Personalization of the immunosuppressive treatment in renal transplant recipients: The great challenge in “omics” medicine

International Journal of Molecular Sciences

Volumn 16, Issue 2, 2015, Pages 4281-4305

  Zaza, Gianluigi ^a   Granata, Simona ^a   Tomei, Paola ^a   Gassa, Alessandra Dalla ^a   Lupo, Antonio ^a  

^a UNIVERSITY OF VERONA   (Italy)

Author keywords

Immunosuppression; Personalized medicine; Pharmacogenetics; Pharmacogenomics; Renal transplantation

Indexed keywords

ALLOANTIBODY; AZATHIOPRINE; B LYMPHOCYTE DIFFERENTIATION FACTOR; BASILIXIMAB; CALCINEURIN; COMPLEMENT COMPONENT C4D; CYCLOPHILIN; CYCLOSPORIN A; CYTOCHROME P450 3A4; CYTOCHROME P450 3A5; EVEROLIMUS; GLUCURONOSYLTRANSFERASE 1A9; GLUTATHIONE TRANSFERASE; IMMUNOGLOBULIN ENHANCER BINDING PROTEIN; IMMUNOPHILIN; INOSINATE DEHYDROGENASE; MEMBRANE METALLOENDOPEPTIDASE; MESSENGER RNA; METHYLPREDNISOLONE; MULTIDRUG RESISTANCE PROTEIN 1; MYCOPHENOLIC ACID 2 MORPHOLINOETHYL ESTER; PEROXISOME PROLIFERATOR ACTIVATED RECEPTOR ALPHA; PREDNISOLONE; RAPAMYCIN; TACROLIMUS; THIOPURINE METHYLTRANSFERASE; THYMOCYTE ANTIBODY; TRANSCRIPTION FACTOR AP 1; TRANSCRIPTION FACTOR NFAT; UNINDEXED DRUG; CALCINEURIN INHIBITOR; IMMUNOSUPPRESSIVE AGENT; MYCOPHENOLATE MOFETIL; MYCOPHENOLIC ACID;

ANEMIA; BONE MARROW TOXICITY; CLINICAL PRACTICE; DRUG DETOXIFICATION; DRUG DISPOSITION; DRUG MECHANISM; DRUG METABOLISM; DRUG PROTEIN BINDING; EDEMA; ENZYME INHIBITION; GENE FREQUENCY; GRAFT RECIPIENT; HIGH THROUGHPUT SCREENING; HUMAN; HYPERLIPIDEMIA; HYPERTRIGLYCERIDEMIA; IMMUNOSUPPRESSIVE TREATMENT; KIDNEY GRAFT; KIDNEY TRANSPLANTATION; LONG TERM SURVIVAL; LUNG FIBROSIS; LYMPHOCYTE PROLIFERATION; NEPHROTOXICITY; PERSONALIZED MEDICINE; PHARMACOGENOMICS; POINT MUTATION; RANDOMIZED CONTROLLED TRIAL (TOPIC); RENAL GRAFT DYSFUNCTION; REVIEW; SINGLE NUCLEOTIDE POLYMORPHISM; ANALOGS AND DERIVATIVES; GRAFT REJECTION; KIDNEY FAILURE, CHRONIC; PHARMACOGENETICS;

AZATHIOPRINE; CALCINEURIN INHIBITORS; GRAFT REJECTION; HUMANS; IMMUNOSUPPRESSIVE AGENTS; KIDNEY FAILURE, CHRONIC; KIDNEY TRANSPLANTATION; MYCOPHENOLIC ACID; PHARMACOGENETICS; PRECISION MEDICINE;

EID: 84923072313     PISSN: 16616596     EISSN: 14220067     Source Type: Journal    
DOI: 10.3390/ijms16024281     Document Type: Review

References (151)

1. Jofre, R.; Lopez-Gomez, J.M.; Moreno, F.; Sanz-Guajardo, D.; Valderrabano, F. Changes in quality of life after renal transplantation. Am. J. Kidney Dis. 1998, 32, 93–100.
2. Karlberg, I.; Nyberg, G. Cost-effectiveness in studies of renal transplantation. Int. J. Technol. Assess. Health Care 1995, 11, 611–622.
3. Schnuelle, P.; Lorenz, D.; Trede, M.; van der Woude, F.J. Impact of renal cadaveric transplantation on survival in end-stage renal failure: Evidence for reduced mortality risk compared with hemodialysis during long-term follow-up. J. Am. Soc. Nephrol. 1998, 9, 2135–2141.
4. Tonelli, M.; Wiebe, N.; Knoll, G.; Bello, A.; Browne, S.; Jadhav, D.; Klarenbach, S.; Gill, J. Systematic review: Kidney transplantation compared with dialysis in clinically relevant outcomes. Am. J. Transplant. 2011, 11, 2093–2109.
5. Rezzani, R.; Rodella, L.; Bianchi, R. Early metabolic changes in peripheral blood cells of renal transplant recipients treated with cyclosporine A. Int. J. Immunopharmacol. 1999, 21, 455–462.
6. U.S. Renal Data System. USRDS 2013 Annual Data Report: Atlas of Chronic Kidney Disease and End-Stage Renal Disease in the United States; National Institutes of Health, National Institute of Diabetes and Digestive and Kidney Diseases: Bethesda, MD, USA, 2013.
7. Cornell, L.D.; Colvin, R.B. Chronic allograft nephropathy. Curr. Opin. Nephrol. Hypertens. 2005, 14, 229–234.
8. Racusen, L.C.; Regele, H. The pathology of chronic allograft dysfunction. Kidney Int. Suppl. 2010, 119, S27–S32.
9. Terasaki, P.I. Humoral theory of transplantation. Am. J. Transplant. 2003, 3, 665–673.
10. Mauiyyedi, S.; Colvin, R.B. Humoral rejection in kidney transplantation: New concepts in diagnosis and treatment. Curr. Opin. Nephrol. Hypertens. 2002, 11, 609–618.
11. Collins, A.B.; Schneeberger, E.E.; Pascual, M.A.; Saidman, S.L.; Williams, W.W.; Tolkoff-Rubin, N.; Cosimi, A.B.; Colvin, R.B. Complement activation in acute humoral renal allograft rejection: Diagnostic significance of C4D deposits in peritubular capillaries. J. Am. Soc. Nephrol. 1999, 10, 2208–2214.
12. Mauiyyedi, S.; Crespo, M.; Collins, A.B.; Schneeberger, E.E.; Pascual, M.A.; Saidman, S.L.; Tolkoff-Rubin, N.E.; Williams, W.W.; Delmonico, F.L.; Cosimi, A.B.; et al. Acute humoral rejection in kidney transplantation: II. Morphology, immunopathology, and pathologic classification. J. Am. Soc. Nephrol. 2002, 13, 779–787.
13. Mauiyyedi, S.; Pelle, P.D.; Saidman, S.; Collins, A.B.; Pascual, M.; Tolkoff-Rubin, N.E.; Williams, W.W.; Cosimi, A.A.; Schneeberger, E.E.; Colvin, R.B. Chronic humoral rejection: Identification of antibody-mediated chronic renal allograft rejection by C4D deposits in peritubular capillaries. J. Am. Soc. Nephrol. 2001, 12, 574–582.
14. Regele, H.; Böhmig, G.A.; Habicht, A.; Gollowitzer, D.; Schillinger, M.; Rockenschaub, S.; Watschinger, B.; Kerjaschki, D.; Exner, M. Capillary deposition of complement split product C4D in renal allografts is associated with basement membrane injury in peritubular and glomerular capillaries: A contribution of humoral immunity to chronic allograft rejection. J. Am. Soc. Nephrol. 2002, 13, 2371–2380.
15. Theruvath, T.P.; Saidman, S.L.; Mauiyyedi, S.; Delmonico, F.L.; Williams, W.W.; Tolkoff-Rubin, N.; Collins, A.B.; Colvin, R.B.; Cosimi, A.B.; Pascual, M. Control of antidonor antibody production with tacrolimus and mycophenolate mofetil in renal allograft recipients with chronic rejection. Transplantation 2001, 72, 77–83.
16. Lindholm, A.; Sawe, J. Pharmacokinetics and therapeutic drug monitoring of immunosuppressants. Ther. Drug Monit. 1995, 17, 570–573.
17. Weinshilboum, R. Inheritance and drug response. N. Engl. J. Med. 2003, 348, 529–537.
18. Evans, W.E.; Relling, M.V. Moving towards individualized medicine with pharmacogenomics. Nature 2004, 429, 464–468.
19. Evans, W.E.; Johnson, J.A. Pharmacogenomics: The inherited basis for interindividual differences in drug response. Annu. Rev. Genomics Hum. Genet. 2001, 2, 9–39.
20. Zaza, G.; Tomei, P.; Granata, S.; Boschiero, L.; Lupo, A. Monoclonal antibody therapy and renal transplantation: Focus on adverse effects. Toxins 2014, 6, 869–891.
21. Rao, A.; Luo, C.; Hogan, P.G. Transcription factors of the NFAT family: Regulation and function. Annu. Rev. Immunol. 1997 15, 707–747.
22. Kamdem, L.K.; Streit, F.; Zanger, U.M.; Brockmöller, J.; Oellerich, M.; Armstrong, V.W.; Wojnowski, L. Contribution of CYP3A5 to the in vitro hepatic clearance of tacrolimus. Clin. Chem. 2005, 51, 1374–1381.
23. Vincent, S.H.; Karanam, B.V.; Painter, S.K.; Chiu, S.H. In vitro metabolism of FK-506 in rat, rabbit, and human liver microsomes: Identification of a major metabolite and of cytochrome P450 3A as the major enzymes responsible for its metabolism. Arch. Biochem. Biophys. 1992, 294, 454–460.
24. Macphee, I.A.; Fredericks, S.; Tai, T.; Syrris, P.; Carter, N.D.; Johnston, A.; Goldberg, L.; Holt, D.W. Tacrolimus pharmacogenetics: Polymorphisms associated with expression of cytochrome p4503A5 and P-glycoprotein correlate with dose requirement. Transplantation 2002, 74, 1486–1489.
25. Thervet, E.; Anglicheau, D.; King, B.; Schlageter, M.H.; Cassinat, B.; Beaune, P.; Legendre, C.; Daly, A.K. Impact of cytochrome p450 3A5 genetic polymorphism on tacrolimus doses and concentration-to-dose ratio in renal transplant recipients. Transplantation 2003, 76, 1233–1235.
26. Haufroid, V.; Mourad, M.; van Kerckhove, V.; Wawrzyniak, J.; de Meyer, M.; Eddour, D.C.; Malaise, J.; Lison, D.; Squifflet, J.P.; 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, 147–154.
27. Jacobson, P.A.; Oetting, W.S.; Brearley, A.M.; Leduc, R.; Guan, W.; Schladt, D.; Matas, A.J.; Lamba, V.; Julian, B.A.; Mannon, R.B.; et al. Novel polymorphisms associated with tacrolimus trough concentrations: Results from a multicenter kidney transplant consortium. Transplantation 2011, 91, 300–308.
28. Hesselink, D.A.; Bouamar, R.; Elens, L.; van Schaik, R.H.; van Gelder, T. The role of pharmacogenetics in the disposition of and response to tacrolimus in solid organ transplantation. Clin. Pharmacokinet. 2014, 53, 123–139.
29. Haufroid, V.; Wallemacq, P.; VanKerckhove, V.; Elens, L.; de Meyer, M.; Eddour, D.C.; Malaise, J.; Lison, D.; Mourad, M. CYP3A5 and ABCB1 polymorphisms and tacrolimus pharmacokinetics in renal transplant candidates: Guidelines from an experimental study. Am. J. Transplant. 2006, 6, 2706–2713.
30. MacPhee, I.A.; Holt, D.W. A pharmacogenetic strategy for immunosuppression based on the CYP3A5 genotype. Transplantation 2008, 85, 163–165.
31. Wang, D.; Guo, Y.; Wrighton, S.A.; Cooke, G.E.; Sadee, W. Intronic polymorphism in CYP3A4 affects hepatic expression and response to statin drugs. Pharmacogenomics J. 2011, 11, 274–286.
32. Elens, L.; Bouamar, R.; Hesselink, D.A.; Haufroid, V.; van der Heiden, I.P.; van Gelder, T.; van Schaik, R.H. A new functional CYP3A4 intron 6 polymorphism significantly affects tacrolimus pharmacokinetics in kidney transplant recipients. Clin. Chem. 2011, 57, 1574–1583.
33. Tavira, B.; Coto, E.; Díaz-Corte, C.; Ortega, F.; Arias, M.; Torres, A.; Díaz, J.M.; Selgas, R.; López-Larrea, C.; Campistol, J.M.; et al. Pharmacogenetics of tacrolimus after renal transplantation: Analysis of polymorphisms in genes encoding 16 drug metabolizing enzymes. Clin. Chem. Lab. Med. 2011, 49, 825–833.
34. Shchepotina, E.G.; Vavilin, V.A.; Goreva, O.B.; Lyakhovich, V.V. Some mutations of exon-7 in cytochrome P450 gene 3A4 and their effect on 6-β-hydroxylation of cortisol. Bull. Exp. Biol. Med. 2006, 141, 701–703.
35. Sata, F.; Sapone, A.; Elizondo, G.; Stocker, P.; Miller, V.P.; Zheng, W.; Raunio, H.; Crespi, C.L.; Gonzalez, F.J. CYP3A4 allelic variants with amino acid substitutions in exons 7 and 12: Evidence for an allelic variant with altered catalytic activity. Clin. Pharmacol. Ther. 2000, 67, 48–56.
36. Evans, W.E.; McLeod, H.L. Pharmacogenomics-drug disposition, drug targets, and side effects. N. Engl. J. Med. 2003, 348, 538–549.
37. Kroetz, D.L.; Pauli-Magnus, C.; Hodges, L.M.; Huang, C.C.; Kawamoto, M.; Johns, S.J.; Stryke, D.; Ferrin, T.E.; DeYoung, J.; Taylor, T.; et al. Sequence diversity and haplotype structure in the human ABCB1 (MDR1, multidrug resistance transporter) gene. Pharmacogenetics 2003, 13, 481–494.
38. 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, 1182–1187.
39. 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, 1730–1732.
40. Zhang, X.; Liu, Z.H.; Zheng, J.M.; Chen, Z.H.; Tang, Z.; Chen, J.S.; Li, L.S. Influence of CYP3A5 and MDR1 polymorphisms on tacrolimus concentration in the early stage after renal transplantation. Clin. Transplant. 2005, 19, 638–643.
41. Roy, J.N.; Barama, A.; Poirier, C.; Vinet, B.; Roger, M. Cyp3A4, Cyp3A5, and MDR-1 genetic influences on tacrolimus pharmacokinetics in renal transplant recipients. Pharmacogenet. Genomics 2006, 16, 659–665.
42. Mourad, M.; Wallemacq, P.; de Meyer, M.; Brandt, D.; van Kerkhove, V.; Malaise, J.; Chaïb Eddour, D.; Lison, D.; Haufroid, V. The influence of genetic polymorphisms of cytochrome P450 3A5 and ABCB1 on starting dose- and weight-standardized tacrolimus trough concentrations after kidney transplantation in relation to renal function. Clin. Chem. Lab. Med. 2006, 44, 1192–1198.
43. Kuypers, D.R.; de Jonge, H.; Naesens, M.; Lerut, E.; Verbeke, K.; Vanrenterghem, Y. CYP3A5 and CYP3A4 but not MDR1 single-nucleotide polymorphisms determine long-term tacrolimus disposition and drug-related nephrotoxicity in renal recipients. Clin. Pharmacol. Ther. 2007, 82, 711–725.
44. Staatz, C.E.; Goodman, L.K.; Tett, S.E. Effect of CYP3A and ABCB1 single nucleotide polymorphisms on the pharmacokinetics and pharmacodynamics of calcineurin inhibitors: Part I. Clin. Pharmacokinet. 2010, 49, 141–175.
45. Bouamar, R.; Hesselink, D.A.; van Schaik, R.H.; Weimar, W.; Macphee, I.A.; de Fijter, J.W.; van Gelder, T. Polymorphisms in CYP3A5, CYP3A4, and ABCB1 are not associated with cyclosporine pharmacokinetics nor with cyclosporine clinical end points after renal transplantation. Ther. Drug Monit. 2011, 33, 178–184.
46. Hesselink, D.A.; van Schaik, R.H.; van der Heiden, I.P.; van der Werf, M.; Gregoor, P.J.; 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, 245–254.
47. Llaudó, I.; Colom, H.; Giménez-Bonafé, P.; Torras, J.; Caldés, A.; Sarrias, M.; Cruzado, J.M.; Oppenheimer, F.; Sánchez-Plumed, J.; Gentil, M.Á.; et al. Do drug transporter (ABCB1) SNPs and P-glycoprotein function influence cyclosporine and macrolides exposure in renal transplant patients? Results of the pharmacogenomic substudy within the symphony study. Transpl. Int. 2013, 26, 177–186.
48. Crettol, S.; Venetz, J.P.; Fontana, M.; Aubert, J.D.; Ansermot, N.; Fathi, M.; Pascual, M.; Eap, C.B. Influence of ABCB1 genetic polymorphisms on cyclosporine intracellular concentration in transplant recipients. Pharmacogenet. Genomics 2008, 18, 307–315.
49. Falck, P.; Asberg, A.; Guldseth, H.; Bremer, S.; Akhlaghi, F.; Reubsaet, J.L.; Pfeffer, P.; Hartmann, A.; Midtvedt, K. Declining intracellular T-lymphocyte concentration of cyclosporine a precedes acute rejection in kidney transplant recipients. Transplantation 2008, 85, 179–184.
50. Naesens, M.; Lerut, E.; de Jonge, H.; van Damme, B.; Vanrenterghem, Y.; Kuypers, D.R. Donor age and renal P-glycoprotein expression associate with chronic histological damage in renal allografts. J. Am. Soc. Nephrol. 2009, 20, 2468–2480.
51. Hauser, I.A.; Schaeffeler, E.; Gauer, S.; Scheuermann, E.H.; Wegner, B.; Gossmann, J.; Ackermann, H.; Seidl, C.; Hocher, B.; Zanger, U.M.; et al. 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, 1501–1511.
52. Cattaneo, D.; Ruggenenti, P.; Baldelli, S.; Motterlini, N.; Gotti, E.; Sandrini, S.; Salvadori, M.; Segoloni, G.; Rigotti, P.; Donati, D.; et al. ABCB1 genotypes predict cyclosporine-related adverse events and kidney allograft outcome. J. Am. Soc. Nephrol. 2009, 20, 1404–1415.
53. Woillard, J.B.; Rerolle, J.P.; Picard, N.; Rousseau, A.; Guillaudeau, A.; Munteanu, E.; Essig, M.; Drouet, M.; le Meur, Y.; Marquet, P. Donor P-gp polymorphisms strongly influence renal function and graft loss in a cohort of renal transplant recipients on cyclosporine therapy in a long-term follow-up. Clin. Pharmacol. Ther. 2010, 88, 95–100.
54. Joy, M.S.; Nickeleit, V.; Hogan, S.L.; Thompson, B.D.; Finn, W.F. Calcineurin inhibitor-induced nephrotoxicity and renal expression of P-glycoprotein. Pharmacotherapy 2005, 25, 779–789.
55. Anglicheau, D.; Pallet, N.; Rabant, M.; Marquet, P.; Cassinat, B.; Méria, P.; Beaune, P.; Legendre, C.; Thervet, E. Role of P-glycoprotein in cyclosporine cytotoxicity in the cyclosporine-sirolimus interaction. Kidney Int. 2006, 70, 1019–1025.
56. Hesselink, D.A.; Bouamar, R.; van Gelder, T. The pharmacogenetics of calcineurin inhibitor-related nephrotoxicity. Ther. Drug Monit. 2010, 32, 387–393.
57. De Meyer, M.; Haufroid, V.; Elens, L.; Fusaro, F.; Patrono, D.; de Pauw, L.; Kanaan, N.; Goffin, E.; Mourad, M. Donor age and ABCB1 1199G>A genetic polymorphism are independent factors affecting long-term renal function after kidney transplantation. J. Surg. Res. 2012, 178, 988–995.
58. Thervet, E.; Loriot, M.A.; Barbier, S.; Buchler, M.; Ficheux, M.; Choukroun, G.; Toupance, O.; Touchard, G.; Alberti, C.; le Pogamp, P.; et al. Optimization of initial tacrolimus dose using pharmacogenetic testing. Clin. Pharmacol. Ther. 2010, 87, 721–726.
59. Allison, A.C.; Eugui, E.M. The design and development of an immunosuppressive drug, mycophenolate mofetil. Springer Semin. Immunopathol. 1993, 14, 353–380.
60. Ting, L.S.; Partovi, N.; Levy, R.D.; Riggs, K.W.; Ensom, M.H. Pharmacokinetics of mycophenolic acid and its phenolic-glucuronide and ACYl glucuronide metabolites in stable thoracic transplant recipients. Ther. Drug Monit. 2008, 30, 282–291.
61. Johnson, A.G.; Rigby, R.J.; Taylor, P.J.; Jones, C.E.; Allen, J.; Franzen, K.; Falk, M.C.; Nicol, D. The kinetics of mycophenolic acid and its glucuronide metabolite in adult kidney transplant recipients. Clin. Pharmacol. Ther. 1999, 66, 492–500.
62. Meier-Kriesche, H.U.; Shaw, L.M.; Korecka, M.; Kaplan, B. Pharmacokinetics of mycophenolic acid in renal insufficiency. Ther. Drug Monit. 2000, 22, 27–30.
63. Girard, H.; Court, M.H.; Bernard, O.; Fortier, L.C.; Villeneuve, L.; Hao, Q.; Greenblatt, D.J.; von Moltke, L.L.; Perussed, L.; Guillemette, C. Identification of common polymorphisms in the promoter of the UGT1A9 gene: Evidence that UGT1A9 protein and activity levels are strongly genetically controlled in the liver. Pharmacogenetics 2004, 14, 501–515.
64. Kuypers, D.R.; Naesens, M.; Vermeire, S.; Vanrenterghem, Y. The impact of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T on early mycophenolic acid dose-interval exposure in de novo renal allograft recipients. Clin. Pharmacol. Ther. 2005, 78, 351–361.
65. Hesselink, D.A.; van Gelder, T. Genetic and nongenetic determinants of between-patient variability in the pharmacokinetics of mycophenolic acid. Clin. Pharmacol. Ther. 2005, 78, 317–321.
66. Van Schaik, R.H.; van Agteren, M.; de Fijter, J.W.; Hartmann, A.; Schmidt, J.; Budde, K.; Kuypers, D.; le Meur, Y.; van der Werf, M.; Mamelok, R.; van Gelder, T. UGT1A9 -275T>A/-2152C>T polymorphisms correlate with low MPA exposure and acute rejection in MMF/tacrolimus-treated kidney transplant patients. Clin. Pharmacol. Ther. 2009, 86, 319–327.
67. Lévesque, E.; Delage, R.; Benoit-Biancamano, M.O.; Caron, P.; Bernard, O.; Couture, F.; Guillemette, C. The impact of UGT1A8, UGT1A9, and UGT2B7 genetic polymorphisms on the pharmacokinetic profile of mycophenolic acid after a single oral dose in healthy volunteers. Clin. Pharmacol. Ther. 2007, 81, 392–400.
68. Sánchez-Fructuoso, A.I.; Maestro, M.L.; Calvo, N.; Viudarreta, M.; Pérez-Flores, I.; Veganzone, S.; de la Orden, V.; Ortega, D.; Arroyo, M.; Barrientos, A. The prevalence of uridine diphosphate-glucuronosyltransferase 1A9 (UGT1A9) gene promoter region single-nucleotide polymorphisms T-275A and C-2152T and its influence on mycophenolic acid pharmacokinetics in stable renal transplant patients. Transplant. Proc. 2009, 41, 2313–2316.
69. Baldelli, S.; Merlini, S.; Perico, N.; Nicastri, A.; Cortinovis, M.; Gotti, E.; Remuzzi, G.; Cattaneo, D. C-440T/T-331C polymorphisms in the UGT1A9 gene affect the pharmacokinetics of mycophenolic acid in kidney transplantation. Pharmacogenomics 2007, 8, 1127–1141.
70. Van Gelder, T.; van Schaik, R.H.; Hesselink, D.A. Pharmacogenetics and immunosuppressive drugs in solid organ transplantation. Nat. Rev. Nephrol. 2014, 10, 725–731.
71. Picard, N.; Yee, S.W.; Woillard, J.B.; Lebranchu, Y.; le Meur, Y.; Giacomini, K.M.; Marquet, P. The role of organic anion-transporting polypeptides and their common genetic variants in mycophenolic acid pharmacokinetics. Clin. Pharmacol. Ther. 2010, 87, 100–108.
72. Bouamar, R.; Hesselink, D.A.; van Schaik, R.H.; Weimar, W.; van der Heiden, I.P.; de Fijter, J.W.; Kuypers, D.R.; van Gelder, T. Mycophenolic acid-related diarrhea is not associated with polymorphisms in SLCO1B nor with ABCB1 in renal transplant recipients. Pharmacogenet. Genomics 2012, 22, 399–407.
73. Jacobson, P.A.; Schladt, D.; Oetting, W.S.; Leduc, R.; Guan, W.; Matas, A.J.; Lamba, V.; Mannon, R.B.; Julian, B.A.; Israni, A.; et al. Genetic determinants of mycophenolate-related anemia and leukopenia after transplantation. Transplantation 2011, 91, 309–316.
74. Woillard, J.B.; Rerolle, J.P.; Picard, N.; Rousseau, A.; Drouet, M.; Munteanu, E.; Essig, M.; Marquet, P.; le Meur, Y. Risk of diarrhoea in a long-term cohort of renal transplant patients given mycophenolate mofetil: The significant role of the UGT1A8*2 variant allele. Br. J. Clin. Pharmacol. 2010, 69, 675–683.
75. Van Agteren, M.; Armstrong, V.W.; van Schaik, R.H.; de Fijter, H.; Hartmann, A.; Zeier, M.; Budde, K.; Kuypers, D.; Pisarski, P.; le Meur, Y.; et al. AcylMPAG plasma concentrations and mycophenolic acid-related side effects in patients undergoing renal transplantation are not related to the UGT2B7–840G>A gene polymorphism. Ther. Drug Monit. 2008, 30, 439–444.
76. Prausa, S.E.; Fukuda, T.; Maseck, D.; Curtsinger, K.L.; Liu, C.; Zhang, K.; Nick, T.G.; Sherbotie, J.R.; Ellis, E.N.; Goebel, J.; et al. UGT genotype may contribute to adverse events following medication with mycophenolate mofetil in pediatric kidney transplant recipients. Clin. Pharmacol. Ther. 2009, 85, 495–500.
77. Digits, J.A.; Hedstrom, L. Species-specific inhibition of inosine 5’-monophosphate dehydrogenase by mycophenolic acid. Biochemistry 1999, 38, 15388–15397.
78. McPhillips, C.C.; Hyle, J.W.; Reines, D. Detection of the mycophenolate-inhibited form of IMP dehydrogenase in vivo. Proc. Natl. Acad. Sci. USA 2004, 101, 12171–12176.
79. Roberts, R.L.; Gearry, R.B.; Barclay, M.L.; Kennedy, M.A. IMPDH1 promoter mutations in a patient exhibiting azathioprine resistance. Pharmacogenomics J. 2007, 7, 312–317.
80. Wang, J.; Yang, J.W.; Zeevi, A.; Webber, S.A.; Girnita, D.M.; Selby, R.; Fu, J.; Shah, T.; Pravica, V.; Hutchinson, I.V.; et al. IMPDH1 gene polymorphisms and association with acute rejection in renal transplant patients. Clin. Pharmacol. Ther. 2008, 83, 711–717.
81. Glander, P.; Hambach, P.; Braun, K.P.; Fritsche, L.; Giessing, M.; Mai, I.; Einecke, G.; Waiser, J.; Neumayer, H.H.; Budde, K. Pre-transplant inosine monophosphate dehydrogenase activity is associated with clinical outcome after renal transplantation. Am. J. Transplant. 2004, 4, 2045–2051.
82. Kagaya, H.; Miura, M.; Saito, M.; Habuchi, T.; Satoh, S. Correlation of IMPDH1 gene polymorphisms with subclinical acute rejection and mycophenolic acid exposure parameters on day 28 after renal transplantation. Basic Clin. Pharmacol. Toxicol. 2010, 107, 631–636.
83. Sombogaard, F.; van Schaik, R.H.; Mathot, R.A.; Budde, K.; van der Werf, M.; Vulto, A.G.; Weimar, W.; Glander, P.; Essioux, L.; van Gelder, T. Interpatient variability in IMPDH activity in MMF-treated renal transplant patients is correlated with IMPDH type II 3757T>C polymorphism. Pharmacogenet. Genomics 2009, 19, 626–634.
84. Grinyó, J.; Vanrenterghem, Y.; Nashan, B.; Vincenti, F.; Ekberg, H.; Lindpaintner, K.; Rashford, M.; Nasmyth-Miller, C.; Voulgari, A.; Spleiss, O.; Truman, M.; et al. Association of four DNA polymorphisms with acute rejection after kidney transplantation. Transpl. Int. 2008, 21, 879–891.
85. Shah, S.; Harwood, S.M.; Döhler, B.; Opelz, G.; Yaqoob, M.M. Inosine monophosphate dehydrogenase polymorphisms and renal allograft outcome. Transplantation 2012, 94, 486–491.
86. Gabardi, S.; Baroletti, S.A. Everolimus: A proliferation signal inhibitor with clinical applications in organ transplantation, oncology, and cardiology. Pharmacotherapy 2010, 30, 1044–1056.
87. Jacobsen, W.; Serkova, N.; Hausen, B.; Morris, R.E.; Benet, L.Z.; Christians, U. Comparison of the in vitro metabolism of the macrolide immunosuppressants sirolimus and RAD. Transplant. Proc. 2001, 33, 514–515.
88. Sattler, M.; Guengerich, F.P.; Yun, C.H.; Christians, U.; Sewing, K.F. Cytochrome P-450 3A enzymes are responsible for biotransformation of FK506 and rapamycin in man and rat. Drug Metab. Dispos. 1992, 20, 753–761.
89. Anglicheau, D.; le Corre, D.; Lechaton, S.; Laurent-Puig, P.; Kreis, H.; Beaune, P.; Legendre, C.; Thervet, E. Consequences of genetic polymorphisms for sirolimus requirements after renal transplant in patients on primary sirolimus therapy. Am. J. Transplant. 2005, 5, 595–603.
90. Le Meur, Y.; Djebli, N.; Szelag, J.C.; Hoizey, G.; Toupance, O.; Rérolle, J.P.; Marquet, P. CYP3A5*3 influences sirolimus oral clearance in de novo and stable renal transplant recipients. Clin. Pharmacol. Ther. 2006, 80, 51–60.
91. Mourad, M.; Mourad, G.; Wallemacq, P.; Garrigue, V.; van Bellingen, C.; van Kerckhove, V.; de Meyer, M.; Malaise, J.; Eddour, D.C.; Lison, D.; et al. Sirolimus and tacrolimus trough concentrations and dose requirements after kidney transplantation in relation to CYP3A5 and MDR1 polymorphisms and steroids. Transplantation 2005, 80, 977–984.
92. Picard, N.; Rouguieg-Malki, K.; Kamar, N.; Rostaing, L.; Marquet, P. CYP3A5 genotype does not influence everolimus in vitro metabolism and clinical pharmacokinetics in renal transplant recipients. Transplantation 2011, 91, 652–656.
93. Renders, L.; Frisman, M.; Ufer, M.; Mosyagin, I.; Haenisch, S.; Ott, U.; Caliebe, A.; Dechant, M.; Braun, F.; Kunzendorf, U.; et al. CYP3A5 genotype markedly influences the pharmacokinetics of tacrolimus and sirolimus in kidney transplant recipients. Clin. Pharmacol. Ther. 2007, 81, 228–234.
94. Woillard, J.B.; Kamar, N.; Coste, S.; Rostaing, L.; Marquet, P.; Picard, N. Effect of CYP3A4*22, POR*28, and PPARA rs4253728 on sirolimus in vitro metabolism and trough concentrations in kidney transplant recipients. Clin. Chem. 2013, 59, 1761–1769.
95. Sam, W.J.; Chamberlain, C.E.; Lee, S.J.; Goldstein, J.A.; Hale, D.A.; Mannon, R.B.; Kirk, A.D.; Hon, Y.Y. Associations of ABCB1 3435C>T and IL-10–1082G>A polymorphisms with long-term sirolimus dose requirements in renal transplant patients. Transplantation 2011, 92, 1342–1347.
96. Abdel-Razzak, Z.; Loyer, P.; Fautrel, A.; Gautier, J.C.; Corcos, L.; Turlin, B.; Beaune, P.; Guillouzo, A. Cytokines down-regulate expression of major cytochrome P-450 enzymes in adult human hepatocytes in primary culture. Mol. Pharmacol. 1993, 44, 707–715.
97. Bertilsson, P.M.; Olsson, P.; Magnusson, K.E. Cytokines influence mRNA expression of cytochrome P450 3A4 and MDRI in intestinal cells. J. Pharm. Sci. 2001, 90, 638–646.
98. Sam, W.J.; Chamberlain, C.E.; Lee, S.J.; Goldstein, J.A.; Hale, D.A.; Mannon, R.B.; Kirk, A.D.; Hon, Y.Y. Associations of ABCB1 and IL-10 genetic polymorphisms with sirolimus-induced dyslipidemia in renal transplant recipients. Transplantation 2012, 94, 971–977.
99. Zaza, G.; Tomei, P.; Ria, P.; Granata, S.; Boschiero, L.; Lupo, A. Systemic and nonrenal adverse effects occurring in renal transplant patients treated with mTOR inhibitors. Clin. Dev. Immunol. 2013, 2013, doi:10.1155/2013/403280.
100. Zaza, G.; Granata, S.; Tomei, P.; Masola, V.; Gambaro, G.; Lupo, A. mTOR inhibitors and renal allograft: Yin and Yang. J. Nephrol. 2014, 27, 495–506.
101. Clamers, A.H.; Knight, P.R. Atkinson MR: 6-thiopurines as substrates and inhibitors of purine oxidases: A pathway for conversion of azathioprine into 6-thiouric acid without release of 6-mercaptopurine. Aust. J. Exp. Biol. Med. Sci. 1969, 47, 263–273.
102. Fink, D.; Aebi, S.; Howell, S.B. The role of DNA mismatch repair in drug resistance. Clin. Cancer Res. 1998, 4, 1–6.
103. Lennard, L. The clinical pharmacology of 6-mercaptopurine. Eur. J. Clin. Pharmacol. 1992, 43, 329–339.
104. McLeod, H.L.; Krynetski, E.Y.; Relling, M.V.; Evans, W.E. Genetic polymorphism of thiopurine methyltransferase and its clinical relevance for childhood acute lymphoblastic leukemia. Leukemia 2000, 14, 567–572.
105. Fabre, M.A.; Jones, D.C.; Bunce, M.; Morris, P.J.; Friend, P.J.; Welsh, K.I.; Marshall, S.E. The impact of thiopurine S-methyltransferase polymorphisms on azathioprine dose 1 year after renal transplantation. Transpl. Int. 2004, 17, 531–539.
106. Weinshilboum, R.M.; Sladek, S.L. Mercaptopurine pharmacogenetics: Monogenic inheritance of erythrocyte thiopurine methyltransferase activity. Am. J. Hum. Genet. 1980, 32, 651–662.
107. Yates, C.R.; Krynetski, E.Y.; Loennechen, T.; Fessing, M.Y.; Tai, H.L.; Pui, C.H.; Relling, M.V.; Evans, W.E. Molecular diagnosis of thiopurine S-methyltransferase deficiency: Genetic basis for azathioprine and mercaptopurine intolerance. Ann. Intern. Med. 1997, 126, 608–614.
108. McLeod, H.L.; Siva, C. The thiopurine S-methyltransferase gene locus—Implication for clinical pharmacogenomics. Pharmacogenomics 2002, 3, 89–98.
109. Krynetski, E.Y.; Evans, W.E. Genetic polymorphism of thiopurine S-methyltransferase: Molecular mechanisms add clinical importance. Pharmacology 2000, 61, 136–146.
110. Krynetski, E.Y.; Schuetz, J.D.; Galpin, A.J.; Pui, C.H.; Relling, M.V.; Evans, W.E. A single point mutation leading to loss of catalytic activity in human thiopurine S-methyltransferase. Proc. Natl. Acad. Sci. USA 1995, 92, 949–953.
111. Tai, H.L.; Krynetski, E.Y.; Yates, C.R.; Loennechen, T.; Fessing, M.Y.; Krynetskaia, N.F.; Evans, W.E. Thiopurine S-methyltransferase deficiency: Two nucleotide transitions define the most prevalent mutant allele associated with loss of catalytic activity in Caucasians. Am. J. Hum. Genet. 1996, 58, 694–702.
112. Schaeffeler, E.; Fischer, C.; Brockmeier, D.; Wernet, D.; Moerike, K.; Eichelbaum, M.; Zanger, U.M.; Schwab, M. Comprehensive analysis of thiopurine S-methyltransferase phenotype-genotype correlation in a large population of German-Caucasians and identification of novel TPMT variants. Pharmacogenetics 2004, 14, 407–417.
113. Evans, W.E.; Hon, Y.Y.; Bomgaars, L.; Coutre, S.; Holdsworth, M.; Janco, R.; Kalwinsky, D.; Keller, F.; Khatib, Z.; Margolin, J.; et al. Preponderance of thiopurine S-methyltransferase deficiency and heterozygosity among patients intolerant to mercaptopurine or azathioprine. J. Clin. Oncol. 2001, 19, 2293–2301.
114. Evans, W.E. Thiopurine S-methyltransferase: A genetic polymorphism that affects a small number of drugs in a big way. Pharmacogenetics 2002, 12, 421–423.
115. Black, A.J.; McLeod, H.L.; Capell, H.A.; Powrie, R.H.; Matowe, L.K.; Pritchard, S.C.; Collie-Duguid, E.S.; Reid, D.M. Thiopurine methyltransferase genotype predicts therapy-limiting severe toxicity from azathioprine. Ann. Intern. Med. 1998, 129, 716–718.
116. Relling, M.V.; Hancock, M.L.; Rivera, G.K.; Sandlund, J.T.; Ribeiro, R.C.; Krynetski, E.Y.; Pui, C.H.; Evans, W.E. Mercaptopurine therapy intolerance related to heterozygosity at the thiopurine methyltransferase gene locus. J. Natl. Cancer Inst. 1999, 91, 2001–2008.
117. Ishioka, S.; Hiyama, K.; Sato, H.; Yamanishi, Y.; McLeod, H.L.; Kumagai, K.; Maeda, H.; Yamakido, M. Thiopurine methyltransferase genotype and the toxicity of azathioprine in Japanese. Intern. Med. 1999, 38, 944–947.
118. Kurzawski, M.; Dziewanowski, K.; Gawrońska-Szklarz, B.; Domański, L.; Droździk, M. The impact of thiopurine S-methyltransferase polymorphism on azathioprine-induced myelotoxicity in renal transplant recipients. Ther. Drug Monit. 2005, 27, 435–441.
119. Dervieux, T.; Médard, Y.; Baudouin, V.; Maisin, A.; Zhang, D.; Broly, F.; Loirat, C.; Jacqz-Aigrain, E. Thiopurine methyltransferase activity and its relationship to the occurrence of rejection episodes in paediatric renal transplant recipients treated with azathioprine. Br. J. Clin. Pharmacol. 1999, 48, 793–800.
120. Thervet, E.; Anglicheau, D.; Toledano, N.; Houllier, A.M.; Noel, L.H.; Kreis, H.; Beaune, P.; Legendre, C. Long-term results of TPMT activity monitoring in azathioprine-treated renal allograft recipients. J. Am. Soc. Nephrol. 2001, 12, 170–176.
121. Thompson, A.J.; Newman, W.G.; Elliott, R.A.; Roberts, S.A.; Tricker, K.; Payne, K. The cost-effectiveness of a pharmacogenetic test: A trial-based evaluation of TPMT genotyping for azathioprine. Value Health 2014, 17, 22–33.
122. Relling, M.V.; Gardner, E.E.; Sandborn, W.J.; Schmiegelow, K.; Pui, C.H.; Yee, S.W.; Stein, C.M.; Carrillo, M.; Evans, W.E.; Hicks, J.K.; et al. Clinical Pharmacogenetics Implementation Consortium guidelines for thiopurine methyltransferase genotype and thiopurine dosing. Clin. Pharmacol. Ther. 2011, 89, 387–391.
123. Lander, E.S.; Linton, L.M.; Birren, B.; Nusbaum, C.; Zody, M.C.; Baldwin, H.; Devon, K.; Dewar, K.; Doyle, M.; FitzHugh, W.; et al. Initial sequencing and analysis of the human genome. Nature 2001, 409, 860–921.
124. Venter, J.C.; Adams, M.D.; Myers, E.W.; Li, P.W.; Mural, R.J.; Sutton, G.G.; Smith, H.O.; Yandell, M.; Evans, C.A.; Holt, R.A.; et al. The sequence of the human genome. Science 2001, 291, 1304–1351.
125. Trent, R.J. Pathology practice and pharmacogenomics. Pharmacogenomics 2010, 11, 105–111.
126. Squassina, A.; Manchia, M.; Manolopoulos, V.G.; Artac, M.; Lappa-Manakou, C.; Karkabouna, S.; Mitropoulos, K.; del Zompo, M.; Patrinos, G.P. Realities and expectations of pharmacogenomics and personalized medicine: Impact of translating genetic knowledge into clinical practice. Pharmacogenomics 2010, 11, 1149–1167.
127. Ventola, C.L. Pharmacogenomics in clinical practice: Reality and expectations. Pharm. Ther. 2011, 36, 412–450.
128. Gage, B.F.; Lesko, L.J. Pharmacogenetics of warfarin: Regulatory, scientific, and clinical issues. J. Thromb. Thrombolysis 2008, 25, 45–51.
129. Innocenti, F.; Ratain, M.J. Pharmacogenetics of irinotecan: Clinical perspectives on the utility of genotyping. Pharmacogenomics 2006, 7, 1211–1221.
130. Guidance for industry. Pharmacogenomic Data Submission (PDF Document in Internet), 2005. Available online: http://www.fda.gov/Cber/gdlns/pharmdtasub.htm (accessed on 29 February 2008).
131. Klein, T.E.; Chang, J.T.; Cho, M.K.; Easton, K.L.; Fergerson, R.; Hewett, M.; Lin, Z.; Liu, Y.; Liu, S.; Oliver, D.E.; et al. Integrating genotype and phenotype information: An overview of the PharmGKB project. Pharmacogenetics Research Network and Knowledge Base. Pharmacogenomics J. 2001, 1, 167–170.
132. Rhead, B.; Karolchik, D.; Kuhn, R.M.; Hinrichs, A.S.; Zweig, A.S.; Fujita, P.A.; Diekhans, M.; Smith, K.E.; Rosenbloom, K.R.; Raney, B.J.; et al. The UCSC genome browser database: Update 2010. Nucleic Acids Res. 2009, 38, D613–D619.
133. Wishart, D.S.; Knox, C.; Guo, A.C.; Shrivastava, S.; Hassanali, M.; Stothard, P.; Chang, Z.; Woolsey, J. DrugBank: A comprehensive resource for in silico drug discovery and exploration. Nucleic Acids Res. 2006, 34, D668–D672.
134. Luciano, J.S. PAX of mind for pathway researchers. Drug Discov. Today 2005, 10, 937–942.
135. Gurwitz, D.; Weizman, A.; Rehavi, M. Education: Teaching pharmacogenomics to prepare future physicians and researchers for personalized medicine. Trends Pharmacol. Sci. 2003, 24, 122–125.
136. Frueh, F.W.; Goodsaid, F.; Rudman, A.; Huang, S.M.; Lesko, L.J. The need for education in pharmacogenomics: A regulatory perspective. Pharmacogenomics J. 2005, 5, 218–220.
137. Hu, J.; Zou, F.; Wright, F.A. Practical FDR-based sample size calculations in microarray experiments. Bioinformatics 2005, 21, 3264–3272.
138. Swen, J.J.; Nijenhuis, M.; de Boer, A.; Grandia, L.; Maitland-van der Zee, A.H.; Mulder, H.; Rongen, G.A.; van Schaik, R.H.; Schalekamp, T.; Touw, D.J.; et al. Pharmacogenetics: From bench to byte—an update of guidelines. Clin. Pharmacol. Ther. 2011, 89, 662–673.
139. Jacobson, P.A.; Schladt, D.; Israni, A.; Oetting, W.S.; Lin, Y.C.; Leduc, R.; Guan, W.; Lamba, V.; Matas, A.J.; DeKAF Investigators. Genetic and clinical determinants of early, acute calcineurin inhibitor-related nephrotoxicity: Results from a kidney transplant consortium. Transplantation 2012, 93, 624–631.
140. Sarwal, M.; Chua, M.S.; Kambham, N.; Hsieh, S.C.; Satterwhite, T.; Masek, M.; Salvatierra, O. Molecular heterogeneity in acute renal allograft rejection identified by DNA microarray profiling. N. Engl. J. Med. 2003, 349, 125–138.
141. Brouard, S.; Mansfield, E.; Braud, C.; Li, L.; Giral, M.; Hsieh, S.C.; Baeten, D.; Zhang, M.; Ashton-Chess, J.; Braudeau, C.; et al. Identification of a peripheral blood transcriptional biomarker panel associated with operational renal allograft tolerance. Proc. Natl. Acad. Sci. USA 2007, 104, 15448–15453.
142. Yabu, J.M.; Vincenti, F. Kidney transplantation: The ideal immunosuppression regimen. Adv. Chronic Kidney Dis. 2009, 16, 226–233.
143. Newell, K.A.; Asare, A.; Kirk, A.D.; Gisler, T.D.; Bourcier, K.; Suthanthiran, M.; Burlingham, W.J.; Marks, W.H.; Sanz, I.; Lechler, R.I.; et al. Identification of a B cell signature associated with renal transplant tolerance in humans. J. Clin. Investig. 2010, 120, 1836–1847.
144. Dell’Oglio, M.P.; Zaza, G.; Rossini, M.; Divella, C.; Pontrelli, P.; Verrienti, R.; Rutigliano, M.; Ditonno, P.; Stifanelli, P.; Ancona, N.; et al. The anti-fibrotic effect of mycophenolic acid-induced neutral endopeptidase. J. Am. Soc. Nephrol. 2010, 21, 2157–2168.
145. Zaza, G.; Rascio, F.; Pontrelli, P.; Granata, S.; Stifanelli, P.; Accetturo, M.; Ancona, N.; Gesualdo, L.; Lupo, A.; Grandaliano, G. Karyopherins: Potential biological elements involved in the delayed graft function in renal transplant recipients. BMC Med. Genomics 2014, 7, doi:10.1186/1755-8794-7-14.
146. Soderholm, J.F.; Bird, S.L.; Kalab, P.; Sampathkumar, Y.; Hasegawa, K.; Uehara-Bingen, M.; Weis, K.; Heald, R. Importazole, a small molecule inhibitor of the transport receptor importin-β. ACS Chem. Biol. 2011, 6, 700–708.
147. Wagstaff, K.M.; Sivakumaran, H.; Heaton, S.M.; Harrich, D.; Jans, D.A. Ivermectin is a specific inhibitor of importin α/β-mediated nuclear import able to inhibit replication of HIV-1 and dengue virus. Biochem. J. 2012, 443, 851–856.
148. Wagstaff, K.M.; Rawlinson, S.M.; Hearps, A.C.; Jans, D.A. An AlphaScreen®-based assay for high-throughput screening for specific inhibitors of nuclear import. J. Biomol. Screen. 2011, 16, 192–200.
149. Kainz, A.; Perco, P.; Mayer, B.; Soleiman, A.; Steininger, R.; Mayer, G.; Mitterbauer, C.; Schwarz, C.; Meyer, T.W.; Oberbauer, R. Gene-expression profiles and age of donor kidney biopsies obtained before transplantation distinguish medium term graft function. Transplantation 2007, 83, 1048–1054.
150. Saint-Mezard, P.; Berthier, C.C.; Zhang, H.; Hertig, A.; Kaiser, S.; Schumacher, M.; Wieczorek, G.; Bigaud, M.; Kehren, J.; Rondeau, E.; et al. Analysis of independent microarray datasets of renal biopsies identifies a robust transcript signature of acute allograft rejection. Transpl. Int. 2009, 22, 293–302.
151. Vogenberg, F.R.; Barash, C.I.; Pursel, M. Personalized medicine: Part 2: Ethical, legal, and regulatory issues. Pharm. Ther. 2010, 35, 624–642.