Background/Aims: α-Klotho is mainly expressed in the kidneys, and its soluble form can prevent vascular calcifications. Inhibition of the mammalian target of rapamycin (mTOR) upregulates Klotho. We assessed serial changes in the levels of soluble Klotho (sKlotho) in recipients before and after renal transplantation and investigated the effects of an mTOR inhibitor. Methods: Serum sKlotho levels were measured in 36 recipients before and 1 year after transplantation and compared between those taking everolimus and those not taking everolimus. Results: sKlotho levels were higher after transplantation than before transplantation (369.3 vs. 211.8 pg/mL). After transplantation, sKlotho levels were significantly higher in recipients taking everolimus than in those not taking everolimus (536.7 vs. 332.4 pg/mL). Conclusion: Our results suggest that mTOR inhibition may augment the increase in sKlotho levels in transplant recipients. Further studies are needed to examine whether mTOR inhibitors suppress the development of vascular complications via upregulation of Klotho expression in renal transplant recipients.

Journal Section:
Research Article
Keywords:
Klotho, Mammalian target of rapamycin inhibitor, Everolimus, End-stage renal disease, Renal transplantation
1.
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, Okawa K, Fujita T, Fukumoto S, Yamashita T: Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006; 444: 770–774.
2.
Kuro-o M, Matsumura Y, Aizawa H, Kawaguchi H, Suga T, Utsugi T, Ohyama Y, Kurabayashi M, Kaname T, Kume E, Iwasaki H, Iida A, Shiraki-Iida T, Nishikawa S, Nagai R, Nabeshima YI: Mutation of the mouse klotho gene leads to a syndrome resembling ageing. Nature 1997; 390: 45–51.
3.
Kuro-o M: Klotho. Pflugers Arch 2010; 459: 333–343.
4.
Imura A, Iwano A, Tohyama O, Tsuji Y, Nozaki K, Hashimoto N, Fujimori T, Nabeshima Y: Secreted Klotho protein in sera and CSF: implication for post-translational cleavage in release of Klotho protein from cell membrane. FEBS Lett 2004; 565: 143–147.
5.
Hu MC, Shi M, Zhang J, Quinones H, Griffith C, Kuro-o M, Moe OW: Klotho deficiency causes vascular calcification in chronic kidney disease. J Am Soc Nephrol 2011; 22: 124–136.
6.
Tan SJ, Crosthwaite A, Langsford D, Obeysekere V, Ierino FL, Roberts MA, Hughes PD, Hewitson TD, Dwyer KM, Toussaint ND: Mineral adaptations following kidney transplantation. Transplant Int 2017; 30: 463–473.
7.
Zhao Y, Zhao MM, Cai Y, Zheng MF, Sun WL, Zhang SY, Kong W, Gu J, Wang X, Xu MJ: Mammalian target of rapamycin signaling inhibition ameliorates vascular calcification via Klotho upregulation. Kidney Int 2015; 88: 711–721.
8.
Solvig J, Ekberg H, Hansen F, Brunkvall J, Lanne T: Accuracy of noninvasive ultrasonic volume measurements on human kidney transplants. Presentation of a new formula. Nephron 1998; 80: 188–193.
9.
Moes DJ, Guchelaar HJ, de Fijter JW: Sirolimus and everolimus in kidney transplantation. Drug Discov Today 2015; 20: 1243–1249.
10.
Hamano T: Klotho upregulation by rapamycin protects against vascular disease in CKD. Kidney Int 2015; 88: 660–662.
11.
Han DH, Piao SG, Song JH, Ghee JY, Hwang HS, Choi BS, Kim J, Yang CW: Effect of sirolimus on calcineurin inhibitor-induced nephrotoxicity using renal expression of KLOTHO, an antiaging gene. Transplantation 2010; 90: 135–141.
12.
Donate-Correa J, Henriquez-Palop F, Martin-Nunez E, Perez-Delgado N, Muros-de-Fuentes M, Mora-Fernandez C, Navarro-Gonzalez JF: Effect of paricalcitol on FGF-23 and Klotho in kidney transplant recipients. Transplantation 2016; 100: 2432–2438.
13.
Lau WL, Leaf EM, Hu MC, Takeno MM, Kuro-o M, Moe OW, Giachelli CM: Vitamin D receptor agonists increase Klotho and osteopontin while decreasing aortic calcification in mice with chronic kidney disease fed a high phosphate diet. Kidney Int 2012; 82: 1261–1270.
14.
Yoon HE, Ghee JY, Piao S, Song JH, Han DH, Kim S, Ohashi N, Kobori H, Kuro-o M, Yang CW: 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: 800–813.
15.
Akimoto T, Kimura T, Watanabe Y, Ishikawa N, Iwazu Y, Saito O, Muto S, Yagisawa T, Kusano E: The impact of nephrectomy and renal transplantation on serum levels of soluble Klotho protein. Transplant Proc 2013; 45: 134–136.
16.
Tranaeus Lindblad Y, Olauson H, Vavilis G, Hammar U, Herthelius M, Axelsson J, Barany P: The FGF23-Klotho axis and cardiac tissue Doppler imaging in pediatric chronic kidney disease-a prospective cohort study. Pediatr Nephrol 2018; 33: 147–157.
17.
Bleskestad IH, Thorsen IS, Jonsson G, Skadberg O, Bergrem H, Goransson LG: Soluble Klotho and intact fibroblast growth factor 23 in long-term kidney transplant patients. Euro J Endocrinol 2015; 172: 343–350.
18.
Cai H, Lu R, Zhang M, Pang H, Zhu M, Zhang W, Ni Z, Qian J, Yan Y: Serum soluble Klotho level is associated with abdominal aortic calcification in patients on maintenance hemodialysis. Blood Purif 2015; 40: 120–126.
19.
Malyszko J, Koc-Zorawska E, Matuszkiewicz-Rowinska J, Malyszko J: FGF23 and Klotho in relation to markers of endothelial dysfunction in kidney transplant recipients. Transplant Proc 2014; 46: 2647–2650.
20.
Przybylowski P, Wasilewski G, Janik L, Kozlowska S, Nowak E, Malyszko J: Fibroblast growth factor 23 and Klotho as cardiovascular risk factors in heart transplant recipients. Transplant Proc 2014; 46: 2848–2851.
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