431

    Article  CAS  PubMed  Google Scholar 

  35. New SE, Aikawa E (2011) Molecular imaging insights into early inflammatory stages of arterial and aortic valve calcification. Circ Res 108:1381–1391

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  36. Herbelin A, Nguyen AT, Zingraff J, Urena P, Descamps-Latscha B (1990) Influence of uremia and hemodialysis on circulating interleukin-1 and tumor necrosis factor alpha. Kidney Int 37:116–125

    Article  CAS  PubMed  Google Scholar 

  37. Kaysen GA (2001) The microinflammatory state in uremia: causes and potential consequences. J Am Soc Nephrol 12:1549–1557

    CAS  PubMed  Google Scholar 

  38. Stenvinkel P, Wanner C, Metzger T, Heimburger O, Mallamaci F, Tripepi G, Malatino L, Zoccali C (2002) Inflammation and outcome in end-stage renal failure: does female gender constitute a survival advantage? Kidney Int 62:1791–1798

    Article  PubMed  Google Scholar 

  39. Jenny NS, Brown ER, Detrano R, Folsom AR, Saad MF, Shea S, Szklo M, Herrington DM, Jacobs DR Jr (2010) Associations of inflammatory markers with coronary artery calcification: results from the Multi-Ethnic Study of Atherosclerosis. Atherosclerosis 209:226–229

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  40. Alman AC, Kinney GL, Tracy RP, Maahs DM, Hokanson JE, Rewers MJ, Snell-Bergeon JK (2013) Prospective association between inflammatory markers and progression of coronary artery calcification in adults with and without type 1 diabetes. Diabetes Care 36:1967–1973

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  41. Tintut Y, Patel J, Territo M, Saini T, Parhami F, Demer LL (2002) Monocyte/macrophage regulation of vascular calcification in vitro. Circulation 105:650–655

    Article  CAS  PubMed  Google Scholar 

  42. Al-Aly Z, Shao JS, Lai CF, Huang E, Cai J, Behrmann A, Cheng SL, Towler DA (2007) Aortic Msx2-Wnt calcification cascade is regulated by TNF-alpha-dependent signals in diabetic Ldlr-/- mice. Arterioscler, Thromb, Vasc Biol 27:2589–2596

    Article  CAS  Google Scholar 

  43. Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Böhm R, Metzger T, Wanner C, Jahnen-Dechent W, Floege J (2003) Association of low fetuin-A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross-sectional study. Lancet 361:827–833

    Article  CAS  PubMed  Google Scholar 

  44. Pfeilschifter J, Chenu C, Bird A, Mundy GR, Roodman GD (1989) Interleukin-1 and tumor necrosis factor stimulate the formation of human osteoclastlike cells in vitro. J Bone Miner Res 4:113–118

    Article  CAS  PubMed  Google Scholar 

  45. Ferreira A, Saraiva M, Behets G, Macedo A, Galvao M, D'Haese P, Drueke TB (2009) Evaluation of bone remodeling in hemodialysis patients: serum biochemistry, circulating cytokines and bone histomorphometry. J Nephrol 22:783–793

    CAS  PubMed  Google Scholar 

  46. Hofbauer LC, Lacey DL, Dunstan CR, Spelsberg TC, Riggs BL, Khosla S (1999) Interleukin-1beta and tumor necrosis factor-alpha, but not interleukin-6, stimulate osteoprotegerin ligand gene expression in human osteoblastic cells. Bone 25:255–259

    Article  CAS  PubMed  Google Scholar 

  47. Kobayashi K, Takahashi N, Jimi E, Udagawa N, Takami M, Kotake S, Nakagawa N, Kinosaki M, Yamaguchi K, Shima N, Yasuda H, Morinaga T, Higashio K, Martin TJ, Suda T (2000) Tumor necrosis factor alpha stimulates osteoclast differentiation by a mechanism independent of the ODF/RANKL-RANK interaction. J Exp Med 191:275–286

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  48. Feyen JH, Elford P, Di Padova FE, Trechsel U (1989) Interleukin-6 is produced by bone and modulated by parathyroid hormone. J Bone Miner Res 4:633–638

    Article  CAS  PubMed  Google Scholar 

  49. Panuccio V, Enia G, Tripepi R, Aliotta R, Mallamaci F, Tripepi G, Zoccali C (2012) Pro-inflammatory cytokines and bone fractures in CKD patients An exploratory single centre study. BMC Nephrol 13:134

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  50. Hjortnaes J, Butcher J, Figueiredo JL, Riccio M, Kohler RH, Kozloff KM, Weissleder R, Aikawa E (2010) Arterial and aortic valve calcification inversely correlates with osteoporotic bone remodelling: a role for inflammation. Eur Heart J 31:1975–1984

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  51. Krishnamurthy VM, Wei G, Baird BC, Murtaugh M, Chonchol MB, Raphael KL, Greene T, Beddhu S (2012) High dietary fiber intake is associated with decreased inflammation and all-cause mortality in patients with chronic kidney disease. Kidney Int 81:300–306

    Article  CAS  PubMed  Google Scholar 

  52. Saisho Y (2015) Metformin and inflammation: its potential beyond glucose-lowering effect. Endocr Metab Immune Disord Drug Targets

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Acknowledgments

Part of this work was presented at the 46th American Society of Nephrology Congress, Atlanta, USA, 5-10/11/2013.

Conflicts of interest

None.

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Authors and Affiliations

  1. Department of Nephrology, Catholic University Leuven, KU Leuven, Belgium

    L. Viaene, K. Claes & P. Evenepoel

  2. Laboratory of Pathophysiology, University of Antwerp, Antwerp, Belgium

    G. J. Behets & P. C. D’Haese

  3. Department of Radiology, University Hospitals Leuven, KU Leuven, Belgium

    S. Heye

  4. Department of Abdominal Transplant Surgery, University Hospitals Leuven, KU Leuven, Belgium

    D. Monbaliu & J. Pirenne

  5. Dienst nefrologie, Universitair Ziekenhuis Gasthuisberg, Herestraat 49, B-3000, Leuven, Belgium

    P. Evenepoel

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  1. L. Viaene
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Correspondence to P. Evenepoel.

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Viaene, L., Behets, G.J., Heye, S. et al. Inflammation and the bone-vascular axis in end-stage renal disease. Osteoporos Int 27, 489–497 (2016). https://doi.org/10.1007/s00198-015-3233-8

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  • DOI: https://doi.org/10.1007/s00198-015-3233-8

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