Specific risk factors for cerebrovascular disorders in patients with chronic kidney disease in the pre-dialysis period

Cerebral vascular disorders are one of the leading causes of disability and mortality in patients with chronic kidney disease (CKD). The article presents the currently available data on risk factors (RF) for the development of cerebrovascular disorders in pre-dialysis patients with CKD. Two groups of RF are identified: traditional and non-traditional (specific). Traditional RF, which include arterial hypertension, diabetes mellitus and hypercholesterolemia, independently affect the cerebral vascular bed and get worse against the background of CKD. Specific RF is associated with features of the CKD pathogenesis. It includes increased blood levels of homocysteine, β2-microglobulin, impaired calcium-phosphorus metabolism, accumulation of uremic toxins and toxins of intestinal bacteria, anemia and other factors. In the present review, special attention is paid to specific RF and pathogenetic mechanisms of the development of cerebrovascular disorders in predialysis patients with CKD. Timely detection of cerebral risk factors may lead to the improvement of early diagnosis and prevention of cerebral vascular disorders, optimization of therapy for patients with CKD.

1. Murkamilov IT, Aitbaev KA, Redzhapova NA, et al. Nephroand cerebroprotection in chronic kidney disease: opportunities of candesartan. Kardiologiia. 2017;6:69-75. (In Russ.) doi:10.18565/cardio.2017.6.69-75.

2. Yagudina RI, Serpik VG, Аbdrashitova GT, et al. Economic burden of chronic kidney disease in the Russian Federation. Farmakoekonomika: Teoriya i Praktika. 2014;2(4):34-9. (In Russ.)

3. Chen YC, Su Y-C, Lee C-C, et al. Chronic kidney disease itself is a causal risk factor for stroke beyond traditional cardiovascular risk factors: a nationwide cohort study in Taiwan. PLoS One. 2012;7(4):1-7. doi:10.1371/journal.pone.0036332.

4. Nesterenko OV, Borodulin VB, Goremykin VI, et al. Importance of hyperhomocysteinemia (HHC) in chronic pyelonephritis. Fundamental research. 2014;7(1):193-6. (In Russ.)

5. Zobova DA, Kozlov SA. The role of homocysteine in pathogenesis of certain diseases. University proceedings. Volga region. Medical sciences. 2016;3:132-44. (In Russ.) doi:10.21685/2072-3032-2016-3-15.

6. Efimov VS, Ozolinia LA, Kashezheva AZ, et al. Hyperhomocysteinemia in clinical practice: manual. M.: GEOTAR-Media; 2013. 80 p. (In Russ.) ISBN 978-5-9704-2320-2.

7. Kuzmichev DE, Skrebov RV, Chirkov SV, et al. Amyloidosis. Zdravoohranenie Ugry: opyt i innovacii. 2016;1:59-64. (In Russ.)

8. Ochiai H, Uezono S, Kawano H. Factors affecting outcome of intracerebral hemorrhage in patients undergoing chronic hemodialysis. Ren Fail. 2010;8(32):9237. doi:10.3109/0886022X.2010.502279.

9. Mineral and osteal disorders in chronic kidney disease (MOD-CKD). https://qps.ru/7dya6. (08 May 2018). (In Russ.)

10. Hruska K, Mathew S, Lund R, et al. Hyperphosphatemia of chronic kidney disease. Kidney Int. 2008;4(2):148-57. doi:10.1038/ki.2008.130.

11. Lau WL, Ix JH. Clinical detection, risk factors, and cardiovascular consequences of medial arterial calcification: a pattern of vascular injury associated with aberrant mineral metabolism. Semin Nephrol. 2013;33(2):93-105. doi:10.1016/j.semnephrol.2012.12.011.

12. Steitz SA, Speer MY, Curinga G, et al. Smooth muscle cell phenotypic transition associated with calcification: upregulation of Cbfa1 and downregulation of smooth muscle lineage markers. Circ Res. 2001;89(12):1147-54. doi:10.1161/hh2401.101070.

13. Hosaka N, Mizobuchi M, Ogata H, et al. Elastin degradation accelerates phosphateinduced mineralization of vascular smooth muscle cells. Calcif Tissue Int. 2009;85(6):523-9.

14. Shroff R, McNair R, Skepper JN, et al. Chronic mineral dysregulation promotes vascular smooth muscle cell adaptation and extracellular matrix calcification. J Am Soc Nephrol. 2010;21(1):103-12. doi:10.1681/ASN.2009060640.

15. Gattineni J, Bates C, Twombley K, et al. FGF23 decreases renal NaPi-2a and NaPi-2c expression and induces hypophosphatemia in vivo predominantly via FGF receptor 1. Am J Physiol Renal Physiol. 2009;297(2):282-91. doi:10.1152/ajprenal.90742.2008.

16. Chen T, Mao H, Chen C, et al. The role and mechanism of α-Klotho in the calcification of rat aortic vascular smooth muscle cells. Biomed Res Int. 2015;2015:17. doi:10.1155/2015/194362.

17. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22(1):124-36. doi:10.1681/ASN.2009121311.

18. Schurgers LJ, Barreto DV, Barreto FC, et al. The circulating inactive form of matrix gla protein is a surrogate marker for vascular calcification in chronic kidney disease: a preliminary report. Clin J Am Soc Nephrol. 2010;5(4):568-75. doi:10.2215/ CJN.07081009.

19. Watanabe K, Watanabe T, Nakayama M. Cerebro-renal interactions: impact of uremic toxins on cognitive function. Neurotoxicology. 2014;44:184-93. doi:10.1016/j.neuro.2014.06.014.

20. Bugnicourt JM, Da Silveira C, Bengrine A, et al. Chronic renal failure alters endothelial function in cerebral circulation in mice. Am J Physiol Heart Circ Physiol. 2011;301:1143-52. doi:10.1152/ajpheart.01237.2010.

21. Watanabe H, Miyamoto Y, Otagiri M et al. Update on the pharmacokinetics and redox properties of protein-bound uremic toxins. J Pharm Sci. 2011;100:3682-95. doi:10.1002/jps.22592.

22. Six I, Maizel J, Barreto FC, et al. Effects of phosphate on vascular function under normal conditions and influence of the uraemic state. Cardiovasc Res. 2012;96:1309. doi:10.1093/cvr/cvs240.

23. Muteliefu G, Enomoto A, Jiang P et al. Indoxyl sulphate induces oxidative stress and the expression of osteoblast-specific proteins in vascular smooth muscle cells. Nephrol Dial Transplant. 2009;24:2051-8. doi:10.1093/ndt/gfn757.

24. Vaziri ND, Yuan J, Rahimi A, et al. Disintegration of colonic epithelial tight junction in uremia: a likely cause of CKD-associated inflammation. Nephrol Dial Transplant. 2012;27(7):2686-93. doi:10.1093/ndt/gfr624.

25. Szeto CC, Kwan BC-H, Chow K-M, et al. Endotoxemia is related to systemic inflammation and atherosclerosis in peritoneal dialysis patients. Clin J Am Soc Nephrol. 2008;3(2):431-6. doi:10.2215/CJN.03600807.

26. Lau WL, Kalantar-Zadeh K, Vaziri ND. The gut as a source of inflammation in chronic kidney disease. Nephron. 2015;130(2):92-8. doi:10.1159/000381990.

27. Vaziri ND, Yuan J, Norris K. Role of urea in intestinal barrier dysfunction and disruption of epithelial tight junction in chronic kidney disease. Am J Nephrol. 2013;37(1):1-6. doi:10.1159/000345969.

28. Lau WL, Liu S-M, Pahlevan S, et al. Role of Nrf2 dysfunction in uremia-associated intestinal inflammation and epithelial barrier disruption. Dig Dis Sci. 2014;60:1215-22.

29. Feroze U, Kalantar-Zadeh K, Sterling KA, et al. Examining associations of circulating endotoxin with nutritional status, inflammation, and mortality in hemodialysis patients. J Ren Nutr. 2012;22(3):317-26. doi:10.1053/j.jrn.2011.05.004.

30. Rossi M, Campbell KL, Johnson DW, et al. Protein-bound uremic toxins, inflammation and oxidative stress: a cross-sectional study in stage 3-4 chronic kidney disease. Arch Med Res. 2014;45(4):309-17. doi:10.1016/j.arcmed.2014.04.002.

31. Tang WH, Wang Z, Kennedy DJ, et al. Gut microbiota-dependent Trimethylamine NOxide (TMAO) pathway contributes to both development of renal insufficiency and mortality risk in chronic kidney disease. Circ Res. 2015;116(3):448-55. doi:10.1161/CIRCRESAHA.116.305360.

32. Yin J, Liao SX, He Y, et al. Dysbiosis of gut microbiota with reduced trimethylamineN-oxide level in patients with large-artery atherosclerotic stroke or transient ischemic attack. J Am Heart Assoc. 2015;4(11):1-12. doi:10.1161/JAHA.115.002699.

33. Korzh AN. Cadiorenal syndrome in patients with cronic kidney disease and coronary heart disease. Pochki. 2015;1:45-51. (In Russ.)

34. Chang YL, Hung SH, Ling W, et al. Association between ischemic stroke and irondeficiency anemia: a population-based study. PLoS One. 2013;8(12):1-7. doi:10.1371/journal.pone.0082952.

35. Seliger SL, Zhang AD, Weir MR, et al. Erythropoiesis-stimulating agents increase the risk of acute stroke in patients with chronic kidney disease. Kidney Int. 2011;80:28894. doi:10.1038/ki.2011.49.

36. Vinhas J, Barreto C, Assuncao J, et al. Treatment of anaemia with erythropoiesisstimulating agents in patients with chronic kidney disease does not lower mortality and may increase cardiovascular risk: a meta-analysis. Nephron Clin Pract. 2012;121:95-101. doi:10.1159/000345158.

37. Palmer SC, Navaneethan SD, Craig JC, et al. Meta-analysis: erythropoiesisstimulating agents in patients with chronic kidney disease. Ann Intern Med. 2010;153:23-33. doi:10.7326/0003-4819-153-1-201007060-00252.

38. Chan KE, Lazarus JM, Thadhani R, et al. Anticoagulant and antiplatelet usage associates with mortality among hemodialysis patients. J Am Soc Nephrol. 2009;20:872-81. doi:10.1681/ASN.2008080824.

39. Lau WL, Huisa BN, Fisher M. The Cerebrovascular-Chronic Kidney Disease Connection: Perspectives and Mechanisms. Transl. Stroke Res. 2017;8:67-76.

40. Charidimou A, Werring DJ. A raging fire in acute lacunar stroke: inflammation, bloodbrain barrier dysfunction and the origin of cerebral. J Neurol Sci. 2014;340(1-2):1-2. doi:10.1016/j.jns.2014.03.004.

41. Xiao L, Sun W, Lan W, et al. Correlation between cerebral microbleeds and S100B/RAGE in acute lacunar stroke patients. J Neurol Sci. 2014;340(1-2):208-12. doi:10.1016/j.jns.2014.03.006.

42. Isoyama N, Leurs P, Qureshi AR, et al. Plasma S100A12 and soluble receptor of advanced glycation end product levels and mortality in chronic kidney disease Stage 5 patients. Nephrol Dial Transplant. 2015;30(1):84-91. doi:10.1093/ndt/gfu259.