Background: Abnormalities in mineral metabolism are common complications of organ transplantation. The role of immunosuppressive agents in alteration of mineral metabolism is not clear. Methods: We conducted an animal study to investigate the effects of cyclosporine A (CsA), tacrolimus, and sirolimus on renal calcium, magnesium and vitamin D metabolism. Results: CsA and tacrolimus induced a 2- to 3-fold and 1.6- to 1.8-fold increase in urinary calcium and magnesium excretion, respectively, while rapamycin had no effects on calcium, but doubled the urinary magnesium excretion. CsA and tacrolimus, but not rapamycin, elevated serum 1,25(OH)2 vitamin D without affecting the parathyroid hormone level. CsA and tacrolimus reduced mRNA abundance in TRPV5 (CsA: 64 ± 3% of control; tacrolimus: 50 ± 3%) calbindin-D28k (CsA: 62 ± 4%; tacrolimus: 43 ± 3%), and vitamin D receptor (CsA: 52 ± 3%; tacrolimus: 58 ± 2%, all p < 0.05). Rapamycin did not affect gene expression in any of studied proteins. The immunofluorescence staining study demonstrated a 50% reduction of TRPV5 and calbindin-D28k by CsA and tacrolimus. Conclusion: The suppression of VDR by calcineurin inhibitors is probably the underlying mechanism of renal calcium wasting. In spite of an increased 1,25(OH)2 vitamin D level, the kidney is not able to reserve calcium, suggesting a role of vitamin D resistance that may be related to bone loss.

Keywords:
Immunosuppressants, Calcium transport, Vitamin D
1.
Kasiske BL, Zeier MG, Chapman JR, Craig JC, Ekberg H, Garvey CA, Green MD, Jha V, Josephson MA, Kiberd BA, Kreis HA, McDonald RA, Newmann JM, Obrador GT, Vincenti FG, Cheung M, Earley A, Raman G, Abariga S, Wagner M, Balk EM: KDIGO clinical practice guideline for the care of kidney transplant recipients: a summary. Kidney Int 2010;77:299–311.
2.
Wong W, Venetz JP, Tolkoff-Rubin N, Pascual M: Immunosuppressive strategies in kidney transplantation: which role for the calcineurin inhibitors? Transplantation 2005;80:289–296.
3.
Cunningham J: Posttransplantation bone disease. Transplantation 2005;79:629–634.
4.
Stempfle HU, Werner C, Siebert U, Assum T, Wehr U, Rambeck WA, Meiser B, Theisen K, Gärtner R: The role of tacrolimus (FK506)-based immunosuppression on bone mineral density and bone turnover after cardiac transplantation: a prospective, longitudinal, randomized, double-blind trial with calcitriol. Transplantation 2002;73:547–552.
5.
Romero DF, Buchinsky FJ, Rucinski B, Cvetkovic M, Bryer HP, Liang XG, Ma YF, Jee WS, Epstein S: Rapamycin: a bone sparing immunosuppressant? J Bone Miner Res 1995;10:760–768.
6.
Campistol JM, Holt DW, Epstein S, Gioud-Paquet M, Rutault K, Burke JT: Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus. Transplant Int 2005;18:1028–1035.
7.
Lee CT, Huynh VM, Lai LW, Lien YH: Cyclosporine A-induced hypercalciuria in calbindin-D28k knockout and wild-type mice. Kidney Int 2002;62:2055–2061.
8.
Nijenhuis T, Hoenderop JG, Bindels, RJ: Downregulation of Ca2+ and Mg2+ transport proteins in the kidney explains tacrolimus (FK506)-induced hypercalciuria and hypomagnesemia. J Am Soc Nephrol 2004;15:549–557.
9.
Andoh TF, Burdmann EA, Fransechini N, Houghton DC, Bennett WM: Comparison of acute rapamycin nephrotoxicity with cyclosporine and FK506. Kidney Int 1996;50:1110–1117.
10.
Stein B, Halloran BP, Reinhardt T, Engstrom GW, Bales CW, Drezner MK, Currie KL, Takizawa M, Adams JS, Epstein S: Cyclosporin-A increases synthesis of 1,25-dihydroxyvitamin D3 in the rat and mouse. Endocrinology 1991;128:1369–1373.
11.
Wu MJ, Wen MC, Chiu YT, Chiou YY, Shu KH, Tang MJ: Rapamycin attenuates unilateral ureteral obstruction-induced renal fibrosis. Kidney Int 2006;69:2029–2036.
12.
Lee CT, Lien YH, Lai LW, Chen JB, Lin CR, Chen HC: Increased renal calcium and magnesium transporter abundance in streptozotocin-induced diabetes mellitus. Kidney Int 2006;69:1786–1791.
13.
Halloran PF, Helms LM, Kung L, Noujaim J: The temporal profile of calcineurin inhibition by cyclosporine in vivo. Transplantation 1999;15:1356–1361.
14.
Moffatt SD, McAlister V, Calne RY, Metcalfe SM: Potential for improved therapeutic index of FK506 in liposomal formulation demonstrated in a mouse cardiac allograft model. Transplantation 1999;15:1205–1208.
15.
Zafar I, Ravichandran K, Belibi FA, Doctor RB, Edelstein CL: Sirolimus attenuates disease progression in an orthologous mouse model of human autosomal dominant polycystic kidney disease. Kidney Int 2010;78:754–761.
16.
Fatemi S, Ryzen E, Flores J, Endres DB, Rude RK: Effect of experimental human magnesium depletion on parathyroid hormone secretion and 1,25-dihydroxyvitamin D metabolism. J Clin Endocrinol Metab 1991;73:1067–1072.
17.
Li YC, Bolt MJG, Cao LP, Sitrin MD: Effects of vitamin D receptor inactivation on the expression of calbindins and calcium metabolism. Am J Physiol Endocrinol Metabol 2001;281:E558–E564.
18.
Zheng W, Xie Y, Li G, Kong J, Feng JQ, Li YC: Critical role of calbindin-D28K in calcium homeostasis revealed by mice lacking both vitamin D receptor and calbindin-D28K. J Biol Chem 2004;279:52406–52413.
19.
Grenet O, Bobadilla M, Chibout SD, Steiner S: Evidence for the impairment of the vitamin D activation pathway by cyclosporine A. Biochem Pharmacol 2000;59:267–272.
20.
Reichel H, Grussinger A, Knehans A, Kühn K, Schmidt-Gayk H, Ritz E: Long-term therapy with cyclosporin A does not influence serum concentrations of vitamin D metabolites in patients with multiple sclerosis. Clin Invest 1992;70:595–599.
21.
Shaw AJ, Hayes ME, Davies M, Edwards BD, Ballardie FW, Chalmers RJ, Mawer EB: Cyclosporin A and vitamin D metabolism: studies in patients with psoriasis and in rats. Clin Sci 1994;86:627–632.
22.
Briner VA, Thiel G, Monier-Faugere MC, Bognar B, Landmann J, Kamber V, Malluche HH: Prevention of cancellous bone loss but persistence of renal bone disease despite normal 1,25 vitamin D levels two years after kidney transplantation. Transplantation 1995;59:1393–1400.
23.
Monier-Faugere MC, Mawad H, Qi Q, Friedler RM, Malluche HH: High prevalence of low bone turnover and occurrence of osteomalacia after kidney transplantation. J Am Soc Nephrol 2000;11:1093–1099.
24.
Montalban C, LM de Francisco A, Marinoso ML, Zubimendi JA, Unzueta MG, Amado JA, Arias M: Bone disease in long-term adult kidney transplant patients with normal renal function. Kidney Int 2003;85:S129–S132.
25.
Van de Graaf SFJ, Bindels RJM, Hoenderop JGJ: Physiology of epithelial Ca2+ and Mg2+ transport. Rev Physiol Biochem Pharmacol 2006;158:77–160.
26.
Raue F, Haag C, Schulze E, Frank-Raue K: The role of the extracellular calcium-sensing receptor in health and disease. Exp Clin Endocrinol Diabetes 2006;114:397–405.
27.
Blanchard A, Jeunemaitre X, Coudol P, Dechaux M, Froissart M, May A, Demontis R, Fournier A, Paillard M, Houillier P: Paracellin-1 is critical for magnesium and calcium reabsorption in the human thick ascending limb of Henle. Kidney Int 2007;59:2206–2215.
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2011
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