- Email: [email protected]
Once- vs Twice-Daily Tacrolimus: Survival Rates and Side Effects: Single-Center Experience
Once- vs Twice-Daily Tacrolimus: Survival Rates and Side Effects: Single-Center Experience Volkan Turunca, Elif Arib,*, Bahtisen Guvenb, Babek Tabendeha, and Aladdin Yildizc a Department of General Surgery, Bahcesehir University, Istanbul, Turkey; bDepartment of Nephrology, Bahcesehir University, Istanbul, Turkey; and cDepartment of Nephrology, Istanbul University, Istanbul, Turkey
ABSTRACT Background. This study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups. Methods. A total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients. Results. Baseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P ¼ .040). Conclusion. This study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.
T
ACROLIMUS is accepted as the mainstay of immunosuppression in kidney transplantation. A new extended formulation of tacrolimus permits once-daily administration without changes in efficacy, safety, and monitoring [1]. Pivotal studies have demonstrated the non-inferiority of prolongedrelease tacrolimus (PR-tacro) vs immediate-release, twicedaily tacrolimus (IR-tacro) in efficacy and safety among de novo kidney transplant recipients [2,3]. The prevalence of post-transplantation diabetes (PTDM) has increased in recent years, despite therapeutic improvements in kidney transplantation [4]. Risk factors associated with 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.01.149
2308
PTDM in kidney transplantation include the type of immunosuppressive regimen used, in addition to demographical factors such as increasing age and higher body mass index [5]. This study aimed to determine whether a de novo, PRtacro-based immunosuppressive regimen affected graft and patient survival when compared to an IR-tacro-based
*Address correspondence to Elif Ari, Department of Nephrology, Bahcesehir University, 34734, Istanbul, Turkey. Tel: (þ90) 532 673 65 97. E-mail: [email protected] ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 2308e2311 (2019)
ONCE- VS TWICE-DAILY TACROLIMUS
regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups. SUBJECTS AND METHODS Subjects A total of 115, standard-risk, kidney transplant recipients were enrolled in this single-center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The study was approved by the local ethics committee and all participants gave written informed consent. Eligible patients were 18 years or older and underwent living or cadaveric kidney transplantation. Patients were excluded if they had received a previous transplant or were receiving ongoing systemic corticosteroids. There were no restrictions on donor age, cold ischemia time, or renal function. Patients received PR-tacro (Advagraf; Astellas Pharma Ltd, Surrey, UK) at an initial dose of 0.2 mg/kg/day on day 2 pre-transplantation or IR-tacro (Prograf; Astellas Pharma Ltd, Surrey, UK) at an initial dose of 0.15 mg/kg/ day on day 2 pre-transplantation. Target tacrolimus trough levels were 8 to 12 ng/mL until day 30, from days 31 to 180 were 8 to 10 ng/mL. After 180 days, target tacrolimus trough levels were 6 to 8 ng/mL. All patients received mycophenolate mofetil (2 gr/day) and corticosteroid (5 mg/day after day 14) as a maintenance immunosuppressive treatment.
Primary Outcome Measures The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection (BPAR), graft and patient survival, and renal function estimated by 24-hour creatinine clearance at week 24.
Secondary Outcome Measures Secondary outcome measures included the incidence of nonadherence, drug-induced tremor; post-transplant diabetes mellitus (PTDM) diagnosis rate; and control of diabetes in pre-transplant diabetic patients at week 24. Adverse events and laboratory parameters were monitored throughout the study. Diabetes mellitus is defined as 1 measurement or more of fasting plasma glucose of 110 mg/dL or more, 1 measurement or more of 2 hour plasma glucose of 160 mg/dL or more, and 1 measurement of A1C 6.5% or more.
Statistical Analysis Descriptive statistics were expressed as mean standard deviation for quantitative data and percentages for qualitative data. Comparisons between groups were performed using the c2 test or Fisher’s exact test for qualitative data and Student’s t test or MannWhitney U test for quantitative data. A P value < .05 was interpreted as statistically significant. All statistical analyses were performed with statistical analysis program (IBM SPSS 13.0 for Windows, IBM, Armonk, NY, United States).
RESULTS
Clinical and demographic characteristics of the study groups are given in Table 1. There were no significant differences in age, body mass index, sex, or primary kidney disease etiology among groups. Mean tacrolimus trough levels were also similar between groups.
2309 Table 1. Clinical and Demographic Characteristics of Study Groups
Age (y) Sex (male/female) BMI (kg/m2) Primary kidney disease (n, %) Diabetes Hypertension Urologic Polycystic kidney disease Glomerulonephritis Other
Prolonged-release tacrolimus group (PR-tacro group) (n ¼ 52)
Immediate-release tacrolimus group (IR-tacro group) (n ¼ 63)
48.22 11.36 32/20 24.09 8.76
49.18 12.44 40/23 26.40 9.04
18 16 08 06 02 02
(34.6%) (30.7%) (15.3%) (11.5%) (3.8%) (3.8%)
23 19 09 08 03 01
(36.5%) (30.1%) (14.2%) (12.6%) (4.7%) (1.5%)
Data is presented as mean standard deviation. Abbreviations: BMI, body mass index; IR, immediate release; PR, prolonged release
Patient and graft survival rates, DGF, graft loss, and BPAR rates are shown in Table 2. No significant differences were observed between study groups for patient and graft survival (P > .05, respectively) at week 24. Delayed graft function (P ¼ .051) and graft loss rates (P ¼ .049) were inclined to be higher in the IR-tacro group when compared to the PR-tacro group, but statistically insignificant (Table 2). BPAR rates (P > .05) and mean levels of creatinine clearance (P > .05) at week 24 were also similar between study groups. In total, 35.52% of patients received treatment for diabetes before transplantation. By week 24, 38.66% of patients had received treatment for diabetes. Incidence of post transplantation diabetes was significantly lower in the PR-tacro group (n ¼ 1 patient, 2.9%) when compared to the IR-tacro group (n ¼ 2 patients, 5.0%) (P ¼ .033). The PRtacro group had significantly lower mean serum levels of fasting glucose in diabetic patients when compared to IRtacro group (P ¼ .034). Similarly, the PR-tacro group had significantly lower mean serum levels of fasting glucose in non-diabetic patients when compared to the IR-tacro group (P ¼ .042) (Table 3). Although mean serum levels of 2 hour glucose were similar both in the PR-tacro group and the IRtacro group of diabetic patients, we observed statistically Table 2. Survival Rates of Study Groups
Patient survival (n, %) Graft survival (n, %) DGF (n, %) Graft loss (n, %) BPAR (n, %) Creatinine clearance (mL/min)
Prolonged-release tacrolimus group (PR-tacro group) (n ¼ 52)
Immediate-release tacrolimus group (IR-tacro group) (n ¼ 63)
P value
52 (100%) 51 (98.07%) 03 (5.76%) 01 (1.96%) 04 (7.69%) 57.66 3.75
63 (100%) 61 (96.89%) 05 (7.93%) 02 (3.77%) 05 (7.93%) 56.24 3.69
NS NS .051 .049 NS NS
Creatinine clearance is presented as mean standard deviation. Abbreviations: BPAR, biopsy proven acute rejection; DGF, delayed graft function; IR, immediate release; NS, not significant; PR, prolonged release.
2310
TURUNC, ARI, GUVEN ET AL
borderline significance of mean serum levels of 2 hour glucose between the PR-tacro group and the IR-tacro group of non-diabetic patients (144 mg/dL vs 152 mg/dL, P ¼ .052) (Table 3). Furthermore, mean serum levels of A1C% were lower in the PR-tacro group when compared to the IR-tacro group in both diabetic and non-diabetic patients (P ¼ .044 and P ¼ .038, respectively) (Table 3). The incidence of tremor was lower in the PR-tacro group when compared to the IR-tacro group (7.64% vs 14.26%, P ¼ .028). There was no significant difference between groups at week 24 in non-adherence rates (3.85% vs 4.72%, P > .05) (Table 3).
DISCUSSION.
In this study, we assessed the efficacy and tolerability of de novo, PR-tacro when compared to an IR-tacro-based regimen in kidney transplant recipients. The results have demonstrated that de novo, PR-tacro is efficacious, associated with a manageable tolerability profile, and has a low incidence of post-transplant diabetes and drug-induced tremor over 24 weeks of treatment. The first main finding of this study is that the incidence of mortality was comparable between PR-tacro and IR-tacro groups at the end of 24 weeks. It is reported that excellent patient survival rates were achieved with PR-tacro [6,7]. Similarly, it is demonstrated that very good graft survival rates were achieved with PR-tacro [6e9]). Our findings are consistent with the literature [6e8]. Follow-up data from previous studies confirm our findings and indicate that PRTable 3. Side Effect Profile of the Study Groups Prolonged-release Immediate-release tacrolimus group tacrolimus group (IR-tacro group) (PR-tacro group) (n ¼ 52) (n ¼ 63) P value
Fasting plasma glucose Diabetic patients Non-diabetic patients 2-h plasma glucose Diabetic patients Non-diabetic patients A1C% Diabetic patients Non-diabetic patients Post-transplant diabetes (n, %) Tremor (n, %) Non-adherence (n, %)
18 148 34 79
(34.62%) (102e224) (65.38%) (74e102)
23 164 40 88
(36.50%) (101e249) (63.49%) (72e108)
NS .034 NS .042
18 196 34 144
(34.62%) (146e284) (65.38%) (138e159)
23 201 40 152
(36.50%) (160e304) (63.49%) (146e161)
NS NS NS .052
18 7.6 34 5.2 1/34
(34.62%) (6.4e8.9) (65.38%) (4.6e5.9) (2.9%)
23 8.1 40 5.6 2/40
(36.50%) (6.5e9.4) (63.49%) (4.7e6.0) (5.0%)
NS .044 NS .038 .033
9/63 (14.26%) 3/63 (4.72%)
.028 .058
4/52 (7.64%) 2/52 (3.85%)
Qualitative data is presented as number, %, and quantitative data is presented as median. Abbreviations: IR, immediate release; NS, not significant; PR, prolonged release.
tacro provides efficacious immunosuppression and good graft function over 24 weeks of time [2,9,10]. We initiated PR-tacro at a dose of 0.2 mg/kg/day 2 days before transplantation - 2 pre-transplant period), with a subsequent lower tacrolimus exposure over the first month. According to our results, PR-tacro was associated with not only similar efficacy that can be demonstrated with survival rates and BPAR rates, but also associated with a significant reduction of well-known complications of IR-tacro. We have also shown that de novo use of PR-tacro has similar 24-hour creatinine clearance levels when compared to IRtacro when started e2 days pre-transplant. A similar pattern was also observed when renal function was measured by the Cockcroft-Gault formula. Kramer et al reported that both tacrolimus formulations in de novo treatment groups show equally well-maintained renal function at 1 year [6]. Recently, Lehner et al also reported that mean levels of creatinine clearance remain stable in kidney transplant recipients while using PR-tacro at the end of 18 months [11]. We have shown that incidences of DGF and graft loss and BPAR rates were comparable between study groups. Van Hooff et al reported that PR-tacro does not increase BPAR rates when compared to IR-tacro in kidney transplant recipients after 4 years of de novo usage [10]. The second main finding of this study is that tolerability profiles were comparable between the study groups. We have observed that PTDM diagnoses were significantly lower in the PR-tacro group when compared to the IR-tacro group (1 patient in PR-tacro group vs 2 patients in IR-tacro groups, P ¼ .033). We used similar induction immunosuppressive therapies in both groups that consisted of antithymocyte globuline 2 mg/kg/day for 4 days, a total 1500 mg methylprednisolone (1000 mg at day e1 and 500 mg at day 0), then a 14-day steroid tapering regimen with subsequent maintenance therapy consisting of mycophenolate mofetil (MMF) 2 g/day, prednisolone 5 mg/day and PRtacro orIR-tacro. Because the incidence of PTDM was lower in the PR-tacro group when compared to the IR-tacro group at the end of 24 weeks, these data indicate that PR-tacro represents a lower diabetogenic effect when compared to IR-tacro. The findings from this study are consistent with the ADVANCE study [12], which reported that PR-tacro, basiliximab, and MMF immunosuppressive regimen has a low incidence of PTDM [12,13]. It is interesting to speculate that lower systemic exposure of the drug, especially in the early post-transplant period leads to a lower diabetogenic effect in our study population. A limitation of our study is that it was retrospective in nature and not a prospective study. It would be interesting to assess the evolution of a donor-specific antibody in a long-term follow-up study with a de novo, PR-tacro-based, immunosuppressive regimen and analyze the possible relationship with the clinical biopsy-proven acute rejections in kidney transplant recipients over time. Furthermore, the evolution of diabetesinduced endothelial function abnormalities and the possible relationship with diabetic complications of kidney transplant recipients with de novo PR-tacro could be assessed.
ONCE- VS TWICE-DAILY TACROLIMUS
CONCLUSION
In conclusion, the present data show that de novo -PR-tacro and IR-tacro-based regimens have similar patient and graft survival in the first 6 months of transplantation. The PRtacrobased regimen seems to have better glucose metabolism control in both diabetic and non-diabetic patients and lower drug-induced tremor rates. Further prospective, randomized, controlled studies are needed to determine the possible beneficial effects of PR-tacro among kidney transplant recipients. REFERENCES [1] Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twice-daily tacrolimus: are the formulations truly equivalent? Drugs 2011;71:1561e77. [2] Silva HT, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant 2007;7:595e608. [3] Kramer BK, Albano L, Banas B, et al. Efficacy of prolonged- and immediate-release tacrolimus in kidney transplantation: a pooled analysis of two large, randomized, controlled trials. Transplant Proc 2017;49:2040e9. [4] First MR, Dhadda S, Croy R, et al. New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials. Transplantation 2013;96:58e64. [5] Ghisdal L, Van Laecke S, Abramowicz MJ, et al. New-onset diabetes after renal transplantation: risk assessment and management. Diabetes Care 2012;35:181e8.
2311 [6] Kramer BK, Charpentier B, Backman L, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant 2010;10:2632e43. [7] Albano L, Banas B, Klempnauer JL, Glyda M, Viklicky O, Kama N. OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation 2013;96:897e903. [8] Tsuchiya T, Ishida H, Tanabe T, et al. Comparison of pharmacokinetics and pathology for low-dose tacrolimus once-daily and twice-daily in living kidney transplantation: prospective trial in oncedaily versus twice-daily tacrolimus. Transplantation 2013;96:198e204. [9] McCormack PL. Extended-release tacrolimus: a review of its use in de novo kidney transplantation. Drugs 2014;74: 2053e64. [10] Van Hooff JP, Alloway RR, Trunecka P, et al. Four-year experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant 2011;25:E1e12. [11] Lehner LJ, Reinke P, Hörstrup JH, et al. Evaluation of adherence and tolerability of prolonged-release tacrolimus (Advagraf) in kidney transplant patients in Germany: a multicenter, noninterventional study. Clin Transplant 2018;32(1). [12] Mourad G, Glyda M, Albano L, et al. Advagraf-based immunosuppression regimen examining new onset diabetes mellitus in kidney transplant recipients (ADVANCE) study investigators. Transplantation 2017;10:1924e34. [13] Caillard S, Moulin B, Buron F, et al. Advagraf, a once-daily prolonged release tacrolimus formulation, in kidney transplantation: literature review and guidelines from a panel of experts. Transpl Int 2016;29:860e9.
ABSTRACT Background. This study aimed to determine whether de novo, prolonged-release tacrolimus- (PR-tacro) based immunosuppressive regimen affected graft and patient survival when compared to an immediate-release, twice-daily, tacrolimus- (IR-tacro) based regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups. Methods. A total of 115 standard risk kidney transplant recipients were enrolled in this single center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection , graft and patient survival, and creatinine clearance. Secondary outcome measures included the incidence of non-adherence, drug-induced tremor; post-transplant diabetes mellitus diagnosis rate; and control of diabetes in pre-transplant diabetic patients. Results. Baseline characteristics and mean tacrolimus trough levels were comparable between groups. Incidence of graft loss, DGF, and graft and patient survival were similar between groups (P > .05). Mean creatinine clearance level was also similar (P > .05). Mean serum levels of fasting glucose (P < .05) and A1C (P < .05) were lower in PR-tacro group when compared to IR-tacro group. Post-transplant diabetes mellitus diagnosis rate was also lower in PR-tacro group when compared to IR-tacro group (P ¼ .040). Conclusion. This study suggests that there is no statistically significant difference between PR-tacro and IR-tacro in terms of patient and graft survival, DGF, and biopsy-proven acute rejection rates in kidney transplant recipients. Post-transplant diabetes mellitus frequency is lower in non-diabetic patients, and glucose metabolism control is better in diabetic patients.
T
ACROLIMUS is accepted as the mainstay of immunosuppression in kidney transplantation. A new extended formulation of tacrolimus permits once-daily administration without changes in efficacy, safety, and monitoring [1]. Pivotal studies have demonstrated the non-inferiority of prolongedrelease tacrolimus (PR-tacro) vs immediate-release, twicedaily tacrolimus (IR-tacro) in efficacy and safety among de novo kidney transplant recipients [2,3]. The prevalence of post-transplantation diabetes (PTDM) has increased in recent years, despite therapeutic improvements in kidney transplantation [4]. Risk factors associated with 0041-1345/19 https://doi.org/10.1016/j.transproceed.2019.01.149
2308
PTDM in kidney transplantation include the type of immunosuppressive regimen used, in addition to demographical factors such as increasing age and higher body mass index [5]. This study aimed to determine whether a de novo, PRtacro-based immunosuppressive regimen affected graft and patient survival when compared to an IR-tacro-based
*Address correspondence to Elif Ari, Department of Nephrology, Bahcesehir University, 34734, Istanbul, Turkey. Tel: (þ90) 532 673 65 97. E-mail: [email protected] ª 2019 Elsevier Inc. All rights reserved. 230 Park Avenue, New York, NY 10169
Transplantation Proceedings, 51, 2308e2311 (2019)
ONCE- VS TWICE-DAILY TACROLIMUS
regimen in kidney transplant recipients. We also aimed to determine the difference between the frequency of side effects, including diabetes control, in study groups. SUBJECTS AND METHODS Subjects A total of 115, standard-risk, kidney transplant recipients were enrolled in this single-center, retrospective study. Fifty-two patients received PR-tacro and 63 patients received IR-tacro as a calcineurin inhibitor. The study was approved by the local ethics committee and all participants gave written informed consent. Eligible patients were 18 years or older and underwent living or cadaveric kidney transplantation. Patients were excluded if they had received a previous transplant or were receiving ongoing systemic corticosteroids. There were no restrictions on donor age, cold ischemia time, or renal function. Patients received PR-tacro (Advagraf; Astellas Pharma Ltd, Surrey, UK) at an initial dose of 0.2 mg/kg/day on day 2 pre-transplantation or IR-tacro (Prograf; Astellas Pharma Ltd, Surrey, UK) at an initial dose of 0.15 mg/kg/ day on day 2 pre-transplantation. Target tacrolimus trough levels were 8 to 12 ng/mL until day 30, from days 31 to 180 were 8 to 10 ng/mL. After 180 days, target tacrolimus trough levels were 6 to 8 ng/mL. All patients received mycophenolate mofetil (2 gr/day) and corticosteroid (5 mg/day after day 14) as a maintenance immunosuppressive treatment.
Primary Outcome Measures The primary outcome measures included incidence of graft loss and delayed graft function (DGF), biopsy-proven acute rejection (BPAR), graft and patient survival, and renal function estimated by 24-hour creatinine clearance at week 24.
Secondary Outcome Measures Secondary outcome measures included the incidence of nonadherence, drug-induced tremor; post-transplant diabetes mellitus (PTDM) diagnosis rate; and control of diabetes in pre-transplant diabetic patients at week 24. Adverse events and laboratory parameters were monitored throughout the study. Diabetes mellitus is defined as 1 measurement or more of fasting plasma glucose of 110 mg/dL or more, 1 measurement or more of 2 hour plasma glucose of 160 mg/dL or more, and 1 measurement of A1C 6.5% or more.
Statistical Analysis Descriptive statistics were expressed as mean standard deviation for quantitative data and percentages for qualitative data. Comparisons between groups were performed using the c2 test or Fisher’s exact test for qualitative data and Student’s t test or MannWhitney U test for quantitative data. A P value < .05 was interpreted as statistically significant. All statistical analyses were performed with statistical analysis program (IBM SPSS 13.0 for Windows, IBM, Armonk, NY, United States).
RESULTS
Clinical and demographic characteristics of the study groups are given in Table 1. There were no significant differences in age, body mass index, sex, or primary kidney disease etiology among groups. Mean tacrolimus trough levels were also similar between groups.
2309 Table 1. Clinical and Demographic Characteristics of Study Groups
Age (y) Sex (male/female) BMI (kg/m2) Primary kidney disease (n, %) Diabetes Hypertension Urologic Polycystic kidney disease Glomerulonephritis Other
Prolonged-release tacrolimus group (PR-tacro group) (n ¼ 52)
Immediate-release tacrolimus group (IR-tacro group) (n ¼ 63)
48.22 11.36 32/20 24.09 8.76
49.18 12.44 40/23 26.40 9.04
18 16 08 06 02 02
(34.6%) (30.7%) (15.3%) (11.5%) (3.8%) (3.8%)
23 19 09 08 03 01
(36.5%) (30.1%) (14.2%) (12.6%) (4.7%) (1.5%)
Data is presented as mean standard deviation. Abbreviations: BMI, body mass index; IR, immediate release; PR, prolonged release
Patient and graft survival rates, DGF, graft loss, and BPAR rates are shown in Table 2. No significant differences were observed between study groups for patient and graft survival (P > .05, respectively) at week 24. Delayed graft function (P ¼ .051) and graft loss rates (P ¼ .049) were inclined to be higher in the IR-tacro group when compared to the PR-tacro group, but statistically insignificant (Table 2). BPAR rates (P > .05) and mean levels of creatinine clearance (P > .05) at week 24 were also similar between study groups. In total, 35.52% of patients received treatment for diabetes before transplantation. By week 24, 38.66% of patients had received treatment for diabetes. Incidence of post transplantation diabetes was significantly lower in the PR-tacro group (n ¼ 1 patient, 2.9%) when compared to the IR-tacro group (n ¼ 2 patients, 5.0%) (P ¼ .033). The PRtacro group had significantly lower mean serum levels of fasting glucose in diabetic patients when compared to IRtacro group (P ¼ .034). Similarly, the PR-tacro group had significantly lower mean serum levels of fasting glucose in non-diabetic patients when compared to the IR-tacro group (P ¼ .042) (Table 3). Although mean serum levels of 2 hour glucose were similar both in the PR-tacro group and the IRtacro group of diabetic patients, we observed statistically Table 2. Survival Rates of Study Groups
Patient survival (n, %) Graft survival (n, %) DGF (n, %) Graft loss (n, %) BPAR (n, %) Creatinine clearance (mL/min)
Prolonged-release tacrolimus group (PR-tacro group) (n ¼ 52)
Immediate-release tacrolimus group (IR-tacro group) (n ¼ 63)
P value
52 (100%) 51 (98.07%) 03 (5.76%) 01 (1.96%) 04 (7.69%) 57.66 3.75
63 (100%) 61 (96.89%) 05 (7.93%) 02 (3.77%) 05 (7.93%) 56.24 3.69
NS NS .051 .049 NS NS
Creatinine clearance is presented as mean standard deviation. Abbreviations: BPAR, biopsy proven acute rejection; DGF, delayed graft function; IR, immediate release; NS, not significant; PR, prolonged release.
2310
TURUNC, ARI, GUVEN ET AL
borderline significance of mean serum levels of 2 hour glucose between the PR-tacro group and the IR-tacro group of non-diabetic patients (144 mg/dL vs 152 mg/dL, P ¼ .052) (Table 3). Furthermore, mean serum levels of A1C% were lower in the PR-tacro group when compared to the IR-tacro group in both diabetic and non-diabetic patients (P ¼ .044 and P ¼ .038, respectively) (Table 3). The incidence of tremor was lower in the PR-tacro group when compared to the IR-tacro group (7.64% vs 14.26%, P ¼ .028). There was no significant difference between groups at week 24 in non-adherence rates (3.85% vs 4.72%, P > .05) (Table 3).
DISCUSSION.
In this study, we assessed the efficacy and tolerability of de novo, PR-tacro when compared to an IR-tacro-based regimen in kidney transplant recipients. The results have demonstrated that de novo, PR-tacro is efficacious, associated with a manageable tolerability profile, and has a low incidence of post-transplant diabetes and drug-induced tremor over 24 weeks of treatment. The first main finding of this study is that the incidence of mortality was comparable between PR-tacro and IR-tacro groups at the end of 24 weeks. It is reported that excellent patient survival rates were achieved with PR-tacro [6,7]. Similarly, it is demonstrated that very good graft survival rates were achieved with PR-tacro [6e9]). Our findings are consistent with the literature [6e8]. Follow-up data from previous studies confirm our findings and indicate that PRTable 3. Side Effect Profile of the Study Groups Prolonged-release Immediate-release tacrolimus group tacrolimus group (IR-tacro group) (PR-tacro group) (n ¼ 52) (n ¼ 63) P value
Fasting plasma glucose Diabetic patients Non-diabetic patients 2-h plasma glucose Diabetic patients Non-diabetic patients A1C% Diabetic patients Non-diabetic patients Post-transplant diabetes (n, %) Tremor (n, %) Non-adherence (n, %)
18 148 34 79
(34.62%) (102e224) (65.38%) (74e102)
23 164 40 88
(36.50%) (101e249) (63.49%) (72e108)
NS .034 NS .042
18 196 34 144
(34.62%) (146e284) (65.38%) (138e159)
23 201 40 152
(36.50%) (160e304) (63.49%) (146e161)
NS NS NS .052
18 7.6 34 5.2 1/34
(34.62%) (6.4e8.9) (65.38%) (4.6e5.9) (2.9%)
23 8.1 40 5.6 2/40
(36.50%) (6.5e9.4) (63.49%) (4.7e6.0) (5.0%)
NS .044 NS .038 .033
9/63 (14.26%) 3/63 (4.72%)
.028 .058
4/52 (7.64%) 2/52 (3.85%)
Qualitative data is presented as number, %, and quantitative data is presented as median. Abbreviations: IR, immediate release; NS, not significant; PR, prolonged release.
tacro provides efficacious immunosuppression and good graft function over 24 weeks of time [2,9,10]. We initiated PR-tacro at a dose of 0.2 mg/kg/day 2 days before transplantation - 2 pre-transplant period), with a subsequent lower tacrolimus exposure over the first month. According to our results, PR-tacro was associated with not only similar efficacy that can be demonstrated with survival rates and BPAR rates, but also associated with a significant reduction of well-known complications of IR-tacro. We have also shown that de novo use of PR-tacro has similar 24-hour creatinine clearance levels when compared to IRtacro when started e2 days pre-transplant. A similar pattern was also observed when renal function was measured by the Cockcroft-Gault formula. Kramer et al reported that both tacrolimus formulations in de novo treatment groups show equally well-maintained renal function at 1 year [6]. Recently, Lehner et al also reported that mean levels of creatinine clearance remain stable in kidney transplant recipients while using PR-tacro at the end of 18 months [11]. We have shown that incidences of DGF and graft loss and BPAR rates were comparable between study groups. Van Hooff et al reported that PR-tacro does not increase BPAR rates when compared to IR-tacro in kidney transplant recipients after 4 years of de novo usage [10]. The second main finding of this study is that tolerability profiles were comparable between the study groups. We have observed that PTDM diagnoses were significantly lower in the PR-tacro group when compared to the IR-tacro group (1 patient in PR-tacro group vs 2 patients in IR-tacro groups, P ¼ .033). We used similar induction immunosuppressive therapies in both groups that consisted of antithymocyte globuline 2 mg/kg/day for 4 days, a total 1500 mg methylprednisolone (1000 mg at day e1 and 500 mg at day 0), then a 14-day steroid tapering regimen with subsequent maintenance therapy consisting of mycophenolate mofetil (MMF) 2 g/day, prednisolone 5 mg/day and PRtacro orIR-tacro. Because the incidence of PTDM was lower in the PR-tacro group when compared to the IR-tacro group at the end of 24 weeks, these data indicate that PR-tacro represents a lower diabetogenic effect when compared to IR-tacro. The findings from this study are consistent with the ADVANCE study [12], which reported that PR-tacro, basiliximab, and MMF immunosuppressive regimen has a low incidence of PTDM [12,13]. It is interesting to speculate that lower systemic exposure of the drug, especially in the early post-transplant period leads to a lower diabetogenic effect in our study population. A limitation of our study is that it was retrospective in nature and not a prospective study. It would be interesting to assess the evolution of a donor-specific antibody in a long-term follow-up study with a de novo, PR-tacro-based, immunosuppressive regimen and analyze the possible relationship with the clinical biopsy-proven acute rejections in kidney transplant recipients over time. Furthermore, the evolution of diabetesinduced endothelial function abnormalities and the possible relationship with diabetic complications of kidney transplant recipients with de novo PR-tacro could be assessed.
ONCE- VS TWICE-DAILY TACROLIMUS
CONCLUSION
In conclusion, the present data show that de novo -PR-tacro and IR-tacro-based regimens have similar patient and graft survival in the first 6 months of transplantation. The PRtacrobased regimen seems to have better glucose metabolism control in both diabetic and non-diabetic patients and lower drug-induced tremor rates. Further prospective, randomized, controlled studies are needed to determine the possible beneficial effects of PR-tacro among kidney transplant recipients. REFERENCES [1] Barraclough KA, Isbel NM, Johnson DW, et al. Once- versus twice-daily tacrolimus: are the formulations truly equivalent? Drugs 2011;71:1561e77. [2] Silva HT, Yang HC, Abouljoud M, et al. One-year results with extended-release tacrolimus/MMF, tacrolimus/MMF and cyclosporine/MMF in de novo kidney transplant recipients. Am J Transplant 2007;7:595e608. [3] Kramer BK, Albano L, Banas B, et al. Efficacy of prolonged- and immediate-release tacrolimus in kidney transplantation: a pooled analysis of two large, randomized, controlled trials. Transplant Proc 2017;49:2040e9. [4] First MR, Dhadda S, Croy R, et al. New-onset diabetes after transplantation (NODAT): an evaluation of definitions in clinical trials. Transplantation 2013;96:58e64. [5] Ghisdal L, Van Laecke S, Abramowicz MJ, et al. New-onset diabetes after renal transplantation: risk assessment and management. Diabetes Care 2012;35:181e8.
2311 [6] Kramer BK, Charpentier B, Backman L, et al. Tacrolimus once daily (ADVAGRAF) versus twice daily (PROGRAF) in de novo renal transplantation: a randomized phase III study. Am J Transplant 2010;10:2632e43. [7] Albano L, Banas B, Klempnauer JL, Glyda M, Viklicky O, Kama N. OSAKA trial: a randomized, controlled trial comparing tacrolimus QD and BD in kidney transplantation. Transplantation 2013;96:897e903. [8] Tsuchiya T, Ishida H, Tanabe T, et al. Comparison of pharmacokinetics and pathology for low-dose tacrolimus once-daily and twice-daily in living kidney transplantation: prospective trial in oncedaily versus twice-daily tacrolimus. Transplantation 2013;96:198e204. [9] McCormack PL. Extended-release tacrolimus: a review of its use in de novo kidney transplantation. Drugs 2014;74: 2053e64. [10] Van Hooff JP, Alloway RR, Trunecka P, et al. Four-year experience with tacrolimus once-daily prolonged release in patients from phase II conversion and de novo kidney, liver, and heart studies. Clin Transplant 2011;25:E1e12. [11] Lehner LJ, Reinke P, Hörstrup JH, et al. Evaluation of adherence and tolerability of prolonged-release tacrolimus (Advagraf) in kidney transplant patients in Germany: a multicenter, noninterventional study. Clin Transplant 2018;32(1). [12] Mourad G, Glyda M, Albano L, et al. Advagraf-based immunosuppression regimen examining new onset diabetes mellitus in kidney transplant recipients (ADVANCE) study investigators. Transplantation 2017;10:1924e34. [13] Caillard S, Moulin B, Buron F, et al. Advagraf, a once-daily prolonged release tacrolimus formulation, in kidney transplantation: literature review and guidelines from a panel of experts. Transpl Int 2016;29:860e9.