Advances in Clinical and Experimental Medicine

Title abbreviation: Adv Clin Exp Med
5-Year IF – 2.0, IF – 1.9, JCI (2024) – 0.43
Scopus CiteScore – 4.3
Q1 in SJR 2024, SJR score – 0.598, H-index: 49 (SJR)
ICV – 161.00; MNiSW – 70 pts
Initial editorial assessment and first decision within 24 h

ISSN 1899–5276 (print), ISSN 2451-2680 (online)
Periodicity – monthly

Download original text (EN)

Advances in Clinical and Experimental Medicine

2008, vol. 17, nr 2, March-April, p. 227–235

Publication type: review article

Language: English

Vascular Calcification in Chronic Kidney Disease

Kalcyfikacja naczyń w przewlekłej chorobie nerek

Kinga Musiał1,, Danuta Zwolińska1,, Konstancja Fornalczyk1,

1 Department of Pediatric Nephrology, Silesian Piasts University of Medicine in Wrocław, Poland

Abstract

The aim of this review is to present current knowledge of vascular calcification in chronic kidney disease. Recent investigations point mainly at the disturbed balance between factors facilitating and protecting extraosseous mineralization as crucial in the creation of calcification of vessels. Chronic kidney disease is associated with multiple abnormalities potentially accelerating calcification, such as hypercalcemia, hyperphosphatemia, dyslipidemia, and inflammation. Their impact triggers the change of vascular smooth muscle cells into osteoblastor chondrocyte−like cells expressing bone−associated proteins. This differentiation induces the production of apoptotic bodies that become nuclei of mineralization. The decreased capacity of calcification inhibitors, such as fetuin−A, osteoprotegerin, and osteopontin, additionally weakens the protection against excessive mineralization. These disturbances are of paramount importance in CKD patients because of the close connection between pathomorphology and clinical outcome. Both medial and intimal calcification affect the cardiovascular system due to the increased vascular stiffness and calcified atherosclerotic lesions, creating a vast clinical panorama of symptoms from stroke to heart failure. Therefore, clarifying the mechanisms responsible for vascular calcification in CKD patients seems to be a key target for effective future prevention.

Streszczenie

Celem pracy jest przedstawienie aktualnego stanu wiedzy na temat kalcyfikacji naczyń w przewlekłej chorobie nerek (p.ch.n.). Badania ostatnich lat wskazują przede wszystkim na rolę zaburzonej równowagi między czynnikami ułatwiającymi pozakostną mineralizację a chroniącymi przed nią, jako kluczowego czynnika w powstawaniu zwapnień naczyniowych. Przewlekłej chorobie nerek towarzyszy wiele nieprawidłowości potencjalnie przyspieszających proces kalcyfikacji, takich jak: hiperkalcemia, hiperfosfatemia, zaburzenia gospodarki lipidowej lub stan zapalny. Ich wpływ powoduje zmianę komórek mięśni gładkich naczyń w komórki osteoblastoi chondrocytopodobne, z ekspresją białek kostnych na ich powierzchni. To różnicowanie komórek prowadzi do tworzenia ciałek apoptotycznych, stających się jądrami krystalizacji. Zaburzona funkcja inhibitorów krystalizacji, do których należą fetuina−A, osteoprotegeryna i osteopontyna, dodatkowo zmniejsza skuteczność ochrony przeciwko nadmiernej mineralizacji. Powyższe zaburzenia odgrywają zasadniczą rolę u pacjentów z p.ch.n., gdzie obraz patomorfologiczny bezpośrednio implikuje stan kliniczny. Zarówno kalcyfikacja błony wewnętrznej, jak i środkowej naczynia uszkadza układ krążenia, zwiększając sztywność naczyń i wywołując tworzenie zwapnień w obrębie blaszek miażdżycowych, co powoduje występowanie różnych objawów klinicznych – od udaru do niewydolności serca. Wyjaśnienie mechanizmów odpowiedzialnych za kalcyfikację naczyń u pacjentów z p.ch.n. ma więc zasadnicze znaczenie w skutecznym zapobieganiu w przyszłości.

Key words

calcium/phosphate metabolism, vascular smooth muscle cells, fetuin−A, osteopontin, osteoprotegerin

Słowa kluczowe

gospodarka wapniowo−fosforanowa, komórki mięśni gładkich naczyń, fetuina A, osteopontyna, osteoprotegeryna

References (40)

  1. Shrof RC, Shanahan CM: The vascular biology of calcification. Semin Dial 2007, 20, 103–109.
  2. Kerr PG, Guerin AP: Arterial calcification and stiffness in chronic kidney disease. Clin Exp Pharmacol Physiol 2007, 34, 683–687.
  3. Stary HC, Chandler AB, Glagov S, Guyton JR, Insull W Jr, Rosenfeld ME, Schaffer SA, Schwartz CJ, Wagner WD, Wissler RW: A definition of initial, fatty streak, and intermediate lesions of atherosclerosis. A report from the Committee on Vascular Lesions of the Council on Arteriosclerosis, American Heart Association. Arterioscler Thromb 1994, 14, 840–856.
  4. Tsirpanlis G: Is inflammation the link between atherosclerosis and vascular calcification in chronic kidney disease? Blood Purif 2007, 25, 179–182.
  5. London GM, Guerin AP, Marchais SJ, Metivier F, Pannier B, Adda H: Arterial media calcification in end−stage renal disease: impact on all−cause and cardiovascular mortality. Nephrol Dial Transplant 2003, 18, 1731–1740.
  6. Goodman WG, Goldin J, Kuizon BD, Yoon C, Gales B, Sider D, Wang Y, Chung J, Emerick A, Greaser L, Elashoff RM, Salusky IB: Coronary−artery calcification in young adults with end stage renal disease who are undergoing dialysis. N Eng J Med 2000, 342, 1478–1483.
  7. Giachelli CM: Vascular calcification mechanisms. J Am Soc Nephrol 2004, 15, 2959–2964.
  8. Brown MS, Goldstein JL: A receptor−mediated pathway for cholesterol homeostasis. Science 1986, 232, 34–47.
  9. Lam MCW, Tan KCB, Lam KSL: Glycoxidized low−density lipoprotein regulates the expression of scavenger receptors in THP−1 macrophages. Atherosclerosis 2004, 177, 313–320.
  10. Parhami F, Morrow AD, Balucan J, Leitinger N, Watson AD, Tintut Y, Berliner JA, Demer LL: Lipid oxidation products have opposite effects on calcifying vascular cell and bone cell differentiation. A possible explanation for the paradox of arterial calcification in osteoporotic patients. Arterioscler Thromb Vasc Biol 1997, 17, 680–687.
  11. Aiello RJ, Bourassa PAK, Lindsey S, Weng W, Natoli E, Rollins BJ, Milos PM: Monocyte chemoattractant protein−1 accelerates atherosclerosis in apolipoprotein E−deficient mice. Arterioscler Thromb Vasc Biol 1999, 19, 1518–1525.
  12. Parenti A, Bellik L, Brogelli L, Filippi S, Ledda F: Endogenous VEGF−A is responsible for mitogenic effects of MCP−1 on vascular smooth muscle cells. Am J Physiol Heart Circ Physiol 2004, 286, H1978–H1984.
  13. Kihara T, Miyata Y, Furukawa M, Noguchi M, Nishikido M, Koga S, Kanetake H: Predictive value of serum macrophage colony−stimulating factor for development of aortic calcification in haemodialysis patients: a 6 year longitudinal study. Nephrol Dial Transplant 2005, 20, 1647–1652.
  14. Lesnik P, Haskell CA, Charo IF: Decreased atherosclerosis in CX3CR1–/– mice reveals a role for fractalkine in atherogenesis. J Clin Invest 2003, 111, 333–340.
  15. Gerszten RE, Garcia−Zapeda EA, Lim YC, Yoshida M, Ding HA, Gimbrone MA Jr, Luster AD, Luscinskas FW, Rosenzweig A: MCP−1 and IL−8 trigger firm adhesion of monocytes to vascular endothelium under flow conditions. Nature 1999, 398, 718–723.
  16. Tintut Y, Patel J, Parhami F, Demer LL: Tumor necrosis factor−alpha promotes in vitro calcification of vascular cells via the cAMP pathway. Circulation 2000, 102, 2636–2642.
  17. Stompor T, Pasowicz M, Sułowicz W, Dembińska−Kieć A, Janda K, Wójcik K, Tracz W, Zdzienicka A, Klameczek P, Janusz−Grzybowska E: An association between coronary artery calcification score, lipid profile, and selected markers of chronic inflammation in ESRD patients treated with peritoneal dialysis. Am J Kidney Dis 2003, 41, 203–211.
  18. Cyrus T, Witztum JL, Rader DJ, Tangirala R, Fazio S, Linton MF, Funk CD: Disruption of the 12/15−lipoxygenase gene diminishes atherosclerosis in apo E−deficient mice. J Clin Invest 1999, 103, 1487–1488.
  19. Conrad DJ, Kühn H, Mulkins M, Highland E, Sigal E: Specific inflammatory cytokines regulate the expression of human monocyte 15−lipoxygenase. Proc Natl Acad Sci USA 1992, 89, 217–221.
  20. O’Donnell VB, Coles B, Lewis MJ, Crews BC, Marnett LJ, Freeman BA: Catalytic consumption of nitric oxide by prostaglandin H synthase−1 regulates platelet function. J Biol Chem 2000, 275, 38239–38244.
  21. Eiserich JP, Baldus S, Brennan ML, Ma W, Zhang C, Tousson A: Myeloperoxidase, a leukocyte−derived vascular NO oxidase. Science 2002, 296, 2391–2394.
  22. Ichikawa T, Liang J, Kitajima S, Koike T, Wang X, Sun H, Morimoto M, Shikama H, Watanabe T, Yamada N, Fan J: Macrophage−derived lipoprotein lipase increases aortic atherosclerosis in cholesterol−fed Tg rabbits. Atherosclerosis 2005, 179, 87–95.
  23. Reynolds JL, Joannides AJ, Skepper JN, McNair R, Schurgers LJ, Proudfoot D, Jahnen−Dechent W, Weissberg PL, Shanahan CM: Human vascular smooth muscle cells undergo vesicle−mediated calcification in response to changes in extracellular calcium and phosphate concentrations: a potential mechanism for accelerated vascular calcification in ESRD. J Am Soc Nephrol 2004, 15, 2857–2867.
  24. Proudfoot D, Skepper JN, McNair R, Joannides AJ, Weissberg PL, Shanahan CM: Mineral ion−induced release of mineralization−competent matrix vesicles from human vascular smooth muscle cells. Cardiovasc Pathol 2004, 13, Suppl. 4, S186–S190.
  25. Klemmer PJ: Calcium loading, calcium accumulation, and associated cardiovascular risks in dialysis patients. Blood Purif 2005, 23, Suppl. 1, 12–19.
  26. Luo G, Ducy P, McKee MD, Pinero GJ, Loyer E, Behringer RR, Karsenty G: Spontaneous calcification of arteries and cartilage in mice lacking matrix Gla protein. Nature 1997, 386, 78–81.
  27. Shanahan CM, Cary NR, Metcalfe JC, Weissberg PL: High expression of genes for calcification−regulating proteins in human atherosclerotic plaques. J Clin Invest 1994, 93, 2393–2402.
  28. Jono S, Ikari Y, Vermeer C, Dissel P, Hasegawa K, Shioi A, Taniwaki H, Kizu A, Nishizawa Y, Saito S: Matrix Gla protein is associated with coronary artery calcification as assessed by electron−beam computed tomography. Throm Haemost 2004, 91, 790–794.
  29. Heiss A, DuChesne A, Denecke B, Grotzinger J, Yamamoto K, Renne T, Jahnen−Dechent W: Structural basis of calcification inhibition by alpha 2−HS glycoprotein/fetuin−A. Formation of colloidal calciprotein particles. J Biol Chem 2003, 278, 13333–13341.
  30. Reynolds JL, Skepper JN, McNair R, Kasama T, Gupta K, Weissberg PL, Jahnen−Dechent W, Shanahan CM: Multifunctional roles for serum protein fetuin−A in inhibiton of human vascular smooth muscle cell calcification. J Am Soc Nephrol 2005, 16, 2920–2930.
  31. Schafer C, Heiss A, Schwarz A, Westenfeld R, Ketteler M, Floege J, Muller−Esterl W, Schinke T, JahnenDechent W: The serum protein alpha 2−Heremans−Schmid glycoprotein/fetuin−A is a systematically acting inhibitor of ectopic calcification. J Clin Invest 2003, 112, 357–366.
  32. Ketteler M, Bongartz P, Westenfeld R, Wildberger JE, Mahnken AH, Bohm R, Metzger T, Wanner C, Jahnen−Dechent W, Floege J: Association of low fetuin−A (AHSG) concentrations in serum with cardiovascular mortality in patients on dialysis: a cross−sectional study. Lancet 2003, 361, 827–833. 234 K. MUSIAŁ, D. ZWOLIŃSKA, K. FORNALCZYK
  33. Li X, Giachelli CM: Sodium−dependent phosphate cotransporters and vascular calcification. Curr Opin Nephrol Hypert 2007, 16, 325–328.
  34. Lomashvili KA, Khawandi W, O’Neill WC: Reduced plasmapyrophosphate levels in hemodialysis patients. J Am Soc Nephrol 2005, 2495–2500.
  35. Steitz SA, Speer MY, McKee MD, Liaw L, Almeida M, Yang H, Giachelli CM: Osteopontin inhibits mineral deposition and promotes regression of ectopic calcification. Am J Pathol 2002, 161, 2035–2046.
  36. Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, Santer P, Smolen J, Poewe W, Willeit J: Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation 2004, 109, 2175–2180.
  37. Boyle WJ, Simonet WS, Lacey DL: Osteoclast differentiation and activation. Nature 2003, 423, 337–342.
  38. Nitta K, Akiba T, Uchida K, Kawashima A, Yumura W, Kabaya T, Nihei H: The progression of vascular calcification and serum osteoprotegerin levels in patients on long−term hemodialysis. Am J Kidney Dis 2003, 42, 303−309.
  39. Ziółkowska H, Roszkowska−Blaim M: Osteoprotegeryna a parametry przemiany wapniowo−fosforanowej u dzieci z przewlekłą niewydolnością nerek. Przegl Lek 2006, 63, supl. 3, 68–71.
  40. Torres PU, Prie D, Molina−Bletry V, Beck L, Silve C, Friedlander G: Klotho: An antiaging protein involved in mineral and vitamin D metabolism. Kidney Int 2007, 71, 730–737.
© Wroclaw Medical University