Background: Bone disorders are next to cardiovascular problems in frequency in renal transplant (RT) recipients. Reduction in 1,25-dihydroxycholecalciferol (1,25D) levels is among the reasons causing bone loss in these patients. Klotho (KL) serves as a co-receptor for fibroblast growth factor 23 (FGF23), and functions in vitamin D metabolism. KL polymorphisms have been identified in several studies, and phenylalanine to valine substitution at amino acid position 352 seemed to be important to KL function. We investigated KL F352V polymorphism and its relation with 1,25D levels in RT recipients. Methods: The study included 25 RT recipients (8 female, 17 male) and 26 (14 female, 12 male) healthy control subjects who were wild (FF) phenotypes in terms of KL F352V polymorphism. RT recipients with (FV, n = 11) and without (FF, n = 14) a heterozygote polymorphism were determined with high resolution DNA melting analysis of KL F352V polymorphism. Serum 1,25D levels were measured using the RIA method. Results: RT recipients with FV phenotype had significantly lower 1,25D levels (17.58 ± 18.38 pg/ml) compared to recipients with FF phenotype (44.91 ± 24.68 pg/ml) and control subjects (28.24 ± 12.13 pg/ml). 1,25D levels in RT recipients with FF phenotype were significantly higher than control subjects. Conclusions: KL F352V polymorphism may increase the expression of FGF23 co-receptor, KL protein and thus may decrease renal expression of 1α-hydroxylase, and/or stimulate 24-hydroxylase in RT recipients. The resultant decrease 1,25D levels may participate in bone loss in these patients.

Keywords:
Bone, Klotho polymorphism, Osteoporosis, Renal transplantation
1.
Rojas E, Carlini RG, Clesca P, et al: The pathogenesis of osteodystrophy after renal transplantation as detected by early alterations in bone remodeling. Kidney Int 2003;63:1915-1923.
2.
Braga Júnior JW, Neves RM, Pinheiro MM, Frisoli Júnior A, Castro CH, Szejnfeld VL, Carvalho AB: Prevalence of low trauma fractures in long-term kidney transplant patients with preserved renal function. Braz J Med Biol Res 2006;39:137-147.
3.
Ferreira A: Development of renal bone disease. Eur J Clin Invest 2006;36(suppl 2):2-12.
4.
Kokado Y, Takahara S, Ichimaru N, et al: Factors influencing vertebral bone density after renal transplantation. Transpl Int 2000;13(suppl 1):S431-S435.
5.
Julian BA, Benfield M, Quarles LD: Bone loss after organ transplantation. Transplant Rev 1993;7:82-95.
6.
Grotz WH, Mundinger FA, Gugel B, Exner VM, Kirste G, Schollmeyer PJ: Bone mineral density after kidney transplantation. A cross-sectional study in 190 graft recipients up to 20 years after transplantation. Transplantation 1995;59:982-986.
7.
Grotz WH, Rump LC, Niessen A, et al: Treatment of osteopenia and osteoporosis after kidney transplantation. Transplantation 1998;66:1004-1008.
8.
Julian BA, Laskow DA, Dubovsky J, Dubovsky EV, Curtis JJ, Quarles LD: Rapid loss of vertebral mineral density after renal transplantation. N Engl J Med 1991;325:544-550.
9.
Brandenburg VM, Westenfeld R, Ketteler M: The fate of bone after renal transplantation. J Nephrol 2004;17:190-204.
10.
O'Shaughnessy EA, Dahl DC, Smith CL, et al: Risk factors for fractures in kidney transplantation. Transplantation 2002;74:362-366.
11.
Durieux S, Mercadal L, Orcel P, et al: Bone mineral density and fracture prevalence in long-term kidney graft recipients. Transplantation 2002;74:496-500.
12.
Mazzaferro S, Diacinti D, Proietti E, et al: Morphometric X-ray absorptiometry in the assessment of vertebral fractures in renal transplant patients. Nephrol Dial Transplant 2006;21:466-471.
13.
Sikgenc MM, Paydas S, Balal M, Demir E, Kurt C, Sertdemir Y, Binokay F, Erken U: Bone disease in renal transplantation and pleotropic effects of vitamin D therapy. Transplant Proc 2010;42:2518-2526.
14.
Ball AM, Gillen DL, Sherrard D, Weiss NS, Emerson SS, Seliger SL, Kestenbaum BR, Stehman-Breen C: Risk of hip fracture among dialysis and renal transplant recipients. JAMA 2002;288:3014-3018.
15.
Cunningham J: Posttransplantation bone disease. Transplantation 2005;79:629-634.
16.
Heaf JG: Bone disease after renal transplantation. Transplantation 2003;75:315-325.
17.
Kurosu H, Yamamoto M, Clark JD, Pastor JV, Nandi A, Gurnani P, McGuinness OP, Chikuda H, Yamaguchi M, Kawaguchi H, Shimomura I, Takayama Y, Herz J, Kahn CR, et al: Suppression of aging in mice by the hormone Klotho. Science 2005;309:1829-1833.
18.
Kuro-o M: Klotho. Pflugers Arch 2010;459:333-343.
19.
Ersoy FF: A short story of Klotho and FGF23: a deuce of dark side or the savior? Int Urol Nephrol 2014;46:577-581.
20.
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.
21.
Roush W: Fast-forward aging in a mutant mouse? Science 1997;278:1013.
22.
Urakawa I, Yamazaki Y, Shimada T, et al: Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444:770-774.
23.
Arking DE, Krebsova A, Macek M Sr, Macek M Jr, Arking A, Mian IS, Fried L, Hamosh A, Dey S, McIntosh I, Dietz HC: Association of human aging with a functional variant of klotho. Proc Natl Acad Sci U S A 2002;99:856-861.
24.
Arking DE, Atzmon G, Arking A, et al: Association between a functional variant of the KLOTHO gene and high-density lipoprotein cholesterol, blood pressure, stroke, and longevity. Circ Res 2005;96:412-418.
25.
Riancho JA, Valero C, Hernández JL, et al: Association of the F352V variant of the Klotho gene with bone mineral density. Biogerontology 2007;8:121-127.
26.
Zarrabeitia MT, Hernández JL, Valero C, et al: Klotho gene polymorphism and male bone mass. Calcif Tissue Int 2007;80:10-14.
27.
Levey AS, Stevens LA, Schmid CH, et al: A new equation to estimate glomerular filtration rate. Ann Intern Med 2009;150:604-612.
28.
Consensus development conference: diagnosis, prophylaxis, and treatment of osteoporosis. Am J Med 1993;94:646-650.
29.
FRAX: World Health Organization Fracture Risk Assessment Tool. World Health Organization, 2011. http://www.shef.ac.uk/FRAX/index.aspx.
30.
Agrawal N, Josephson MA: Posttransplant bone disease. Transplant Rev 2007;21:143-154.
31.
Van Cleemput J, Daenen W, Geusens P, Dequeker P, Van De Werf F, VanHaecke J: Prevention of bone loss in cardiac transplant recipients. A comparison of biphosphonates and vitamin D. Transplantation 1996;61:1495-1499.
32.
Bacic D, Wagner CA, Hernando N, Kaissling B, Biber J, Murer H: Novel aspects in regulated expression of the renal type IIa Na/Pi-cotransporter. Kidney Int Suppl 2004;91:S5-S12.
33.
Sirilak S, Chatsrisak K, Ingsathit A, Kantachuvesiri S, Sumethkul V, Stitchantrakul W, et al: Renal phosphate loss in long-term kidney transplantation. Clin J Am Soc Nephrol 2012;7:323-331.
34.
Evenepoel P: Recovery versus persistence of disordered mineral metabolism in kidney transplant recipients. Semin Nephrol 2013;33:191-203.
35.
Omdahl JL, Morris HA, May BK: Hydroxylase enzymes of the vitamin D pathway: expression, function, and regulation. Annu Rev Nutr 2002;22:139-166.
36.
Nabeshima Y: Klotho: a fundamental regulator of aging. Ageing Res Rev 2002;1:627-638.
37.
Kawano K, Ogata N, Chiano M, Molloy H, Kleyn P, Spector TD, Uchida M, Hosoi T, Suzuki T, Orimo H, Inoue S, Nabeshima Y, Nakamura K, Kuro-o M, Kawaguchi H: Klotho gene polymorphisms associated with bone density of aged postmenopausal women. J Bone Miner Res 2002;17:1744-1751.
38.
Ogata N, Matsumura Y, Shiraki M, Kawano K, Koshizuka Y, Hosoi T, Nakamura K, Kuro-o M, Kawaguchi H: Association of klotho gene polymorphism with bone density and spondylosis of the lumbar spine in postmenopausal women. Bone 2002;31:37-42.
39.
Yamada Y, Ando F, Niino N, Shimokata H: Association of polymorphisms of the androgen receptor and klotho genes with bone mineral density in Japanese women. J Mol Med (Berl) 2005;83:50-57.
40.
Mullin BH, Wilson SG, Islam FM, Calautti M, Dick IM, Devine A, Prince RL: Klotho gene polymorphisms are associated with osteocalcin levels but not bone density of aged postmenopausal women. Calcif Tissue Int 2005;77:145-151.
41.
Riancho JA, Valero C, Hernández JL, Ortiz F, Zarrabeitia A, Alonso MA, Peña N, Pascual MA, González-Macías J, Zarrabeitia MT: Association of the F352V variant of the Klotho gene with bone mineral density. Biogerontology 2007;8:121-127.
42.
Urakawa I, Yamazaki Y, Shimada T, Iijima K, Hasegawa H, et al: Klotho converts canonical FGF receptor into a specific receptor for FGF23. Nature 2006;444:770-774.
43.
Liu S, Tang W, Zhou J, et al: Fibroblast growth factor 23 is a counter-regulatory phosphaturic hormone for vitamin D. J Am Soc Nephrol 2006;17:1305-1315.
44.
Madeira M, Zen MS, Lacativa PGS, Torres CH, Lázaro APP, Gonçalves RT, Carvalho de Mendonça LM, Fleiuss de Farias ML: Decreased bone mineral density in patients submitted to kidney transplantation is related to age, body mass index, time on dialysis, and hyperparathyroidism. Adv Endocrinol 2014;2014:716051.
45.
Marcén R, Caballero C, Uriol O, Fernández A, et al: Prevalence of osteoporosis, osteopenia, and vertebral fractures in long-term renal transplant recipients. Transplant Proc 2007;39:2256-2258.
46.
Almond MK, Kwan JT, Evans K, et al: Loss of regional bone mineral density in the first 12 months following renal transplantation. Nephron 1994;66:52-57.
47.
Horber FF, Casez JP, Steiger U, et al: Changes in bone mass early after kidney transplantation. J Bone Miner Res 1994;9:1-9.
48.
Suthanthiran M, Morris RE, Strom TB: Immunosuppressants: cellular and molecular mechanisms of action. Am J Kidney Dis 1996;28:159-172.
49.
Gouadon E, Lecerf F, German-Fattal M: Differential effects of cyclosporin A and tacrolimus on magnesium influx in CaCo2 cells. J Pharm Pharm Sci 2012;15:389-398.
50.
Lee CT, Ng HY, Lien YH, Lai LW, Wu MS, Lin CR, et al: Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. Am J Nephrol 2011;34:87-94.
51.
Jeffery JR, Leslie WD, Karpinski ME, Nickerson PW, Rush DN: A randomized prospective trial of calcitriol versus alendronate for the treatment of osteopenia in renal transplant recipients. Am J Transplant 2003;3:353.
52.
de Nijs RN, Jacobs JW, Algra A, Lems WF, Bijlsma JW: Prevention and treatment of glucocorticoid-induced osteoporosis with active vitamin D3 analogues: a review with meta-analysis of randomized controlled trials including organ transplantation studies. Osteoporos Int 2004;15:589-602.
53.
Palmer S, McGregor DO, Strippoli GF: Interventions for preventing bone disease in kidney transplant recipients. Cochrane Database Syst Rev 2005;18:CD005015.
© 2015 S. Karger AG, Basel
2015
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.