Decreased Serum Levels of Klotho Protein in Chronic Kidney Disease Patients: Clinical Imortance

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Abstract


Objective: to determine the role of serum Klotho (s-Klotho) protein levels changes in patients with different stages of chronic kidney disease (CKD).

Methods: The study involved 130 patients with CKD stages 1–5D (mean age ― 41±6.7 years). Serum levels of parathyroid hormone (PTH), calcium, phosphorus and s-Klotho protein (ELISA method) at baseline and after 1 year of follow-up were examined in all the patients so as the blood pressure (BP), including central (aortic), pulse wave velocity ― with the help of «Sphygmоcor» (Australia), echocardiography, radiography of the abdominal aorta in a lateral projection were also performed.

Results: when comparing the s-Klotho levels in patients with different CKD stages, it was found that the level change associated with the reduction of glomerular filtration rate (GFR) ahead of phosphorus and PTH increase in serum, stared at 3A CKD, whereas hyperphosphatemia and PTH increase started at 4–5 CKD stages. According to ROC analysis, decreasing of s-Klotho levels below 387 pg/ml was indicated a calcification risk of abdominal aorta increased with an 80% sensitivity and 75% specificity. In addition, a strong negative relationship of low s-Klotho levels and heart remodeling was found. When comparing the patients with hypertension who were receiving antihypertensive monotherapy, the highest serum levels of Klotho protein were observed in those of them whose target blood pressure level was achieved primarily through Angiotensin II Receptors Blockers (ARB), compared to those who was administered another drug group (p<0.01) or has not reached the target blood pressure level (p=0,008).

Conclusion: The change of serum Klotho levels (decrease) in CKD progression is associated with the degree (increase) of cardiovascular calcification and remodeling (the development of left ventricular hypertrophy, and cardiomyopathy) and it can be seen as an early independent marker of the cardiovascular system lesions in CKD. Our preliminary data of the effect of blood pressure correction on s-Klotho levels may indicate the possibility of drug maintaining serum Klotho levels and it requires further research.


L. Y. Milovanova

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Author for correspondence.
Email: Ludm.milovanova@gmail.com

Russian Federation MD, PhD, assistance professor

N. A. Mukhin

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: Moukhin-nephro@yandex.ru

Russian Federation MD, PhD, Professor

L. V. Kozlovskaya

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: fake@neicon.ru

Russian Federation MD, PhD, Professor

Y. S. Milovanov

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: ymil@mail.ru

Russian Federation MD, PhD, Professor

G. G. Kiyakbaev

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: anton.borisov.2016@gmail.com

Russian Federation student

I. V. Rogova

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: gajratki@mail.ru

кандидат медицинских наук, ассистент кафедры внутренних, профессиональных болезней и пульмонологии МПФ Адрес: 119435, Москва, ул. Россолимо, д. 11, стр. 4

M. V. Lebedeva

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: marinaamica@mail.ru

кандидат медицинских наук, доцент кафедры внутренних, профессиональных болезней и пульмонологии МПФ Адрес: 119435, Москва, ул. Россолимо, д. 11, стр. 4

T. V. Androsova

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: androsova@mail.ru

кандидат медицинских наук, ассистент кафедры внутренних,
профессиональных болезней и пульмонологии МПФ Адрес: 119435, Москва, ул. Россолимо, д. 11, стр. 4

S. Y. Milovanova

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: sveta@mail.ru

доктор медицинских наук, ведущий научный сотрудник НОКЦ Первый МГМУ им. И.М. Сеченова Адрес: 119435, Москва, ул. Россолимо, д. 11, стр. 4

A. Y. Gil

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: artyom5@mail.ru

кандидат медицинских наук, доцент кафедры ВШМ Первый МГМУ им. И.М. Сеченова Адрес: 119435, Москва, ул. Россолимо, д. 11, стр. 4

M. V. Taranova

I.M. Sechenov First Moscow State Medical University, Moscow, Russian Federation

Email: taranova@mail.ru

кандидат медицинских наук, доцент кафедры внутренних, профессиональных болезней и пульмонологии МПФ Адрес: 119435, Москва, ул. Россолимо, д. 11, стр. 4

  1. Couser WG, Remuzzi G, Mendis S, Tonelli M. The contribution of chronic kidney disease to the global burden of major noncommunicable diseases. Kidney Int. 2011;80(12):1258–1270. doi: 10.1038/ki.2011.368.
  2. KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of Chronic Kidney Disease-Mineral and Bone Disorder (CKD-MBD). Kidney Int Suppl. 2009;(113):S1– 130. doi: 10.1038/ki.2009.188.
  3. Hruska KA, Seifert M, Sugatani T. Pathophysiology of the chronic kidney disease-mineral bone disorder. Curr Opin Nephrol Hypertens.2015;24(4):303–309. doi: 10.1097/MNH.0000000000000132.
  4. Bae EH. Is Klotho deficiency independently associated with cardiovascular risk in chronic kidney disease? Kidney Res Clin Pract. 2016;35(1):1–2. doi: 10.1016/j.krcp.2016.01.001.
  5. Abdallah E, Mosbah O, Khalifa G, et al. Assessment of the relationship between serum soluble Klotho and carotid intimamedia thickness and left ventricular dysfunction in hemodialysis patients. Kidney Res Clin Pract. 2016;35(1):42–49. doi: 10.1016/j.krcp.2015.12.006.
  6. Oh HJ, Nam BY, Lee MJ, et al. Decreased circulating klotho levels in patients undergoing dialysis and relationship to oxidative stress and inflammation. Perit Dial Int. 2015;35(1):43–51. doi: 10.3747/
  7. pdi.2013.00150.
  8. Pavlatou MG, Remaley AT, Gold PW. Klotho: a humeral mediator in CSF and plasma that influences longevity and susceptibility to multiple complex disorders, including depression. Transl Psychiatry. 2016;6(8):e876. doi: 10.1038/tp.2016.135.
  9. Hu MC, Kuro-o M, Moe OW. Klotho and chronic kidney disease. Contrib Nephrol. 2013;180:47–63. doi: 10.1159/000346778.
  10. Kuro-o M. Klotho in chronic kidney disease what’s new? Nephrol Dial Transplant. 2009;24(6):1705–1708. doi: 10.1093/ndt/gfp069.
  11. Hu MC, Kuro-o M, Moe O. Renal and extra-renal actions of Klotho. Semin Nephrol. 2013;33(2):118–129. doi: 10.1016/j.semnephrol. 2012.12.013.
  12. Devereux RB. The value of noninvasive measurements in hypertension. JAMA. 1990;264(21):2798–2799. doi: 10.1001/jama.264.21.2798.
  13. Garland JS, Holden RM, Groome PA, et al. Prevalence and associations of coronary artery calcification in patients with stages 3 to 5 CKD without cardiovascular disease. Am J Kidney Dis. 2008;52(5):849–858. doi: 10.1053/j.ajkd.2008.04.012.
  14. Middleton RJ, Parfrey PS, Foley RN. Left ventricular hypertrophy in the renal patient. J Am Soc Nephrol. 2001;12(5):1079–1084.
  15. Levin A, Singer J, Thompson CR, et al. Prevalent left ventricular hypertrophy in the predialysis population: identifying opportunities for intervention. Am J Kidney Dis. 1996;27(3):347–354. doi: 10.1016/s0272-6386(96)90357-1.
  16. Hu MC, Shi M, Zhang J, et al. Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol. 2011;22(1):124–136. doi: 10.1681/ASN.2009121311.
  17. Sharaf El Din UAA, Salem MM, Abdulazim DO. Vascular calcification: When should we interfere in chronic kidney disease patients and how? World J Nephrol. 2016;5(5):398–417. doi: 10.5527/wjn. v5.i5.398.
  18. Zhu D, Mackenzie NC, Millan JL, et al. The appearance and modulation of osteocyte marker expression during calcification of vascular smooth muscle cells. PLoS One. 2011;6(5):e19595. doi: 10.1371/journal.pone.0019595.
  19. Yoon HE, Ghee JY, Piao S, et al. Angiotensin II blockade upregulates the expression of Klotho, the anti-ageing gene, in an experimental model of chronic cyclosporine nephropathy. Nephrol Dial Transplant. 2011;26(3):800–813. doi: 10.1093/ndt/gfq537.
  20. Roman-Garcia P, Carrillo-Lopez N, Fernandez-Martin JL, et al. High phosphorus diet induces vascular calcification, a related decrease in bone mass and changes in the aortic gene expression. Bone. 2010;46(1):121–128. doi: 10.1016/j.bone.2009.09.006.
  21. Benigni A, Corna D, Zoja C, et al. Disruption of the Ang II type 1 receptor promotes longevity in mice. J Clin Invest. 2009;119(3):524–530. doi: 10.1172/JCI36703.
  22. Pedraza-Chaverri J, Sanchez-Lozada LG, Osorio-Alonso H, et al. New pathogenic concepts and therapeutic approaches to oxidative stress in chronic kidney disease. Oxid Med Cell Longev. 2016;2016:6043601. doi: 10.1155/2016/6043601.
  23. Inselmann G, Hannemann J, Baumann K. Cyclosporine A induced lipid peroxidation and influence on glucose-6-phosphatase in rat hepatic and renal microsomes. Res Commun Chem Pathol Pharmacol. 1990;68(2):189–203.
  24. Karalliedde J, Maltese G, Hill B, et al. Effect of renin-angiotensin system blockade on soluble Klotho in patients with type 2 diabetes, systolic hypertension, and albuminuria. Clin J Am Soc Nephrol. 2013;8(11):1899–1905. doi: 10.2215/CJN.02700313.
  25. Yamamoto M, Clark JD, Pastor JV, et al. Regulation of oxidative stress by the anti-aging hormone klotho. J Biol Chem. 2005;280(45):38029–38034. doi: 10.1074/jbc.M509039200.
  26. Kurosu H, Yamamoto M, Clark JD, et al. Suppression of aging in mice by the hormone Klotho. Science. 2005;309(5742):1829–1833. doi: 10.1126/science.1112766.
  27. Kuro-o M. Klotho in health and disease. Curr Opin Nephrol Hypertens. 2012;21(4):362–368. doi: 10.1097/MNH.0b013e32835422ad.
  28. Karalliedde J, Smith A, DeAngelis L, et al. Valsartan improves arterial stiffness in type 2 diabetes independently of blood pressure lowering. Hypertension. 2008;51(6):1617–1623. doi: 10.1161/ HYPERTENSIONAHA.108.111674.

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