The Calcineurin Inhibitor-Sparing (CIS) Trial - individualised calcineurin-inhibitor treatment by immunomonitoring in renal allograft recipients: protocol for a randomised controlled trial

详细信息    查看全文

• 作者：Claudia Sommerer (1)
  Matthias Schaier (1)
  Christian Morath (1)
  Vedat Schwenger (1)
  Geraldine Rauch (2)
  Thomas Giese (3)
  Martin Zeier (1)
  
  1. Department of Nephrology ; University Hospital Heidelberg ; Im Neuenheimer Feld 162 ; D-69120 ; Heidelberg ; Germany
  2. Institute of Medical Biometry and Informatics ; University of Heidelberg ; Im Neuenheimer Feld 305 ; D-69120 ; Heidelberg ; Germany
  3. Department of Immunology ; University Hospital Heidelberg ; Im Neuenheimer Feld 305 ; D-69120 ; Heidelberg ; Germany
  
• 关键词：Immunomonitoring ; Renal transplantation ; Calcineurin inhibitor ; Ciclosporin A ; Gene expression ; CIS study ; Minimisation ; Immunosuppression ; NFAT
• 刊名：Trials
• 出版年：2014
• 出版时间：December 2014
• 年：2014
• 卷：15
• 期：1
• 全文大小：407 KB
• 参考文献：1. Meier-Kriesche, HU, Li, S, Gruessner, RW, Fung, JJ, Bustami, RT, Barr, ML, Leichtman, AB (2006) Immunosuppression: evolution in practice and trends, 1994-2004. Am J Transplant 6: pp. 1111-1131 CrossRef
  2. Hariharan, S, Johnson, CP, Bresnahan, BA, Taranto, SE, McIntosh, MJ, Stablein, D (2000) Improved graft survival after renal transplantation in the United States, 1988 to 1996. N Engl J Med 342: pp. 605-612 CrossRef
  3. Ojo, AO (2006) Cardiovascular complications after renal transplantation and their prevention. Transplantation 82: pp. 603-611 CrossRef
  4. Mar茅chal, C, Coche, E, Goffin, E, Dragean, A, Schlieper, G, Nguyen, P, Floege, J, Kanaan, N, Devuyst, O, Jadoul, M (2012) Progression of coronary artery calcification and thoracic aorta calcification in kidney transplant recipients. Am J Kidney Dis 59: pp. 258-269 CrossRef
  5. Nankivell, BJ, Borrows, RJ, Fung, CL, O鈥機onnell, PJ, Allen, RD, Chapman, JR (2003) The natural history of chronic allograft nephropathy. N Engl J Med 349: pp. 2326-2333 CrossRef
  6. Budde, K, Becker, T, Arns, W, Sommerer, C, Reinke, P, Eisenberger, U, Kramer, S, Fischer, W, Gschaidmeier, H, Pietruck, F (2011) Everolimus-based, calcineurin-inhibitor-free regimen in recipients of de-novo kidney transplants: an open-label, randomised, controlled trial. Lancet 377: pp. 837-847 CrossRef
  7. Rostaing, L, Vincenti, F, Griny贸, J, Rice, KM, Bresnahan, B, Steinberg, S, Gang, S, Gaite, LE, Moal, MC, Mondrag贸n-Ramirez, GA, Kothari, J, Pupim, L, Larsen, CP (2013) Long-term belatacept exposure maintains efficacy and safety at 5聽years: results from the long-term extension of the BENEFIT study. Am J Transplant 13: pp. 2875-2883 CrossRef
  8. Everly, MJ, Rebellato, LM, Haisch, CE, Ozawa, M, Parker, K, Briley, KP, Catrou, PG, Bolin, P, Kendrick, WT, Kendrick, SA, Harland, RC, Terasaki, PI (2013) Incidence and impact of de novo donor-specific alloantibody in primary renal allografts. Transplantation 95: pp. 410-417 CrossRef
  9. Ekberg, H, Tedesco-Silva, H, Demirbas, A, V铆tko, S, Nashan, B, G眉rkan, A, Margreiter, R, Hugo, C, Griny贸, JM, Frei, U, Vanrenterghem, Y, Daloze, P, Halloran, PF (2007) Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 357: pp. 2562-2575 CrossRef
  10. Glander, P, Sommerer, C, Arns, W, Ariatabar, T, Kramer, S, Vogel, EM, Shipkova, M, Fischer, W, Zeier, M, Budde, K (2010) Pharmacokinetics and pharmacodynamics of intensified versus standard dosing of mycophenolate sodium in renal transplant patients. Clin J Am Soc Nephrol 5: pp. 503-511 CrossRef
  11. Sommerer, C, Glander, P, Arns, W, Ariatabar, T, Kramer, S, Vogel, EM, Shipkova, M, Fischer, W, Liefeldt, L, Hackenberg, R, Schmidt, J, Zeier, M, Budde, K (2011) Safety and efficacy of intensified versus standard dosing regimens of enteric-coated mycophenolate sodium in de novo renal transplant patients. Transplantation 91: pp. 779-785
  12. de Jonge, H, Naesens, M, Kuypers, DR (2009) New insights into the pharmacokinetics and pharmacodynamics of the calcineurin inhibitors and mycophenolic acid: possible consequences for therapeutic drug monitoring in solid organ transplantation. Ther Drug Monit 31: pp. 416-435 CrossRef
  13. Clipstone, NA, Crabtree, GR (1992) Identification of calcineurin as a key signalling enzyme in T-lymphocyte activation. Nature 357: pp. 695-697 CrossRef
  14. O鈥橩eefe, SJ, Tamura, J, Kincaid, RL, Tocci, MJ, O鈥橬eill, EA (1992) FK-506- and CsA-sensitive activation of the interleukin-2 promoter by calcineurin. Nature 357: pp. 692-694 CrossRef
  15. Kel, A, Kel-Margoulis, O, Babenko, V, Wingender, E (1999) Recognition of NFATp/AP-1 composite elements within genes induced upon the activation of immune cells. J Mol Biol 288: pp. 353-376 CrossRef
  16. Giese, T, Zeier, M, Schemmer, P, Uhl, W, Schoels, M, Dengler, T, B眉chler, M, Meuer, S (2004) Monitoring of NFAT-regulated gene expression in the peripheral blood of allograft recipients: a novel perspective toward individually optimized drug doses of ciclosporin A. Transplantation 77: pp. 339-344 CrossRef
  17. Sommerer, C, Meuer, S, Zeier, M, Giese, T (2012) Calcineurin inhibitors and NFAT-regulated gene expression. Clin Chim Acta 413: pp. 1379-1386 CrossRef
  18. Sommerer, C, Konstandin, M, Dengler, T, Schmidt, J, Meuer, S, Zeier, M, Giese, T (2006) Pharmacodynamic monitoring of ciclosporin A in renal allograft recipients shows a quantitative relationship between immunosuppression and the occurrence of recurrent infections and malignancies. Transplantation 82: pp. 1280-1285 CrossRef
  19. Sommerer, C, Giese, T, Schmidt, J, Meuer, S, Zeier, M (2008) Ciclosporin A tapering monitored by NFAT-regulated gene expression: a new concept of individual immunosuppression. Transplantation 85: pp. 15-21 CrossRef
  20. Sommerer, C, Hartschuh, W, Enk, A, Meuer, S, Zeier, M, Giese, T (2008) Pharmacodynamic immune monitoring of NFAT-regulated genes predicts skin cancer in elderly long-term renal transplant recipients. Clin Transplant 22: pp. 549-554 CrossRef
  21. Sommerer, C, Schnitzler, P, Meuer, S, Zeier, M, Giese, T (2011) Pharmacodynamic monitoring of cyclosporin A reveals risk of opportunistic infections and malignancies in renal transplant recipients 65聽years and older. Ther Drug Monit 33: pp. 694-698 CrossRef
  22. Dannewitz, B, Kruck, EM, Staehle, HJ, Eickholz, P, Giese, T, Meuer, S, Kaever, V, Zeier, M, Sommerer, C (2011) Cyclosporine-induced gingival overgrowth correlates with NFAT-regulated gene expression: a pilot study. J Clin Periodontol 38: pp. 984-991 CrossRef
  23. Zahn, A, Schott, N, Hinz, U, Stremmel, W, Schmidt, J, Ganten, T, Gotthardt, D, Meuer, S, Zeier, M, Giese, T, Sommerer, C (2011) Immunomonitoring of nuclear factor of activated T-cell-regulated gene expression: the first clinical trial in liver allograft recipients. Liver Transpl 17: pp. 466-473 CrossRef
  24. Steinebrunner, N, Sandig, C, Sommerer, C, Hinz, U, Giese, T, Stremmel, W, Zahn, A (2014) Reduced residual gene expression of nuclear factor of activated T-cell-regulated genes correlates with the risk of cytomegalovirus infection after liver transplantation. Transpl Infect Dis 16: pp. 379-386 CrossRef
  25. Steinebrunner, N, Sandig, C, Sommerer, C, Hinz, U, Giese, T, Stremmel, W, Zahn, A (2014) Pharmacodynamic monitoring of nuclear factor of activated T-cell-regulated gene expression in liver allograft recipients on immunosuppressive therapy with calcineurin inhibitors in the course of time and correlation with acute rejection episodes鈥揳 prospective study. Ann Transplant 19: pp. 32-40 CrossRef
  26. Konstandin, MH, Sommerer, C, Doesch, A, Zeier, M, Meuer, SC, Katus, HA, Dengler, TJ, Giese, T (2007) Pharmacodynamic cyclosporine A-monitoring: relation of gene expression in lymphocytes to cyclosporine blood levels in cardiac allograft recipients. Transpl Int 20: pp. 1036-1043 CrossRef
  27. Billing, H, Giese, T, Sommerer, C, Zeier, M, Feneberg, R, Meuer, S, T枚nshoff, B (2010) Pharmacodynamic monitoring of cyclosporine A by NFAT-regulated gene expression and the relationship with infectious complications in pediatric renal transplant recipients. Pediatr Transplant 14: pp. 844-851 CrossRef
  28. Laurent, S, Cockcroft, J, Van Bortel, L, Boutouyrie, P, Giannattasio, C, Hayoz, D, Pannier, B, Vlachopoulos, C, Wilkinson, I, Struijker-Boudier, H (2006) Expert consensus document on arterial stiffness: Methodological issues and clinical applications. Eur Heart J 27: pp. 2588-2605 CrossRef
  29. Bahous, SA, Stephan, A, Barakat, W, Blacher, J, Asmar, R, Safar, ME (2004) Aortic pulse wave velocity in renal transplant patients. Kidney Int 66: pp. 1486-1492 CrossRef
  30. Seckinger, J, Sommerer, C, Hinkel, UP, Hoffmann, O, Zeier, M, Schwenger, V (2008) Switch of immunosuppression from ciclosporin A to everolimus: impact on pulse wave velocity in stable de novo renal allograft recipients. J Hypertens 26: pp. 2213-2219 CrossRef
  31. Committee for Medicinal Products for Human Use (CHMP). European Medicines Agency: Guideline on clinical investigation of immunosuppressants for solid organ transplantation. [ http://www.ema.europa.eu/docs/en_GB/document_library/Scientific_guideline/2009/09/WC500003593.pdf Accessed 29 Aprile 2014]
  32. Wilson, PWF, D鈥橝gostino, RB, Levy, D, Belanger, AM, Silbershatz, H, Kannel, WB (1998) Prediction of coronary heart disease using risk factor categories. Circulation 97: pp. 1837-1847 CrossRef
  33. Franke, GH, Reimer, J, Kohnle, M, Luetkes, P, Maehner, N, Heemann, U (1999) Quality of life in end-stage renal disease patients after successful kidney transplantation: development of the ESRD symptom checklist - transplantation module. Nephron 83: pp. 31-39 CrossRef
  34. Ware, J, Kiosinski, M, Keller, SD (1996) A 12-Item Short-Form Health Survey: construction of scales and preliminary tests of reliability and validity. Med Care 34: pp. 220-233 CrossRef
  35. Hirai, T, Furusawa, M, Omoto, K, Ishida, H, Tanabe, K (2014) Analysis of predictive and preventive factors for de novo DSA in kidney transplant recipients. Transplantation 98: pp. 443-450 CrossRef
  36. Sommerer, C, M眉ller-Krebs, S, Schaier, M, Glander, P, Budde, K, Schwenger, V, Mikus, G, Zeier, M (2010) Pharmacokinetic and pharmacodynamic analysis of enteric-coated mycophenolate sodium: limited sampling strategies and clinical outcome in renal transplant patients. Br J Clin Pharmacol 69: pp. 346-357 CrossRef
  37. van Gelder, T, Silva, HT, de Fijter, JW, Budde, K, Kuypers, D, Tyden, G, Lohmus, A, Sommerer, C, Hartmann, A, Le Meur, Y, Oellerich, M, Holt, DW, Tonshoff, B, Keown, P, Campbell, S, Mamelok, RD (2008) Comparing mycophenolate mofetil regimens for de novo renal transplant recipients: the fixed-dose concentration controlled trial. Transplantation 86: pp. 1043-1051 CrossRef
  38. Schulz, KF, Altman, DG, Moher, D (2010) CONSORT 2010 statement: updated guidelines for reporting parallel group randomised trials. BMJ 340: pp. c332 CrossRef
  39. Mancia, G, De Backer, G, Dominiczak, A, Cifkova, R, Fagard, R, Germano, G, Grassi, G, Heagerty, AM, Kjeldsen, SE, Laurent, S, Narkiewicz, K, Ruilope, L, Rynkiewicz, A, Schmieder, RE, Struijker Boudier, HA, Zanchetti, A, Vahanian, A, Camm, J, De Caterina, R, Dean, V, Dickstein, K, Filippatos, G, Funck-Brentano, C, Hellemans, I, Kristensen, SD, McGregor, K, Sechtem, U, Silber, S, Tendera, M, Widimsky, P (2007) Guidelines for the management of arterial hypertension: The Task Force for the Management of Arterial Hypertension of the European Society of Hypertension (ESH) and of the European Society of Cardiology (ESC). Eur Heart J 2007: pp. 1462-1536
  40. Claes, KJ, Heye, S, Bammens, B, Kuypers, DR, Meijers, B, Naesens, M, Vanrenterghem, Y, Evenepoel, P (2013) Aortic calcifications and arterial stiffness as predictors of cardiovascular events in incident renal transplant recipients. Transpl Int 26: pp. 973-981
  41. Verbeke, F, Mar茅chal, C, Van Laecke, S, Van Biesen, W, Devuyst, O, Van Bortel, LM, Jadoul, M, Vanholder, R (2011) Aortic stiffness and central wave reflections predict outcome in renal transplant recipients. Hypertension 58: pp. 833-838 CrossRef
  
• 刊物主题：Medicine/Public Health, general; Biomedicine general; Statistics for Life Sciences, Medicine, Health Sciences;
• 出版者：BioMed Central
• ISSN：1745-6215

文摘

Background Adequate monitoring tools are required to optimise the immunosuppressive therapy of an individual patient. Particularly, in calcineurin inhibitors, as critical dose drugs with a narrow therapeutic range, the optimal monitoring strategies are discussed in terms of safety and efficacy. Nevertheless, no pharmacokinetic monitoring markers reflect the biological activity of the drug. A new quantitative analysis of gene expression was employed to directly measure the functional effects of calcineurin inhibition: the transcriptional activities of the nuclear factor of activated T-cell (NFAT)-regulated genes in the peripheral blood. Methods/Design The CIS study is a randomised prospective controlled trial, comparing a ciclosporin A (CsA)-based immunosuppressive regimen monitored by CsA trough levels to a CsA-based immunosuppressive regimen monitored by residual NFAT-regulated gene expression. Pulse wave velocity as an accepted surrogate marker of the cardiovascular risk is assessed in both study groups. Our hypothesis is that an individualised CsA therapy monitored by residual NFAT-regulated gene expression results in a significantly lower cardiovascular risk compared to CsA therapy monitored by CsA trough levels. Discussion There is a lack of evidence in individualising standard immunosuppression in renal allograft recipients. The CIS study will consider the feasibility of individualised ciclosporin A immunosuppression by pharmacodynamic monitoring and evaluate the opportunity to reduce cardiovascular risk while maintaining sufficient immunosuppression. Trial registration EudraCT identifier 2011-003547-21, registration date 18 July 2011 https://www.clinicaltrialsregister.eu