CIRCULATING FORM OF KLOTHO PROTEIN — A NOVEL INHIBITOR OF VASCULAR CALCIFICATION IN CHRONIC KIDNEY DISEASE

Objective. To study associations between serum soluble Klotho level and vascular calcification in patients with chronic kidney disease (CKD) 1–5 stages.

Design and methods. We examined 70 patients with different stages of CKD, including 41 patients with chronic glomerulonephritis, among them 10 with systemic diseases, 22 with tubulo-interstitial nephritis (bacterial, gout and drug-induced) and 7 with hypertensive nephrosclerosis. All 70 patients with 1–5 stages of CRD underwent clinical examination and blood tests for serum Klotho levels by enzyme-linked immunosorbent assay. Vascular stiffness was assessed in 57 patients by applanation tonometry method (SphygmoCor, AtCor Medical, Australia).

 Results. Serum Klotho levels differed depending on the stage of CKD. When patients with different stages of CKD were compared, a reverse correlation between serum Klotho level and serum phosphorus level and intact parathormone was found in CKD progression. There is a correlation between serum Klotho level and an increase in left ventricular posterior wall thickness in patients with CKD and hypertension (n = 49). Also reduction in serum Klotho level is associated with a greater frequency of calcifications in heart and major arteries, increased vascular stiffness and reduced blood flow in the tibial arteries (ankle-brachial index).

Conclusions. Thus, circulating Klotho plays an important role in mineral metabolism in CKD and demonstrates pleiotropic effects that might modify cardiovascular risk through the impact on vascular calcification and cardiovascular remodeling. 

1. Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group. KDIGO clinical practice guideline for the diagnosis, evalution, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int. 2009;76(Suppl 113):1–130.

2. Hu MC, Shi M, Zhang J et al. Klotho deficiency causes vascular calcification in chronic kidney disease. Am J Soc Nephrol. 2011;22(1):124–36.

3. Chung-Yi C, Makoto K, Razzaque MS. Molecular regulation of phosphate metabolism by fibroblast growth factor-23-Klotho system. Adv Chronic Kidney Dis. 2011;18(2):91–7.

4. Maltese G, Karalliedde J. The putative role of the antiageing protein Klotho in cardiovascular and renal disease. Int J Hypertens. 2012;2012:757–69.

5. Kuro-o M. Klotho in chronic kidney disease — what’s new? Nephrol Dial Transplant. 2009;24(6):1705–8.

6. Semba RD, Cappola AR, Sun K et al. Plasma Klotho and cardiovascular disease in adults. Am J Geriatr Soc. 2011;59(9):1596–601.

7. Haruna Y, Kashihara N, Satoh M et al. Amelioration of progressive renal injury by genetic manipulation of Klotho gene. Proc Natl Acad Sci USA. 2007:104;2331–36.

8. Mitani H, Ishizaka N, Aizawa T et al. In vivo Klotho gene transfer ameliorates angiotensin II-induced renal damage. Hypertension. 2002;39(4):838–43.

9. Wang Y, Sun Z. Klotho gene delivery prevents the progression of spontaneous hypertension and renal damage. Hypertension. 2009;54(4):810–17.

10. Donate-Correa J, Mora-Fernández C, MartínezSanz R et al. Expression of FGF23/KLOTHO system in human vascular tissue. Int J Cardiol. 2013;165(1):179–83.

11. Milovanova LYu, Milovanov YuS, Kozlovskaya LV. The place of paricalcitol in nephroprotrctive strategy of predialysis chronic kidney disease due to systemic diseases. Arh Evromed. 2011;3:69–78.

12. Dobronravov VA. The modern view of the pathophysiology of secondary hyperparathyroidism: the role of fibroblast growth factor 23 and Klotho. Nephrology. 2011;15(4):11–20. In Russian.

13. Gosse P, Roudaut R, Dallocchio M. Is echocardiography an adequate method to evaluate left ventricular hypertrophy regression? Eur Heart J. 1990;11(Suppl G):107–12.

14. Devereux RB. The value of noninvasive measurements in hypertension. J Am Med Assoc. 1990;264 (21):2798–9.

15. Borst MH, Vervloet MG. Cross talk between the renin-angiotensin-aldosterone system and vitamin D-FGF‑23 -klotho in chronic kidney disease. Am J Soc Nephrol. 2011;22(9):1603–1609.

16. Milovanova L, Milovanov Y, Plotnikova A. Phosphorus and calcium metabolism disorders assosiated with chronic kidney disease stage III–IV (systematic review and meta-analysis). Chronic kidney disease and renal transplantation. Ed. by Manisha Sahay. INTECH; 2012. p. 95–118.