OJOTS  Vol.3 No.2 , May 2013
Modern Immunosuppressive Therapy in Kidney Transplantation
Abstract: Immunosuppressive therapy is a key component for successful kidney transplantation. It is commonly believed that more intensive immunosuppression is needed initially to prevent rejection episodes and less immunosuppression is subsequently maintained to minimize the overall risk of infection and malignancy. The selection of drugs should be guided by a comprehensive assessment of the immunologic risk, patient comorbidities, financial cost, drug efficacy and adverse effects. Lymphocyte-depleting antibody induction is recommended for patients with high immunologic risk, while IL-2R antibody can be used for low or moderate risk patients. Patients with very low risk may be induced with intravenous steroids without using an antibody. A maintenance regimen typically consists of a low-dose of steroid combined with two of the four class drugs: calcineurin inhibitor (tacrolimus or cyclosporine), antimetabolite (mycophenolate mofetil or enteric coated mycophenolate sodium), mTOR inhibitor (sirolimus or everolimus) and costimulation blocker (belatacept). Currently in the USA, the most popular maintenance is the combination of corticosteroid, mycophenolic acid and tacrolimus. Steroid minimization, or calcineurin inhibitor free or withdrawal should be limited to the highly selected patients with low immunological risk. Recently, the novel biological agent belatacept-based maintenance has demonstrated a significantly better renal function and improved cardiovascular and metabolic profile, which may provide hope for an ultimate survival benefit.
Cite this paper: Zhang, R. (2013) Modern Immunosuppressive Therapy in Kidney Transplantation. Open Journal of Organ Transplant Surgery, 3, 22-31. doi: 10.4236/ojots.2013.32005.

[1]   US Department of Health and Human Services, “2011 Annual Report of the Organ Procurement and Transplantation Network and the Scientific Registry of Transplant Recipients,” American Journal of Transplantation, Vol. 13, No. S1, 2013, pp. 1-36. doi:10.5500/wjt.v2.i2.19

[2]   K. Chouhan and R. Zhang, “Editorial Review: Antibody Induction Therapy in Adult Kidney Transplantation: A Controversy Continues,” World Journal of Transplantation, Vol. 2, No. 2, 2012, pp. 19-26.

[3]   P. L. Hibberd, N. E. Tolkoff-Rubin, A. B. Cosimi, R. T. Schooley, D. Isaacson, M. Doran, A. Delvecchio, F. L. Delmonico, H. Auchincloss Jr. and R. H. Rubin, “Symptomatic Cytomegalovirus Disease in the Cytomegalovirus Antibody Seropositive Renal Transplant Recipient Treated with OKT3,” Transplantation, Vol. 53, No. 1, 1992, pp. 68-72. doi:10.1097/00007890-199201000-00013

[4]   J. R. Thistlethwaite Jr., J. K. Stuart, J. T. Mayes, A. O. Gaber, S. Woodle, M. R. Buckingham and F. P. Stuart, “Complications and Monitoring of OKT3 Therapy,” American Journal of Kidney Diseases, Vol. 11, No. 2, 1988, pp. 112-119.

[5]   L. J. Swinnen, M. R. Costanzo-Nordin, S. G. Fisher, E. J. O’Sullivan, M. R. Johnson, A. L. Heroux, G. J. Dizikes, R. Pifarre and R. I. Fisher, “Increased Incidence of Lymphoproliferative Disorder after Immunosuppression with the Monoclonal Antibody OKT3 in Cardiac-Transplant Recipients,” The New England Journal of Medicine, Vol. 323, No. 25, 1990, pp. 1723-1728. doi:10.1056/NEJM199012203232502

[6]   D. C. Brennan, K. Flavin, J. A. Lowell, T. K. Howard, S. Shenoy, S. Burgess, S. Dolan, J. M. Kano, M. Mahon, M. A. Schnitzler, R. Woodward, W. Irish and G. G. Singer, “A Randomized, Double-Blinded Comparison of Thymoglobulin versus Atgam for Induction Immunosuppressive Therapy in Adult Renal Transplant Recipients,” Transplantation, Vol. 67, No. 7, 1999, pp. 1011-1018. doi:10.1097/00007890-199904150-00013

[7]   K. L. Hardinger, M. A. Schnitzler, B. Miller, J. A. Lowell, S. Shenoy, M. J. Koch, D. Enkvetchakul, C. Ceriotti and D. C. Brennan, “Five-Year Follow up of Thymoglobulin versus ATGAM Induction in Adult Renal Transplantation,” Transplantation, Vol. 78, No. 1, 2004, pp. 136-141. doi:10.1097/01.TP.0000132329.67611.3F

[8]   K. L. Hardinger, S. Rhee, P. Buchanan, M. Koch, B. Miller, D. Enkvetchakul, R. Schuessler, M. A. Schnitzler and D. C. Brennan, “A Prospective, Randomized, Double-Blinded Comparison of Thymoglobulin versus Atgam for Induction Immunosuppressive Therapy: 10-Year Results,” Transplantation, Vol. 86, No. 7, 2008, pp. 947-952. doi:10.1097/TP.0b013e318187bc67

[9]   W. C. Goggins, M. A. Pascual, J. A. Powelson, C. Magee, N. Tolkoff-Rubin, M. L. Farrell, D. S. Ko, W. W. Williams, A. Chandraker, F. L. Delmonico, H. Auchincloss and A. B. Cosimi, “A Prospective, Randomized, Clinical Trial of Intraoperative versus Postoperative Thymoglobulin in Adult Cadaveric Renal Transplant Recipients,” Transplantation, Vol. 76, No. 5, 2003, pp. 798-802. doi:10.1097/01.TP.0000081042.67285.91

[10]   W. Wong, N. Agrawal, M. Pascual, D. C. Anderson, H. H. Hirsch, K. Fujimoto, F. Cardarelli, W. C. Winkelmayer, A. B. Cosimi and N. Tolkoff-Rubin, “Comparison of Two Dosages of Thymoglobulin Used as a Short-Course for Induction in Kidney Transplantation,” Transplant International, Vol. 19, No. 8, 2006, pp. 629-635. doi:10.1111/j.1432-2277.2006.00270.x

[11]   R. B. Stevens, D. F. Mercer, W. J. Grant, A. G. Freifeld, J. T. Lane, G. C. Groggel, T. H. Rigley, K. J. Nielsen, M. E. Henning, J. Y. Skorupa, A. J. Skorupa, K. A. Christensen, J. P. Sandoz, A. M. Kellogg, A. N. Langnas and L. E. Wrenshall, “Randomized Trial of Single-Dose versus Divided-Dose Rabbit Anti-Thymocyte Globulin Induction in Renal Transplantation: An Interim Report,” Transplantation, Vol. 85, No. 10, 2008, pp. 1391-1399. doi:10.1097/TP.0b013e3181722fad

[12]   F. Vincenti, R. Kirkman, S. Light, G. Bumgardner, M. Pescovitz, P. Halloran, J. Neylan, A. Wilkinson, H. Ekberg, R. Gaston, L. Backman and J. Burdick (Daclizumab Triple Therapy Study Group), “Interleukin-2-Receptor Blockade with Daclizumab to Prevent Acute Rejection in Renal Transplantation,” The New England Journal of Medicine, Vol. 338, 1998, pp. 161-165. doi:10.1056/NEJM199801153380304

[13]   B. D. Kahan, P. R. Rajagopalan and M. Hall (United States Simulect Renal Study Group), “Reduction of the Occurrence of Acute Cellular Rejection among Renal Allograft Recipients Treated with Basiliximab, a Chimeric Anti-Interleukin-2-Receptor Monoclonal Antibody,” Transplantation, Vol. 67, 1999, pp. 276-284. doi:10.1097/00007890-199901270-00016

[14]   J. G. Lawen, E. A. Davies, G. Mourad, F. Oppenheimer, M. G. Molina, L. Rostaing, A. H. Wilkinson, L. L. Mulloy, B. J. Bourbigot, H. Prestele, A. Korn and D. Girault, “Randomized Double-Blind Study of Immunoprophylaxis with Basiliximab, a Chimeric Anti-Interleukin-2 Receptor Monoclonal Antibody, in Combination with Mycophenolate Mofetil-Containing Triple Therapy in Renal Transplantation,” Transplantation, Vol. 75, 2003, pp. 37- 43. doi:10.1097/00007890-200301150-00007

[15]   A. C. Webster, E. G. Playford, G. Higgins, J. R. Chapman and J. C. Craig, “Interleukin 2 Receptor Antagonists for Renal Transplant Recipients: A Meta Analysis of Randomized Trials,” Transplantation, Vol. 77, 2004, pp. 166- 176. doi:10.1097/01.TP.0000109643.32659.C4

[16]   A. D. Kirk, D. A. Hale, S. J. Swanson and R. B. Mannon, “Autoimmune Thyroid Disease after Renal Transplantation Using Depletional Induction with Alemtuzumab,” American Journal of Transplantation, Vol. 6, No. 5, 2006, pp. 1084-1085. doi:10.1111/j.1600-6143.2006.01258.x

[17]   J. Pascual, J. D. Mezrich, A. Djamali, G. Leverson, L. T. Chin, J. Torrealba, D. Bloom, B. Voss, B. N. Becker, S. J. Knechtle, H. W. Sollinger, J. D. Pirsch and M. D. Samaniego, “Alemtuzumab Induction and Recurrence of Glomerular Disease after Kidney Transplantation,” Transplantation, Vol. 83, No. 11, 2007, pp. 1429-1434. doi:10.1097/

[18]   M. J. Hanaway, E. Steve Woodle, S. Mulgaonkar, V. Ram Peddi, D. B. Kaufman, M. Roy First, R. Croy and J. Holman, (for the INTAC Study Group), “Alemtuzumab Induction in Renal Transplantation,” The New England Journal of Medicine, Vol. 364, No. 12, 2011, pp. 1909-1919.

[19]   H. P. Tan, J. Donaldson, A. Basu, M. Unruh, P. Randhawa, V. Sharma, C. Morgan, J. McCauley, C. Wu, N. Shah, A. Zeevi and R. Shapiro, “Two Hundred Living Donor Kidney Transplantations under Alemtuzumab Induction and Tacrolimus Monotherapy: 3-Year Follow-Up,” American Journal of Transplantation, Vol. 9, No. 2, 2009, pp. 355-366. doi:10.1111/j.1600-6143.2008.02492.x

[20]   D. B. Kaufman, J. R. Leventhal, D. Axelrod, L. G. Gallon, M. A. Parker and F. P. Stuart, “Alemtuzumab Induction and Prednisone-Free Maintenance Immunotherapy in Kidney Transplantation: Comparison with Basiliximab Induction—Long-Term Results,” American Journal of Transplantation, Vol. 5, No. 10, 2005, pp. 2539-2548. doi:10.1111/j.1600-6143.2005.01067.x

[21]   S. M. Flechner, P. J. Friend, J. Brockmann, H. R. Ismail, M. Zilvetti, D. Goldfarb, C. Modlin, B. Mastroianni, K. Savas, A. Devaney, M. Simmonds and D. J. Cook, “Alemtuzumab Induction and Sirolimus plus Mycophenolate Mofetil Maintenance for CNI and Steroid-Free Kidney Transplant Immunosuppression,” American Journal of Transplantation, Vol. 5, 2005, pp. 3009-3014. doi:10.1111/j.1600-6143.2005.01123.x

[22]   A. A. Vo, M. Lukovsky, M. Toyoda, J. Wang, N. L. Reinsmoen, C. H. Lai, A. Peng, R. Villicana and S. C. Jordan, “Rituximab and Intravenous Immune Globulin for Desensitization during Renal Transplantation,” The New England Journal of Medicine, Vol. 359, No. 3, 2008, pp. 242-251. doi:10.1056/NEJMoa0707894

[23]   W. R. Mulley, F. J. Hudson, B. D. Tait, A. M. Skene, J. P. Dowling, P. G. Kerr, et al., “A Single Low-Fixed Dose of Rituximab to Salvage Renal Transplants from Refractory Antibody-Mediated Rejection,” Transplantation, Vol. 87, No. 2, 2009, pp. 286-289. doi:10.1097/TP.0b013e31819389cc

[24]   Kidney Disease: Improving Global Outcomes (KDIGO) Transplant Work Group, “KDIGO Clinical Practice Guideline for the Care of Kidney Transplant Recipients,” American Journal of Transplantation, Vol. 9, Suppl. 3, 2009, pp. S1-155. doi:10.1111/j.1600-6143.2009.02834.x

[25]   R. M. Jindal, N. P. Das, R. T. Neff, F. P. Hurst, E. M. Falta, E. A. Elster and K. C. Abbott, “Outcomes in African-Americans vs. Caucasians Using Thymoglobulin or Interleukin-2 Inhibitor Induction: Analysis of USRD Database,” American Journal of Nephrology, Vol. 29, 2009, pp. 501-508. doi:10.1159/000182816

[26]   D. C. Brennan, J. A. Daller, K. D. Lake, D. Cibrik and D. Del Castillo, “Rabbit Antithymocyte Globulin versus Basiliximab in Renal Transplantation,” The New England Journal of Medicine, Vol. 355, 2006, pp. 1967-1977. doi:10.1056/NEJMoa060068

[27]   V. Patlolla, X. Zhong, G. W. Reed and D. A. Mandelbrot, “Efficacy of Anti IL2 Receptor Antibodies Compared to No Induction and to Antilymphocyte Antibodies in Renal Transplantation,” American Journal of Transplantation, Vol. 7, 2007, pp. 832-1842. doi:10.1111/j.1600-6143.2007.01860.x

[28]   F. L. Luan, D. E. Schaubel, H. Zhang, X. Jia, S. J. Pelletier, F. K. Port, J. C. Magee and R. S. Sung, “Impact of Immunosuppressive Regimen on Survival of Kidney Transplant Recipients with Hepatitis C,” Transplantation, Vol. 85, No. 11, 2008, pp. 1601-1606. doi:10.1097/TP.0b013e3181722f3a

[29]   P. G. Stock, B. Barin, B. Murphy, D. Hanto, J. M. Diego, J. Light, C. Davis, E. Blumberg, D. Simon, A. Subramanian, J. M. Millis, G. M. Lyon, K. Brayman, D. Slakey, R. Shapiro, J. Melancon, J. M. Jacobson, V. Stosor, J. L. Olson, D. M. Stablein and M. E. Roland, “Outcomes of Kidney Transplantation in HIV-Infected Recipients,” The New England Journal of Medicine, Vol. 363, No. 21, 2010, pp. 2004-2014. doi:10.1056/NEJMoa1001197

[30]   S. J. Patel, R. J. Knight, W. N. Suki, A. Abdellatif, B. T. Duhart Jr., A. G. Krauss, S. Mannan, N. Nezakatgoo and A. Osama Gaber, “Rabbit Antithymocyte Induction and Dosing in Deceased Donor Renal Transplant Recipients over 60 yr of Age,” Clinical Transplantation, Vol. 25, No. 3, 2011, E250-E256. doi:10.1111/j.1399-0012.2010.01393.x

[31]   R. L. Morton, K. Howard, A. C. Webster, G. Wong and J. C. Craig, “The Cost Effectiveness of Induction Immunosuppression in Kidney Transplantation,” Nephrology Dialysis Transplantation, Vol. 24, No. 7, 2009, pp. 2258-2269. doi:10.1093/ndt/gfp174

[32]   P. F. Halloran, “Immunosuppressive Drugs for Kidney Transplantation,” The New England Journal of Medicine, Vol. 351, No. 26, 2004, pp. 2715-2729. doi:10.1056/NEJMra033540

[33]   A. B. Leichtman, “Balancing Efficacy and Toxicity in Kidney-Transplant Immunosuppression,” The New England Journal of Medicine, Vol. 357, No. 25, 2007, pp. 2625-2627. doi:10.1056/NEJMe078181

[34]   D. E. Hricik, W. Y. Almawi and T. B. Strom, “Trends in the Use of Glucocorticoids in Renal Transplantation,” Transplantation, Vol. 57, No. 7, 1994, pp. 979-989.

[35]   K. Midtvedt, J. Hjelmesaeth, A. Hartmann, K. Lund, D. Paulsen, T. Egeland, et al., “Insulin Resistance after Renal Transplantation: The Effect of Steroid Dose Reduction and Withdrawal,” Journal of the American Society of Nephrology, Vol. 15, No. 12, 2004, pp. 3233-3239. doi:10.1097/01.ASN.0000145435.80005.1E

[36]   The Canadian Multicentre Transplant Study Group, “A Randomized Clinical Trial of Cyclosporine in Cadaveric Renal Transplantation. Analysis at Three Years,” The New England Journal of Medicine, Vol. 314, No. 19, pp. 1219-1225.

[37]   E. A. Mueller, J. M. Kovarik, J. B. van Bree, A. E. Lison and K. Kutz, “Pharmacokinetics and Tolerability of a Microemulsion Formulation of Cyclosporine in Renal Allograft Recipients—A Concentration-Controlled Comparison with the Commercial Formulation,” Transplantation, Vol. 57, No. 8, 1994, pp. 1178-1182. doi:10.1097/00007890-199404270-00007

[38]   M. D. Pescovitz, G. Barone, M. G. Choc Jr., D. E. Hricik, D. S. Hwang, J. H. Jin, et al., “Safety and Tolerability of Cyclosporine Microemulsion versus Cyclosporine: Two-Year Data in Primary Renal Allograft Recipients: A Report of the Neoral Study Group,” Transplantation, Vol. 63, No. 5, 1997, pp. 778-780. doi:10.1097/00007890-199703150-00027

[39]   C. Ponticelli, L. Minetti, F. Q. Di Palo, A. Vegeto, L. Belli, G. Corbetta, et al., “The Milan Clinical Trial with Cyclosporine in Cadaveric Renal Transplantation: A Three-Year Follow-Up,” Transplantation, Vol. 45, No. 5, 1988, pp. 908-913. doi:10.1097/00007890-198805000-00013

[40]   S. R. Knight and P. J. Morris, “The Clinical Benefits of Cyclosporine C2-Level Monitoring: A Systematic Review,” Transplantation, Vol. 83, No. 12, 2007, pp. 1525-1535. doi:10.1097/

[41]   G. A. Knoll and R. C. Bell, “Tacrolimus versus Cyclosporin for Immunosuppression in Renal Transplantation: Meta-Analysis of Randomised Trials,” British Medical Journal, Vol. 318, No. 7191, 1999, pp. 1104-1107. doi:10.1136/bmj.318.7191.1104

[42]   K. L. Hardinger, D. L. Bohl, M. A. Schnitzler, M. Lockwood, G. A. Storch and D. C. Brennan, “A Randomized, Prospective, Pharmacoeconomic Trial of Tacrolimus versus Cyclosporine in Combination with Thymoglobulin in Renal Transplant Recipients,” Transplantation, Vol. 80, No. 1, 2005, pp. 41-46. doi:10.1097/01.TP.0000162980.68628.5A

[43]   R. Margreiter (European Tacrolimus vs Ciclosporin Microemulsion Renal Transplantation Study Group), “Efficacy and Safety of Tacrolimus Compared with Ciclosporin Microemulsion in Renal Transplantation: A Randomised Multicentre Study,” Lancet, Vol. 359, No. 9308, 2002, pp. 741-746. doi:10.1016/S0140-6736(02)07875-3

[44]   A. C. Webster, R. C. Woodroffe, R. S. Taylor, J. R. Chapman and J. C. Craig, “Tacrolimus versus Ciclosporin as Primary Immunosuppression for Kidney Transplant Recipients: Meta-Analysis and Meta-Regression of Randomised Trial Data,” British Medical Journal, Vol. 331, No. 7520, 2005, p. 810. doi:10.1136/bmj.38569.471007.AE

[45]   B. K. Kr?mer, D. Del Castillo, R. Margreiter, H. Sperschneider, C. J. Olbricht, J. Ortu?o, U. Sester, U. Kunzendorf, K. H. Dietl, V. Bonomini, P. Rigotti, C. Ronco, J. M. Tabernero, M. Rivero, B. Banas, F. Mühlbacher, M. Arias and G. Montagnino, “Efficacy and Safety of Tacrolimus Compared with Ciclosporin A in Renal Transplantation: Three-Year Observational Results,” Nephrol Dial Transplant, Vol. 23, No. 7, 2008, pp. 2386-2392. doi:10.1093/ndt/gfn004

[46]   H. T. Silva Jr., H. C. Yang, M. Abouljoud, P. C. Kuo, K. Wisemandle, P. Bhattacharya, et al., “One-Year Results with Extended-Release Tacrolimus/MMF, Tarolimus/ MMF and Cyclosporine/MMF in De Novo Kidney Transplant Recipients,” American Journal of Transplantation, Vol. 7, No. 3, 2007, pp. 595-608. doi:10.1111/j.1600-6143.2007.01661.x

[47]   S. Bergan, H. E. Rugstad, O. Bentdal, G. Sodal, A. Hartmann, T. Leivestad, et al., “Monitored High-Dose Azathioprine Treatment Reduces Acute Rejection Episodes after Renal Transplantation,” Transplantation, Vol. 66, No. 3, 1998, pp. 334-339. doi:10.1097/00007890-199808150-00010

[48]   G. Remuzzi, P. Cravedi, M. Costantini, M. Lesti, M. Ganeva, G. Gherardi, et al., “Mycophenolate Mofetil versus Azathioprine for Prevention of Chronic Allograft Dysfunction in Renal Transplantation: The MYSS Follow-Up Randomized, Controlled Clinical Trial,” Journal of American Society of Nephrology, Vol. 18, No. 6, 2007, pp. 1973-1985. doi:10.1681/ASN.2006101153

[49]   B. D. Kahan (The Rapamune US Study Group), “Efficacy of Sirolimus Compared with Azathioprine for Reduction of Acute Renal Allograft Rejection: A Randomised Multicentre Study,” Lancet, Vol. 356, No. 9225, 2000, pp. 194-202. doi:10.1016/S0140-6736(00)02480-6

[50]   H. U. Meier-Kriesche, B. J. Steffen, A. M. Hochberg, R. D. Gordon, M. N. Liebman, J. A. Morris, et al., “Long-Term Use of Mycophenolate Mofetil Is Associated with a Reduction in the Incidence and Risk of Late Rejection,” American Journal of Transplantation, Vol. 3, No. 1, 2003, pp. 68-73. doi:10.1034/j.1600-6143.2003.30112.x

[51]   J. F. Neylan (US Renal Transplant Mycophenolate Mofetil Study Group), “Immunosuppressive Therapy in High-Risk Transplant Patients: Dose-Dependent Efficacy of Mycophenolate Mofetil in African-American Renal Allograft Recipients,” Transplantation, Vol. 64, No. 9, 1997, pp. 1277-1282. doi:10.1097/00007890-199711150-00008

[52]   H. W. Sollinger (US Renal Transplant Mycophenolate Mofetil Study Group), “Mycophenolate Mofetil for the Prevention of Acute Rejection in Primary Cadaveric Renal Allograft Recipients,” Transplantation, Vol. 60, No. 3, 1995, pp. 225-232. doi:10.1097/00007890-199508000-00003

[53]   The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group, “A Blinded, Randomized Clinical Trial of Mycophenolate Mofetil for the Prevention of Acute Rejection in Cadaveric Renal Transplantation,” Transplantation, Vol. 61, No. 7, 1996, pp. 1029-1037. doi:10.1097/00007890-199604150-00008

[54]   S. Kofler, N. Shvets, A. K. Bigdeli, M. A. Konig, P. Kaczmarek, M. A. Deutsch, et al., “Proton Pump Inhibitors Reduce Mycophenolate Exposure in Heart Transplant Recipients—A Prospective Case-Controlled Study,” American Journal of Transplantation, Vol. 9, No. 7, 2009, pp. 1650-1656. doi:10.1111/j.1600-6143.2009.02682.x

[55]   B. A. Kiberd, M. Wrobel, R. Dandavino, P. Keown and S. Gourishankar, “The Role of Proton Pump Inhibitors on Early Mycophenolic Acid Exposure in Kidney Transplantation: Evidence from the CLEAR Study,” Therapeutic Drug Monitoring, Vol. 33, No. 1, 2011, pp. 120-123. doi:10.1097/FTD.0b013e318206a1b1

[56]   P. Bolin, B. Tanriover, G. B. Zibari, M. L. Lynn, J. D. Pirsch, L. Chan, et al., “Improvement in 3-Month Patient-Reported Gastrointestinal Symptoms after Conversion from Mycophenolate Mofetil to Enteric-Coated Mycophenolate Sodium in Renal Transplant Patients,” Transplantation, Vol. 84, No. 11, 2007, pp. 1443-1451. doi:10.1097/

[57]   S. Bunnapradist, K. L. Lentine, T. E. Burroughs, B. W. Pinsky, K. L. Hardinger, D. C. Brennan, et al., “Mycophenolate Mofetil Dose Reductions and Discontinuations after Gastrointestinal Complications Are Associated with Renal Transplant Graft Failure,” Transplantation, Vol. 82, No. 1, 2006, pp. 102-107. doi:10.1097/

[58]   A. J. Langone, L. Chan, P. Bolin and M. Cooper, “Enteric-Coated Mycophenolate Sodium versus Mycophenolate Mofetil in Renal Transplant Recipients Experiencing Gastrointestinal Intolerance: A Multicenter, Double-Blind, Randomized Study,” Transplantation, 2011 Vol. 91, No. 4, pp. 470-478.

[59]   A. S. Chong, H. Zeng, D. A. Knight, J. Shen, G. T. Meister, J. W. Williams, et al., “Concurrent Antiviral and Immunosuppressive Activities of Leflunomide in Vivo,” American Journal of Transplantation, Vol. 6, No. 1, 2006, pp. 69-75. doi:10.1111/j.1600-6143.2005.01152.x

[60]   M. A. Josephson, D. Gillen, B. Javaid, P. Kadambi, S. Meehan, P. Foster, et al., “Treatment of Renal Allograft Polyoma BK Virus Infection with Leflunomide,” Transplantation, Vol. 81, No. 5, 2006, pp. 704-710. doi:10.1097/

[61]   C. G. Groth, L. Backman, J. M. Morales, R. Calne, H. Kreis, P. Lang, et al. ( Sirolimus European Renal Transplant Study Group), “Sirolimus (Rapamycin)-Based Therapy in Human Renal Transplantation: Similar Efficacy and Different Toxicity Compared with Cyclosporine,” Transplantation, Vol. 67, No. 7, 1999, pp. 1036-1042. doi:10.1097/00007890-199904150-00017

[62]   H. U. Meier-Kriesche, J. D. Schold, T. R. Srinivas, R. J. Howard, S. Fujita and B. Kaplan, “Sirolimus in Combination with Tacrolimus Is Associated with Worse Renal Allograft Survival Compared to Mycophenolate Mofetil Combined with Tacrolimus,” American Journal of Transplantation, Vol. 5, No. 9, 2005, pp. 2273-2280. doi:10.1111/j.1600-6143.2005.01019.x

[63]   H. U. Meier-Kriesche, B. J. Steffen, A. H. Chu, J. J. Loveland, R. D. Gordon, J. A. Morris, et al., “Sirolimus with Neoral versus Mycophenolate Mofetil with Neoral Is Associated with Decreased Renal Allograft Survival,” American Journal of Transplantation, Vol. 4, No. 12, 2004, pp. 2058-2066. doi:10.1111/j.1600-6143.2004.00624.x

[64]   K. Budde, T. Becker, W. Arns, C. Sommerer, P. Reinke, U. Eisenberger, et al., “Everolimus-Based, Calcineurin-Inhibitor-Free Regimen in Recipients of De-Novo Kidney Transplants: An Open-Label, Randomised, Controlled Trial,” Lancet, Vol. 377, No. 9768, 2011, pp. 837-847. doi:10.1016/S0140-6736(10)62318-5

[65]   G. Ciancio, G. W. Burke, J. J. Gaynor, P. Ruiz, D. Roth, W. Kupin, et al., “A Randomized Long-Term Trial of Tacrolimus/Sirolimus versus Tacrolimums/Mycophenolate versus Cyclosporine/Sirolimus in Renal Transplantation: Three-Year Analysis,” Transplantation, Vol. 81, No. 6, 2006, pp. 845-852. doi:10.1097/

[66]   F. Vincenti, C. Larsen, A. Durrbach, T. Wekerle, B. Nashan, G. Blancho, et al., “Costimulation Blockade with Belatacept in Renal Transplantation,” The New England Journal of Medicine, Vol. 353, No. 8, 2005, pp. 770-781. doi:10.1056/NEJMoa050085

[67]   A. Durrbach, J. M. Pestana, T. Pearson, F. Vincenti, V. D. Garcia, J. Campistol, et al., “A Phase III Study of Belatacept versus Cyclosporine in Kidney Transplants from Extended Criteria Donors (BENEFIT-EXT Study),” American Journal of Transplantation, Vol. 10, No. 3, 2010, pp. 547-557. doi:10.1111/j.1600-6143.2010.03016.x

[68]   F. Vincenti, B. Charpentier, Y. Vanrenterghem, L. Rostaing, B. Bresnahan, P. Darji, et al., “A Phase III Study of Belatacept-Based Immunosuppression Regimens versus Cyclosporine in Renal Transplant Recipients (BENE- FIT Study),” American Journal of Transplantation, Vol. 10, No. 3, 2010, pp. 535-546. doi:10.1111/j.1600-6143.2009.03005.x

[69]   F. Vincenti, G. Blancho, A. Durrbach, P. Friend, J. Grinyo, P. F. Halloran, et al., “Five-Year Safety and Efficacy of Belatacept in Renal Transplantation,” Journal of American Society of Nephrology, Vol. 21, No. 9, 2010, pp. 1587-1596. doi:10.1681/ASN.2009111109

[70]   M. Toyoda, A. Pao, A. Petrosian and S. C. Jordan, “Pooled Human Gammaglobulin Modulates Surface Molecule Expression and Induces Apoptosis in Human B Cells,” American Journal of Transplantation, Vol. 3, No. 2, 2003, pp. 156-166. doi:10.1034/j.1600-6143.2003.00011.x

[71]   P. P. Luke, V. P. Scantlebury, M. L. Jordan, C. A. Vivas, T. R. Hakala, A. Jain, et al., “Reversal of Steroid-and Anti-Lymphocyte Antibody-Resistant Rejection Using Intravenous Immunoglobulin (Ivig) in Renal Transplant Recipients,” Transplantation, Vol. 72, No. 3, 2001, pp. 419-422. doi:10.1097/00007890-200108150-00010

[72]   P. N. Rocha, D. W. Butterly, A. Greenberg, D. N. Reddan, J. Tuttle-Newhall, B. H. Collins, et al., “Beneficial Effect of Plasmapheresis and Intravenous Immunoglobulin on Renal Allograft Survival of Patients with Acute Humoral Rejection,” Transplantation, Vol. 75, No. 9, 2003, pp. 1490-1495. doi:10.1097/01.TP.0000060252.57111.AC

[73]   D. H. Casadei, M. del C Rial, G. Opelz, J. C. Golberg, J. A. Argento, G. Greco, et al., “A Randomized and Prospective Study Comparing Treatment with High-Dose Intravenous Immunoglobulin with Monoclonal Antibodies for Rescue of Kidney Grafts with Steroid-Resistant Rejection,” Transplantation, Vol. 71, No. 1, 2001, pp. 53-58. doi:10.1097/00007890-200101150-00009

[74]   M. J. Everly, J. J. Everly, B. Susskind, P. Brailey, L. J. Arend, R. R. Alloway, et al., “Bortezomib Provides Effective Therapy for Antibody-and Cell-Mediated Acute Rejection,” Transplantation, Vol. 86, No. 12, 2008, pp. 1754-1761. doi:10.1097/TP.0b013e318190af83

[75]   J. E. Locke, C. M. Magro, A. L. Singer, D. L. Segev, M. Haas, A. T. Hillel, et al., “The Use of Antibody to Complement Protein C5 for Salvage Treatment of Severe Antibody-Mediated Rejection,” American Journal of Transplantation, Vol. 9, No. 1, 2009, pp. 231-235. doi:10.1111/j.1600-6143.2008.02451.x

[76]   F. Vincenti, F. P. Schena, S. Paraskevas, I. A. Hauser, R. G. Walker, J. Grinyo, et al., “A Randomized, Multicenter Study of Steroid Avoidance, Early Steroid Withdrawal or Standard Steroid Therapy in Kidney Transplant Recipients,” American Journal of Transplantation, Vol. 8, No. 2, 2008, pp. 307-316. doi:10.1111/j.1600-6143.2007.02057.x

[77]   E. S. Woodle, M. R. First, J. Pirsch, F. Shihab, A. O. Gaber, P. Van Veldhuisen, et al., “A Prospective, Ran- domized, Double-Blind, Placebo-Controlled Multicenter trial Comparing Early (7 Day) Corticosteroid Cessation versus Long-Term, Low-Dose Corticosteroid Therapy,” Annals of Surgery, Vol. 248, No. 4, 2008, pp. 564-577.

[78]   M. J. Hanaway, E. S. Woodle, S. Mulgaonkar, V. R. Peddi, D. B. Kaufman, M. R. First, R. Croy, J. Holman (INTAC Study Group), “Alemtuzumab Induction in Renal Transplantation,” The New England Journal of Medicine, Vol. 364, No. 20, 2011, pp. 1909-1919. doi:10.1056/NEJMoa1009546

[79]   D, Chhabra, A. I. Skaro, J. R. Leventhal, P. Dalal, G. Shah, E. Wang, et al., “Long-Term Kidney Allograft Function and Survival in Prednisone-Free Regimens: Tacrolimus/Mycophenolate Mofetil versus Tacrolimus/ Sirolimus,” Clinical Journal of the American Society of Nephrology, Vol. 7, No. 3, 2012, pp. 504-512. doi:10.2215/CJN.06940711

[80]   R. L. Heilman, K. Younan, H. M. Wadei, M. L. Mai, K. S. Reddy, H. A. Chakkera, et al., “Results of a Prospective Randomized Trial of Sirolimus Conversion in Kidney Transplant Recipients on Early Corticosteroid Withdrawal,” Transplantation, Vol. 92, No. 7, 2011, pp. 767-773. doi:10.1097/TP.0b013e31822805d7

[81]   H. Ekberg, J. Grinyó, B. Nashan, Y. Vanrenterghem, F. Vincenti, A. Voulgari, M. Truman, C. Nasmyth-Miller and M. Rashford, “Cyclosporine Sparing with Mycophenolate Mofetil, Daclizumab and Corticosteroids in Renal Allograft Recipients: The CAESAR Study,” American Journal of Transplantation, Vol. 7, No. 3, 2007, pp. 560-70. doi:10.1111/j.1600-6143.2006.01645.x

[82]   H. Ekberg, H. Tedesco-Silva, A. Demirbas, S. Vitko, B. Nashan, A. Gurkan, et al., “Reduced Exposure to Calcineurin Inhibitors in Renal Transplantation,” The New England Journal of Medicine, Vol. 357, No. 25, 2007, pp. 2562-2575. doi:10.1056/NEJMoa067411

[83]   H. Ekberg, C. Bernasconi, H. Tedesco-Silva, S. Vítko, C. Hugo, A. Demirbas, R. R. Acevedo, J. Grinyó, U. Frei, Y. Vanrenterghem, P. Daloze and P. Halloran, “Calcineurin Inhibitor Minimization in the Symphony Study: Observational Results 3 Years after Transplantation,” American Journal of Transplantation, Vol. 9, No. 8, 2009, pp. 1876-1885. doi:10.1111/j.1600-6143.2009.02726.x

[84]   G. Guerra, G. Ciancio, J. J. Gaynor, A. Zarak, R. Brown, L. Hanson, et al., “Randomized Trial of Immunosuppressive Regimens in Renal Transplantation,” Journal of American Society of Nephrology, Vol. 22, No. 9, 2011, pp. 1758-1768. doi:10.1681/ASN.2011010006

[85]   T. R. Srinivas, J. D. Schold, G. Guerra, A. Eagan, C. M. Bucci and H. U. Meier-Kriesche, “Mycophenolate Mofetil/Sirolimus Compared to Other Common Immunosuppressive Regimens in Kidney Transplantation,” American Journal of Transplantation, Vol. 7, No. 3, 2007, pp. 586-594. doi:10.1111/j.1600-6143.2006.01658.x

[86]   M. R. Weir, S. Mulgaonkar, L. Chan, H. Shidban, T. H. Waid, D. Preston, et al., “Mycophenolate Mofetil-Based Immunosuppression with Sirolimus in Renal Transplation: A Randomized, Controlled Spare-the-Nephron Trial,” Kidney International, Vol. 79, No. 8, 2011, pp. 897-907.

[87]   S. M. Flechner, M. Glyda, S. Cockfield, J. Grinyo, C. Legendre, G. Russ, et al., “The ORION Study: Comparison of Two Sirolimus-Based Regimens versus Tacrolimus and Mycophenolate Mofetil in Renal Allograft Recipients,” American Journal of Transplantation, Vol. 11, No. 8, 2011, pp. 1633-1644. doi:10.1111/j.1600-6143.2011.03573.x