Chronic kidney disease-mineral and bone disorder (CKD-MBD) is common in kidney transplant recipients (KTRs), where secondary hyperparathyroidism (HPTH) and post-transplantation bone disease (PTBD) are potential effectors of both graft and vascular aging. Reduced 25(OH)D levels are highly prevalent in KTRs. Experimental and clinical evidence support the direct involvement of deranged vitamin D metabolism in CKD-MBD among KTRs. This review analyzes the pathophysiology of vitamin D derangement in KTRs and its fall out on patient and graft outcome, highlighting the roles of both nutritional and active vitamin D compounds to treat PTBD, cardiovascular disease (CVD) and graft dysfunction. Fibroblast growth factor-23-parathyroid hormone (PTH)-vitamin D axis, immunosuppressive therapy and previous bone status have been associated with PTBD. Although several studies reported reduced PTH levels in KTRs receiving nutritional vitamin D, its effects on bone mineral density (BMD) remain controversial. Active vitamin D reduced PTH levels and increased BMD after transplantation, but paricalcitol treatment was not accompanied by benefits on osteopenia. Vitamin D is considered protective against CVD due to the widespread pleiotropic effects, but data among KTRs remain scanty. Although vitamin deficiency is associated with lower glomerular filtration rate (GFR) and faster estimated GFR decline and data on the anti-proteinuric effects of vitamin D receptor activation (VDRA) in KTRs sound encouraging, reports on related improvement on graft survival are still lacking. Clinical data support the efficacy of VDRA against HPTH and show promising evidence of VDRA's effect in counteracting post-transplant proteinuria. New insights are mandatory to establish if the improvement of surrogate outcomes will translate into better patient and graft outcome.

1.
Wolfe RA, Ashby VB, Milford EL, et al: Comparison of mortality in all patients on dialysis, patients on dialysis awaiting transplantation, and recipients of a first cadaveric transplant. N Engl J Med 1999;341:1725-1730.
2.
Tonelli M, Wiebe N, Knoll G, et al: Systematic review: kidney transplantation compared with dialysis in clinically relevant outcomes. Am J Transplant 2011;11:2093-2109.
3.
Sellarés J, de Freitas DG, Mengel M, et al: Understanding the causes of kidney transplant failure: the dominant role of antibody-mediated rejection and nonadherence. Am J Transplant 2012;12:388-399.
4.
Weiner DE, Carpenter MA, Levey AS, et al: Kidney function and risk of cardiovascular disease and mortality in kidney transplant recipients: the FAVORIT trial. Am J Transplant 2012;12:2437-2445.
5.
Ojo AO, Morales JM, González-Molina M, et al; Scientific Registry of Transplant Recipients and; Spanish Chronic Allograft Study Group: Comparison of the long-term outcomes of kidney transplantation: USA versus Spain. Nephrol Dial Transplant 2013;28:213-220.
6.
Galassi A, Bellasi A, Papagni S, et al: Which vitamin D in CKD-MBD? The time of burning questions. Biomed Res Int 2013;2013:864012.
7.
Courbebaisse M, Souberbielle JC, Thervet E: Potential nonclassical effects of vitamin D in transplant recipients. Transplantation 2010;89:131-137.
8.
Holick MF: Vitamin D deficiency. N Engl J Med 2007;357:266-281.
9.
Ormsby RT, Findlay DM, Kogawa M, et al: Analysis of vitamin D metabolism gene expression in human bone: evidence for autocrine control of bone remodelling. J Steroid Biochem Mol Biol 2014;144:110-113.
10.
Vaidya A, Williams JS: Vitamin D and insulin sensitivity: can gene association and pharmacogenetic studies of the vitamin D receptor provide clarity? Metabolism 2012;61:759-761.
11.
Gonzalez-Parra E, Rojas-Rivera J, Tuñón J, et al: Vitamin D receptor activation and cardiovascular disease. Nephrol Dial Transplant 2012;27(suppl 4):iv17-iv21.
12.
Thacher TD, Clarke BL: Vitamin D insufficiency. Mayo Clin Proc 2011;86:50-60.
13.
Bover J, Cozzolino M: Mineral and bone disorders in chronic kidney disease and end-stage renal disease patients: new insights into vitamin D receptor activation. Kidney Int Suppl (2011) 2011;1:122-129.
14.
Li YC, Qiao G, Uskokovic M, et al: Vitamin D: a negative endocrine regulator of the renin-angiotensin system and blood pressure. J Steroid Biochem Mol Biol 2004;89-90:387-392.
15.
Zhang Z, Sun L, Wang Y, et al: Renoprotective role of the vitamin D receptor in diabetic nephropathy. Kidney Int 2008;73:163-171.
16.
Tan X, Li Y, Liu Y: Paricalcitol attenuates renal interstitial fibrosis in obstructive nephropathy. J Am Soc Nephrol 2006;17:3382-3393.
17.
de Borst MH, Hajhosseiny R, Tamez H, et al: Active vitamin D treatment for reduction of residual proteinuria: a systematic review. J Am Soc Nephrol 2013;24:1863-1871.
18.
Boudville NC, Hodsman AB: Renal function and 25-hydroxyvitamin D concentrations predict parathyroid hormone levels in renal transplant patients. Nephrol Dial Transplant 2006;21:2621-2624.
19.
Querings K, Girndt M, Geisel J, et al: 25-Hydroxyvitamin D deficiency in renal transplant recipients. J Clin Endocrinol Metab 2006;91:526-529.
20.
Sadlier DM, Magee CC: Prevalence of 25(OH) vitamin D (calcidiol) deficiency at time of renal transplantation: a prospective study. Clin Transplant 2007;21:683-688.
21.
Keyzer CA, Riphagen IJ, Joosten MM, et al: Associations of 25(OH) and 1,25(OH)2 vitamin D with long-term outcomes in stable renal transplant recipients. J Clin Endocrinol Metab 2015;100:81-89.
22.
Bienaimé F, Girard D, Anglicheau D, et al: Vitamin D status and outcomes after renal transplantation. J Am Soc Nephrol 2013;24:831-841.
23.
Barros X, Fuster D, Rodríguez N, et al: Rapid calcitriol increase and persistent calcidiol insufficiency in the first 6 months after kidney transplantation. Nucl Med Commun 2015;36:489-493.
24.
Douthat WG, Chiurchiu CR, Massari PU: New options for the management of hyperparathyroidism after renal transplantation. World J Transplant 2012;2:41-45.
25.
Economidou D, Dovas S, Papagianni A, et al: FGF-23 Levels before and after renal transplantation. J Transplant 2009;2009:379082.
26.
Evenepoel P, Meijers BK, de Jonge H, et al: Recovery of hyperphosphatoninsm and renal phosphorus wasting one year after successful renal transplantation. Clin J Am Soc Nephrol 2008;3:1829-1836.
27.
Sánchez Fructuoso AI, Maestro ML, Pérez-Flores I, et al: Serum level of fibroblast growth factor 23 in maintenance renal transplant patients. Nephrol Dial Transplant 2012;27:4227-4235.
28.
Mazzaferro S, Pasquali M, Pugliese F, et al: Distinct impact of vitamin D insufficiency on calcitriol levels in chronic renal failure and renal transplant patients: a role for FGF23. J Nephrol 2012;25:1108-1118.
29.
Dusso AS, Finch J, Brown A, et al: Extrarenal production of calcitriol in normal and uremic humans. J Clin Endocrinol Metab 1991;72:157-164.
30.
Alshayeb HM, Josephson MA, Sprague SM: CKD-mineral and bone disorder management in kidney transplant recipients. Am J Kidney Dis 2013;61:310-325.
31.
Sanchez Fructuoso AI, Maestro ML, Calvo N, et al: Role of fibroblast growth factor 23 (FGF23) in the metabolism of phosphorus and calcium immediately after kidney transplantation. Transplant Proc 2012;44:2551-2554.
32.
Krajisnik T, Olauson H, Mirza MA, et al: Parathyroid Klotho and FGF-receptor 1 expression decline with renal function in hyperparathyroid patients with chronic kidney disease and kidney transplant recipients. Kidney Int 2010;78:1024-1032.
33.
Olauson H, Lindberg K, Amin R, et al: Parathyroid-Specific deletion of klotho unravels a novel calcineurin-dependent FGF23 signaling pathway that regulates PTH secretion. PLoS Genet 2013;9:e1003975.
34.
Pascussi JM, Robert A, Nguyen M, et al: Possible involvement of pregnane X receptor-enhanced CYP24 expression in drug-induced osteomalacia. J Clin Invest 2005;115:177-186.
35.
Akeno N, Matsunuma A, Maeda T, et al: Regulation of vitamin D-1alpha-hydroxylase and -24-hydroxylase expression by dexamethasone in mouse kidney. J Endocrinol 2000;164:339-348.
36.
Neves CL, dos Reis LM, Batista DG, et al: Persistence of bone and mineral disorders 2 years after successful kidney transplantation. Transplantation 2013;96:290-296.
37.
Bacchetta J, Dubourg L, Harambat J, et al: The influence of glomerular filtration rate and age on fibroblast growth factor 23 serum levels in pediatric chronic kidney disease. J Clin Endocrinol Metab 2010;95:1741-1748.
38.
Wesseling-Perry K, Tsai EW, Ettenger RB, et al: Mineral abnormalities and long-term graft function in pediatric renal transplant recipients: a role for FGF-23? Nephrol Dial Transplant 2011;26:3779-3784.
39.
Filipov JJ, Zlatkov BK, Dimitrov EP, et al: Relationship between vitamin D status and immunosuppressive therapy in kidney transplant recipients. Biotechnol Biotechnol Equip 2015;29:331-335.
40.
Lee CT, Ng HY, Lien YH, et al: Effects of cyclosporine, tacrolimus and rapamycin on renal calcium transport and vitamin D metabolism. Am J Nephrol 2011;34:87-94.
41.
Grenet O, Bobadilla M, Chibout SD, et al: Evidence for the impairment of the vitamin D activation pathway by cyclosporine A. Biochem Pharmacol 2000;59:267-272.
42.
Brandenburg VM, Politt D, Ketteler M, et al: Early rapid loss followed by long-term consolidation characterizes the development of lumbar bone mineral density after kidney transplantation. Transplantation 2004;77:1566-1571.
43.
Kodras K, Haas M: Effect of kidney transplantation on bone. Eur J Clin Invest 2006;36(suppl 2):63-75.
44.
Carlini RG, Rojas E, Weisinger JR, et al: Bone disease in patients with long-term renal transplantation and normal renal function. Am J Kidney Dis 2000;36:160-166.
45.
Ball AM, Gillen DL, Sherrard D, Weiss NS, et al: Risk of hip fracture among dialysis and renal transplant recipients. JAMA 2002;288:3014-3018.
46.
Brandenburg VM, Westenfeld R, Ketteler M: The fate of bone after renal transplantation. J Nephrol 2004;17:190-204.
47.
Lehmann G, Ott U, Stein G, et al: Renal osteodystrophy after successful renal transplantation: a histomorphometric analysis in 57 patients. Transplant Proc 2007;39:3153-3158.
48.
Borchhardt K, Sulzbacher I, Benesch T, et al: Low-turnover bone disease in hypercalcemic hyperparathyroidism after kidney transplantation. Am J Transplant 2007;7:2515-2521.
49.
Perrin P, Caillard S, javier RM, et al: Persistent hyperparathyroidism is a major risk factor for fractures in the five years after kidney transplantation. Am J Transplant 2013;13:2653-2663.
50.
Giannini S, D'Angelo A, Nobile M, et al: The effects of vitamin D receptor polymorphism on secondary hyperparathyroidism and bone density after renal transplantation. J Bone Miner Res 2002;17:1768-1773.
51.
Mazzaferro S, Pasquali M, Taggi F, et al: Progression of coronary artery calcification in renal transplantation and the role of secondary hyperparathyroidism and inflammation. Clin J Am Soc Nephrol 2009;4:685-690.
52.
Gwinner W, Suppa S, Mengel M, et al: Early calcification of renal allografts detected by protocol biopsies: causes and clinical implications. Am J Transplant 2005;5:1934-1941.
53.
Nankivell BJ, Borrows RJ, Fung CL, et al: The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:2326-2333.
54.
Schwarz A, Mengel M, Gwinner W, et al: Risk factors for chronic allograft nephropathy after renal transplantation: a protocol biopsy study. Kidney Int 2005;67:341-348.
55.
Fukunaga J, Yamaai T, Yamachika E, et al: Expression of osteoclast differentiation factor and osteoclastogenesis inhibitory factor in rat osteoporosis induced by immunosuppressant FK506. Bone 2004;34:425-431.
56.
Hirotani H, Tuohy NA, Woo JT, et al: The calcineurin/nuclear factor of activated T cells signaling pathway regulates osteoclastogenesis in RAW264.7 cells. J Biol Chem 2004;279:13984-13992.
57.
Westenfeld R, Schlieper G, Wöltje M, et al: Impact of sirolimus, tacrolimus and mycophenolate mofetil on osteoclastogenesis - implications for post-transplantation bone disease. Nephrol Dial Transplant 2011;26:4115-4123.
58.
Giannini S, Sella S, Silva Netto F, et al: Persistent secondary hyperparathyroidism and vertebral fractures in kidney transplantation: role of calcium-sensing receptor polymorphism and vitamin D deficiency. J Bone Miner Res 2010;25:841-848.
59.
Campistol JM, Holt DW, Epstein S, et al; Sirolimus European Renal Transplant Study Group: Bone metabolism in renal transplant patients treated with cyclosporine or sirolimus. Transpl Int 2005;18:1028-1035.
60.
Kahwaji J, Bunnapradist S, Hsu JW, et al: Cause of death with graft function among renal transplant recipients in an integrated healthcare system. Transplantation 2011;91:225-230.
61.
Marcén R, Jimenez S, Fernandez-Rodriguez A, et al: Are low levels of 25-hydroxyvitamin D a risk factor for cardiovascular diseases or malignancies in renal transplantation? Nephrol Dial Transplant 2012;27(suppl 4):iv47-iv52.
62.
Yilmaz MI, Sonmez A, Saglam M, et al: Longitudinal analysis of vascular function and biomarkers of metabolic bone disorders before and after renal transplantation. Am J Nephrol 2013;37:126-134.
63.
Obi Y, Hamano T, Ichimaru N, et al: Vitamin D deficiency predicts decline in kidney allograft function: a prospective cohort study. J Clin Endocrinol Metab 2014;99:527-535.
64.
Lee JR, Dadhania D, August P, et al: Circulating levels of 25-hydroxyvitamin D and acute cellular rejection in kidney allograft recipients. Transplantation 2014;98:292-299.
65.
Amer H, Cosio FG: Significance and management of proteinuria in kidney transplant recipients. J Am Soc Nephrol 2009;20:2490-2492.
66.
Astor BC, Matsushita K, Gansevoort RT, et al: Lower estimated glomerular filtration rate and higher albuminuria are associated with mortality and end-stage renal disease. A collaborative meta-analysis of kidney disease population cohorts. Kidney Int 2011;79:1331-1340.
67.
Gansevoort RT, Matsushita K, van der Velde M, et al: Lower estimated GFR and higher albuminuria are associated with adverse kidney outcomes. A collaborative meta-analysis of general and high-risk population cohorts. Kidney Int 2011;80:93-104.
68.
Ruggenenti P, Perna A, Mosconi L, et al: Urinary protein excretion rate is the best independent predictor of ESRF in non-diabetic proteinuric chronic nephropathies. ‘Gruppo Italiano di Studi Epidemiologici in Nefrologia' (GISEN). Kidney Int 1998;53:1209-1216.
69.
Shamseddin MK, Knoll GA: Posttransplantation proteinuria: an approach to diagnosis and management. Clin J Am Soc Nephrol 2011;6:1786-1793.
70.
Kidney Disease: Improving Global Outcomes (KDIGO) CKD-MBD Work Group: KDIGO clinical practice guideline for the diagnosis, evaluation, prevention, and treatment of chronic kidney disease-mineral and bone disorder (CKD-MBD). Kidney Int 2009;113:S1-S130.
71.
Courbebaisse M, Xu-Dubois YC, Thervet E, et al: Cholecalciferol supplementation does not protect against renal allograft structural and functional deterioration: a retrospective study. Transplantation 2011;91:207-212.
72.
Courbebaisse M, Alberti C, Colas S, et al: Vitamin D supplementation in renal transplant recipients (VITALE): a prospective, multicentre, double-blind, randomized trial of vitamin D estimating the benefit and safety of vitamin D3 treatment at a dose of 100,000 UI compared with a dose of 12,000 UI in renal transplant recipients: study protocol for a double-blind, randomized, controlled trial. Trials 2014;15:430.
73.
Thiem U, Heinze G, Segel R, et al: VITA-D: cholecalciferol substitution in vitamin D deficient kidney transplant recipients: a randomized, placebo-controlled study to evaluate the post-transplant outcome. Trials 2009;10:36.
74.
Gonzalez E, Rojas-Rivera J, Polanco N, et al: Effects of oral paricalcitol on secondary hyperparathyroidism and proteinuria of kidney transplant patients. Transplantation 2013;95:e49-e52.
75.
Trillini M, Cortinovis M, Ruggenenti P, et al: Paricalcitol for secondary hyperparathyroidism in renal transplantation. J Am Soc Nephrol 2015;26:1205-1214.
76.
de Zeeuw D, Agarwal R, Amdahl M, Audhya P, et al: Selective vitamin D receptor activation with paricalcitol for reduction of albuminuria in patients with type 2 diabetes (VITAL study): a randomised controlled trial. Lancet 2010;376:1543-1551.
77.
Agarwal R, Hynson JE, Hecht TJ, et al: Short-term vitamin D receptor activation increases serum creatinine due to increased production with no effect on the glomerular filtration rate. Kidney Int 2011;80:1073-1079.
78.
Amer H, Griffin MD, Stegall MD, et al: Oral paricalcitol reduces the prevalence of posttransplant hyperparathyroidism: results of an open label randomized trial. Am J Transplant 2013;13:1576-1585.
79.
KDIGO CKD Work Group: KDIGO 2012 clinical practice guideline for the evaluation and management of chronic kidney disease. Kidney Int Suppl 2013;3:1-150.
80.
Anderson PH, Lam NN, Turner AG, et al: The pleiotropic effects of vitamin D in bone. J Steroid Biochem Mol Biol 2013;136:190-194.
81.
Goldsmith DJ, Covic A, Fouque D, et al: Endorsement of the kidney disease improving global outcomes (KDIGO) chronic kidney disease-mineral and bone disorder (CKD-MBD) guidelines: a European renal best practice (ERBP) commentary statement. Nephrol Dial Transplant 2010;25:3823-3831.
82.
NICE National Institute for Health and Care Excellence: Chronic Kidney Disease: Early Identification and Management of Chronic Kidney Disease in Adults in Primary and Secondary Care, 2014.
83.
Wissing KM, Broeders N, Moreno-Reyes R, et al: A controlled study of vitamin D3 to prevent bone loss in renal-transplant patients receiving low doses of steroids. Transplantation 2005;79:108-115.
84.
Sahin G, Yasar NS, Sirmagul B, Bal C, Yalcin AU: The effect of low-dose cholecalciferol and calcium treatment on posttransplant bone loss in renal transplant patients: a prospective study. Ren Fail 2008;30:992-999.
85.
Courbebaisse M, Thervet E, Souberbielle JC, et al: Effects of vitamin D supplementation on the calcium-phosphate balance in renal transplant patients. Kidney Int 2009;75:646-651.
86.
Steiner RW, Ziegler M, Halasz NA, et al: Effect of daily oral vitamin D and calcium therapy, hypophosphatemia, and endogenous 1-25 dihydroxycholecalciferol on parathyroid hormone and phosphate wasting in renal transplant recipients. Transplantation 1993;56:843-846.
87.
Cueto-Manzano AM, Konel S, Freemont AJ, et al: Effect of 1,25-dihydroxyvitamin D3 and calcium carbonate on bone loss associated with long-term renal transplantation. Am J Kidney Dis 2000;35:227-236.
88.
Torres A, García S, Gómez A, et al: Treatment with intermittent calcitriol and calcium reduces bone loss after renal transplantation. Kidney Int 2004;65:705-712.
89.
Mainra R, Elder GJ: Individualized therapy to prevent bone mineral density loss after kidney and kidney-pancreas transplantation. Clin J Am Soc Nephrol 2010;5:117-124.
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