- Email: [email protected]
Delayed Initiation of Tacrolimus Is Safe and Effective in Renal Transplant Recipients With Delayed and Slow Graft Function
Delayed Initiation of Tacrolimus Is Safe and Effective in Renal Transplant Recipients With Delayed and Slow Graft Function Y. Liu, H. Liu, Y. Shen, Y. Chen, and Y. Cheng* Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, Kaohsiung, Taiwan
ABSTRACT Background. Tacrolimus is widely used in renal transplantation to help prevent acute and chronic rejection, but the nephrotoxicity of tacrolimus may compromise renal function. This study investigates the safety and efficacy in delayed initiation of tacrolimus after antilymphocyte induction therapy in kidney transplant recipients. Methods. This retrospective cohort analysis involved data from 68 kidney transplant recipients receiving standard induction therapy (basiliximab [Simulect] or thymoglobulin) combined with tacrolimus. The patients were divided into 2 groups according to whether the start time of tacrolimus therapy was before or after 24 hours posttransplantation. Acute rejection, common complications of immunosuppression, and graft survival were compared. Results. The mean (SD) timing of tacrolimus administered in the Delayed group was 4 (1.9) days after transplantation. The Delayed group patients had a higher percentage of slow graft function and delayed graft function than the No-delay group. Compared with the Nodelay group, delayed initiation of tacrolimus did not increase risk of biopsy-proven acute rejection, infection, posttransplant diabetes mellitus, graft survival, and patient survival. Conclusions. Our study confirmed delayed initiation of tacrolimus after antilymphocyte induction therapy is safe and effective in renal transplant recipients with slow or delayed graft function.
T
ACROLIMUS, a kind of macrolide calcineurin inhibitor (CNI), is widely used in renal transplantation to help prevent acute and chronic rejection and subsequent loss of the kidney allograft [1]. Kidney Disease: Improving Global Outcomes guidelines for the care of kidney transplant recipients suggest that tacrolimus be started before or at the time of transplantation [2,3]. In the modern era of kidney transplantation, antilymphocyte biological agent induction therapy is regularly used and effectively prevents acute rejection in the early posttransplant period. Previous studies have also shown that there is no correlation between tacrolimus level and risk of rejection [4]. In 5 randomized controlled studies, there were no differences in acute rejection, graft failure, or kidney function in early vs delayed cyclosporine initiation [2]. However, there are few studies in delayed initiation of tacrolimus. As nephrotoxicity has long been recognized as an adverse effect of tacrolimus [5], 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.03.101
2368
initiation of tacrolimus treatment was implemented after sign of functioning graft in our hospital. This study investigates the safety and efficacy in delayed initiation of tacrolimus in modern induction therapy. MATERIALS AND METHODS This retrospective study collects data on 74 consecutive patients with end-stage renal disease who received deceased kidney transplantation at our institution from March 2011 to March 2017. All patients receive standard induction therapy with basiliximab
*Address correspondence to Yuan-tso Cheng, Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Da-Pi Road, Niao song Dist, Kaohsiung, Taiwan 833. Tel: þ886-7-7317123 ext 8094. Fax: þ886-7-7317123 ext 8004. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 2368e2370 (2018)
TACROLIMUS EFFECTIVE IN RECIPIENTS WITH SLOW GRAFT FUNCTION (Simulect, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States) or thymoglobulin according to immunologic risk. Methylprednisolone 500 mg postoperative day (POD) 1 shifting to oral formulation and mycophenolate mofetil 1000 mg twice daily was administered since POD 1. Patients who did not use tacrolimus and were followed up for less than 1 year were excluded. A total of 68 kidney transplant patients were included and were divided into 2 groups according to whether the start time of tacrolimus therapy was before or after 24 hours postoperation. The No-delay group (NDG) had their tacrolimus administered within 24 hours of transplantation and the Delay group (DG) had their tacrolimus administered after 24 hours of transplantation. Data analysis included baseline characteristics of the 68 patients, such as age, body mass index, comorbidity, and preoperative creatinine level. As in a previous study, slow graft function (SGF) was defined as creatinine > 3 mg/dL at POD 5 without need for dialysis. Delayed graft function (DGF) was defined as a patient requiring dialysis in the first week after transplant [6,7]. Patient survival in both groups was 100%, and the primary endpoint of the study was the incidence of acute rejection; the secondary endpoints were infection rate and posttransplant diabetes mellitus. All patients in the DG received at least 1 protocol biopsy within the first posttransplant month. Statistical analyses were performed by SPSS Statistics 21 (IBM SPSS, Chicago, Ill, United States). A P value of less than .05 was considered statistically significant in this study.
RESULTS
Clinical features of patients in the NDG and DG are summarized in Table 1. There were 30 and 38 patients in the NDG and DG, respectively. The mean timing of tacrolimus administered in the DG was 4 (1.9) days after transplantation, and mean follow-up time was 39 months. Table 1. Recipient Characteristics No-delay
Delay
N ¼ 30
N ¼ 38
P Value
Age, mean (SD), y 41.68 (10.64) 47.77 (11.90) .03 BMI, mean (SD), kg/m2 22.89 (3.76) 23.45 (4.54) .61 Length of pretransplant 7.57 (3.88) 10.15 (5.43) .04 dialysis, mean (SD), y OP time, mean (SD), min 293.67 (49.86) 317.87 (63.08) .09 Warm ischemia time, 48.35 (13.77) 46.48 (8.91) .53 mean (SD), min Baseline Cr, mean (SD) 8.68 (2.66) 9.75 (4.05) .22 Post-OP Cr, mean (SD) 7.75 (2.64) 8.05 (3.31) .67 Hospitalization, 16.0 (12e18.5) 17.0 (14e21.25) .04 median (IQR), d Underlying disease, No. (%) HTN 13 (43.3) 22 (57.9) .22 DM 2 (6.7) 1 (2.6) .58 CAD 1 (3.3) 1 (2.6) >.99 CVA Donor type, No. (%) 0 (0.0) 1 (2.6) >.99 SCD 26 (45.6) 31 (54.4) .49 ECD 3 (33.3) 6 (66.7) .49 Abbreviations: BMI, body mass index; CAD, coronary artery disease; Cr, creatinine; CVA, cerebrovascular accident; DM, diabetes mellitus; ECD, expanded criteria donor; HTN, hypertension; IQR, interquartile range; OP, operative; SCD, standard criteria donors.
2369
Patients with SGF and DGF usually had to delay the initiation of tacrolimus. The DG patients had a higher percentage of SGF (71.1% vs 33.3%; P ¼ .002) and DGF (50% vs 23.3%; P ¼ .03) than the NDG. With antibody induction therapy, biopsy-proven acute rejection (BPAR) was very low in both groups (NDG ¼ 6.7%; DG ¼ 7.9%) in this cohort. Compared with the NDG, delayed initiation of tacrolimus did not increase risk of BPAR. There were no differences between groups in infection, posttransplant diabetes mellitus, graft survival, and patient survival (Table 2). Fig 1 shows the change in estimated glomerular filtration rate values between the NDG and DG.
DISCUSSION
Early randomized trials have shown that antilymphocyte biological agent induction reduces early acute rejection, prompting recommendations by Kidney Disease: Improving Global Outcomes that induction be used routinely in firstline therapy after kidney transplantation. The nephrotoxic effects of tacrolimus are crucial in the early period after kidney transplantation [8e10]. We believe antilymphocyte induction therapy is effective in preventing acute rejection, which can help in delayed initiation of tacrolimus to avoid early tacrolimus-related nephrotoxicity. In this cohort, the overall incidence of BPAR was 7.3% (n ¼ 68) within 1 month after transplantation. Of note, there was no difference in the risk of acute rejection when tacrolimus administration was delayed (7.9% vs 6.7%). In longer-term follow-up, 1-year graft survival was 97.1% and patient survival was 100%; there was still no statistical difference between the 2 groups in both graft survival and patient survival. A previous study showed DGF increased risk of early or late graft loss [11,12]. In our study, the DG patients were older and had longer duration of pretransplant dialysis, which reflected the higher proportion of DGF in the DG, so the equivalent graft survival of the DG and NDG is promised in the long term. However, our finding is still too early to validate the benefits of delayed initiation of Table 2. Features of Posttransplantation
No. (%)
SGF DGF Infection BKV CMV UTI BPAR PTDM Graft survival Patient survival
No-delay
Delay
N ¼ 30
N ¼ 38
10 7 16 5 2 11 2 4 29 30
(33.3) (23.3) (55.2) (16.7) (6.7) (36.7) (6.7) (13.3) (96.7) (100)
27 19 20 5 4 15 3 2 37 38
(71.1) (50.0) (52.6) (13.2) (10.5) (39.5) (7.9) (5.3) (97.4) (100)
P Value
.002 .03 .84 .69 .69 .81 >.99 .39 >.99 >.99
Abbreviations: BKV, polyomavirus BK; BPAR, biopsy-proven acute rejection; CMV, cytomegalovirus; DGF, delayed graft function (need for dialysis in the first week posttransplant); PTDM, posttransplant diabetes mellitus; SGF, slow graft function (creatinine >3 mg/dL on postoperative day 5, but no need for dialysis); UTI, urinary tract infection.
2370
LIU, LIU, SHEN ET AL
tacrolimus after anti-lymphocyte induction therapy is safe and effective in renal transplant recipients with slow or delayed graft function.
REFERENCES
Figure 1. Changes in renal function between no-delay and delay cohorts. Abbreviations: POD, postoperative day; eGFR, estimated glomerular filtration rate.
tacrolimus. Nevertheless, our study did confirm the delayed initiation of tacrolimus did not increase risk of acute rejection or compromise graft survival. In the modern era of solid organ transplantation, tacrolimus combined with induction therapy is associated with lower rates of acute rejection [13,14]. Studies have shown that reduced overall tacrolimus exposure can help in avoiding subsequent nephrotoxicity. Sharif et al showed that delayed introduction of CNI is effective in improving graft function without evidence of increased rejection and thereby minimizes renal toxicity post-kidney transplant [15]. They also validated that avoidance of CNI could be achieved after certain induction therapy without increased risk of acute rejection. The contemporary protocols were associated with reduction in new onset diabetes, which will affect the long-term outcome of kidney transplant. However, most transplant centers are still using protocols with tacrolimus as a main immunosuppressant. We do not know how long an allograft can be safely treated without tacrolimus. Previous pharmacodynamics studies have shown antilymphocyte induction protects allograft from acute rejection for at least 4 weeks [16,17]. With antilymphocyte antibody induction therapy, we believe delayed initiation of tacrolimus in the first week could be safely implemented in renal transplant recipients. CONCLUSION
Recent evidence has shown tacrolimus level is irrelevant to rejection and graft survival in the first week under antibody induction therapy. Our study confirmed delayed initiation of
[1] Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet (London, England) 1989;2:1000e4. [2] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9(Suppl. 3):S1e155. [3] Tai E, Chapman JR. The KDIGO review of the care of renal transplant recipient. Pol Arch Med Wewn 2010;120:237e42. [4] Bouamar R, Shuker N, Hesselink DA, Weimar W, Ekberg H, Kaplan B, et al. Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials. Am J Transplant 2013;13:1253e61. [5] Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481e508. [6] Yarlagadda SG, Klein CL, Jani A. Long-term renal outcomes after delayed graft function. Adv Chronic Kidney Dis 2008;15: 248e56. [7] Humar A, Johnson EM, Payne WD, Wrenshall L, Sutherland DE, Najarian JS, et al. Effect of initial slow graft function on renal allograft rejection and survival. Clin Transplant 1997;11:623e7. [8] Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care 2001;7:384e9. [9] Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y, Nickeleit V, Ryffel B. The side-effects of ciclosporine-A and tacrolimus. Clin Nephrol 1998;49:356e63. [10] Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C, et al. Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients. Clin Transplant 1997;11:237e42. [11] Yarlagadda SG, Coca SG, Formica RN, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant 2009;24:1039e47. [12] Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 1997;63:968e74. [13] Charpentier B, Rostaing L, Berthoux F, Lang P, Civati G, Touraine JL, et al. A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Transplantation 2003;75:844e51. [14] Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357: 2562e75. [15] 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;22:2107e18. [16] Salis P, Caccamo C, Verzaro R, Gruttadauria S, Artero M. The role of basiliximab in the evolving renal transplantation immunosuppression protocol. Biologics 2008;2:175e88. [17] Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P, et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 2012;14:1258e75.
ABSTRACT Background. Tacrolimus is widely used in renal transplantation to help prevent acute and chronic rejection, but the nephrotoxicity of tacrolimus may compromise renal function. This study investigates the safety and efficacy in delayed initiation of tacrolimus after antilymphocyte induction therapy in kidney transplant recipients. Methods. This retrospective cohort analysis involved data from 68 kidney transplant recipients receiving standard induction therapy (basiliximab [Simulect] or thymoglobulin) combined with tacrolimus. The patients were divided into 2 groups according to whether the start time of tacrolimus therapy was before or after 24 hours posttransplantation. Acute rejection, common complications of immunosuppression, and graft survival were compared. Results. The mean (SD) timing of tacrolimus administered in the Delayed group was 4 (1.9) days after transplantation. The Delayed group patients had a higher percentage of slow graft function and delayed graft function than the No-delay group. Compared with the Nodelay group, delayed initiation of tacrolimus did not increase risk of biopsy-proven acute rejection, infection, posttransplant diabetes mellitus, graft survival, and patient survival. Conclusions. Our study confirmed delayed initiation of tacrolimus after antilymphocyte induction therapy is safe and effective in renal transplant recipients with slow or delayed graft function.
T
ACROLIMUS, a kind of macrolide calcineurin inhibitor (CNI), is widely used in renal transplantation to help prevent acute and chronic rejection and subsequent loss of the kidney allograft [1]. Kidney Disease: Improving Global Outcomes guidelines for the care of kidney transplant recipients suggest that tacrolimus be started before or at the time of transplantation [2,3]. In the modern era of kidney transplantation, antilymphocyte biological agent induction therapy is regularly used and effectively prevents acute rejection in the early posttransplant period. Previous studies have also shown that there is no correlation between tacrolimus level and risk of rejection [4]. In 5 randomized controlled studies, there were no differences in acute rejection, graft failure, or kidney function in early vs delayed cyclosporine initiation [2]. However, there are few studies in delayed initiation of tacrolimus. As nephrotoxicity has long been recognized as an adverse effect of tacrolimus [5], 0041-1345/18 https://doi.org/10.1016/j.transproceed.2018.03.101
2368
initiation of tacrolimus treatment was implemented after sign of functioning graft in our hospital. This study investigates the safety and efficacy in delayed initiation of tacrolimus in modern induction therapy. MATERIALS AND METHODS This retrospective study collects data on 74 consecutive patients with end-stage renal disease who received deceased kidney transplantation at our institution from March 2011 to March 2017. All patients receive standard induction therapy with basiliximab
*Address correspondence to Yuan-tso Cheng, Department of Urology, Kaohsiung Chang Gung Memorial Hospital and Chang Gung University College of Medicine, 123 Da-Pi Road, Niao song Dist, Kaohsiung, Taiwan 833. Tel: þ886-7-7317123 ext 8094. Fax: þ886-7-7317123 ext 8004. E-mail: [email protected] ª 2018 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 50, 2368e2370 (2018)
TACROLIMUS EFFECTIVE IN RECIPIENTS WITH SLOW GRAFT FUNCTION (Simulect, Novartis Pharmaceuticals Corporation, East Hanover, NJ, United States) or thymoglobulin according to immunologic risk. Methylprednisolone 500 mg postoperative day (POD) 1 shifting to oral formulation and mycophenolate mofetil 1000 mg twice daily was administered since POD 1. Patients who did not use tacrolimus and were followed up for less than 1 year were excluded. A total of 68 kidney transplant patients were included and were divided into 2 groups according to whether the start time of tacrolimus therapy was before or after 24 hours postoperation. The No-delay group (NDG) had their tacrolimus administered within 24 hours of transplantation and the Delay group (DG) had their tacrolimus administered after 24 hours of transplantation. Data analysis included baseline characteristics of the 68 patients, such as age, body mass index, comorbidity, and preoperative creatinine level. As in a previous study, slow graft function (SGF) was defined as creatinine > 3 mg/dL at POD 5 without need for dialysis. Delayed graft function (DGF) was defined as a patient requiring dialysis in the first week after transplant [6,7]. Patient survival in both groups was 100%, and the primary endpoint of the study was the incidence of acute rejection; the secondary endpoints were infection rate and posttransplant diabetes mellitus. All patients in the DG received at least 1 protocol biopsy within the first posttransplant month. Statistical analyses were performed by SPSS Statistics 21 (IBM SPSS, Chicago, Ill, United States). A P value of less than .05 was considered statistically significant in this study.
RESULTS
Clinical features of patients in the NDG and DG are summarized in Table 1. There were 30 and 38 patients in the NDG and DG, respectively. The mean timing of tacrolimus administered in the DG was 4 (1.9) days after transplantation, and mean follow-up time was 39 months. Table 1. Recipient Characteristics No-delay
Delay
N ¼ 30
N ¼ 38
P Value
Age, mean (SD), y 41.68 (10.64) 47.77 (11.90) .03 BMI, mean (SD), kg/m2 22.89 (3.76) 23.45 (4.54) .61 Length of pretransplant 7.57 (3.88) 10.15 (5.43) .04 dialysis, mean (SD), y OP time, mean (SD), min 293.67 (49.86) 317.87 (63.08) .09 Warm ischemia time, 48.35 (13.77) 46.48 (8.91) .53 mean (SD), min Baseline Cr, mean (SD) 8.68 (2.66) 9.75 (4.05) .22 Post-OP Cr, mean (SD) 7.75 (2.64) 8.05 (3.31) .67 Hospitalization, 16.0 (12e18.5) 17.0 (14e21.25) .04 median (IQR), d Underlying disease, No. (%) HTN 13 (43.3) 22 (57.9) .22 DM 2 (6.7) 1 (2.6) .58 CAD 1 (3.3) 1 (2.6) >.99 CVA Donor type, No. (%) 0 (0.0) 1 (2.6) >.99 SCD 26 (45.6) 31 (54.4) .49 ECD 3 (33.3) 6 (66.7) .49 Abbreviations: BMI, body mass index; CAD, coronary artery disease; Cr, creatinine; CVA, cerebrovascular accident; DM, diabetes mellitus; ECD, expanded criteria donor; HTN, hypertension; IQR, interquartile range; OP, operative; SCD, standard criteria donors.
2369
Patients with SGF and DGF usually had to delay the initiation of tacrolimus. The DG patients had a higher percentage of SGF (71.1% vs 33.3%; P ¼ .002) and DGF (50% vs 23.3%; P ¼ .03) than the NDG. With antibody induction therapy, biopsy-proven acute rejection (BPAR) was very low in both groups (NDG ¼ 6.7%; DG ¼ 7.9%) in this cohort. Compared with the NDG, delayed initiation of tacrolimus did not increase risk of BPAR. There were no differences between groups in infection, posttransplant diabetes mellitus, graft survival, and patient survival (Table 2). Fig 1 shows the change in estimated glomerular filtration rate values between the NDG and DG.
DISCUSSION
Early randomized trials have shown that antilymphocyte biological agent induction reduces early acute rejection, prompting recommendations by Kidney Disease: Improving Global Outcomes that induction be used routinely in firstline therapy after kidney transplantation. The nephrotoxic effects of tacrolimus are crucial in the early period after kidney transplantation [8e10]. We believe antilymphocyte induction therapy is effective in preventing acute rejection, which can help in delayed initiation of tacrolimus to avoid early tacrolimus-related nephrotoxicity. In this cohort, the overall incidence of BPAR was 7.3% (n ¼ 68) within 1 month after transplantation. Of note, there was no difference in the risk of acute rejection when tacrolimus administration was delayed (7.9% vs 6.7%). In longer-term follow-up, 1-year graft survival was 97.1% and patient survival was 100%; there was still no statistical difference between the 2 groups in both graft survival and patient survival. A previous study showed DGF increased risk of early or late graft loss [11,12]. In our study, the DG patients were older and had longer duration of pretransplant dialysis, which reflected the higher proportion of DGF in the DG, so the equivalent graft survival of the DG and NDG is promised in the long term. However, our finding is still too early to validate the benefits of delayed initiation of Table 2. Features of Posttransplantation
No. (%)
SGF DGF Infection BKV CMV UTI BPAR PTDM Graft survival Patient survival
No-delay
Delay
N ¼ 30
N ¼ 38
10 7 16 5 2 11 2 4 29 30
(33.3) (23.3) (55.2) (16.7) (6.7) (36.7) (6.7) (13.3) (96.7) (100)
27 19 20 5 4 15 3 2 37 38
(71.1) (50.0) (52.6) (13.2) (10.5) (39.5) (7.9) (5.3) (97.4) (100)
P Value
.002 .03 .84 .69 .69 .81 >.99 .39 >.99 >.99
Abbreviations: BKV, polyomavirus BK; BPAR, biopsy-proven acute rejection; CMV, cytomegalovirus; DGF, delayed graft function (need for dialysis in the first week posttransplant); PTDM, posttransplant diabetes mellitus; SGF, slow graft function (creatinine >3 mg/dL on postoperative day 5, but no need for dialysis); UTI, urinary tract infection.
2370
LIU, LIU, SHEN ET AL
tacrolimus after anti-lymphocyte induction therapy is safe and effective in renal transplant recipients with slow or delayed graft function.
REFERENCES
Figure 1. Changes in renal function between no-delay and delay cohorts. Abbreviations: POD, postoperative day; eGFR, estimated glomerular filtration rate.
tacrolimus. Nevertheless, our study did confirm the delayed initiation of tacrolimus did not increase risk of acute rejection or compromise graft survival. In the modern era of solid organ transplantation, tacrolimus combined with induction therapy is associated with lower rates of acute rejection [13,14]. Studies have shown that reduced overall tacrolimus exposure can help in avoiding subsequent nephrotoxicity. Sharif et al showed that delayed introduction of CNI is effective in improving graft function without evidence of increased rejection and thereby minimizes renal toxicity post-kidney transplant [15]. They also validated that avoidance of CNI could be achieved after certain induction therapy without increased risk of acute rejection. The contemporary protocols were associated with reduction in new onset diabetes, which will affect the long-term outcome of kidney transplant. However, most transplant centers are still using protocols with tacrolimus as a main immunosuppressant. We do not know how long an allograft can be safely treated without tacrolimus. Previous pharmacodynamics studies have shown antilymphocyte induction protects allograft from acute rejection for at least 4 weeks [16,17]. With antilymphocyte antibody induction therapy, we believe delayed initiation of tacrolimus in the first week could be safely implemented in renal transplant recipients. CONCLUSION
Recent evidence has shown tacrolimus level is irrelevant to rejection and graft survival in the first week under antibody induction therapy. Our study confirmed delayed initiation of
[1] Starzl TE, Todo S, Fung J, Demetris AJ, Venkataramman R, Jain A. FK 506 for liver, kidney, and pancreas transplantation. Lancet (London, England) 1989;2:1000e4. [2] KDIGO clinical practice guideline for the care of kidney transplant recipients. Am J Transplant 2009;9(Suppl. 3):S1e155. [3] Tai E, Chapman JR. The KDIGO review of the care of renal transplant recipient. Pol Arch Med Wewn 2010;120:237e42. [4] Bouamar R, Shuker N, Hesselink DA, Weimar W, Ekberg H, Kaplan B, et al. Tacrolimus predose concentrations do not predict the risk of acute rejection after renal transplantation: a pooled analysis from three randomized-controlled clinical trials. Am J Transplant 2013;13:1253e61. [5] Naesens M, Kuypers DR, Sarwal M. Calcineurin inhibitor nephrotoxicity. Clin J Am Soc Nephrol 2009;4:481e508. [6] Yarlagadda SG, Klein CL, Jani A. Long-term renal outcomes after delayed graft function. Adv Chronic Kidney Dis 2008;15: 248e56. [7] Humar A, Johnson EM, Payne WD, Wrenshall L, Sutherland DE, Najarian JS, et al. Effect of initial slow graft function on renal allograft rejection and survival. Clin Transplant 1997;11:623e7. [8] Olyaei AJ, de Mattos AM, Bennett WM. Nephrotoxicity of immunosuppressive drugs: new insight and preventive strategies. Curr Opin Crit Care 2001;7:384e9. [9] Mihatsch MJ, Kyo M, Morozumi K, Yamaguchi Y, Nickeleit V, Ryffel B. The side-effects of ciclosporine-A and tacrolimus. Clin Nephrol 1998;49:356e63. [10] Katari SR, Magnone M, Shapiro R, Jordan M, Scantlebury V, Vivas C, et al. Clinical features of acute reversible tacrolimus (FK 506) nephrotoxicity in kidney transplant recipients. Clin Transplant 1997;11:237e42. [11] Yarlagadda SG, Coca SG, Formica RN, Poggio ED, Parikh CR. Association between delayed graft function and allograft and patient survival: a systematic review and meta-analysis. Nephrol Dial Transplant 2009;24:1039e47. [12] Ojo AO, Wolfe RA, Held PJ, Port FK, Schmouder RL. Delayed graft function: risk factors and implications for renal allograft survival. Transplantation 1997;63:968e74. [13] Charpentier B, Rostaing L, Berthoux F, Lang P, Civati G, Touraine JL, et al. A three-arm study comparing immediate tacrolimus therapy with antithymocyte globulin induction therapy followed by tacrolimus or cyclosporine A in adult renal transplant recipients. Transplantation 2003;75:844e51. [14] Ekberg H, Tedesco-Silva H, Demirbas A, Vítko S, Nashan B, Gürkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357: 2562e75. [15] 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;22:2107e18. [16] Salis P, Caccamo C, Verzaro R, Gruttadauria S, Artero M. The role of basiliximab in the evolving renal transplantation immunosuppression protocol. Biologics 2008;2:175e88. [17] Bosch M, Dhadda M, Hoegh-Petersen M, Liu Y, Hagel LM, Podgorny P, et al. Immune reconstitution after anti-thymocyte globulin-conditioned hematopoietic cell transplantation. Cytotherapy 2012;14:1258e75.