Hüseyin KOÇAK, Gültekin SÜLEYMANLAR, Ramazan ÇETİNKAYA, F. Fevzi ERSOY, Ayhan DİNÇKAN, Vural Taner YILMAZ

Böbrek Nakli Hastalarında Kalsinörin İnhibitörleri ile m-TOR İnhibitörlerinin Karşılaştırılması

amaç: Çalışmamızda böbrek nakli hastalarında kalsinörin inhibitörleri KNİ ile m-TORi’nin m-Target of Rapamisin İnhibitor etkinlik ve güvenilirliklerinin karşılaştırılması amaçlanmıştır. Gereç ve yöntemler: Çalışmaya 2005-2009 yılları arasında merkezimizde böbrek nakli yapılmış olan 983 hasta alındı. Hastalar immünosupresif tedavi protokollerine göre iki gruba ayrıldı. Grup 1: KNİ kullanılanlar: 632 hasta, Grup 2: m-TORi kullanılanlar: 351 hasta. Grupların greft ve hasta sağkalım süreleri, rejeksiyon oranları, gecikmiş greft fonksiyonu GGF , kronik allogreft disfonksiyon KAD , nakil sonrası gelişen diabetes mellitus NSDM ve greft fonksiyonları karşılaştırıldı. bulgular: Grupların demografik özellikleri benzerdi. Akut rejeksiyon oranları, hasta sağkalım süreleri, GGF, KAD ve greft fonksiyonlarının benzer, greft sağkalım süresinin ikinci grupta p= 0,007 , NSDM oranının ise 1.grupta p=0,001 daha yüksek olduğu tespit edildisonuç: M-TORi’nin greft sağkalımı açısından KNİ’den daha etkin olduğu gösterildi

Anahtar Kelimeler:

Böbrek nakli, Takrolimus, Siklosporin, Sirolimus, Everolimus

Comparison of Calcineurin Inhibitors with M-Tor Inhibitors in Renal Transplant Patients

Objective: Our aim was to compare the efficacy and safety of calcineurin inhibitors with m-Tor inhibitors m-TORi in renal transplant patients.Material and Methods: We recruited 983 patients who had undergone renal transplantation between 2005 and 2009 at our center. Patients were evaluated in two groups according to their immunosuppressive protocol. Group 1 consisted of 632 patients treated with a regimen including calcineurin inhibitors and Group 2 consisted of 351 patients treated with a regimen including m-TORi. The two groups were compared in terms of graft and patient survival times, rejection rates, delayed graft function DGF , chronic allograft dysfunction CAD , post transplant diabetes mellitus PTDM and graft functions.results: Demographic characteristics of the two groups were similar. The acute rejection rates and patient survival times were also similar, but the graft survival times were better in the second group p=0.007 . DGF, CAD and graft functions did not differ between the two groups. The PTDM ratio was higher in the first group p=0.001 . conclusion: We found that m-TORi are more effective than calcineurin inhibitors in terms of graft survival

Keywords:

Kidney transplantation, Tacrolimus, Cyclosporine, Sirolimus, Everolimus,

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1. Bobadilla NA, Gamba G. New insights into the pathophysiology of cyclosporine nephrotoxicity: A role of aldosterone. Am J Physiol Renal Physiol 2007;293(1):2- 9.
2. Hortelano S, Castilla M, Torres AM, Tejedor A, Bosca L. Potentiation by nitric oxide of cyclosporin A and FK506- induced apoptosis in renal proximal tubule cells. J Am Soc Nephrol 2000;11:2315-23.
3. Yılmaz VT, Gürkan A, Süleymanlar İ, Dinçkan A, Koçak H, Ersoy FF, Yakupoğlu G, Süleymanlar G. Maintenance ımmunosuppressive therapy in renal transplantation: General considerations and Akdeniz University experience. Turkiye Klinikleri J Nephrol-Special Topics 2010;3:18-34.
4. Clive DM. Renal transplant-associated hyperuricemia and gout. J Am Soc Nephrol 2000;11:974-9.
5. Alexander RT, Hoenderop JG, Bindels RJ. Molecular determinants of magnesium homeostasis: Insights from human disease. J Am Soc Nephrol 2008;19:1451-8.
6. Rostaing L, Cantarovich D, Mourad G, et al. Corticosteroidfree immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation. Transplantation 2005;79:807-14.
7. Gonwa TA, Hricik DE, Brinker K, Grinyo JM, Schena FP; Sirolimus Renal Function Study Group: Improved renal function in sirolimus-treated renal transplant patients after early cyclosporine elimination. Transplantation 2002;74:1560-7.
8. Butani L. Investigation of pediatric renal transplant recipients with heavy proteinuria after sirolimus rescue. Transplantation 2004;78:1362-6.
9. Letavernier E, Pe’raldi MN, Pariente A, Morelon E, Legendre C. Proteinuria following a switch from calcineurin inhibitors to sirolimus. Transplantation 2005;80:1198-203.
10. Boratyńska M, Banasik M, Watorek E, Falkiewicz K, Patrzałek D, Szyber P, Klinger M. Conversion to sirolimus from cyclosporine may induce nephrotic proteinuria and progressive deterioration of renal function in chronic allograft nephropathy patients. Transplant Proc 2006;38:101-4.
11. Vincenti F, Friman S, Scheuermann E, Rostaing L, Jenssen T, Campistol JM, Uchida K, Pescovitz MD, Marchetti P, Tuncer M, Citterio F, Wiecek A, Chadban S, El-Shahawy M, Budde K, Goto N; DIRECT (Diabetes Incidence after Renal Transplantation: Neoral C Monitoring Versus Tacrolimus) Investigators. Results of an international randomized trial comparing glucose metabolism disorders and outcome with cyclosporine versus tacrolimus. American Journal of Transplantation 2007;7:1506-14
12. Heisel O, Heisel R, Balshaw R, Keown P. New onset diabetes mellitus in patients receiving calcineurin inhibitors: A systematic review and meta-analysis. Am J Transplant 2004;4:583-95.
13. Racusen LC, Solez K, Colvin RB, Bonsib SM, Castro MC, Cavallo T, Croker BP, Demetris AJ, Drachenberg CB, Fogo AB, Furness P, Gaber LW, Gibson IW, Glotz D, Goldberg JC, Grande J, Halloran PF, Hansen HE, Hartley B, Hayry PJ, Hill CM, Hoffman EO, Hunsicker LG, Lindblad AS, Yamaguchi Y, et al. The Banff 97 working classification of renal allograft pathology. Kidney International 1999;55:713- 23.
14. Bonato V, Barni R, Cataldo D, Collini A, Ruggieri G, De Bartolomeis C, Dotta F, Carmellini M. Analysis of posttransplant diabetes mellitus prevalence in a population of kidney transplant recipients. Transplant Proc 2008;40:1888- 90.
15. Egbuna OI, Davis RB, Chudinski R, Pavlakis M, Rogers C, Molakatalla P, Johnson SR, Karp S, Monaco AP, Tang H, Hanto DW, Mandelbrot DA. Outcomes with conversion from calcineurin inhibitors to sirolimus after renal transplantation in the context of steroid withdrawal or steroid continuation. Transplantation 2009; 88:684-92.
16. Chhabra D, Grafals M, Cabral B, Leventhal J, Parker M, Gallon L. Late conversion of tacrolimus to sirolimus in a prednisone-free immunosuppression regimen in renal transplant patients. Clin Transplant 2010;24:199-206.
17. Flechner SM, Kobashigawa J, Klintmalm G. Calcineurin inhibitor-sparing regimens in solid organ transplantation: Focus on improving renal function and nephrotoxicity. Clin Transplant 2008;22:1-15.
18. Schena FP, Pascoe MD, Alberu J, del Carmen Rial M, Oberbauer R, Brennan DC, Campistol JM, Racusen L, Polinsky MS, Goldberg-Alberts R, Li H, Scarola J, Neylan JF; Sirolimus CONVERT Trial Study Group. Sirolimus CONVERT Trial Study Group. Conversion from calcineurin inhibitors to sirolimus maintenance therapy in renal allograft recipients: 24-month efficacy and safety results from the CONVERT trial. Transplantation 2009;87:233- 42.
19. Tedesco-Silva H Jr, Vitko S, Pascual J, Eris J, Magee JC, Whelchel J, Civati G, Campbell S, Alves-Filho G, Bourbigot B, Garcia VD, Leone J, Esmeraldo R, Rigotti P, Cambi V, Haas T; 2306 and 2307 Study Groups.;12-month safety and efficacy of everolimus with reduced exposure cyclosporine in de novo renal transplant recipients. Transpl Int 2007;20:27- 36.
20. Pascual J. Concentration-controlled everolimus (Certican): Combination with reduced dose calcineurin inhibitors. Transplantation 2005;79:76- 9.
21. Luan FL, Zhang H, Schaubel DE, Miles CD, Cibrik D, Norman S, Ojo AO. Comparative risk of impaired glucose metabolism associated with cyclosporine versus takrolimus in the late posttransplant period. American Journal of Transplantation 2008;8:1871-7.
22. Sharif A, Shabir S, Chand S, Cockwell P, Ball S, Borrows R. Meta-analysis of calcineurin-inhibitor-sparing regimens in kidney transplantation. J Am Soc Nephrol 2011;22:2107-18.
23. Cardinal H, Froidure A, Dandavino R, Daloze P, Hébert MJ, Colette S, Boucher A. Conversion from calcineurin ınhibitors to sirolimus in kidney transplant recipients: A Retrospective cohort study. Transplantation Proceedings 2009;41:3308-10.
24. Mulay AV, Cockfield S, Stryker R, Fergusson D, Knoll GA. Conversion from calcineurin inhibitors to sirolimus for chronic renal allograft dysfunction: A systematic review of the evidence. Transplantation 2006;82:1153-55.
25. Pascual J. Calcineurin inhibitors minimisation and antiproliferative strategies. Nephrol Ther 2008;4:29-35.
26. Mulay AV, Hussain N, Fergusson D, Knoll GA. Calcineurin inhibitor withdrawal from sirolimus-based therapy in kidney transplantation: A systematic review of randomized trials. Am J Transplant 2005;5:1748-56.
27. Sert M, Celik A, Kural K, Ersan S, Ataca P, Atila K, Cavdar C, Sifil A, Bora S, Gulay H, Camsari T. Results of 4-year analysis of conversion from calcineurin inhibitors to mTOR inhibitors in renal transplant patients: Single-center experience. Ren Fail 2011;33:789-94.
28. Basu A, Banerjee P, Contreras AG, Flynn E, Pal S. Calcineurin inhibitor-induced and Ras-mediated overexpression of VEGF in renal cancer cells involves mTOR through the regulation of PRAS40. PLoS One 2011;6:e23919.
29. Alberú J. Clinical insights for cancer outcomes in renal transplant patients. Transplant Proc 2010;42(9):36-40.
30. Feldmeyer L, Hofbauer GF, Böni T, French LE, Hafner J. Mammalian target of rapamycin (mTOR) inhibitors slow skin carcinogenesis, but impair wound healing. Br J Dermatol 2012;166:422-4.
31. Stojanova J, Caillard S, Rousseau A, Marquet P. Posttransplant lymphoproliferative disease (PTLD): Pharmacological, virological and other determinants. Pharmacol Res 2011;63:1-7.
32. Epailly E, Albanell J, Andreassen A, Bara C, Campistol JM, Delgado JF, Eisen H, Fiane AE, Mohacsi P, Schubert S, Sebbag L, Turazza FM, Valantine H, Zuckermann A, Potena L. Proliferation signal inhibitors and post-transplant malignancies in heart transplantation: Practical clinical management questions. Clin Transplant 2011;25:475-86.
33. Jiménez-Romero C, Manrique A, Marqués E, Calvo J, Sesma AG, Cambra F, Abradelo M, Sterup RM, Olivares S, Justo I, Colina F, Moreno E. Switching to sirolimus monotherapy for de novo tumors after liver transplantation. A preliminary experience. Hepatogastroenterology 2011;58:115-21.