Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub. 2010, 154(4):297-306 | DOI: 10.5507/bp.2010.045

CALCINEURIN INHIBITOR–INDUCED RENAL ALLOGRAFT NEPHROTOXICITY

Karel Krejci*a, Tomas Tichyb, Petr Bachledac, Josef Zadrazila
a 3rd Department of Internal Medicine and Nephrology, University Hospital Olomouc, Czech Republic
b Institute of Pathology, University Hospital Olomouc
c 2nd Surgical Department and Transplant Centrum, University Hospital Olomouc

Background: The introduction of the calcineurin inhibitors (CI) cyclosporine and tacrolimus into immunosuppressive protocols initiated a new era in organ transplantation with excellent short-term graft survival. Nevertheless, the chronic nephrotoxicity of these drugs represents a significant adverse factor limiting their long-term use. Patients treated with a CI can be at risk for developing renal failure and this problem is especially pronounced in patients after renal transplantation.

Methods and Results: In a review paper we summarize the clinical aspects, histological manifestations and pitfalls of diagnostics of acute and chronic CI nephrotoxicity in patients after kidney transplantation. We look in detail at the disputed relationship between blood concentrations of cyclosporine and tacrolimus and histological manifestation of toxicity and summarize data showing that for toxic effects, local renal exposure to CI and their metabolites can play a more significant role than systemic exposure. We also include recent views on the pathophysiologic and molecular mechanisms underlying these changes; factors influencing local susceptibility to CI nephrotoxicity are discussed, including variability of expression and activity of P-glycoprotein and cytochrome P450. Last but not least we summarize our own experience with clinically manifest and subclinical forms of nephrotoxicity and their impact on the progression of chronic graft changes.

Conclusions: Owing to their unique effects, CI remain the cornerstone of most immunosuppressive protocols for renal transplantation. Together with optimization of local kidney exposure to CI and their metabolites, efforts to reduce systemic levels as much as possible are the most important preventive measure for reducing toxic renal graft damage.

Keywords: Calcineurin inhibitors, Cyclosporine and tacrolimus, Renal allograft, Nephrotoxicity, Risk factors, Prevention

Received: May 24, 2010; Accepted: November 12, 2010; Published: December 1, 2010  Show citation

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Krejci, K., Tichy, T., Bachleda, P., & Zadrazil, J. (2010). CALCINEURIN INHIBITOR–INDUCED RENAL ALLOGRAFT NEPHROTOXICITY. Biomedical papers154(4), 297-306. doi: 10.5507/bp.2010.045
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References

  1. Calne RY, White DJ, Thiru S, Evans DB, McMaster P, Dunn DC, Craddock GN, Pentlow BD, Rolles K. Cyclosporin A in patients receiving renal allografts from cadaver donors. Lancet 1978;2:1323 1327. Go to original source... Go to PubMed...
  2. Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet 1989;2:10001004. Go to original source...
  3. Halloran PF. Immunosuppressive drugs for kidney transplantation. N Engl J Med 2004;351:27152729. Go to original source... Go to PubMed...
  4. Andreoni KA, Brayman KL, Guidinger MK, Sommers CM, Sung RS. Kidney and pancreas transplantation in the United States, 19962005. Am J Transplant 2007;7:13591375. Go to original source... Go to PubMed...
  5. Schreiber SL, Crabtree GR. The mechanism of action of cyclosporine A and FK-506. Immunol Today 1992;12:136142. Go to original source... Go to PubMed...
  6. Liu EH, Siegel RM, Harlan DM, OShea JJ. T cell-directed therapies: Lessons learned and future prospects. Nat Immunol 2007;8:2530. Go to original source... Go to PubMed...
  7. Chapman JR, Nankivell BJ. Nephrotoxicity of ciclosporin A: shortterm gain, long-term pain? Nephrol Dial Transplant 2006;21:2060 2063. Go to original source... Go to PubMed...
  8. Naesens M, Lerut E, Damme BV, Vanrenterghem Y, Kuypers DR. Tacrolimus exposure and evolution of renal allograft histology in the first year after transplantation. Am J Transplant 2007;7:2114 2123. Go to original source... Go to PubMed...
  9. Lanese DM, Conger JD. Effects of endothelin receptor antagonist on cyclosporine-induced vasoconstriction in isolated rat renal arterioles. J Clin Invest 1993;91:21442149. Go to original source... Go to PubMed...
  10. Lamas S. Cellular mechanisms of vascular injury mediated by calcineurin inhibitors. Kidney Int 2005;68:898907. Go to original source... Go to PubMed...
  11. Bobadilla NA, Gamba G. New insights into the pathophysiology of cyclosporine nephrotoxicity: A role of aldosterone. Am J Physiol Renal Physiol 2007;293:F2F9. Go to original source...
  12. Wissmann C, Frey FJ, Ferrari P, Uehlinger DE. Acute cyclosporineinduced nephrotoxicity in renal transplant recipients: The role of the transplanted kidney. J Am Soc Nephrol 1996;7:26772681. Go to original source...
  13. Kurtz A, Della BR, Kuhn K. Cyclosporine A enhances renin secretion and production in isolated juxtaglomerular cells. Kidney Int 1988;33:947953. Go to original source... Go to PubMed...
  14. Ruster C, Wolf G. Renin-angiotensin-aldosterone systém and progression of renal disease. J Am Soc Nephrol 2006;17:29852991. Go to original source... Go to PubMed...
  15. Iijima K, Hamahira K, Kobayashi A, Nakamura H, Yoshikawa N. Immunohistochemical analysis of renin aktivity in chronic cyclosporine nephropathy in childhood neohrotiv syndrome. J Am Soc Nephrol 2000;11:22652271. Go to original source...
  16. Zhong Z, Arteel GE, Connor HD, Yin M, Frankenberg MV, Stachlewitz RF, Raleigh JA, Mason RP, Thurman RG. Cyclosporin A increases hypoxia and free radical production in rat kidneys: Prevention by dietary glycine. Am J Physiol 1988;275:F595F604. Go to original source... Go to PubMed...
  17. Diederich D, Skopec J, Diederich A, Dai FX. Cyclosporine produces endothelial dysfunction by increased production of superoxide. Hypertension 1994;23:957961. Go to original source... Go to PubMed...
  18. Navarro-Antolin J, Lopez-Munoz MJ, Klatt P, Soria J, Michel T, Lamas S. Formation of peroxynitrite in vascular endothelial cells exposed to cyclosporine A. FASEB J 2001;15:12911293. Go to original source... Go to PubMed...
  19. Sugimoto T, Haneda M, Sawano H, Isshiki K, Maeda S, Koya D, Inoki K, Yasuda H, Kashiwagi A, Kikkawa R. Endothelin-1 induces cyclooxygenase-2 expression via nuclear factor of activated T-cell transcription factor in glomerular mesangial cells. J Am Soc Nephrol 2001;12:13591368. Go to original source...
  20. Hocherl K, Dreher F, Vitzthum H, Kohler J, Kurtz A. Cyclosporine A suppresses cyclooxygenase-2 expression in the rat kidney. J Am Soc Nephrol 2002;13:24272436. Go to original source... Go to PubMed...
  21. Mihatsch MJ, Thiel G, Basler V, Ryffel B, Landmann J, von Overbeck J, Zollinger HU. Morphological patterns in cyclosporinetreated renal transplant recipients. Transplant Proc 1985;17:101 116.
  22. Morozumi K, Takeda A, Uchida K, Mihatsch MJ. Cyclosporine nephrotoxicity: how does it affect renal allograft function and transplant morphology? Transpl Proc 2004;36:S251S256. Go to original source...
  23. Pallet N, Rabant M, Xu-Dubois YC, Lecorre D, Mucchielli MH, Imbeaud S, Agier N, Hertig A, Thervet E, Legendre C, Beaune P, Anglicheau D. Response of human renal tubular cells to cyclosporine and sirolimus: a toxicogenomic study. Toxicol Appl Pharmacol 2008;229:184196. Go to original source... Go to PubMed...
  24. Bouvier N, Flinois JP, Gilleron J, Sauvage FL, Legendre C, Beaune P, Thervet E, Anglicheau D, Pallet N. Cyclosporine triggers endoplasmic reticulum stress in endothelial cells: a role for endothelial phenotypic changes and death. Am J Physiol Renal Physiol 2009;296:F160F169. Go to original source... Go to PubMed...
  25. Pallet N, Bouvier N, Bendjallabah A, Rabant M, Flinois JP, Hertig A, Legendre C, Beaune P, Thervet E, Anglicheau D. Cyclosporineinduced endoplasmic reticulum stress triggers tubular phenotypic changes and death. Am J Transplant 2008;8:22832296. Go to original source... Go to PubMed...
  26. Han SW, Li C, Ahn KO, Lim SW, Song HG, Jang YS, Cho YM, Jang YM, Ghee JY, Kim JY, Kim SH, Kim J, Kwon OJ, Yang CW. Prolonged endoplasmic reticulum stress induces apoptotic cell death in an experimental model of chronic cyclosporine nephropathy. Am J Nephrol 2008;28:707714. Go to original source... Go to PubMed...
  27. Du S, Hiramatsu N, Hayakawa K, Kasai A, Okamura M, Huang T, Yao J, Takeda M, Araki I, Sawada N, Paton AW, Paton JC, Kitamura M. Suppression of NF-B by cyclosporine A and tacrolimus (FK506) via induction of the C/EBP family: implication for unfolded protein response. J Immunol 2009;182:72017211. Go to original source... Go to PubMed...
  28. Naesens M, Kambham N, Concepcion W, Salvatierra O, Jr., Sarwal M. The evolution of non-immune histological injury and its clinical relevance in adult-sized kidney grafts in pediatric recipients. Am J Transplant 2007;7:25042514. Go to original source... Go to PubMed...
  29. Franz M, Regele H, Schmaldienst S, Stummvoll HK, Horl WH, Pohanka E. Posttransplant hemolytic uremic syndrome in adult retransplanted kidney graft recipients: Advantage of FK506 therapy? Transplantation 1998;66:12581262. Go to original source...
  30. Ponticelli C. De novo thrombotic microangiopathy. An underrated complication of renal transplantation. Clin Nephrol 2007;67:335 340. Go to original source... Go to PubMed...
  31. Oyen O, Strom EH, Midtvedt K, Bentdal O, Hartmann A, Bergan S, Pfeffer P, Brekke IB. Calcineurin inhibitor-free immunosuppression in renal allograft recipients with thrombotic microangiopathy/ hemolytic uremic syndrome. Am J Transplant 2006;6:412418. Go to original source... Go to PubMed...
  32. Bren A, Pajek J, Grego K, Buturovic J, Ponikvar R, Lindic J, Knap B, Vizjak A, Ferluga D, Kandus A. Follow-up of kidney graft recipients with cyclosporine-associated hemolytic-uremic syndrome and thrombotic microangiopathy. Transplant Proc 2005;37:18891891. Go to original source... Go to PubMed...
  33. Ashman N, Chapagain A, Dobbie H, Raftery MJ, Sheaff MT, Yaqoob MM. Belatacept as maintenance immunosuppression for postrenal transplant de novo drug-induced thrombotic microangiopathy. Am J Transplant 2009;9:424427. Go to original source... Go to PubMed...
  34. Randhawa PS, Shapiro R, Jordan ML, Starzl TE, Demetris AJ. The histopathological changes associated with allograft rejection and drug toxicity in renal transplant recipients maintained on FK506. Clinical significance and comparison with cyclosporine. Am J Surg Pathol 1993;17:6068. Go to original source... Go to PubMed...
  35. Williams D, Haragsim L. Calcineurin nephrotoxicity. Adv Chronic Kidney Dis 2006;13:4755. Go to original source... Go to PubMed...
  36. Nieves-Cintron M, Amberg GC, Nichols CB, Molkentin JD, Santana LF. Activation of NFATc3 down-regulates the beta1 subunit of large conductance, calcium-activated K+ channels in arterial smooth muscle and contributes to hypertension. J Biol Chem 2007;282:32313240. Go to original source... Go to PubMed...
  37. Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y, Nickeleit V, Ryffel B. The side-effects of ciclosporine-A and tacrolimus. Clin Nephrol 1998;49:356363.
  38. Collins BS, Davis CL, Marsh CL, McVicar JP, Perkins JD, Alpers CE. Reversible cyclosporine arteriolopathy. Transplantation 1992;54:732734. Go to original source... Go to PubMed...
  39. Djamali A. Oxidative stress as a common pathway to chronic tubulointerstitial injury in kidney allografts. Am J Physiol Renal Physiol 2007;293:F445F455. Go to original source... Go to PubMed...
  40. Shihab FS, Yi H, Bennett WM, Andoh TF. Effect of nitric oxide modulation on TGF-beta1 and matrix proteins in chronic cyclosporine nephrotoxicity. Kidney Int 2000;58:11741185. Go to original source... Go to PubMed...
  41. Pichler RH, Franceschini N, Young BA, Hugo C, Andoh TF, Burdmann EA, Shankland SJ, Alpers CE, Bennett WM, Couser WG. Pathogenesis of cyclosporine nephropathy: roles of angiotensin II and osteopontin. J Am Soc Nephrol 1995;6:11861196. Go to original source...
  42. Feldman G, Kiely B, Martin N, Ryan G, McMorrow T, Ryan MP. Role for TGF-beta in cyclosporine-induced modulation of renal epithelial barrier function. J Am Soc Nephrol 2007;18:16621671. Go to original source... Go to PubMed...
  43. Hertig A, Anglicheau D, Verine J, Pallet N, Touzot M, Ancel PY, Mesnard L, Brousse N, Baugey E, Glotz D, Legendre C, Rondeau E, Xu-Dubois YC. Early epithelial phenotypic changes predict graft fibrosis. J Am Soc Nephrol 2008;19:15841591. Go to original source... Go to PubMed...
  44. Viklický O, Matl I, Voska L, Böhmová R, Jarešová M, Lácha J, Lodererová A, Stříž I, Teplan V, Vítko S. TGF-beta1 expression and chronic allograft nephropathy in protocol kidney graft biopsy. Physiol Res 2003;52:353360.
  45. Ling H, Li X, Jha S, Wang W, Karetskaya L, Pratt B, Ledbetter S. Therapeutic role of TGF-beta-neutralizing antibody in mouse cyclosporin A nephropathy: morphologic improvement associated with functional preservation. J Am Soc Nephrol 2003;14:377388. Go to original source... Go to PubMed...
  46. Remuzzi G, Cattaneo D, Perico N. The aggravating mechanisms of aldosterone on kidney fibrosis. J Am Soc Nephrol 2008;19:1459 1462. Go to original source... Go to PubMed...
  47. Nankivell B, Richard J, Borrows R, Fung CL-S, OConnell PJ, Allen R, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003;349:23262333. Go to original source... Go to PubMed...
  48. Nankivell BJ, Borrows RJ, Fung C L-S, OConnell PJ, Chapman JR, Allen RD. Calcineurin-inhibitor nephrotoxicity: Longitudinal assessment by protocol histology. Transplantation 2004;78:557 565. Go to original source... Go to PubMed...
  49. Woolley AC, Rosenberg ME, Burke BA, Nath KA. De novo focal glomerulosclerosis after kidney transplantation. Am J Med 1988;84:310314. Go to original source... Go to PubMed...
  50. Heering P, Grabensee B. Influence of ciclosporin A on renal tubular function after kidney transplantation. Nephron 1991;59:6670. Go to original source... Go to PubMed...
  51. Lea JP, Sands JM, McMahon SJ, Tumlin JA. Evidence that the inhibition of Na+/K(+)-ATPase activity by FK506 involves calcineurin. Kidney Int 1994;46:647652. Go to original source... Go to PubMed...
  52. Younes-Ibrahim M, Barnese M, Burth P, Castro-Faria MV. Inhibition of purified human kidney Na+,K+-ATPase by cyclosporine A: A possible mechanism for drug human nephrotoxicity. Ann N Y Acad Sci 2003;986:633635. Go to original source... Go to PubMed...
  53. Heering PJ, Klein-Vehne N, Fehsel K. Decreased mineralocorticoid receptor expression in blood cells of kidney transplant recipients undergoing immunosuppressive treatment: Cost efficient determination by quantitative PCR. J Clin Pathol 2004;57:3336. Go to original source... Go to PubMed...
  54. Chang CT, Hung CC, Tian YC, Yang CW, Wu MS. Ciclosporin reduces paracellin-1 expression and magnesium transport in thick ascending limb cells. Nephrol Dial Transplant 2007;22:10331040. Go to original source...
  55. Alexander RT, Hoenderop JG, Bindels RJ. Molecular determinants of magnesium homeostasis: Insights from human disease. J Am Soc Nephrol 2008;19:14511458. Go to original source... Go to PubMed...
  56. Miura K, Nakatani T, Asai T, Yamanaka S, Tamada S, Tashiro K, Kim S, Okamura M, Iwao H. Role of hypomagnesemia in chronic cyclosporine nephropathy. Transplantation 2002;73:340347. Go to original source... Go to PubMed...
  57. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol 2000;11:974979. Go to original source...
  58. Woywodt A, Bahlmann FH, De Groot K, Haller H, Haubitz M. Circulating endothelial cells: life, death, detachment and repair of the endothelial cell layer. Nephrol Dial Transplant 2002;17:1728 1730. Go to original source...
  59. Koo DD, Roberts IS, Quiroga I, Procter J, Barnardo MC, Sutton M, Cerundolo L, Davies DR, Friend PJ, Morris PJ, Fuggle SV. C4d deposition in early renal allograft protocol biopsies. Transplantation 2004;78:398403. Go to original source... Go to PubMed...
  60. Krejčí K, Zadražil J, Tichý T, Al-Jabry S, Horčička V, Štrebl P, Bachleda P. Sonographic findings in borderline changes and subclinical acute renal allograft rejection. Eur J Radiol 2009;71:288 295. Go to original source... Go to PubMed...
  61. Solez K, Vincenti F, Filo R. Histopathologic findings from 2-year protocol biopsies from a US multicenter kidney transplant trial comparing tacrolimus versus ciclosporine. Transplantation 1998;66:17361740. Go to original source... Go to PubMed...
  62. Klein IH, Abrahams A, van ET, Hene RJ, Koomans HA, Ligtenberg G. Different effects of tacrolimus and cyclosporine on renal hemodynamics and blood pressure in healthy subjects. Transplantation 2002;73:732736. Go to original source... Go to PubMed...
  63. Jain S, Bicknell G, Nicholson ML. Tacrolimus has less fibrogenic potential than cyclosporin A in a model of renal ischaemia-reperfusion injury. Br J Surg 2000;87:15631568. Go to original source... Go to PubMed...
  64. OGrady JG, Burroughs A, Hardy P, Elbourne D, Truesdale A. Tacrolimus versus microemulsified ciclosporin in liver transplantation: The TMC randomised controlled trial. Lancet 2002;360:1119 1125. Go to original source...
  65. Rowshani AT, Scholten EM, Bemelman F, Eikmans M, Idu M, Roos-van Groningen MC, Surachno JS, Mallat MJ, Paul LC, de Fijter JW, Bajema IM, ten Berge I, Florquin S. No difference in degree of interstitial Sirius redstained area in serial biopsies from area under concentration-over-time curvesguided cyclosporine versus tacrolimus-treated renal transplant recipients at one zdar. J Am Soc Nephrol 2006;17:305312. Go to original source... Go to PubMed...
  66. Vural A, Yilmaz MI, Caglar K, Aydin A, Sonmez A, Eyileten T, Acikel C, Gulec B, Kozak O, Oner K. Assessment of oxidative stress in the early posttransplant period: comparison of cyclosporine A and tacrolimus-based regimens. Am J Nephrol 2005; 25:250255. Go to original source... Go to PubMed...
  67. Zadražil J, Štrebl P, Krejčí K, Horčička V, Horák P, Dostálová J, Zdařilová A, Kajabová M, Schneidera P. Effect of different calcineurin inhibitors on AOPP and TAS after kidney transplantation. Clin Biochem 2010;43:559565. Go to original source... Go to PubMed...
  68. Webster AC, Woodroffe RC, Taylor RS, Chapman JR, Craig JC. Tacrolimus versus ciclosporin as primary immunosuppression for kidney transplant recipients: Meta-analysis and meta-regression of randomised trial data. BMJ 2005;331:810814. Go to original source... Go to PubMed...
  69. Zadrazil J, Krejci K, Al Jabry S, Horcicka V Jr, Tichy T, Hrabalova M, Bachleda P. Protocol biopsy and subclinical rejection in patients after kidney transplantation treated by tacrolimus (Prograf). Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2003;147:193196. Go to original source...
  70. Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nathan B, Gurkan A, Margreiter R, Hugo C, Grinyo JM, Frei U, Vanrenterghem Y, Daloze P, Halloran PF. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007; 357:25622575. Go to original source... Go to PubMed...
  71. Zadrazil J, Horak P, Zahalkova J, Strebl P, Horcicka V, Krejci K, Bachleda P, Dedochova J, Valkovsky I. Improvement of cardiovascular risk factors and cosmetic side effects in kidney transplant recipients after conversion to tacrolimus. Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub 2009;153:6773. Go to original source... Go to PubMed...
  72. Vincenti F, Friman S, Scheuermann E, Rostaing L, Nenesen T, Campistol JM, Uchida K, Pescovitz MD, Marchetti P, Tuncer M, Citterio F, Wiecek A, Chadban S, El-Shahawy M, Budde K, Goto N. Results of an international, randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. Am J Transplant 2007;7:15061514. Go to original source... Go to PubMed...
  73. Wilkinson GR. Drug metabolism and variability among patients in drug response. N Engl J Med 2005;352:22112221. Go to original source... Go to PubMed...
  74. Oellerich M, Armstrong VW. The role of therapeutic drug monitoring in individualizing immunosuppressive drug therapy: Recent developments. Ther Drug Monit 2006;28:720725. Go to original source...
  75. Canadian Neoral Renal Transplantation Study Group: Absorption profiling of cyclosporine microemulsion (neoral) during the first 2 weeks after renal transplantation. Transplantation 2001;72:10241032. Go to original source...
  76. International Neoral Renal Transplantation Study Group: Cyclosporine microemulsion (Neoral) absorption profilig and sparse-sample predictors during the first 3 months after renal transplantation. Am J Transplant 2002;2:148156. Go to original source... Go to PubMed...
  77. Krejčí K, Tichý T, Hrubý M, Horák P, Ciferská H, Horčička V, Štrebl P, Al-Jabry S, Bachleda P, Zadražil J. Subclinical toxicity of calcineurin inhibitors in repeated protocol biopsies: an independent risk factor for chronic kidney allograft damage. Transpl Int 2010;23:364373. Go to original source... Go to PubMed...
  78. Benet LZ, Izumi T, Zhang Y, Silverman JA, Wacher VJ. Intestinal MDR transport proteins and P-450 enzymes as barriers to oral drug delivery. J Control Release 1999;62:2531. Go to original source... Go to PubMed...
  79. Lown KS, Mayo RR, Leichtman AB, Hsiao HL, Turgeon DK, Schmiedlin-Ren P, Brown MB, Guo W, Rossi SJ, Benet LZ, Watkins PB. Role of intestinal P-glycoprotein (mdr1) in interpatient variation in the oral bioavailability of cyclosporine. Clin Pharmacol Ther 1997;62:248260. Go to original source... Go to PubMed...
  80. Min DI, Ellingrod VL. Association of the CYP3A4*1B 5 flanking region polymorphism with cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit 2003;25:305309. Go to original source... Go to PubMed...
  81. Hesselink DA, van Gelder T, van Schaik RH, Balk AH, van der Heiden IP, van Dam T, van der Werf M, Weimar W, Mathot RA. Population pharmacokinetics of cyclosporine in kidney and heart transplant recipients and the influence of ethnicity and genetic polymorphisms in theMDR-1,CYP3A4, and CYP3A5 genes. Clin Pharmacol Ther 2004;76:545556. Go to original source... Go to PubMed...
  82. Rivory LP, Qin H, Clarke SJ, Eris J, Duggin G, Ray E, Trent RJ, Bishop JF. Frequency of cytochrome P450 3A4 variant genotype in transplant population and lack of association with cyclosporin clearance. Eur J Clin Pharmacol 2000;56:395398. Go to original source... Go to PubMed...
  83. von Ahsen N, Richter M, Grupp C, Ringe B, Oellerich M, Armstrong VW. No influence of the MDR-1 C3435T polymorphism or a CYP3A4 promoter polymorphism (CYP3A4-V allele) on dose-adjusted cyclosporin A trough concentrations or rejection incidence in stable renal transplant recipients. Clin Chem 2001;47:10481052. Go to original source...
  84. Min DI, Ellingrod VL, Marsh S, McLeod H. CYP3A5 polymorphism and the ethnic differences in cyclosporine pharmacokinetics in healthy subjects. Ther Drug Monit 2004;26:524528. Go to original source... Go to PubMed...
  85. Haufroid V, Mourad M, Van Kerckhove V, Wawrzyniak J, De Meyer M, Eddour DC, Malaise J, Lison D, Squifflet JP, Wallemacq P. The effect of CYP3A5 and MDR1 (ABCB1) polymorphisms on cyclosporine and tacrolimus dose requirements and trough blood levels in stable renal transplant patients. Pharmacogenetics 2004; 14:147154. Go to original source... Go to PubMed...
  86. Crettol S, Venetz JP, Fontana M, Aubert JD, Pascual M, Eap CB. CYP3A7, CYP3A5, CYP3A4, and ABCB1 genetic polymorphisms, cyclosporine concentration, and dose requirement in transplant recipients. Ther Drug Monit 2008;30:689699. Go to original source... Go to PubMed...
  87. Singh R, Srivastava A, Kapoor R, K Sharma R, D Mittal R. Impact of CYP3A5 and CYP3A4 gene polymorphisms on dose requirement of calcineurin inhibitors, cyclosporine and tacrolimus, in renal allograft recipients of North India. Naunyn Schmied Arch Pharmacol 2009;380:169177. Go to original source... Go to PubMed...
  88. Kreutz R, Zürcher H, Kain S, Martus P, Offermann G, Beige J. The effect of variable CYP3A5 expression on cyclosporine dosing, blood pressure and long-term graft survival in renal transplant patients. Pharmacogenetics 2004;14:665671. Go to original source... Go to PubMed...
  89. Zhao Y, Song M, Guan D, Bi S, Meng J, Li Q, Wang W. Genetic polymorphisms of CYP3A5 genes and concentration the cyclosporine and tacrolimus. Transplant Proc 2005;37:178181. Go to original source... Go to PubMed...
  90. Coto E, Tavira B. Pharmacogenetics of calcineurin inhibitors in renal transplantation. Transplantation 2009;88(3 Suppl):S6267. Go to original source... Go to PubMed...
  91. Anglicheau D, Thervet E, Etienne I, Hurault De Ligny B, Le Meur Y, Touchard G, Büchler M, Laurent-Puig P, Tregouet D, Beaune P, Daly A, Legendre C, Marquet P. CYP3A5 and MDR1 genetic polymorphisms and cyclosporine pharmacokinetics after renal transplantation. Clin Pharmacol Ther 2004;75:422433. Go to original source... Go to PubMed...
  92. Foote CJ, Greer W, Kiberd B, Fraser A, Lawen J, Nashan B, Belitsky P. Polymorphisms of multidrug resistance gene (MDR1) and cyclosporine absorption in de novo renal transplant patients. Transplantation 2007;83:13801384. Go to original source... Go to PubMed...
  93. Mai I, Störmer E, Goldammer M, Johne A, Krüger H, Budde K, Roots I. MDR1 haplotypes do not affect the steady-state pharmacokinetics of cyclosporine in renal transplant patients. J Clin Pharmacol 2003;43:11011107. Go to original source... Go to PubMed...
  94. Hesselink DA, van Schaik RH, van der Heiden IP, van der Werf M, Gregoor PJ, Lindemans J, Weimar W, van Gelder T. Genetic polymorphisms of the CYP3A4, CYP3A5, and MDR-1 genes and pharmacokinetics of the calcineurin inhibitors cyclosporine and tacrolimus. Clin Pharmacol Ther 2003;74:245254. Go to original source... Go to PubMed...
  95. Op den Buijsch RA, Christiaans MH, Stolk LM, de Vries JE, Cheung CY, Undre NA, van Hooff JP, van Dieijen-Visser MP, Bekers O. Tacrolimus pharmacokinetics and pharmacogenetics: influence of adenosine triphosphate-binding cassette Bi (ABCB1) and cytochrome (CYP) 3A polymorphisms. Fundam Clin Pharmacol 2007;21:427435. Go to original source... Go to PubMed...
  96. Renders L, Frisman M, Ufer M, Mosyagin I, Haenisch S, Ott U, Caliebe A, Dechant M, Braun F, Kunzendorf U, Cascorbi I. CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients. Clin Pharmacol Ther 2007;81:228234. Go to original source... Go to PubMed...
  97. Jun KR, Lee W, Jang MS, Chun S, Song GW, Park KT, Lee SG, Han DJ, Kang C, Cho DY, Kim JQ, Min WK. Tacrolimus concentrations in relation to CYP3A and ABCB1 polymorphisms among solid organ transplant recipients in Korea. Transplantation 2009;87:12251231. Go to original source... Go to PubMed...
  98. Akbas SH, Bilgen T, Keser I, Tuncer M, Yucetin L, Tosun O, Gultekin M, Luleci G. The effect of MDR1 (ABCB1) polymorphism on the pharmacokinetic of tacrolimus in Turkish renal transplant recipients. Transplant Proc 2006;38:12901292. Go to original source... Go to PubMed...
  99. Li D, Gui R, Li J, Huang Z, Nie X. Tacrolimus dosing in Chinese renal transplant patients is related to MDR1 gene C3435T polymorphisms. Transplant Proc 2006;38:28502852. Go to original source... Go to PubMed...
  100. Tsuchiya N, Satoh S, Tada H, Li Z, Ohyama C, Sato K, Suzuki T, Habuchi T, Kato T. Influence of CYP3A5 and MDR1 (ABCB1) polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplantation 2004;78:11821187. Go to original source... Go to PubMed...
  101. Tada H, Tsuchiya N, Satoh S, Kagaya H, Li Z, Sato K, Miura M, Suzuki T, Kato T, Habuchi T. Impact of CYP3A5 and MDR1 (ABCB1) C3435T polymorphisms on the pharmacokinetics of tacrolimus in renal transplant recipients. Transplant Proc 2005; 37:17301732. Go to original source... Go to PubMed...
  102. Halloran PF, Helms LM, Kung L, Noujaim J. The tempoval profile of calcineurin inhibition by cyclosporine in vivo. Transplantation 1999;68:13561361. Go to original source... Go to PubMed...
  103. Iwasaki K, Shiraga T, Matsuda H, Teramura Y, Kawamura A, Hata T, Ninomiya S, Esumi Y. Absorption, distribution, metabolism and excretion of tacrolimus (FK506) in the rat. Drug Metab Pharmacokinet 1998;13:259265. Go to original source...
  104. Podder H, Stepkowski SM, Napoli KL, Clark J, Verani RR, Chou TC, Kahan BD. Pharmacokinetic interactions augment toxicities of sirolimus/cyclosporine combinations. J Am Soc Nephrol 2001;12:10591071. Go to original source...
  105. Saeki T, Ueda K, Tanigawara Y, Hori R, Komano T. Human P-glycoprotein transports cyclosporin A and FK506. J Biol Chem 1993;268:60776080. Go to original source...
  106. del Moral RG, Andujar M, Ramirez C, Gomez-Morales M, Masseroli M, Aguilar M, Olmo A, Arrebola F, Guillen M, Garcia- Chicano MJ, Nogales FF, OValle F. Chronic cyklosporin A nephrotoxicity, P-glycoprotein overexpression, and relationships with intrarenal angiotensin II deposits. Am J Pathol 1997;151:1705 1714.
  107. Hauser IA, Schaeffeler E, Gauer S, Scheuermann EH, Wegner B, Gossmann J, Ackermann H, Seidl C, Hocher B, Zanger UM, Geiger H, Eichelbaum M, Schwab M. ABCB1 genotype of the donor but not of the recipient is a major risk factor for cyclosporine-related nephrotoxicity after renal transplantation. J Am Soc Nephrol 2005;16:15011511. Go to original source... Go to PubMed...
  108. Roby KA, Shaw LM. Effects of cyclosporine and its metabolites in the isolated perfused rat kidney. J Am Soc Nephrol 1993;4:168 177. Go to original source...
  109. Copeland KR, Thliveris JA, Yatscoff RW. Toxicity of cyclosporine metabolites. Ther Drug Monit 1990;12:525532. Go to original source... Go to PubMed...
  110. Christians U, Kohlhaw K, Budniak J, Bleck JS, Schottmann R, Schlitt HJ, Almeida VM, Deters M, Wonigeit K, Pichlmayr R. Cyclosporine metabolite pattern in blood and urine of liver graft recipients. I. Association of cyclosporine metabolites with nephrotoxicity. Eur J Clin Pharmacol 1991;41:285290. Go to original source... Go to PubMed...
  111. Kuehl P, Zhang J, Lin Y, Lamba J, Assem M, Schuetz J, Watkins PB, Daly A, Wrighton SA, Hall SD, Maurel P, Relling M, Brimer C, Yasuda K, Venkataramanan R, Strom S, Thummel K, Boguski MS, Schuetz E. Sequence diversity in CYP3A promoters and characterization of the genetic basis of polymorphic CYP3A5 expression. Nat Genet 2001;27:383391. Go to original source... Go to PubMed...
  112. Kuypers DR, de Jonge H, Naesens M, Lerut E, Verbeke K, Vanrenterghem Y. CYP3A5 and CYP3A4 but not MDR1 singlenucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin Pharmacol Ther 2007;82:711725. Go to original source... Go to PubMed...
  113. Schmitt R, Cantley LG. The impact of aging on kidney repair. Am J Physiol Renal Physiol 2008;294:F1265F1272. Go to original source...
  114. Jennings P, Koppelstaetter C, Aydin S, Abberger T, Wolf AM, Mayer G, Pfaller W. Cyclosporine A induces senescence in renal tubular epithelial cells. Am J Physiol Renal Physiol 2007;293:F831F838. Go to original source... Go to PubMed...
  115. Altman RD, Perez GO, Sfakianakis GN. Interaction of cyclosporine A and nonsteroidal anti-inflammatory drugs on renal function in patients with rheumatoid arthritis. Am J Med 1992;93:396402. Go to original source... Go to PubMed...
  116. Soubhia RM, Mendes GE, Mendonca FZ, Baptista MA, Cipullo JP, Burdmann EA. Tacrolimus and nonsteroidal anti-inflammatory drugs: An association to be avoided. Am J Nephrol 2005;25:327 334. Go to original source... Go to PubMed...
  117. van de Wetering J, Weimar CH, Balk AH, Roodnat JI, Holweg CT, Baan CC, van Domburg RT, Weimar W. The impact of transforming growth factor-beta1 gene polymorphism on end-stage renal failure after heart transplantation. Transplantation 2006;82:1744 1748. Go to original source... Go to PubMed...
  118. Broekroelofs J, Stegeman CA, Navis G, Tegzess AM, De ZD, De Jong PE. Risk factors for long-term renal survival after renal transplantation: A role for angiotensin-converting enzyme (insertion/ deletion) polymorphism? J Am Soc Nephrol 1998;9:20752081. Go to original source...
  119. Srinivas TR, Meier-Kriesche HU. Minimizing immunosuppression, an alternative approach to reducing side effects: Objectives and interim result. Clin J Am Soc Nephrol 2008;3:S101S116. Go to original source... Go to PubMed...
  120. Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor- sparing regimens in solid organ transplantation: Focus on improving renal function and nephrotoxicity. Clin Transplant 2008;22:115. Go to original source... Go to PubMed...
  121. Rahn KH, Barenbrock M, Fritschka E, Heinecke A, Lippert J, Schroeder K, Hauser I, Wagner K, Neumayer HH. Effect of nitrendipine on renal function in renal-transplant patiens treated with cyclosporin: A randomised trial. Lancet 1999;354:14151420. Go to original source... Go to PubMed...
  122. Kuypers DR, Neumayer H-H, Fritsche L, Budde K, Rodicio J, Vanrenterghem Y, Lacidipine Study Group. Calcium channel blockade and preservation of renal graft function in cyclosporinetreated recipients: A prospective randomized placebo-controlled 2-year study. Transplantation 2004;78:12041211. Go to original source... Go to PubMed...
  123. Morales JM, Rodriguez-Paternina E, Araque A, Andres A, Hernandez E, Ruilope LM, Rodicio JL. Long-term protective effect of a calcium antagonist on renal function in hypertensive renal transplant patients on cyclosporine therapy: A 5-year prospective randomized study. Transplant Proc 1994;26:25982599.
  124. Hannedouche TP, Natov S, Boitard C, Lacour B, Grunfeld JP. Angiotensin converting enzyme inhibition and chronic cyclosporine- induced renal dysfunction in type 1 diabetes. Nephrol Dial Transplant 1996;11:673678. Go to original source... Go to PubMed...
  125. Campistol JM, Inigo P, Jimenez W, Lario S, Clesca PH, Oppenheimer F, Rivera F. Losartan decreases plasma levels of TGF-beta1 in transplant patients with chronic allograft nephropathy. Kidney Int 1999;56:714719. Go to original source... Go to PubMed...
  126. Inigo P, Campistol JM, Lario S, Piera C, Campos B, Bescos M, Oppenheimer F, Rivera F. Effects of losartan and amlodipine on intrarenal hemodynamics and TGF-beta(1) plasma levels in a crossover trial in renal transplant recipients. J Am Soc Nephrol 2001;12:822827. Go to original source...
  127. Asai T, Nakatani T, Tamada S, Kuwabara N, Yamanaka S, Tashiro K, Nakao T, Komiya T, Okamura M, Kim S, Iwao H, Miura K. Activation of transcription factors AP-1 and NF-kappaB in chronic cyclosporine A nephrotoxicity: Role in beneficial effects of magnesium supplementation. Transplantation 2003;75:10401044. Go to original source... Go to PubMed...
  128. Li C, Sun BK, Lim SW, Song JC, Kang SW, Kim YS, Kang DH, Cha JH, Kim J, Yang CW. Combined effects of losartan and pravastatin on interstitial inflammation and fibrosis in chronic cyclosporine-induced nephropathy. Transplantation 2005; 79:15221529. Go to original source... Go to PubMed...
  129. Tariq M, Morais C, Sobki S, Al Sulaiman M, Al Khader A. N-acetylcysteine attenuates cyclosporin-induced nephrotoxicity in rats. Nephrol Dial Transplant 1999;14:923929. Go to original source... Go to PubMed...
  130. Jenkins JK, Huang H, Ndebele K, Salahudeen AK. Vitamin E inhibits renal mRNA expression of COX II, HO I, TGFbeta, and osteopontin in the rat model of cyclosporine nephrotoxicity. Transplantation 2001;71:331334. Go to original source... Go to PubMed...
  131. Lessio C, de Assuncao SF, Gloria MA, Di Tommaso AB, Gori MM, Di Marco GS, Schor N, Higa EM. Cyclosporine A and NAC on the inducible nitric oxide synthase expression and nitric oxide synthesis in rat renal artery cultured cells. Kidney Int 2005;68:25082516. Go to original source... Go to PubMed...
  132. Galletti P, Di Gennaro CNI, Migliardi V, Indaco S, Della RF, Manna C, Chiodini P, Capasso G, Zappia V. Diverse effects of natural antioxidants on cyclosporin cytotoxicity in rat renal tubular cells. Nephrol Dial Transplant 2005;20:15511558. Go to original source... Go to PubMed...