Outcomes of mTORi-involving minimized immunosuppression protocols in renal transplantation

Yıl 2021, , 71 - 77, 21.01.2021

Mehmet Emin Demir , Özgür Merhametsiz , Murathan Uyar , Murat Sevmis , Sema Aktas

https://doi.org/10.32322/jhsm.835670

Öz

Amaç
Böbrek alıcılarında sitomegalovirüs (CMV), poliyoma B-K virüs (BKV) ve kalsinörün inhibitörü (KNİ) toksisitesi ve malignite geliştiğinde immünosupresyonu azaltmak gerekir. İmmünosupresyon azaltma protokolleri genellikle standart doz KNİ’nin azaltılması ve bir mTORi eklenmesini içerir. Bu çalışmada standart bir immünsupresyon protokolünden mTORi içeren düşük immünosupresyon protokolüne geçtikten sonra ki greft fonksiyonlarını incelemeyi amaçladık.
Metod
Bu tek-merkezli, retrospektif ve gözlemsel çalışma 2014-2016 yılları arasında yapılmış böbrek nakillerinin sonuçlarını içermektedir. Toplan 322 alıcı incelendi ve bunların 231’i çalışmaya alındı. En az 12 ay mTORi alanlar mTORi kolunda değerlendirildi. CMV ve BKV test sonuçları ve hiç greft biyopsisi olmayan alıcılar çalışma dışı bırakıldı. Geriye kalan alıcılar mTORi içermeyen gurubu oluşturdu. mTORi öncesi ve mTORi sonrası birinci ve üçüncü yıl greft sağkalımları ve fonksiyonları karşılaştırıldı.
Sonuçlar
Toplam 231 alıcı ortalama 5 yıl takip edildi. mTORi kolunda CMV ve BKV pozitifliği daha sıktı (p=0,001). Ayrıca, mTORi kolunda akut rejeksiyon sıklığı daha fazlaydı; p=0,001. Tahmini glomerüler filtrasyon hızı (tGFH) mTORi sonrası birinci ve üçüncü yılda daha azdı (p=0,001). Ancak, mTORi sonrası birinci ve üçüncü yıl greft sağ kalım oranları mTORi kullanmayanlar ile benzerdi (p=0,52 ve p=0,72, sırasıyla).
Sonuç
Böbrek alıcılarında mTORi, genellikle immünsupresyon dozunun azaltılmak zorunda olduğu durumlarda (CMV ve BKV viremisi varlığı, KNİ ilişkili nefrotoksisite gibi) düşük doz KNİ’ler ile birlikte kullanılır. Tüm dezavantajlara rağmen mTORi standart protokollere benzer greft sağkalımı sağlayabilir. Ancak, mTORi kullanımı daha fazla akut rejeksiyon ile ilişkilidir ve tGFH’da azalmayı engelleyemeyebilir.

Anahtar Kelimeler

Renal allograft, mTORi, renal transplantation

Kaynakça

• Kajiwara M, Masuda S. Role of mTOR Inhibitors in Kidney Disease. Int J Mol Sci 2016 Jun 21; 17: 975.
• Badve SV, Pascoe EM, Burke M, et al. Mammalian target of rapamycin inhibitors and clinical outcomes in adult kidney transplant recipients. Clin J Am Soc Nephrol 2016; 11: 1845-55.
• Farouk SS, Rein JL. The many faces of calcineurin inhibitor toxicity-what the FK? Adv Chronic Kidney Dis 2020; 27: 56-66.
• Nankivell BJ, Borrows RJ, Fung CL, O'Connell PJ, Allen RD, Chapman JR. The natural history of chronic allograft nephropathy. N Engl J Med 2003; 349: 2326-33.
• Prashar R, Venkat KK. Immunosuppression minimization and avoidance protocols: when less is not more. Adv Chronic Kidney Dis 2016; 23: 295-300.
• Farkas SA, Schnitzbauer AA, Kirchner G, Obed A, Banas B, Schlitt HJ. Calcineurin inhibitor minimization protocols in liver transplantation. Transpl Int 2009; 22: 49-60.
• Rostaing L, Wéclawiak H, Mengelle C, Kamar N. Viral infections after kidney transplantation. Minerva Urol Nefrol 2011; 63: 59-71.
• Malvezzi P, Jouve T, Rostaing L. Negative impact of CMV and BKV infections on kidney-allograft function at 1-year post-transplantation: can it be changed by modifying immunosuppression? EBioMedicine 2018; 34: 2-3.
• Tedesco-Silva H, Felipe C, Ferreira A, et al. Reduced incidence of cytomegalovirus infection in kidney transplant recipients receiving everolimus and reduced tacrolimus doses. Am J Transplant 2015; 15: 2655-64.
• Jouve T, Rostaing L, Malvezzi P. Place of mTOR inhibitors in management of BKV infection after kidney transplantation. J Nephropathol 2016; 5: 1-7.
• Malvezzi P, Rostaing L. Renal transplantation in 2016: Novel approaches to improve recipient and allograft outcomes. Nat Rev Nephrol 2017; 13: 73-74.
• Sawinski D, Trofe-Clark J, Leas B, et al. Calcineurin inhibitor minimization, conversion, withdrawal, and avoidance strategies in renal transplantation: a systematic review and meta-analysis. Am J Transplant 2016; 16: 2117-38.
• Meier-Kriesche HU, Schold JD, Srinivas TR, Kaplan B. Lack of improvement in renal allograft survival despite a marked decrease in acute rejection rates over the most recent era. Am J Transplant 2004; 4: 378-83.
• Tantravahi J, Womer KL, Kaplan B. Why hasn't eliminating acute rejection improved graft survival? Annu Rev Med 2007; 58: 369-85.
• Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009; 4: 481-508.
• Zununi Vahed S, Ardalan M, Samadi N, Omidi Y. Pharmacogenetics and drug-induced nephrotoxicity in renal transplant recipients. Bioimpacts 2015; 5: 45-54.
• Moscarelli L, Caroti L, Antognoli G, et al. Everolimus leads to a lower risk of BKV viremia than mycophenolic acid in de novo renal transplantation patients: a single-center experience. Clin Transplant 2013; 27: 546-54.
• Hirsch HH, Yakhontova K, Lu M, Manzetti J. BK polyomavirus replication in renal tubular epithelial cells is inhibited by Sirolimus, but activated by tacrolimus through a pathway involving FKBP-12. Am J Transplant 2016; 16: 821-32.
• Ramanan P, Razonable RR. Cytomegalovirus infections in solid organ transplantation: a review. Infect Chemother 2013; 45: 260-71.
• Selvey LA, Lim WH, Boan P, et al. Cytomegalovirus viraemia and mortality in renal transplant recipients in the era of antiviral prophylaxis. Lessons from the western Australian experience. BMC Infect Dis 2017; 17: 501.
• Cordero E, Casasola C, Ecarma R, Danguilan R. Cytomegalovirus disease in kidney transplant recipients: incidence, clinical profile, and risk factors. Transplant Proc 2012; 44: 694-700.
• Durlik M, Siennicka J, Litwińska B, et al. Clinical manifestations and diagnosis of cytomegalovirus infection in renal allograft recipients. Transplant Proc 2001; 33: 1237-9.
• Avery RK. Low-dose valganciclovir for cytomegalovirus prophylaxis in organ transplantation: is less really more? Clin Infect Dis 2011; 52: 322-4.
• Asberg A, Jardine AG, Bignamini AA, et al. VICTOR Study Group. Effects of the intensity of immunosuppressive therapy on outcome of treatment for CMV disease in organ transplant recipients. Am J Transplant 2010; 10: 1881-8.
• Anglicheau D, Lautrette A, Scieux C, Flamant M, Morinet F, Legendre C. Efficacy and safety of lowering immunosuppression to treat CMV infection in renal transplant recipients on valaciclovir prophylaxis: a pilot study. Nephrol Dial Transplant 2003; 18: 1654-6.
• Hasanzamani B, Hami M, Zolfaghari V, Torkamani M, Ghorban Sabagh M, Ahmadi Simab S. The effect of cytomegalovirus infection on acute rejection in kidney transplanted patients. J Renal Inj Prev 2016; 5: 85-8.
• Sagedal S, Nordal KP, Hartmann A, et al. The impact of cytomegalovirus infection and disease on rejection episodes in renal allograft recipients. Am J Transplant 2002; 2: 850-6.
• Stolt A, Sasnauskas K, Koskela P, Lehtinen M, Dillner J. Seroepidemiology of the human polyomaviruses. J Gen Virol 2003; 84: 1499-504.
• Knowles WA. Discovery and epidemiology of the human polyomaviruses BK virus (BKV) and JC virus (JCV). Adv Exp Med Biol 2006; 577: 19-45.
• Hirsch HH, Knowles W, Dickenmann M, et al. Prospective study of polyomavirus type BK replication and nephropathy in renal-transplant recipients. N Engl J Med 2002; 347: 488-96.
• Brennan DC, Agha I, Bohl DL, et al. Incidence of BK with tacrolimus versus cyclosporine and impact of preemptive immunosuppression reduction. Am J Transplant 2005; 5: 582-94.
• Hirsch HH. BK virus: opportunity makes a pathogen. Clin Infect Dis 2005; 41: 354-60.
• Sawinski D, Forde KA, Trofe-Clark J, et al. Persistent BK viremia does not increase intermediate-term graft loss but is associated with de novo donor-specific antibodies. J Am Soc Nephrol 2015; 26: 966-75.
• Haas M, Loupy A, Lefaucheur C, et al. The Banff 2017 Kidney Meeting Report: Revised diagnostic criteria for chronic active T cell-mediated rejection, antibody-mediated rejection, and prospects for integrative endpoints for next-generation clinical trials. Am J Transplant 2018; 18: 293-307.
• Schold JD, Rehman S, Kayle LK, Magliocca J, Srinivas TR, Meier-Kriesche HU. Treatment for BK virus: incidence, risk factors and outcomes for kidney transplant recipients in the United States. Transpl Int 2009; 22: 626-34.
• Sawinski D, Goral S. BK virus infection: an update on diagnosis and treatment. Nephrol Dial Transplant 2015; 30: 209-17.