Уровень неорганического фосфата в сыворотке крови независимо ассоциирован с индексом массы миокарда левого желудочка у пациентов с хронической болезнью почек 1–4-й стадий

Актуальность. Среди причин смерти пациентов с хронической болезнью почек (ХБП) сердечная недостаточность (СН) занимает ведущее место. Роль гиперфосфатемии при ХБП среди прочих факторов ремоделирования миокарда оставалась неизученной.

Цель исследования — оценка ассоциации между уровнем неорганического фосфата (Pi) сыворотки крови и индексом массы миокарда левого желудочка (ИММЛЖ) в популяции пациентов с ХБП 1–4-й стадий.

Материалы и методы. В когортное срезовое исследование были включены 1213 пациентов с ХБП (48 % мужчин, средний возраст 48 ± 16 лет, расчетная скорость клубочковой фильтрации (рСКФ) 58 (36; 82) мл/мин/1,73 м2 ). Оценивали клинико-демографические показатели, эхокардиографические параметры, уровень Pi сыворотки и показатели его почечной экскреции, почечную экскрецию электролитов, протеинурию и рСКФ. Для анализа ассоциации между Pi и ИММЛЖ использовали скорректированные линейную и логистическую регрессии в сочетании с методами псевдорандомизации — подбора групп 1 : 1 по индексу склонности (propensity score matching, PSM) и взвешиванию по обратной вероятности развития гипертрофии левого желудочка (ГЛЖ) (inverse probability of treatment weighting, IPТW) для минимизации конфаундинга.

Результаты. Пациенты с ГЛЖ (n = 571) имели более высокие уровни Pi по сравнению с группой без ГЛЖ (1,31 [1,12–1,43] vs 1,19 [1,09– 1,31] ммоль/л; p < 0,0001). Многофакторный регрессионный анализ показал, что Pi независимо от других клинических индексов связан с ИММЛЖ (B = 13,67 ± 3,31; p < 0,0001; скорректированный R2 = 0,37). В IPTW и 1:1 PSM регрессионных моделях при уровне Pi > 1,37 ммоль/л увеличение ИММЛЖ составляло 5,7–11,3 г/м².

Заключение. У пациентов с ХБП концентрация неорганического фосфата в сыворотке крови может быть независимым фактором ремоделирования левого желудочка и целью лечебных интервенций для улучшения сердечно-сосудистого прогноза.

1. Go AS, Chertow GM, Fan D, McCulloch CE, Hsu CY. Chronic kidney disease and the risks of death, cardiovascular events, and hospitalization. N Engl J Med. 2004;351(13):1296–1305. https://doi.org/10.1056/NEJMoa041031

2. Weiner DE, Tighiouart H, Amin MG, Stark PC, MacLeod B, Griffith JL, et al. Chronic kidney disease as a risk factor for cardiovascular disease and all-cause mortality: a pooled analysis of community-based studies. J Am Soc Nephrol. 2004;15(5):1307– 1315. https://doi.org/10.1097/01.asn.0000123691.46138.e2

3. Bansal N, Katz R, Robinson-Cohen C, Odden MC, Dalrymple L, Shlipak MG, et al. Absolute rates of heart failure, coronary heart disease, and stroke in chronic kidney disease: an analysis of 3 community-based cohort studies. J Am Med Assoc Cardiol. 2017;2(3):314–318. https://doi.org/10.1001/jamacardio.2016.4652

4. Di Lullo L, Gorini A, Russo D, Santoboni A, Ronco C. Left ventricular hypertrophy in chronic kidney disease patients: from pathophysiology to treatment. Cardiorenal Med. 2015;5(4):254– 266. https://doi.org/10.1159/000435838

5. Major RW, Cheng MRI, Grant RA, Shantikumar S, Xu G, Oozeerally I, et al. Cardiovascular disease risk factors in chronic kidney disease: a systematic review and meta-analysis. PLoS One. 2018;13(3): e0192895. https://doi.org/10.1371/journal.pone.0192895

6. Radhakrishnan A, Pickup LC, Price AM, Law JP, Edwards NC, Steeds RP, et al. Coronary microvascular dysfunction: a key step in the development of uraemic cardiomyopathy? Heart. 2019;105(17):1302–1309. https://doi.org/10.1136/heartjnl2019-315138

7. de Albuquerque Suassuna PG, Sanders-Pinheiro H, de Paula RB. Uremic cardiomyopathy: a new piece in the chronic kidney disease-mineral and bone disorder puzzle. Front Med (Lausanne). 2018;5:206. https://doi.org/10.3389/fmed.2018.00206

8. Wang X, Shapiro JI. Evolving concepts in the pathogenesis of uraemic cardiomyopathy. Nat Rev Nephrol. 2019;15(3):159–175. https://doi.org/10.1038/s41581-018-0101-8

9. Zhou C, Wang F, Wang JW, Zhang LX, Zhao MH. Mineral and bone disorder and its association with cardiovascular parameters in Chinese patients with chronic kidney disease. Chin Med J (Engl). 2016;129(19):2275–2280. https://doi.org/10.4103/0366-6999.190678

10. Yamada S, Nakano T. Role of chronic kidney disease (CKD)- mineral and bone disorder (MBD) in the pathogenesis of cardiovascular disease in CKD. J Atheroscler Thromb. 2023;30(8):835–850. https://doi.org/10.5551/jat.RV22006

11. Grabner A, Faul C. The role of FGF23 and Klotho in uremic cardiomyopathy. Curr Opin Nephrol Hypertens. 2016;25(4):314– 324. https://doi.org/10.1097/MNH.0000000000000231

12. Zhou C, Shi Z, Ouyang N, Ruan X. Hyperphosphatemia and cardiovascular disease. Front Cell Dev Biol. 2021;9:644363. https://doi.org/10.3389/fcell.2021.644363

13. Fan Z, Li R, Pan M, Jiang Y, Li Y, Liu L, et al. Relationship between serum phosphorus and mortality in non-dialysis chronic kidney disease patients: evidence from NHANES 2001–2018. BMC Nephrol. 2024;25(1):89. https://doi.org/10.1186/s12882-024-03525-x

14. Palmer SC, Hayen A, Macaskill P, Pellegrini F, Craig JC, Elder GJ, et al. Serum levels of phosphorus, parathyroid hormone, and calcium and risks of death and cardiovascular disease in individuals with chronic kidney disease: a systematic review and metaanalysis. J Am Med Assoc. 2011;305(11):1119–1127. https://doi.org/10.1001/jama.2011.308

15. Bogdanova E, Sadykov A, Ivanova G, Beresneva O, Zhuravlev A, Semenova N, et al. Dysregulation of bone and myocardial inorganic phosphate transporters and downstream cell signals in early-stage mild chronic kidney disease-mineral and bone disorder: an experimental study. Bone. 2025;201:117653. https://doi.org/10.1016/j.bone.2025.117653

16. Shao S, Cai W, Sheng J, Yin L. Role of SDF 1 and Wnt signaling pathway in the myocardial fibrosis of hypertensive rats. Am J Transl Res. 2015;7(8):1345–1356.

17. Qian L, Hong J, Zhang Y, Zhu M, Wang X, Zhang Ya, et al. Downregulation of S100A4 alleviates cardiac fibrosis via Wnt/β-catenin pathway in mice. Cell Physiol Biochem. 2018;46(6):2551–2560. https://doi.org/10.1159/000489683

18. Turner ME, Beck L, Hill Gallant KM, Chen Y, Moe OW, Kuro-O M, et al. Phosphate in cardiovascular disease: from new insights into molecular mechanisms to clinical implications. Arterioscler Thromb Vasc Biol. 2024;44(3):584–602. https://doi.org/10.1161/ATVBAHA.123.319198

19. Chue CD, Edwards NC, Moody WE, Steeds RP, Townend JN, Ferro CJ. Serum phosphate is associated with left ventricular mass in patients with chronic kidney disease: a cardiac magnetic resonance study. Heart. 2012;98(3):219–224. https://doi.org/10.1136/heartjnl-2011-300570

20. Lang RM, Badano LP, Mor-Avi V, Afilalo J, Armstrong A, Ernande L, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. J Am Soc Echocardiogr. 2015;28(1):1–39.e14. https://doi.org/10.1016/j.echo.2014.10.003

21. Алехин М. Н., Бартош-Зеленая С.Ю., Берестень Н.Ф., Бощенко А.А., Врублевский А.В., Глазун Л.О. и др. Стандартизация проведения трансторакальной эхокардиографии у взрослых: консенсус экспертов Российской ассоциации специалистов ультразвуковой диагностики в медицине (РАСУДМ) и Российской ассоциации специалистов функциональной диагностики (РАСФД). Ультразвуковая и функциональная диагностика. 2021;(2):63–79. https://doi.org/10.24835/1607-0771-2021-2-63-79

22. Stevens PE, Levin A. Kidney Disease: Improving Global Outcomes Chronic Kidney Disease Guideline Development Work Group Members. Evaluation and management of chronic kidney disease: synopsis of the kidney disease: improving global outcomes 2012 clinical practice guideline. Ann Intern Med. 2013;158(11):825– 830. https://doi.org/10.7326/0003-4819-158-11-201306040-00007

23. Maroni BJ, Steinman TI, Mitch WE. A method for estimating nitrogen intake of patients with chronic renal failure. Kidney Int. 1985;27(1):58–65. https://doi.org/10.1038/ki.1985.10

24. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivariate Behav Res. 2011;46(3):399–424. https://doi.org/10.1080/00273171.2011.568786

25. R Core Team. R: Alanguage and environment for statistical computing [Internet]. Vienna, Austria: R Foundation for Statistical Computing; 2022 [cited 2024 Feb 18]. Available from: http://www.rproject.org/index.html

26. Marx-Schütt K, Cherney DZI, Jankowski J, Matsushita K, Nardone M, Marx N. Cardiovascular disease in chronic kidney disease. Eur Heart J. 2025;46(23):2148–2160. https://doi.org/10.1093/eurheartj/ehaf167

27. Vogt I, Haffner D, Leifheit-Nestler M. FGF23 and phosphate-cardiovascular toxins in CKD. Toxins (Basel). 2019;11(11):647. https://doi.org/10.3390/toxins11110647

28. Michigami T, Kawai M, Yamazaki M, Ozono K. Phosphate as a signaling molecule and its sensing mechanism. Physiol Rev. 2018;98(4):2317–2348. https://doi.org/10.1152/physrev.00022.2017

29. Kritmetapak K, Kumar R. Phosphate as a signaling molecule. Calcif Tissue Int. 2021;108(1):16–31. https://doi.org/10.1007/s00223-019-00636-8

30. Tatsumi S, Miyagawa A, Kaneko I, Shiozaki Y, Segawa H, Miyamoto K. Regulation of renal phosphate handling: interorgan communication in health and disease. J Bone Miner Metab. 2016;34(1):1–10. https://doi.org/10.1007/s00774-015-0705-z

31. Добронравов В.А. Фосфат, почки, кости и сердечно-сосудистая система. Нефрология. 2016;20(4):10–24.

32. Leifheit-Nestler M, Vogt I, Haffner D, Richter B. Phosphate is a cardiovascular toxin. Adv Exp Med Biol. 2022;1362:107–134. https://doi.org/10.1007/978-3-030-91623-7-11

33. Hu MC, Shi M, Cho HJ, Adams-Huet B, Paek J, Hill K, et al. Klotho and phosphate are modulators of pathologic uremic cardiac remodeling. J Am Soc Nephrol. 2015;26(6):1290–1302. https://doi.org/10.1681/ASN.2014050465

34. Liu ES, Thoonen R, Petit E, Yu B, Buys ES, Scherrer-Crosbie M, et al. Increased circulating FGF23 does not lead to cardiac hypertrophy in the male Hyp mouse model of XLH. Endocrinology. 2018;159(5):2165–2172. https://doi.org/10.1210/en.2018-00174

35. Amann K, Törnig J, Kugel B, Gross ML, Tyralla K, El-Shakmak A, et al. Hyperphosphatemia aggravates cardiac fibrosis and microvascular disease in experimental uremia. Kidney Int. 2003;63(4):1296–1301. https://doi.org/10.1046/j.1523-1755.2003.00864.x

36. Neves KR, Graciolli FG, dos Reis LM, Pasqualucci CA, Moysés RM, Jorgetti V. Adverse effects of hyperphosphatemia on myocardial hypertrophy, renal function, and bone in rats with renal failure. Kidney Int. 2004;66(6):2237–2244. https://doi.org/10.1111/j.1523-1755.2004.66013.x

37. Maizel J, Six I, Dupont S, Secq E, Dehedin B, Barreto FC, et al. Effects of sevelamer treatment on cardiovascular abnormalities in mice with chronic renal failure. Kidney Int. 2013;84(3):491–500. https://doi.org/10.1038/ki.2013.110

38. Beck L, Leroy C, Salaün C, Margall-Ducos G, Desdouets C, Friedlander G. et al. Identification of a novel function of PiT1 critical for cell proliferation and independent of its phosphate transport activity. J Biol Chem. 2009;284(45):31363–31374. https://doi.org/10.1074/jbc.M109.053132

39. Salaün C, Gyan E, Rodrigues P, Heard JM. Pit2 assemblies at the cell surface are modulated by extracellular inorganic phosphate concentration. J Virol. 2002;76(9):4304–4311. https://doi.org/10.1128/JVI.76.9.4304-4311.2002.

40. Chande S, Caballero D, Ho BB, Fetene J, Serna J, Pesta D, et al. Slc20a1/Pit1 and Slc20a2/Pit2 are essential for normal skeletal myofiber function and survival. Sci Rep. 2020;10(1):3069. https://doi.org/10.1038/s41598-020-59430-4

41. Arita NA, Pelaez D, Cheung HS. Activation of the extracellular signal-regulated kinases 1 and 2 (ERK1/2) is needed for the TGFβ-induced chondrogenic and osteogenic differentiation of mesenchymal stem cells. Biochem Biophys Res Commun. 2011;405(4):564–569. https://doi.org/10.1016/j.bbrc.2011.01.068

42. Zhang Z, Yang Z, Wang S, Wang X, Mao J. Targeting MAPK-ERK/JNK pathway: a potential intervention mechanism of myocardial fibrosis in heart failure. Biomed Pharmacother. 2024;173:116413. https://doi.org/10.1016/j.biopha.2024.116413

43. Wittrant Y, Bourgine A, Khoshniat S, Alliot-Licht B, Masson M, Gatius M, et al. Inorganic phosphate regulates Glvr 1 and –2 expression: role of calcium and ERK1/2. Biochem Biophys Res Commun. 2009;381(2):259–263. https://doi.org/10.1016/j.bbrc.2009.02.034

44. Michigami T. Extracellular phosphate as a signaling molecule. Contrib Nephrol. 2013;180:14–24. https://doi.org/10.1159/000346776

45. Kestenbaum B, Sampson JN, Rudser KD, Patterson DJ, Seliger SL, Young B, et al. Serum phosphate levels and mortality risk among people with chronic kidney disease. J Am Soc Nephrol. 2005;16:520–528. https://doi.org/10.1681/ASN.2004070602

46. Ogata H, Sugawara H, Yamamoto M, Ito H. Phosphate and coronary artery disease in patients with chronic kidney disease. J Atheroscler Thromb. 2024;31(1):1–14. https://doi.org/10.5551/jat.RV22012

47. Zanoli L, Lentini P, Briet M, Castellino P, House AA, London GM, et al. Arterial stiffness in the heart disease of CKD. J Am Soc Nephrol. 2019;30(6):918–928. https://doi.org/10.1681/ASN.2019020117

48. McGovern AP, de Lusignan S, van Vlymen J, Liyanage H, Tomson CR, Gallagher H, et al. Serum phosphate as a risk factor for cardiovascular events in people with and without chronic kidney disease: a large community based cohort study. PLoS One. 2013;8(9): e74996. https://doi.org/10.1371/journal.pone.0074996

49. Dhingra R, Gona P, Benjamin EJ, Wang TJ, Aragam J, D’Agostino RB Sr, et al. Relations of serum phosphorus levels to echocardiographic left ventricular mass and incidence of heart failure in the community. Eur J Heart Fail. 2010;12(8):812–818. https://doi.org/10.1093/eurjhf/hfq106

50. Kestenbaum B, Glazer NL, Köttgen A, Felix JF, Hwang SJ, Liu Y, et al. Common genetic variants associate with serum phosphorus concentration. J Am Soc Nephrol. 2010;21(7):1223–1232. https://doi.org/10.1681/ASN.2009111104