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Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes

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Abstract

Over the last decade, it has become increasingly clear that the cardiovascular and renal systems are interdependent. Primary disorders of either system have been shown to disturb the other system. As a result, a class of cardiorenal syndromes (CRS) has been identified wherein a vicious cycle is established as an acute/chronic dysfunction of either the kidney or the heart exacerbates the loss of function in the other organ. Progressive loss of kidney function observed in patients with CRS (mostly types 2 and 4) leads to reduced production of calcitriol (active vitamin D) and an imbalance in calcium and phosphorus levels, which are correlated with increased rates of cardiovascular events and mortality. In addition, hypocalcemia can lead to prolonged and excessive secretion of parathyroid hormone (PTH), eventually leading to development of secondary hyperparathyroidism. Therefore, based on this important mechanism of organ damage, one of the major goals of therapy for patients with CRS is to restore regulatory control of PTH. Although administration of calcitriol increases serum calcium levels and reduces PTH levels, it is also associated with elevated serum levels of calcium–phosphorus product. Therefore, compounds that selectively activate vitamin D receptors, potentially reducing calcium × phosphate toxicity, are likely to enhance cardiorenal protection and provide significant clinical benefit.

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References

  1. Ronco C, McCullough PA, Anker SD, Anand I, Aspromonte N, Bagshaw SM, Bellomo R, Berl T, Bobek I, Cruz DN, Daliento L, Davenport A, Haapio M, Hillege H, House AA, Katz N, Maisel A, Mankad S, Zanco P, Mebazaa A, Palazzuoli A, Ronco F, Shaw A, Sheinfeld G, Soni S, Vescovo G, Zamperetti N, Ponikowski P (2010) Acute dialysis quality initiative (ADQI) consensus group. Cardio-renal syndromes: report from the consensus conference of the acute dialysis quality initiative. Eur Heart J 31:703–711

    Google Scholar 

  2. Berl T, Henrich W (2006) Kidney-heart interactions: epidemiology, pathogenesis, and treatment. Clin J Am Soc Nephrol 1:8–18

    Article  PubMed  CAS  Google Scholar 

  3. Herzog CA (2002) Dismal long-term survival of dialysis patients after acute myocardial infarction: can we alter the outcome? Nephrol Dial Transplant 17:7–10

    Article  PubMed  Google Scholar 

  4. Bongartz LG, Cramer MJ, Doevendans PA, Joles JA, Braam B (2005) The severe cardiorenal syndrome: ‘Guyton revisited’. Eur Heart J 26:11–17

    Article  PubMed  Google Scholar 

  5. US Renal Data System (2004) USRDS 2004 Annual data report: atlas of end-stage renal disease in the United States, National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD

  6. Hage FG, Venkataraman R, Zoghbi GJ, Perry GJ, DeMattos AM, Iskandrian AE (2009) The scope of coronary heart disease in patients with chronic kidney disease. J Am Coll Cardiol 53:2129–2140

    Article  PubMed  Google Scholar 

  7. Thomas R, Kanso A, Sedor JR (2008) Chronic kidney disease and its complications. Prim Care 35:329–44, vii

    Google Scholar 

  8. Ronco C, Haapio M, House AA, Anavekar N, Bellomo R (2008) Cardiorenal syndrome. J Am Coll Cardiol 52:1527–1539

    Article  PubMed  Google Scholar 

  9. McAlister FA, Ezekowitz J, Tonelli M, Armstrong PW (2004) Renal insufficiency and heart failure: prognostic and therapeutic implications from a prospective cohort study. Circulation 109:1004–1009

    Article  PubMed  Google Scholar 

  10. Breidthardt T, Mebazaa A, Mueller CE (2009) Predicting progression in nondiabetic kidney disease: the importance of cardiorenal interactions. Kidney Int 75:253–255

    Article  PubMed  CAS  Google Scholar 

  11. Ronco C, Chionh C-Y, Haapio M, Anavekar NS, House A, Bellomo R (2009) The cardiorenal syndrome. Blood Purif 27:114–126

    Article  PubMed  Google Scholar 

  12. Ronco C, Cruz DN, Ronco F (2009) Cardiorenal syndromes. Curr Opin Crit Care 15:384–391

    Article  PubMed  Google Scholar 

  13. Geisberg C, Butler J (2006) Addressing the challenges of cardiorenal syndrome. Cleve Clin J Med 73:485–491

    Article  PubMed  Google Scholar 

  14. Bover J, Farré N, Andrés E, Canal C, Olaya MT, Alonso M, Quílez B, Ballarín J (2009) Update on the treatment of chronic kidney disease-mineral and bone disorder. J Ren Care 35(Suppl. 1):19–27

    Article  PubMed  Google Scholar 

  15. Smith KR, Smelt SC (2009) Consequences of chronic kidney disease—mineral and bone disorder: a progressive disease. Nephrol Nurs J 36:49–55

    PubMed  Google Scholar 

  16. Vitamin D (2008) Altern Med Rev 13:153–164

    Google Scholar 

  17. Ketteler M, Biggar PH (2009) As nature did not predict dialysis—what we can learn from FGF23 in end-stage renal disease? Nephrol Dial Transplant 24:2618–2620

    Article  PubMed  Google Scholar 

  18. Isakova T, Gutiérrez OM, Wolf M (2009) A blueprint for randomized trials targeting phosphorus metabolism in chronic kidney disease. Kidney Int 76:705–716

    Article  PubMed  CAS  Google Scholar 

  19. Hruska KA, Mathew S, Lund R, Qiu P, Pratt R (2008) Hyperphosphatemia of chronic kidney disease. Kidney Int 74:148–157

    Article  PubMed  CAS  Google Scholar 

  20. Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL (2007) Prevalence of abnormal serum vitamin D PTH, calcium, and phosphorus in patients with chronic kidney disease: results of the study to evaluate early kidney disease. Kidney Int 71:31–38

    Article  PubMed  CAS  Google Scholar 

  21. Alsafwah S, LaGuardia SP, Arroyo M, Dockery BK, Bhattacharya SK, Ahokas RA, Newman KP (2007) Congestive heart failure is a systemic illness: a role for minerals and micronutrients. Clin Med Res 5:238–243

    Article  PubMed  CAS  Google Scholar 

  22. Brown AJ, Dusso AS, Slatopolsky E (2002) Vitamin D analogues for secondary hyperparathyroidism. Nephrol Dial Transplant 17(Suppl. 10):10–19

    Article  PubMed  CAS  Google Scholar 

  23. Locatelli F, Cannata-Andía JB, Drüeke TB, Hörl WH, Fouque D, Heimburger O, Ritz E (2002) Management of disturbances of calcium and phosphate metabolism in chronic renal insufficiency, with emphasis on the control of hyperphosphataemia. Nephrol Dial Transplant 17:723–731

    Article  PubMed  CAS  Google Scholar 

  24. Joy MS, Karagiannis PC, Peyerl FW (2007) Outcomes of secondary hyperparathyroidism in chronic kidney disease and the direct costs of treatment. J Manag Care Pharm 13:397–411

    PubMed  Google Scholar 

  25. Slinin Y, Foley RN, Collins AJ (2005) Calcium, phosphorus, parathyroid hormone, and cardiovascular disease in hemodialysis patients: the USRDS waves 1, 3, and 4 study. J Am Soc Nephrol 16:1788–1793

    Article  PubMed  CAS  Google Scholar 

  26. Moe S, Drüeke 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  PubMed  CAS  Google Scholar 

  27. Rix M, Andreassen H, Eskildsen P, Langdahl B, Olgaard K (1999) Bone mineral density and biochemical markers of bone turnover in patients with predialysis chronic renal failure. Kidney Int 56:1084–1093

    Article  PubMed  CAS  Google Scholar 

  28. Nickolas TL, McMahon DJ, Shane E (2006) Relationship between moderate to severe kidney disease and hip fracture in the United States. J Am Soc Nephrol 17:3223–3232

    Article  PubMed  Google Scholar 

  29. Mittalhenkle A, Gillen DL, Stehman-Breen CO (2004) Increased risk of mortality associated with hip fracture in the dialysis population. Am J Kidney Dis 44:672–679

    PubMed  Google Scholar 

  30. Kaneko TM, Foley RN, Gilbertson DT, Collins AJ (2007) Clinical epidemiology of long-bone fractures in patients receiving hemodialysis. Clin Orthop Relat Res 457:188–193

    PubMed  Google Scholar 

  31. Block GA, Spiegel DM, Ehrlich J, Mehta R, Lindbergh J, Dreisbach A, Raggi P (2005) Effects of sevelamer and calcium on coronary artery calcification in patients new to hemodialysis. Kidney Int 68:1815–1824

    Article  PubMed  CAS  Google Scholar 

  32. Brancaccio D, Tetta C, Gallieni M, Panichi V (2002) Inflammation, CRP, calcium overload and a high calcium-phosphate product: a ‘liaison dangereuse’. Nephrol Dial Transplant 17:201–203

    Article  PubMed  Google Scholar 

  33. Kerr DNS (1997) Hypercalcemia and metastatic calcification. Cardiovasc Res 36:293–297

    Article  PubMed  CAS  Google Scholar 

  34. London GM, Guérin AP, Marchais SJ, Métivier F, Pannier B, Adda H (2003) Arterial media calcification in end-stage renal disease: impact on all-cause and cardiovascular mortality. Nephrol Dial Transplant 18:1731–1740

    Article  PubMed  Google Scholar 

  35. Cozzolino M, Mazzaferro S, Pugliese F, Brancaccio D (2008) Vascular calcification and uremia: what do we know? Am J Nephrol 28:339–346

    Article  PubMed  Google Scholar 

  36. Jono S, McKee MD, Murry CE, Shioi A, Nishizawa Y, Mori K, Morii H, Giachelli CM (2000) Phosphate regulation of vascular smooth muscle cell calcification. Circ Res 87:E10–E17

    PubMed  CAS  Google Scholar 

  37. Snijder MB, Lips P, Seidell JC, Visser M, Deeg DJ et al (2007) Vitamin D status and parathyroid hormone levels in relation to blood pressure: a population-based study in older men and women. J Intern Med 261:558–565

    Article  PubMed  CAS  Google Scholar 

  38. Zhao G, Ford ES, Li C (2010) Associations of serum concentrations of 25-hydroxyvitamin D and parathyroid hormone with surrogate markers of insulin resistance among US. Adults without physician-diagnosed diabetes: NHANES, 2003–2006. Diabetes Care 33:344–347

    Article  PubMed  CAS  Google Scholar 

  39. Fraser A, Williams D, Lawlor DA (2010) Associations of serum 25-hydroxyvitamin D, parathyroid hormone and calcium with cardiovascular risk factors: analysis of 3 NHANES cycles (2001–2006). PLoS One 5(11):e13882

    Google Scholar 

  40. Kochupillai N (2008) The physiology of vitamin D: current concepts. Indian J Med Res 127:256–262

    PubMed  CAS  Google Scholar 

  41. Nagpal S, Na S, Rathnachalam R (2005) Noncalcemic actions of vitamin D receptor ligands. Endocr Rev 26:662–687

    Article  PubMed  CAS  Google Scholar 

  42. Tian J, Liu Y, Williams LA, de Zeeuw D (2007) Potential role of active vitamin D in retarding the progression of chronic kidney disease. Nephrol Dial Transplant 22:321–328

    Article  PubMed  Google Scholar 

  43. Dusso A, Arcidiacono MV, Yang J, Tokumoto M (2010) Vitamin D inhibition of TACE and prevention of renal osteodystrophy and cardiovascular mortality. J Steroid Biochem Mol Biol 121(1–2):193–198

    Article  PubMed  CAS  Google Scholar 

  44. Tishkoff DX, Nibbelink KA, Holmberg KH, Dandu L, Simpson RU (2008) Functional vitamin D receptor (VDR) in the t-tubules of cardiac myocytes: VDR knockout cardiomyocyte contractility. Endocrinology 149:558–564

    Article  PubMed  CAS  Google Scholar 

  45. Li YC, Kong J, Wei M, Chen ZF, Liu SQ, Cao LP (2002) 1, 25-Dihydroxyvitamin D(3) is a negative endocrine regulator of the renin-angiotensin system. J Clin Invest 110:229–238

    PubMed  CAS  Google Scholar 

  46. Staeva-Vieira TP, Freedman LP (2002) 1, 25-Dihydroxyvitamin D3 inhibits IFN-gamma and IL-4 levels during in vitro polarization of primary murine CD4 + T cells. J Immunol 168:1181–1189

    PubMed  CAS  Google Scholar 

  47. Pfeifer M, Begerow B, Minne HW, Nachtigall D, Hansen C (2001) Effects of a short-term vitamin D(3) and calcium supplementation on blood pressure and parathyroid hormone levels in elderly women. J Clin Endocrinol Metab 86:1633–1637

    Article  PubMed  CAS  Google Scholar 

  48. Artaza JN, Mehrotra R, Norris KC (2009) Vitamin D and the cardiovascular system. Clin J Am Soc Nephrol 4:1515–1522

    Article  PubMed  CAS  Google Scholar 

  49. Andress D (2007) Nonclassical aspects of differential vitamin D receptor activation: implications for survival in patients with chronic kidney disease. Drugs 67:1999–2012

    Article  PubMed  CAS  Google Scholar 

  50. Zittermann A, Schleithoff SS, Gotting C, Dronow O, Fuchs U, Kuhn J, Kleesiek K, Tenderich G, Koerfer R (2008) Poor outcome in end-stage heart failure patients with low circulating calcitriol levels. Eur J Heart Fail 10:321–332

    Article  PubMed  CAS  Google Scholar 

  51. Giovannucci E, Liu Y, Hollis BW, Rimm EB (2008) 25-hydroxyvitamin D and risk of myocardial infarction in men: a prospective study. Arch Intern Med 168:1174–1180

    Article  PubMed  CAS  Google Scholar 

  52. Liu LCY et al (2010) Prognostic value of vitamin D in heart failure. P 5675, ESC 2010 Congress. Eur Heart J 31:1054

    Article  Google Scholar 

  53. Mancuso P, Rahman A, Hershey SD, Dandu L, Nibbelink KA, Simpson RU (2008) 1, 25-Dihydroxyvitamin-D3 treatment reduces cardiac hypertrophy and left ventricular diameter in spontaneously hypertensive heart failure-prone (cp/+) rats independent of changes in serum leptin. J Cardiovasc Pharmacol 51(6):559–564

    Article  PubMed  CAS  Google Scholar 

  54. Bodyak N, Ayus JC, Achinger S, Shivalingappa V, Ke Q, Chen YS, Rigor DL, Stillman I, Tamez H, Kroeger PE, Wu-Wong RR, Karumanchi SA, Thadhani R, Kang PM (2007) Activated vitamin D attenuates left ventricular abnormalities induced by dietary sodium in Dahl salt-sensitive animals. Proc Natl Acad Sci USA 104:16810–16815

    Article  PubMed  CAS  Google Scholar 

  55. Cozzolino M, Brandenburg V (2009) Paricalcitol and outcome: a manual on how a vitamin D receptor activator (VDRA) can help us to get down the “U”. Clin Nephrol 71:593–601

    PubMed  CAS  Google Scholar 

  56. Nemerovski CW, Dorsch MP, Simpson RU, Bone HG, Aaronson KD, Bleske BE (2009) Vitamin D and cardiovascular disease. Pharmacotherapy 29:691–708

    Article  PubMed  CAS  Google Scholar 

  57. Watson KE, Abrolat ML, Malone LL, Hoeg JM, Doherty T, Detrano R, Demer LL (1997) Active serum vitamin D levels are inversely correlated with coronary calcification. Circulation 96:1755–1760

    PubMed  CAS  Google Scholar 

  58. Wang TJ, Pencina MJ, Booth SL, Jacques PF, Ingelsson E, Lanier K, Benjamin EJ, D’Agostino RB, Wolf M, Vasan RS (2008) Vitamin D deficiency and risk of cardiovascular disease. Circulation 117:503–511

    Article  PubMed  CAS  Google Scholar 

  59. Melamed ML, Muntner P, Michos ED, Uribarri J, Weber C, Sharma J, Raggi P (2008) Serum 25-hydroxyvitamin D levels and the prevalence of peripheral arterial disease: results from NHANES 2001 to 2004. Arterioscler Thromb Vasc Biol 28:1179–1185

    Article  PubMed  CAS  Google Scholar 

  60. Malluche HH, Mawad H, Koszewski NJ (2002) Update on vitamin D and its newer analogues: actions and rationale for treatment in chronic renal failure. Kidney Int 62:367–374

    Article  PubMed  CAS  Google Scholar 

  61. Schleithoff SS, Zittermann A, Tenderich G, Berthold HK, Stehle P, Koerfer R (2006) Vitamin D supplementation improves cytokine profiles in patients with congestive heart failure: a double-blind, randomized, placebo-controlled trial. Am J Clin Nutr 83:754–759

    PubMed  CAS  Google Scholar 

  62. Baker LR, Abrams L, Roe CJ, Faugere MC, Fanti P, Subayti Y, Malluche HH (1989) 1, 25(OH)2D3 administration in moderate renal failure: a prospective double-blind trial. Kidney Int 35:661–669

    Article  PubMed  CAS  Google Scholar 

  63. Wolf M, Thadhani R (2007) Vitamin D in patients with renal failure: a summary of observational mortality studies and steps moving forward. J Steroid Biochem Mol Biol 103:487–490

    Article  PubMed  CAS  Google Scholar 

  64. Kooienga L, Fried L, Scragg R, Kendrick J, Smits G, Chonchol M (2009) The effect of combined calcium and vitamin D3 supplementation on serum intact parathyroid hormone in moderate CKD. Am J Kidney Dis 53(3):408–416

    Article  PubMed  CAS  Google Scholar 

  65. Matias PJ, Jorge C, Ferreira C, Borges M, Aires I, Amaral T, Gil C, Cortez J, Ferreira A (2010) Cholecalciferol supplementation in hemodialysis patients: effects on mineral metabolism, inflammation, and cardiac dimension parameters. Clin J Am Soc Nephrol 5(5):905–911

    Article  PubMed  CAS  Google Scholar 

  66. Jean G, Souberbielle JC, Chazot C (2009) Monthly cholecalciferol administration in haemodialysis patients: a simple and efficient strategy for vitamin D supplementation. Nephrol Dial Transplant 24(12):3799–3805

    Article  PubMed  CAS  Google Scholar 

  67. Marchais SJ, Metivier F, Guerin AP, London GM (1999) Association of hyperphosphataemia with haemodynamic disturbances in end-stage renal disease. Nephrol Dial Transplant 14:2178–2183

    Article  PubMed  CAS  Google Scholar 

  68. Sprague SM, Llach F, Amdahl M, Taccetta C, Batlle D (2003) Paricalcitol versus calcitriol in the treatment of secondary hyperparathyroidism. Kidney Int 63:1483–1490

    Article  PubMed  CAS  Google Scholar 

  69. de Zeeuw D, Agarwal R, Amdahl M, Audhya P, Coyne D, Garimella T, Parving HH, Pritchett Y, Remuzzi G, Ritz E, Andress D (2010) Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 376(9752):1543–1551

    Google Scholar 

  70. Teng M, Wolf M, Lowrie E, Ofsthun N, Lazarus JM, Thadhani R (2003) Survival of patients undergoing hemodialysis with paricalcitol or calcitriol therapy. N Engl J Med 349:446–456

    Article  PubMed  CAS  Google Scholar 

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Ronco, C., Cozzolino, M. Mineral metabolism abnormalities and vitamin D receptor activation in cardiorenal syndromes. Heart Fail Rev 17, 211–220 (2012). https://doi.org/10.1007/s10741-011-9232-8

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