Updated mechanisms of calcification of cardiovascular system and its correction in chronic kidney disease

In chronic kidney disease (CKD), progressive decline in kidney function leads to disorders of mineral metabolism, which are usually called secondary hyperparathyroidism. An increase in the serum concentration of the parathyroid hormone is associ­ated with a decrease in the level of calcium and calcitriol and/or an increase in the level of fibroblast growth factor-23 and inorganic phosphate in serum. CKD-related disorders of mineral and bone metabolism are associated with other metabolic disorders, such as acidosis, protein-energy wasting, inflammation, and accumulation of uremic toxins. This contributes to vascular calcification, which is a consequence of an imbalance between numerous inhibitors and promoters of soft tissue min­eralization. Vascular calcification is a degenerative process characterized by the accumulation of calcium and phosphate salts in the artery wall. This is observed in almost all vascular areas and can develop in the media, intima, or both vascular layers of the arteries. Calcification of the intima usually occurs due to atherosclerosis and may be responsible for coronary ischemic events. Conversely, media calcification is non-exclusive and predominantly develops along elastic fibers. As a result, media calcification increases vascular stiffness, aortic pulse wave velocity, systolic and pulse blood pressure, contributing to the de­velopment of left ventricular hypertrophy and heart failure. This review examines the current understanding of the mechanisms that lead to the development of vascular calcification in CKD. The participation of factors such as inflammation, age glycation end products, indoxyl sulfate, and others in calcification processes is discussed. Promising therapeutic goals associated with a new understanding of the mechanisms of cardiovascular calcification in CKD are identified.

1. Pereira L, Frazao JM. The bone-vessel axis in chronic kid­ney disease: An update on biochemical players and its future role in laboratory medicine. Clin Chim Acta 2020;508:221-227. doi: 10.1016/j.cca.2020.05.023

2. O'Neill WC. Understanding the pathogenesis of vascular calcification: timing is everything. Kidney Int 2017;92(6):1316- 1318. doi: 10.1016/j.kint.2017.07.020

3. Hortells L, Sosa C, Guillen N et al. Identifying early patho­genic events during vascular calcification in uremic rats. Kidney Int 2017;92(6):1384-1394.doi:10.1016/j

4. Smirnov AV, Volkov MM. The role of vitamin D in progres­sion of chronic kidney disease. Nephrology (Saint-Petersburg). 2008;12(4):20-27 (In Russ.), https://doi.org/10.24884/1561-6274-2008-12-4-20-27

5. Novokshonov К, Karelina J, Zemchenkov AYu et al. Chronic kidney disease mineral and bone disorder markers in screening study among dialysis patients in North-West federal region of Rus­sia. Nephrology (Saint-Petersburg) 2016;20(1):36-50 (In Russ.)

6. Rumyantcev AS, Rafrafi Н, Galkina OV. Calcification of the aortic valve in patients on program hemodialysis. Nephrology (Saint-Petersburg) 2018;22(4):90-95 (In Russ.). https://doi. org/10.24884/1561-6274-2018-22-4-90-95

7. Bao SM, GuoW, DiaoZLet al. Bone marrow mesenchymal stem cell-derived exosomes alleviate high phosphorus-induced vascular smooth muscle cells calcification by modifying microR- NA profiles. Funct Integr Genomics 2019;19(4):633-643. doi: 10.1007/S10142-019-00669-0

8. Herrmann M, Babler A, Moshkova I et al. Lumenal calcifi­cation and microvasculopathy in fetuin-A-deficient mice lead to multiple organ morbidity. PLoS ONE 2020;15(2):e0228503. doi: 10.1371/journal.pone.0228503

9. Babler A, SchmitzC, Buescher Aetal. Microvasculopathy and soft tissue calcification in mice are governed by fetuin-A, magnesium and pyrophosphate. PLoS ONE2020; 15(2):e0228938. doi: 10.1371/journal.pone.02289386

10. Kaesler N, Babler A, Floege J et al. Cardiac Remodel­ing in Chronic Kidney Disease. Toxins 2020;12(3):161-171. doi: 10.3390/toxins12030161

11. Takeshi N, Masayoshi N, Takahiro К et al. The patho­genesis of CKD complications; Attack of dysregulated iron and phosphate metabolism. Free Radio Biol Med 2020;21:Epub 2020 Jan 21. doi: 10.1007/s11883-020-0821-7

12. DaisukeS, NoriakiT, Motoko Tefal. Associations Between Corrected Serum Calcium and Phosphorus Levels and Outcome in Dialysis Patients in the Kumamoto Prefecture. HemodialInt 2020; 24(2):202-211. doi: 10.1111/hdi.12824

13. Mazzetti T, Hopman WM, Couture L et al. Phosphorus Consumption Within 1 Hour Prior to Blood Work and Associated Serum Levels of Phosphate, Calcium, and PTH in Adult Patients Receiving Hemodialysis Treatment. Can J Kidney Health Dis 2019;2054358119856891. doi: 10.1177/2054358119856891

14. Palmer SC, Teixeira-PintoA, SaglimbeneVetal. Association of Drug Effects on Serum Parathyroid Hormone, Phosphorus, and Calcium LevelsWith Mortalityin CKD: A Meta-analysis. Am J Kidney Dis 2015;66(6):962-971. doi: 10.1053/j.ajkd.2015.03.036

15. Coscas R, Bensussan M, Jacob MP et al. Free DNA precipitates calcium phosphate apatite crystals in the arterial wall in vivo. Atherosclerosis 2017;259:60-67. doi: 10.1016/j. atherosclerosis.2017.03.005

16. Ewence AE, Bootman M, Roderick HL et al. Calcium phosphate crystals induce cell death in human vascular smooth muscle cells: a potential mechanism in atherosclerotic plaque destabilization. Circ Res 2008;103:e28-e34. doi: 10.1161/ CIRCRESAHA.108.181305

17. Villa-Bellosta R, Hamczyk MR, Andres V et al. Novel Phosphate-Activated Macrophages Prevent Ectopic Calcification by Increasing Extracellular ATP and Pyrophosphate. PLoS One 2017;12(3):e0174998.doi: 10.1371/journal.pone.0174998

18. Law J P, Price AM, Pickup L. Clinical Potential of Target­ing Fibroblast Growth Factor-23 and aKIotho in the Treatment of Uremic Cardiomyopathy. J Am Heart Assoc 2020;9(7):e016041. doi: 10.1161/JAHA.120.016041

19. Zhang W, Xue D, Hu D et al. Secreted klotho protein attenuates osteogenic differentiation of human bone marrow mesenchymal stem cells in vitro via inactivation of the FGFR1/ ERK signaling pathway. Growth Factors 2015;33:356-365. doi: 10.3109/08977194.2015.1108313

20. Braake A, Smit A, BosCetal. Magnesium prevents vascu­lar calcification in Klotho deficiency. Kidney Int 2020;97:487-501. doi: 10.1016/j.kint.2019.09.034

21. Takashi X Wakino S, Minakuchi H et al. Circulating FGF23 is not associated with cardiac dysfunction, atherosclerosis, infec­tion or inflammation in hemodialysis patients. JBone MinerMetab 2020;38(1):70-77. doi:10.1007/s00774-019-010277

22. Cho Kl, Sakuma I, Sohn IS, Jo SH. Inflammatory and metabolic mechanisms underlying the calcific aortic valve disease. Atherosclerosis 2018;277:60-65. doi: 10.1016/j. atherosclerosis.2018.08.029

23. Li X SunZ, Zhang L et al. Role of Macrophages in the Progression and Regression of Vascular Calcification. Front Phar­macol 2020;11:661-668.doi: 10.3389/fphar.2020.00661

24. Benz K, Varga I, Neureiter Detal. Vascular inflammation and media calcification are already present in early stages of chronic kidney disease. Cardiovasc Pathol 2017;27:57-67. doi: 10.1016/j.carpath.2017.01.004

25. Sun M, Chang Q,Xin Metal. Endogenous bone morphoge­netic protein 2 plays a role in vascular smooth muscle cell calcifica­tion induced by interleukin 6 in vitro. IntJImmunopatholPharmacol 2017;30(3):227-237. doi: 10.1177/0394632016689571

26. Singh S, Grabner A, Yanucil С et al. Fibroblast growth factor 23 directly targets hepatocytes to promote inflammation in chronic kidney disease. Kidney Int 2016;90(5):985-996. doi: 10.1016/j.kint.2016.05.019

27. Fishman SI, Sonmez H, Craig Basman С et al. The role of advanced glycation end-products in the development of coronary artery disease in patients with and without diabetes mellitus: a review. Mol Med 2018;24(1):59. doi: 10.1186/s10020-018- 0060-3

28. Liu X Wang WM, Zhang XL et al. AGE/RAGE promotes the calcification of human aortic smooth muscle cells via the Wnt/p-catenin axis. Am J Trans! Res 2016;8(12):4644-4456. doi: 10.1039/c7fo01383c

29. Chen NX, Srinivasan S, O'Neill Ketal. Effect of Advanced Glycation End-Products (AGE) Lowering Drug ALT-711 on Bio­chemical, Vascular, and Bone Parameters in a Rat Model of CKD- MBD. JBMR 2020;35:608-617. doi: 10.1002/jbmr.3925

30. Asadipooya K, Uy EM. Advanced glycation end prod­ucts (AGEs), receptor for ages, diabetes, and bone: review of the literature. J Endocr Soc 2019;3:1799-1818. doi: 10.1210/ js.2019-00160

31. Ryu JH, Jeon EX Kim SJ. Indoxyl Sulfate-Induced Extra­cellular Vesicles Released from Endothelial Cells Stimulate Vas­cular Smooth Muscle Cell Proliferation by Inducing Transforming Growth Factor-Beta Production. J Vase Res 2019;56:129-138. doi: 10.1159/000496796

32. Lano G, Burtey S, Sallee M. Indoxyl Sulfate, a Uremic Endotheliotoxin. Toxins (Basel) 2020;12(4):229. doi: 10.3390/ toxins12040229

33. Shafi T, Sirich TL, Meyer TW et al. Results of the НЕМО Study suggest that p-cresol sulfate and indoxyl sulfate are not as­sociated with cardiovascular outcomes. Kidney Int 2017;92:1484- 1492. doi: 10.1016/j.kint.2017.05.012

34. Lano G, Burtey S, Sallee M. Indoxyl Sulfate, a Uremic Endotheliotoxin. Toxins (Basel) 2020;12(4):229. doi: 10.3390/ toxins12040229

35. Santana Machado T, Poitevin S, Paul P et al. Indoxyl Sulfate Upregulates Liver Р-Glycoprotein Expression and Activity through Aryl Hydrocarbon Receptor Signaling. JAm Soc Nephrol 2018;29(3):906-918. doi: 10.1681/ASN.2017030361

36. Liu W-C, TominoX Kuo-Cheng Lu K-C. Impacts of In­doxyl Sulfate and p-Cresol Sulfate on Chronic Kidney Disease and Mitigating Effects of AST-120. Toxins (Base!) 2018;10(9):367. doi: 10.3390/toxins10090367

37. Wu M, Rementer C, Giachelli CM. Vascular calcification: an update on mechanisms and challenges in treatment. Calcif Tissue Int 2013;93:365-373. doi: 10.1007/s00223-013-9712

38. Block GA, Chertow GM, Sullivan JT et al. An integrated analysis of safety and tolerability of etelcalcetide in patients receiv­ing hemodialysis with secondary hyperparathyroidism. PLoS ONE 2019;14(3):e0213774. doi:10.1371/journal.pone.0213774

39. Zununi VS, Mostafavi S, Hosseiniyan SM et al. Vascular Calcification: An Important Understanding in Nephrology. Vase Health Risk Manag 2020;16:167-180. doi: 10.2147/VHRM. S242685

40. ShigematsuT, Fukagawa M,YokoyamaKetal. Long-term effects of etelcalcetide as intravenous calcimimetic therapy in hemodialysis patients with secondary hyperparathyroidism. Clini­cal & Experimental Nephrology 2018;2:426-436. doi: 10.1007/ S10157-017-1442-5

41. Block GA, Bushinsky DA, Cunningham J et al. Effect of etelcalcetide vs placebo on serum parathyroid hormone in patients receiving hemodialysis with secondary hyperparathyroidism: two randomized clinical trials. JAMA 2017;317(2):146-155. doi: 10.1001/jama.2016.19456

42. Block GA, Bushinsky DA, Cheng S et al. Effect of Etelcal­cetide vs Cinacalcet on Serum Parathyroid Hormone in Patients Receiving Hemodialysis With Secondary Hyperparathyroidism. A Randomized Clinical Trial. JAMA 2017;317(2):156-164. doi: 10.1001/jama.2016.19468

43. Rodelo-Haad C, Rodrfguez-Ortiz ME, Martin-Malo A et al. Phosphate control in reducing FGF23 levels in hemodialysis patients. PLoS One 2018;13(8):e0201537. doi: 10.1371/journal. pone.0201537

44. Ketteler M, Sprague S, Covic A, Rastogi A. Effects of sucroferric oxyhydroxide and sevelamer carbonate on chronic kidney disease-mineral bone disorder parameters in dialysis patients. Nephrol Dial Transplant 2019;34(7):1163-1170. doi: 10.1093/ndt/gfy127

45. Molony DA, Parameswaran V, Ficociello LHetal. Sucrofer­ric Oxyhydroxide as Part of Combination Phosphate Binder Therapy among Hemodialysis Patients. Kidney 2020;1(4):263-272. doi: 10.34067/KID.0000332019

46. Kendrick J, ParameswaranV, Ficociello Letal. One-Year Historical Cohort Study of the Phosphate Binder Sucroferric Oxy­hydroxide in Patients on Maintenance Hemodialysis. J Ren Nutr 2019;29(5):428-437.doi: 10.1053/j.jrn.2018.11.002

47. Mizobuchi M, Ogata H, Koiwa F. Secondary Hyperpara­thyroidism: Pathogenesis and Latest Treatment. Therapeutic Apheresis and Dialysis 2019;23:309-318. doi: 10.1111/1744­9987.12772

48. Lau WL,Vaziri ND, Nunes ACFetal. The Phosphate Binder Ferric Citrate Alters the Gut Microbiome in Rats with Chronic Kidney Disease. Journal of Pharmacology and Experimental Therapeutics 2018;367(3):452-460. doi: 10.1124/jpet.118.251389

49. BuenodeB, StinghenAE, MassydZA.Vitamin К role in min­eral and bone disorder of chronic kidney disease. Clinica chemica Acta 2020;502:66-72. doi: 10.1016/j.cca.2019.11.040

50. Shioi A, MoriokaT, ShojiT, Emoto M. The Inhibitory Roles of Vitamin К in Progression of Vascular Calcification. Nutrients 2020;12(2):583. doi: 10.3390/nu12020583

51. Cozzolino M, Giuseppe-Cianciolo G, Podesta MA et al. Current Therapy in CKD Patients Can Affect Vitamin К Status. Nutrients 2020;t2(6):1609. doi: 10.3390/nu12061609

52. Molnar AO, Biyani M, Hammond letal. Lower serum mag­nesium is associated with vascular calcification in peritoneal dialy­sis patients: a cross sectional study. BMC Nephrol 2017;18(1):129. doi: 10.1186/s12882-017-0549-y

53. Zeper LW, de Baaij JHF. Magnesium and calciprotein particles in vascular calcification: the good cop and the bad cop. CurrOpin Nephrol Hypertens 2019;28(4):368-374. doi: 10.1097/ MNH.0000000000000509

54. NakagawaX Komaba H, Fukagawa M etal. Magnesium as a Janus-faced inhibitor of calcification. Kidney Int 2020;97(3):448- 450. doi: 10.1016/j.kint.2019.11.035

55. Jung J, Bae GH, Kang M. Statins and All Cause Mor­tality in Patients Undergoing Hemodialysis. J Am Heart Assoc 2020;9(5):e014840. doi: 10.1161/JAHA.119.014840

56. Lee KM, Chan GCW, Tang SCW. Not even a peripheral role for statins in end-stage renal disease? Nephrol Dial Transplant 2020;9:1-9.doi:10.1093/ndt/gfaa051

57. Chen Z, Qureshi AR, Parini P et al. Does statins promote vascular calcification in chronic kidney disease? EurJ Clin Invest 2017;47(2):137-148.doi: 10.1111/eci.12718

58. Lee SJ, Lee IK, Jeon GH. Vascular Calcification - New Insights into Its Mechanism. Int J Mol Sci 2020; 21(8):2685. doi: 10.3390/ijms21082685

59. Trojanowicz B, Ulrich C, Fiedler R et al. Impact of serum and dialysates obtained from chronic hemodialysis patients maintained on high cut-off membranes on inflammation profile in human THP-1 monocytes. Hemodial Int 2017;21:348-358. doi: 10.1111/hdi.12494

60. Sena B, Figueiredo J L, Aikawa E. Cathepsin S As an In­hibitor of Cardiovascular Inflammation and Calcification in Chronic Kidney Disease. Frontiers in Cardiovascular Medicine 2018;4:88. doi: 10.3389/fcvm.2017.00088

61. Henaut L, CandellierA, Boudot C. New Insights into the

62. Roles of Monocytes/Macrophages in Cardiovascular Calcification Associated with Chronic Kidney Disease. Toxins 2019;11(9):529. doi: 10.3390/toxins11090529

63. Girndt M, Fiedler R, Martus Petal. High cut-off dialysis in chronic haemodialysis patients.EurJC//n/nvesf2015;45(2): 1333­1340. doi: 10.1111/eci.12559

64. Kurabayashi M. Molecular Mechanism of Vascu­lar Calcification. Clin Calcium 2019;29(2):157-163. doi: 10.20837/4201902157

65. Yubero-Serrano EM, Woodward M, Poretsky L et AGE­less Study Group. Effects of Sevelamer Carbonate on Advanced Glycation End Products and Antioxidant/Pro-Oxidant Status in Patients with Diabetic Kidney Disease. Clin J Am Soc Nephrol 2015;10(5):759-766. doi: 10.2215/CJN.07750814

66. Snelson M, Coughlan MT. Dietary Advanced Glycation End Products: Digestion, Metabolism and Modulation of Gut Microbial Ecology. Nutrients 2019;11(2):215. doi: 10.3390/ nu11020215

67. Kaesler N, Babler A, Floege J, Kramann R. Cardiac Re­modeling in Chronic Kidney Disease. Toxins 2020;12(3):161. doi: 10.3390/toxins12030161