Pediatric Nephrology

, Volume 25, Issue 4, pp 769–778 | Cite as

Cardiovascular risk in chronic kidney disease (CKD): the CKD-mineral bone disorder (CKD-MBD)

  • Keith A. Hruska
  • Eric T. Choi
  • Imran Memon
  • T. Keefe Davis
  • Suresh Mathew


Recent advances in our understanding of the excess mortality of chronic kidney disease (CKD) due to cardiovascular complications, obtained through observational studies, demonstrate that vascular calcification and hyperphosphatemia are major cardiovascular risk factors. Mechanistic studies demonstrate that these two risk factors are related and that hyperphosphatemia directly stimulates vascular calcification. The role of hyperphosphatemia in stimulating vascular calcification in CKD is associated with a block to the skeletal reservoir function in phosphate balance due to excess bone resorption. This has led to the realization that renal osteodystrophy is linked to vascular calcification by disordered mineral homeostasis (phosphate) and that a multiorgan system fails in CKD, leading to cardiovascular mortality. In children with renal disease, the multiorgan system fails, just as in adults, but the outcomes have been less well studied, and perceptions of differences from adults are possibly incorrect. Vascular calcification and cardiovascular mortality are less prevalent among pediatric patients, but they are present. However, CKD-induced vascular disease causes stiffness of the arterial tree causing, in turn, systolic hypertension and left ventricular hypertrophy as early manifestations of the same pathology in the adult. Because of the role of the skeleton in these outcomes, renal osteodystrophy has been renamed as the CKD mineral bone disorder (CKD-MBD). This review, which focuses on the pediatric patient population, describes our current state of knowledge with regards to the pathophysiology of the CKD-MBD, including the new discoveries related to early stages of CKD. As a new necessity, cardiovascular function issues are incorporated into the CKD-MBD, and new advances in our knowledge of this critical component of the disorder will lead to improved outcomes in CKD.


Cardiovascular disease Fetuin-A Matrix Gla protein Phosphorus Vascular calcifications Vascular smooth muscle Vitamin D 



The writing of this manuscript was supported by NIH grants DK070790, and AR41677, and research grants from Shire, Genzyme, Fresenius and Abbott.


  1. 1.
    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 69:1945–1953CrossRefPubMedGoogle Scholar
  2. 2.
    Stevens LA, Djurdjev O, Cardew S, Cameron EC, Levin A (2004) Calcium, phosphate, and parathyroid hormone levels in combination and as a function of dialysis duration predict mortality: Evidence for the complexity of the association between mineral metabolism and outcomes. J Am Soc Nephrol 15:770–779CrossRefPubMedGoogle Scholar
  3. 3.
    Block GA, Hulbert-Shearon TE, Levin NW, Port FK (1998) Association of serum phosphorus and calcium X phosphate product with mortality risk in chronic hemodialysis patients: a national study. Am J Kidney Dis 31:607–617CrossRefPubMedGoogle Scholar
  4. 4.
    Davies MR, Lund RJ, Mathew S, Hruska KA (2005) Low turnover osteodystrophy and vascular calcification are amenable to skeletal anabolism in an animal model of chronic kidney disease and the metabolic syndrome. J Am Soc Nephrol 16:917–928CrossRefPubMedGoogle Scholar
  5. 5.
    Lund RJ, Davies MR, Brown AJ, Hruska KA (2004) Successful treatment of an adynamic bone disorder with bone morphogenetic protein-7 in a renal ablation model. J Am Soc Nephrol 15:359–369CrossRefPubMedGoogle Scholar
  6. 6.
    Foley RN, Parfrey PS, Sarnak MJ (1998) Clinical epidemiology of cardiovascular disease in chronic renal disease. Am J Kidney Dis 32:S112–S119CrossRefPubMedGoogle Scholar
  7. 7.
    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 16:1788–1793CrossRefPubMedGoogle Scholar
  8. 8.
    Shlipak MG, Sarnak MJ, Katz R, Fried LF, Seliger SL, Newman AB, Siscovick DS, Stehman-Breen C (2005) Cystatin C and the risk of death and cardiovascular events among elderly persons. N Engl J Med 352:2049–2060CrossRefPubMedGoogle Scholar
  9. 9.
    Foley RN, Collins AJ, Herzog CA, Ishani A, Kalra PA (2009) Serum phosphorus levels associate with coronary atherosclerosis in young adults. J Am Soc Nephrol 20:397–404CrossRefPubMedGoogle Scholar
  10. 10.
    Malluche HH, Faugere MC (1990) Renal bone disease 1990: challenge for nephrologists. Kidney Int 38:193–211CrossRefPubMedGoogle Scholar
  11. 11.
    Bacchetta J, Boutroy S, Vilayphiou N, Juillard L, Guebre-Egziabher F, Rognant N, Sornay-Rendu E, Szulc P, Laville M, Delmas PD, Fouque D, Chapurlat R (2009) Early impairment of trabecular microarchitecture assessed with HR-pQCT in patients with stage II–IV chronic kidney disease. J Bone Miner Res. doi: 0.1359/jbmr.090831 PubMedGoogle Scholar
  12. 12.
    Pereira RC, Juppner H, Azucena-Serrano CE, Yadin O, Salusky IB, Wesseling-Perry K (2009) Patterns of FGF-23, DMP1 and MEPE expression in patients with chronic kidney disease. Bone. doi: 10.1016/j.bone.2009.08.008 PubMedGoogle Scholar
  13. 13.
    Kokubo T, Ishikawa N, Uchida H, Chasnoff SE, Xie X, Mathew S, Hruska KA, Choi ET (2009) CKD accelerates development of neointimal hyperplasia in arteriovenous fistulas. J Am Soc Nephrol 20:1236–1245CrossRefPubMedGoogle Scholar
  14. 14.
    Fang Y, Zhang Y, Mathew S, Futhey J, Lund RJ, Hruska KA (2009) Early chronic kidney disease (CKD) stimulates vascular calcification (VD) and decreased bone formation rates prior to positive phosphate balance (abstract). J Am Soc Nephrol 20:36 A (abstract TH - FC 153)Google Scholar
  15. 15.
    Quarles LD (2003) FGF23, PHEX, and MEPE regulation of phosphate homeostasis and skeletal mineralization. Am J Physiol Endocrinol Metab 285:1–9Google Scholar
  16. 16.
    Shimada T, Kakitani M, Yamazaki Y, Hasegawa H, Takeuchi Y, Fujita T, Fukumoto S, Tomizuka K, Yamashita T (2004) Targeted ablation of FGF23 demonstrates an essential physiological role of FGF23 in phosphate and vitamin D metabolism. J Clin Invest 113:561–568PubMedGoogle Scholar
  17. 17.
    Lee NK, Sowa H, Hinoi E, Ferron M, Ahn JD, Confavreux C, Dacquin R, Mee PJ, McKee MD, Jung DY, Zhang Z, Kim JK, Mauvais-Jarvis F, Ducy P, Karsenty G (2007) Endocrine regulation of energy metabolism by the skeleton. Cell 130:456–469CrossRefPubMedGoogle Scholar
  18. 18.
    Hruska KA, Mathew S (2008) The chronic kidney disease mineral bone disorder (CKD-MBD). In: Rosen CJ (ed) Primer on the metabolic bone diseases and disorders of mineral metabolism. Am Soc Bone Miner Res, Washington D.C, pp 343–349Google Scholar
  19. 19.
    Calvi LM, Adams GB, Weibrecht KW, Weber JM, Olson DP, Knight MC, Martin RP, Schipani E, Divieti P, Bringhurst FR, Milner LA, Kronenberg HM, Scadden DT (2003) Osteoblastic cells regulate the haematopoietic stem cell niche. Nature 425:841–846CrossRefPubMedGoogle Scholar
  20. 20.
    Zhang J, Niu C, Ye L, Huang H, He XI, Tong W-G, Ross J, Haug J, Johnson T, Feng JQ, Harris S, Wiedemann LM, Mishina Y, Li L (2003) Identification of the haematopoietic stem cell niche and control of the niche size. Nature 425:836–841CrossRefPubMedGoogle Scholar
  21. 21.
    Malluche HH, Ritz E, Lange HP (1976) Bone histology in incipient and advanced renal failure. Kidney Int 9:355–362CrossRefPubMedGoogle Scholar
  22. 22.
    Larsson T, Nisbeth U, Ljunggren O, Juppner H, Jonsson KB (2003) Circulating concentration of FGF-23 increases as renal function declines in patients with chronic kidney disease, but does not change in response to variation in phosphate intake in healthy volunteers. Kidney Int 64:2272–2279CrossRefPubMedGoogle Scholar
  23. 23.
    Craver L, Marco MP, Martinez I, Rue M, Borras M, Martin ML, Sarro F, Valdivielso JM, Fernandez E (2007) Mineral metabolism parameters throughout chronic kidney disease stages 1–5–achievement of K/DOQI target ranges. Nephrol Dial Transplant 22:1171–1176CrossRefPubMedGoogle Scholar
  24. 24.
    Levin A, Bakris GL, Molitch M, Smulders M, Tian J, Williams LA, Andress DL (2006) 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 71:31–38CrossRefPubMedGoogle Scholar
  25. 25.
    Liaw L, Skinner MP, Raines EW, Ross R, Cheresh DA, Schwartz SM, Giachelli CM (1995) The adhesive and migratory effects of osteopontin are mediated via distinct cell surface integrins. Role of αvβ3 in smooth muscle cell migration to osteopontin in vitro. J Clin Invest 95:713–724CrossRefPubMedGoogle Scholar
  26. 26.
    Chen NX, O’Neill KD, Duan D, Moe SM (2002) Phosphorus and uremic serum up-regulate osteopontin expression in vascular smooth muscle cells. Kidney Int 62:1724–1731CrossRefPubMedGoogle Scholar
  27. 27.
    Li X, Yang HY, Giachelli CM (2008) BMP-2 promotes phosphate uptake, phenotypic modulation, and calcification of human vascular smooth muscle cells. Atherosclerosis 199:271–277CrossRefPubMedGoogle Scholar
  28. 28.
    The ADHR consortium (Group 1: White KE, Evans WE, O’Riordan JLH, Speer MC, Econs JJ, Groups 2: Lorenz-Depiereux B, Grabowski M, Meitinger T, Strom TM) (2000) Autosomal dominant hypophosphatemic rickets is associated with mutations in FGF23. Nat Genet 26:345–348Google Scholar
  29. 29.
    White KE, Jonsson KB, Carn G, Hampson G, Spector TD, Mannstadt M, Lorenz-Depiereux B, Miyauchi A, Yang IM, Ljunggren O, Meitinger T, Strom TM, Juppner H, Econs MJ (2001) The autosomal dominant hypophosphatemic rickets (ADHR) gene is a secreted polypeptide overexpressed by tumors that cause phosphate wasting. J Clin Endocrinol Metab 86:497–500CrossRefPubMedGoogle Scholar
  30. 30.
    Shimada T, Muto T, Urakawa I, Yoneya T, Yamazaki Y, Okawa K, Takeuchi Y, Fujita T, Fukumoto S, Yamashita T (2002) Mutant FGF-23 responsible for autosomal dominant hypophosphatemic rickets is resistant to proteolytic cleavage and causes hypophosphatemia in vivo. Endocrinology 143:3179–3182CrossRefPubMedGoogle Scholar
  31. 31.
    Goodman WG, Quarles LD (2007) Development and progression of secondary hyperparathyroidism in chronic kidney disease: Lessons from molecular genetics. Kidney Int 74:276–288CrossRefPubMedGoogle Scholar
  32. 32.
    Naveh-Many T, Marx R, Keshet E, Pike JW, Silver J (1990) Regulation of 1, 25-dihydroxyvitamin D3 receptor gene expression by 1, 25-dihydroxyvitamin D3 in the parathyroid in vivo. J Clin Invest 86:1968–1975CrossRefPubMedGoogle Scholar
  33. 33.
    Silver J, Russell J, Sherwood LM (1985) Regulation by vitamin D metabolites of messenger ribonucleic acid for preproparathyroid hormone in isolated bovine parathyroid cells. Proc Natl Acad Sci USA 82:4270–4273CrossRefPubMedGoogle Scholar
  34. 34.
    Wu-Wong JR, Noonan W, Ma J, Dixon D, Nakane M, Bolin AL, Koch KA, Postl S, Morgan SJ, Reinhart GA (2006) Role of phosphorus and vitamin D analogs in the pathogenesis of vascular calcification. J Pharmacol Exp Ther 318:90–98CrossRefPubMedGoogle Scholar
  35. 35.
    Mizobuchi M, Finch JL, Martin DR, Slatopolsky E (2007) Differential effects of vitamin D receptor activators on vascular calcification in uremic rats. Kidney Int 72:709–715CrossRefPubMedGoogle Scholar
  36. 36.
    Mathew S, Lund RJ, Chaudhary LR, Geurs T, Hruska KA (2008) Vitamin D receptor activators can protect against vascular calcification. J Am Soc Nephrol 19:1509–1519CrossRefPubMedGoogle Scholar
  37. 37.
    Mathew S, Strebeck F, Hruska KA (2007) Vascular calcification (VC) protective actions of doxercalciferol in CKD. In: Gendreau MA, Mangili A, Zavod A (eds) Vitamin D therapy in dialysis patients: impact on survival and vascular calcification. Millennium CME Institute, HamptonGoogle Scholar
  38. 38.
    Slatopolsky E, Robson AM, Elkan I, Bricker NS (1968) Control of phosphate excretion in uremic man. J Clin Invest 47:1865–1874PubMedCrossRefGoogle Scholar
  39. 39.
    Kurz P, Monier-Faugere M-C, Bognar B, Werner E, Roth P, Vlachojannis J, Malluche HH (1994) Evidence for abnormal calcium homeostasis in patients with adynamic bone disease. Kidney Int 46:855–861CrossRefPubMedGoogle Scholar
  40. 40.
    Moallem E, Kilav R, Silver J, Naveh-Many T (1998) RNA-protein binding and post-transcriptional regulation of parathyroid hormone gene expression by calcium and phosphate. J Biol Chem 273:5253–5259CrossRefPubMedGoogle Scholar
  41. 41.
    Naveh-Many T, Rahamimov R, Livni N, Silver J (1995) Parathyroid cell proliferation in normal and chronic renal failure rats. J Clin Invest 96:1786–1793CrossRefPubMedGoogle Scholar
  42. 42.
    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–e17PubMedGoogle Scholar
  43. 43.
    Li X, Yang HY, Giachelli CM (2006) Role of the sodium-dependent phosphate cotransporter, Pit-1, in vascular smooth muscle cell calcification. Circ Res 98:905–912CrossRefPubMedGoogle Scholar
  44. 44.
    Brown EM, Gamba G, Riccardi D, Lombardi M, Butters R, Kifor O, Sun A, Hediger MA, Lytton J, Hebert SC (1993) Cloning and characterization of an extracellular Ca2 + -sensing receptor from bovine parathyroid. Nature 366:575–580CrossRefPubMedGoogle Scholar
  45. 45.
    Brown EM, Hebert SC (1995) A cloned Ca2+ sensing receptor: a mediator of direct effects of extracellular Ca2+ on renal function? J Am Soc Nephrol 6:1530–1540PubMedGoogle Scholar
  46. 46.
    Langub MC Jr, Koszewski NJ, Turner HV, Monier-Faugere MC, Geng Z, Malluche HH (1996) Bone resorption and mRNA expression of IL-6 and IL-6 receptor in patients with renal osteodystrophy. Kidney Int 50:515–520CrossRefPubMedGoogle Scholar
  47. 47.
    Stenvinkel P, Barany P, Heimburger O, Pecoits-Filho R, Lindholm B (2002) Mortality, malnutrition, and atherosclerosis in ESRD: What is the role of interleukin-6? Kidney Int 61:S103–S108CrossRefGoogle Scholar
  48. 48.
    Simmons EM, Himmelfarb J, Sezer MT, Chertow GM, Mehta RL, Paganini EP, Soroko S, Freedman S, Becker K, Spratt D, Shyr Y, Ikizler TA (2004) Plasma cytokine levels predict mortality in patients with acute renal failure. Kidney Int 65:1357–1365CrossRefPubMedGoogle Scholar
  49. 49.
    Pecoits-Filho R, Barany P, Lindholm B, Heimburger O, Stenvinkel P (2002) Interleukin-6 is an independent predictor of mortality in patients starting dialysis treatment. Nephrol Dial Transplant 17:1684–1688CrossRefPubMedGoogle Scholar
  50. 50.
    Hruska KA (1998) Growth factors and cytokines in renal osteodystrophy. In: Bushinsky DA (ed) Renal osteodystrophy. Lippincott-Raven, Philadelphia, pp 221–261Google Scholar
  51. 51.
    Bushinsky DA (1995) The contribution of acidosis to renal osteodystrophy. Kidney Int 47:1816–1832CrossRefPubMedGoogle Scholar
  52. 52.
    Krieger NS, Sessler NE, Bushinsky DA (1992) Acidosis inhibits osteoblastic and stimulates osteoclastic activity in vitro. Am J Physiol 262:F442–F448PubMedGoogle Scholar
  53. 53.
    Alem AM, Sherrard DJ, Gillen DL, Weiss NS, Beresford SA, Heckbert SR, Wong C, Stehman-Breen C (2000) Increased risk of hip fracture among patients with end-stage renal disease. Kidney Int 58:396–399CrossRefPubMedGoogle Scholar
  54. 54.
    Cunningham J, Sprague S, 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 43:566–571CrossRefPubMedGoogle Scholar
  55. 55.
    Stehman-Breen C (2004) Osteoporosis and chronic kidney disease. Semin Nephrol 24:78–81CrossRefPubMedGoogle Scholar
  56. 56.
    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 56:1084–1093CrossRefPubMedGoogle Scholar
  57. 57.
    Bonyadi M, Waldman SD, Liu D, Aubin JE, Grynpas MD, Stanford WL (2003) Mesenchymal progenitor self-renewal deficiency leads to age-dependent osteoporosis in Sca-1/Ly-6A null mice. Proc Natl Acad Sci USA 100:5840–5845CrossRefPubMedGoogle Scholar
  58. 58.
    Stehman-Breen C (2001) Bone mineral density measurements in dialysis patients. Semin Dial 14:228–229CrossRefPubMedGoogle Scholar
  59. 59.
    Stehman-Breen C, Sherrard D, Walker A, Sadler R, Alem A, Lindberg J (1999) Racial differences in bone mineral density and bone loss among end-stage renal disease patients. Am J Kidney Dis 33:941–946CrossRefPubMedGoogle Scholar
  60. 60.
    Coco M, Rush H (2000) Increased incidence of hip fractures in dialysis patients with low serum parathyroid hormone. Am J Kidney Dis 36:1115–1121CrossRefPubMedGoogle Scholar
  61. 61.
    Hruska KA, Saab G, Mathew S, Lund R (2007) Renal osteodystrophy, phosphate homeostasis, and vascular calcification. Semin Dial 20:309–315CrossRefPubMedGoogle Scholar
  62. 62.
    Khosla S, Burr D, Cauley J, Dempster DW, Ebeling PR, Felsenberg D, Gagel RF, Gilsanz V, Guise T, Koka S, McCauley LK, McGowan J, McKee MD, Mohla S, Pendrys DG, Raisz LG, Ruggiero SL (2007) Bisphosphonate-associated osteonecrosis of the jaw: report of a task force of the American society for bone and mineral research. J Bone Miner Res 22:1479–1491CrossRefPubMedGoogle Scholar
  63. 63.
    Ichikawa S, Imel EA, Kreiter ML, Yu X, Mackenzie DS, Sorenson AH, Goetz R, Mohammadi M, White KE, Econs MJ (2007) A homozygous missense mutation in human KLOTHO causes severe tumoral calcinosis. J Clin Invest 117:2684–2691CrossRefPubMedGoogle Scholar
  64. 64.
    Ichikawa S, Lyles KW, Econs MJ (2005) A novel GALNT3 mutation in a pseudoautosomal dominant form of tumoral calcinosis: Evidence that the disorder is autosomal recessive. J Clin Endocrinol Metab 90:2420–2423CrossRefPubMedGoogle Scholar
  65. 65.
    Benet-Pages A, Orlik P, Strom TM, Lorenz-Depiereux B (2005) An FGF23 missense mutation causes familial tumoral calcinosis with hyperphosphatemia. Hum Mol Genet 14:385–390CrossRefPubMedGoogle Scholar
  66. 66.
    Schiavi SC, Kumar R (2004) The phosphatonin pathway: New insights in phosphate homeostasis. Kidney Int 65:1–14CrossRefPubMedGoogle Scholar
  67. 67.
    Kurosu H, Ogawa Y, Miyoshi M, Yamamoto M, Nandi A, Rosenblatt KP, Baum MG, Schiavi S, Hu MC, Moe OW, Kuro-o M (2006) Regulation of fibroblast growth factor-23 signaling by Klotho. J Biol Chem 281:6120–6123CrossRefPubMedGoogle Scholar

Copyright information

© IPNA 2009

Authors and Affiliations

  • Keith A. Hruska
    • 1
    • 4
  • Eric T. Choi
    • 2
  • Imran Memon
    • 1
  • T. Keefe Davis
    • 1
  • Suresh Mathew
    • 3
  1. 1.Division of Pediatric NephrologyWashington UniversitySt. LouisUSA
  2. 2.Department of SurgeryWashington UniversitySt. LouisUSA
  3. 3.Department of PediatricsWashington UniversitySt. LouisUSA
  4. 4.St. LouisUSA

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