Does Diltiazem Provide Benefits on Allograft Functions in Kidney Transplant Recipients?

Öz

Background: Acute and chronic calcineurin inhibitors (CNI) nephrotoxicity is a common concern in kidney transplant (KT) recipients. It is unclear whether diltiazem use can reduce CNI induced acute and chronic nephrotoxicity in (KT) recipients. In this study, we investigated the impact of diltiazem on 1 –year allograft survival and function.
Materials and Methods: This single-center retrospective study included 312 kidney transplant recipients and donors. Diltiazem receiving and diltiazem-free recipients were compared for 1-year allograft survival and functions. Available allograft biopsies were investigated for the evidence pieces of CNI induced nephrotoxicity. Factors may have a potential impact on allograft functions were evaluated (cytomegalovirus and polyoma BK viremia positivity, acute rejection episodes, donors and recipients ages and body mass indexes). A statistical package program was used for data analysis. P<0.05 was assigned significant.
Results: Seventy-three recipients in diltiazem arm and 239 in diltiazem-free arm were compared. In diltiazem and diltiazem-free arms, 1- year mortality, allograft survival rates and CNI induced nephrotoxicity incidences were 4.1% vs 3.8% (P=0.89), and 13.7% vs 7.1% (P=0.08), 18.8% vs 10.5% (P=0.27), respectively. However, 12-month estimated glomerular filtration rate was worse in diltiazem arm (62.75 ml/dk/1.73m2) compared to diltiazem-free group (73.19 ml/dk/1.73m2) (P=0.03). CNI toxicity had a weak impact on low eGFR in regression analysis (P=0.055 and 95% confidence interval).
Conclusions: Despite diltiazem use allows to CNI dose reduction, it might have undesirable impacts on long-term allograft functions, which is the main target of the allograft care.

Key Words: Allograft function, Diltiazem, Kidney transplantation

Anahtar Kelimeler

• Allograft survival
• Diltiazem
• Kidney transplantation

Diltiazem Böbrek Alıcılarında Greft Fonksiyonlarını İyileştirir mi?

Öz

Amaç: Akut ve kronik kalsinörin inhibitörü (KNİ) toksisitesi böbrek naklinde önemli bir sorundur. Diltiazem kullanımının KNİ toksisitesini azaltıp azaltmadığı net değildir. Bu çalışmada KNİ kullanımının 1 yıllık greft sağkalımı ve fonksiyonu üzerine etkilerini araştırdık.
Materyal ve Metod: Bu tek merkezli retrospektif çalışmada 312 böbrek alıcısı ve vericisi incelendi. Alıcılar diltiazem kullanan ve kullanmayan guruplar olarak ikiye ayrıldı. 1 yıllık alıcı ve greft sağkalımları araştırıldı. Greft biyopsilerinde KNİ toksisitesi ile 1 yıllık greft sağ kalımı arasındaki ilişki incelendi. Sitomegalovirüs ve polyoma BK virüs viremisi varlığı, akut rejeksiyon atakları, alıcı ve vericinin yaşları ve vücut kitle indekslerinin 1 yıllık greft sağ kalımı üzerine etkileri araştırıldı. Veriler bir istatistik paket programda değerlendirildi, P<0,05 anlamlı kabul edildi.
Bulgular: Alıcıların 73’ü diltiazem kullandı, 239’u diltiazem kullanmadı. 1 yıllık mortalite, greft sağ kalımı, Kalsinörin inhibitörü ilişkili nefrotoksisite diltiazem kolunda ve diltiazem kullanmayan gurupta sırasıyla; %4,1 e karşı %3,8 (P=0,89), %13,7’ye karşı %7,1 (P=0.08) ve %18,8’e karşı %10,5 (P=0,27) idi. 12 ay sonunda tahmini glomerüler filtrasyon hızı diltiazem kolunda daha kötü idi; 62,75 ml/dk/1.73m2’ye karşı 73,19 ml/dk/1,73m2 (P=0.03). Kalsinörin inhibitörü toksisitesinin kötü greft fonksiyonları üzerine %95 güven aralığında zayıf bir etkisi görüldü (P=0.055).
Sonuç: Diltiazem KNİ doz azaltımına imkân sağlasa da esasen istenen uzun dönem greft fonksiyonları üzerine olumsuz etkilere sahip olabilir.

Anahtar Kelimeler

• Böbrek Nakli
• Diltiazem
• Greft sağkalımı

Kaynakça

1. 1. Karpe KM, Talaulikar GS, Walters GD. Calcineurin inhibitor withdrawal or tapering for kidney transplant recipients. Cochrane Database Syst Rev. 2017;21;7(7):CD006750.
2. 2. Bentata Y. Tacrolimus: 20 years of use in adult kidney transplantation. What we should know about its nephrotoxicity. Artif Organs. 2020;44(2):140-52.
3. 3. 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(24):2326-33.
4. 4. Farouk SS, Rein JL. The Many Faces of Calcineurin Inhibitor Toxicity-What the FK? Adv Chronic Kidney Dis. 2020;27(1):56-66.
5. 5. Robert N, Wong GW, Wright JM. Effect of cyclosporine on blood pressure. Cochrane Database Syst Rev. 2010;20;(1):CD007893.
6. 6. Tory R, Sachs-Barrable K, Hill JS, Wasan KM. Cyclosporine A and Rapamycin induce in vitro cholesteryl ester transfer protein activity, and suppress lipoprotein lipase activity in human plasma. Int J Pharm. 2008;358(1-2):219-23.
7. 7. Awan AA, Niu J, Pan JS, Erickson KF, Mandayam S, Winkelmayer WC, Navaneethan SD, Ramanathan V. Trends in the Causes of Death among Kidney Transplant Recipients in the United States (1996-2014). Am J Nephrol. 2018;48(6):472-81.
8. 8. Weiner DA, Cutler SS, Klein MD. Efficacy and safety of sustained-release diltiazem in stable angina pectoris. D'Amico D, Tepper SJ. Prophylaxis of migraine: general principles and patient acceptance. Neuropsychiatr Dis Treat. 2008;4(6):1155-67.

9. 9. Islam S, Masiakos P, Schnitzer JJ, Doody DP, Ryan DP. Diltiazem reduces pulmonary arterial pressures in recurrent pulmonary hypertension associated with pulmonary hypoplasia. J Pediatr Surg. 1999;34(5):712-4.
10. 10. Choong CL, Wong HS, Lee FY, Lee CK, Kho JV, Lai YX, Vikneswaran T. Dose-Response Relationship Between Diltiazem and Tacrolimus and Its Safety in Renal Transplant Recipients. Transplant Proc. 2018;50(8):2515-20.
11. 11. Takano M, Yumoto R, Murakami T. Expression and function of efflux drug transporters in the intestine. Pharmacol Ther. 2006;109(1-2):137-61.
12. 12. Steuber TD, Lee J, Holloway A, Andrus MR. Nondihydropyridine Calcium Channel Blockers for the Treatment of Proteinuria: A Review of the Literature. Ann Pharmacother. 2019;53(10):1050-9.
13. 13. Xue W, Song Y, Tian P, Ding X, Pan X, Yan H, Hou J, Feng X, Xiang H, Tian X. The effects of diltiazem in renal transplantation patients treated with cyclosporine A. J Biomed Res. 2010;24(4):317-23.
14. 14. Azmandian J, Sohrevardi SM, Fazeli F, Sarrafzadeh F, Etminan A, Savari O, et al. Diltiazem Co-Treatment in Renal Transplant Patients Receiving Cyclosporine with Respect to Concentration at two Hours (C2). Iranina Journal of Pharmaceutical Sciences. 2011;7(1):3-6.
15. 15. Hebert MF, Lam AY. Diltiazem increases tacrolimus concentrations. Ann Pharmacother. 1999;33(6):680-2.
16. 16. McDonald SP, Russ GR. Associations between use of cyclosporine-sparing agents and outcome in kidney transplant recipients. Kidney Int. 2002;61(6):2259-65.
17. 17. Smith CL, Hampton EM, Pederson JA, Pennington LR, Bourne DW. Clinical and medicoeconomic impact of the cyclosporine-diltiazem interaction in renal transplant recipients. Pharmacotherapy. 1994;14(4):471-81.
18. 18. Ladefoged SD, Pedersen E, Hammer M, Rasmussen KC, Hansen FM, Andersen CB. Influence of diltiazem on renal function and rejection in renal allograft recipients receiving triple-drug immunosuppression: a randomized, double-blind, placebo-controlled study. Nephrol Dial Transpl. 1994; 9(5): 543–7.
19. 19. Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol. 2009 Feb;4(2):481-508. doi: 10.2215/CJN.04800908. PMID: 19218475.Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y, Nickeleit V, Ryffel B. The side-effects of ciclosporine-A and tacrolimus. Clin Nephrol. 1998;49(6):356-63.
20. 20. Böttiger Y, Brattström C, Tydén G, Säwe J, Groth CG. Tacrolimus whole blood concentrations correlate closely to side-effects in renal transplant recipients. Br J Clin Pharmacol. 1999;48(3):445-8.
21. 21. Curtis JJ, Luke RG, Dubovsky E, Diethelm AG, Whelchel JD, Jones P. Cyclosporin in therapeutic doses increases renal allograft vascular resistance. Lancet. 1986;2(8505):477-9.
22. 22. Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care. 2001;7(6):384-9.
23. 23. Liu Y, Liu H, Shen Y, Chen Y, Cheng Y. Delayed Initiation of Tacrolimus Is Safe and Effective in Renal Transplant Recipients With Delayed and Slow Graft Function. Transplant Proc. 2018;50(8):2368-70.
24. 24. Elzinga LW, Rosen S, Bennett WM. Dissociation of glomerular filtration rate from tubulointerstitial fibrosis in experimental chronic cyclosporine nephropathy: role of sodium intake. J Am Soc Nephrol. 1993;4(2):214-21.
25. 25. Maluf DG, Dumur CI, Suh JL, Lee JK, Cathro EP, King AL, Gallon L, Brayman KL, Mas VR. Evaluation of molecular profiles in calcineurin inhibitor toxicity post-kidney transplant: input to chronic allograft dysfunction. Am J Transplant. 2014;14(5):1152-63.
26. 26. Nankivell BJ, PʼNg CH, OʼConnell PJ, Chapman JR. Calcineurin Inhibitor Nephrotoxicity Through the Lens of Longitudinal Histology: Comparison of Cyclosporine and Tacrolimus Eras. Transplantation. 2016;100(8):1723-31.
27. 27. Chrysostomou A, Walker RG, Russ GR, d'Apice AJ, Kincaid-Smith P, Mathew TH. Diltiazem in renal allograft recipients receiving cyclosporine. Transplantation. 1993;55(2):300-4.
28. 28. López-Oliva MO, Flores J, Madero R, Escuin F, Santana MJ, Bellón T, Selgas R, Jiménez C. Cytomegalovirus infection after kidney transplantation and long-term graft loss. Nefrologia. 2017;37(5):515-25.
29. 29. 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.
30. 30. Koo EH, Jang HR, Lee JE, Park JB, Kim SJ, Kim DJ, Kim YG, Oh HY, Huh W. The impact of early and late acute rejection on graft survival in renal transplantation. Kidney Res Clin Pract. 2015;34(3):160-4.
31. 31. Winnicki E, Dharmar M, Tancredi DJ, Nguyen S, Butani L. Effect of BMI on allograft function and survival in pediatric renal transplant recipients. Pediatr Nephrol. 2018;33(8):1429-35.
32. 32. Massarweh NN, Clayton JL, Mangum CA, Florman SS, Slakey DP. High body mass index and short- and long-term renal allograft survival in adults. Transplantation. 2005;80(10):1430-4.