- Email: [email protected]
Experiences on Conversion to Once-Daily Advagraf and Sirolimus Combination in Stable Kidney Recipients
Experiences on Conversion to Once-Daily Advagraf and Sirolimus Combination in Stable Kidney Recipients H. Jun, C.-W. Jung, M.-G. Kim, and K.-T. Park ABSTRACT In transplant recipients, nephrotoxicity due to long-term use of calcineurin inhibitor (CNI) is a serious problem that cannot be overlooked. Medication compliance can cause graft failure in transplant recipients who are bound to long-term medication. In this study, 36 patients who underwent conversion to once-daily Advagraft and sirolimus combination at Korea University Anam Hospital from September 2011 to March 2013 were retrospectively reviewed at 3 and 6 months for laboratory findings, mean arterial pressure (MAP), and so on. After conversion, serum creatinine level and glomerular filtration rate (GFR) decreased significantly at 3 months (P ¼ .024 and P < .001, respectively). Fasting serum glucose level and proteinuria increased significantly at 6 months (P ¼ .016 and P ¼ .030, respectively). The impact of time after conversion at 3 months was significantly related to the increase in postoperative estimated glomerular filtration rate (eGFR). Graft rejection, morbidity, and mortality did not occur within the study period. A once-daily Advagraf and sirolimus regimen can be a novel standard regimen in stable kidney recipients due to its effects in improving renal function and convenience for patients.
T
HE MAIN concerns of stable kidney recipients are the function of the transplanted kidney and the adherence to immunosuppressants. Medications for kidney transplant recipients are often somewhat complex and a high incidence of medication nonadherence results in late rejection and graft loss [1]. Following tacrolimus, Advagraf (Astellas Pharma Inc., Tokyo, Japan) was recently developed to promote once-daily prescription. Unlike the traditional twice-daily formulation, Advagraf is expected to improve medical adherence [2]. Henrik et al reported that reduction in calcineurin inhibitor (CNI) dose decreases CNI toxicity, bringing improved renal function, improved allograft survival, and decreased allograft rejection [3]. The purpose of this study was to report the efficacy and safety of conversion from tacrolimus to a once-daily Advagraf and sirolimus regimen in stable kidney recipients. METHODS Out of stable kidney recipients, a few were selected according to the inclusion and exclusion criteria based on a few studies [4] (Table 1). The patients were evaluated prior to conversion to Advagraf and sirolimus with physical examination, chest X-ray, and laboratory tests to exclude wound, infection, pneumonia, and so on. The conversion to Advagraf followed the same procedure as the previous daily tacrolimus dosage. The patients were followed up on 1, 3, 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2014.01.004 400
and 6 months after conversion. The target trough level (C0) of Advagraf was 2e4 ng/mL and the target of sirolimus was 6e10 ng/mL. Within the study period, 4 of 40 patients (10.0%) were excluded. Two (5.0%) were excluded due to worsened diabetes mellitus (DM), 1 (2.5%) due to recurrent urinary tract infection, and 1 (2.5%) due to aggravated proteinuria. Thirty-six patients of mean age 41.7 10.3 years who underwent conversion to the once-daily Advagraft and sirolimus combination at Korea University Anam Hospital from September 2011 to March 2013 were retrospectively reviewed at 3 and 6 months for renal function, lipid profile, proteinuria, mean arterial pressure (MAP), and so on (Table 2). With the statistical software (SPSS for Windows version 17.0; SPSS Inc., Chicago, Ill, United States), statistical analysis was performed by using c2 testing for categorical variables and t test for continuous variables. Results were reported as mean standard deviation (SD). The independent prognostic value of significant
From the Department of Transplantation and Vascular Surgery (H.J., C.-W.J., K.-T.P.), Nephrology (M.-G.K.), Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea. Address reprint request to Kwan-Tae Park, MD, PhD, Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Inchon-ro 73, Seoungbuk-gu, Seoul 136705, Korea. E-mail: [email protected] ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 400e402 (2014)
CONVERSION TO ONCE-DAILY ADVAGRAF AND SIROLIMUS
401
Table 1. The Inclusion and Exclusion Criteria of Conversion to Once-Daily Advagraf and Sirolimus Combination in Korea University Anam Hospital Inclusion Criteria
Exclusion Criteria
More than 6 mo after KT Serum creatinine <1.5 mg/dL Glomerular filtration rate <60 mL/min Creatinine variance <30% within 3 mo 24-h urine protein <400 mg
Any types of infection, including recurrent lymphadenitis and urinary tract infection Uncontrollable hyperlipidemia Uncontrollable hypertension History of diabetes mellitus Any types of malignancies, including lymphoma Chronic wound with impaired healing History of recurrent BK or cytomegalovirus infection Chronic gastrointestinal trouble, including diarrhea and abdominal pain
Abbreviation: KT, kidney transplantation.
clinical factors on the increase in estimated glomerular filtration rate (eGFR) was ascertained by multivariate mixed regression model. All P values were 2-sided, and P < .05 was considered statistically significant.
Adverse effects after conversion included gastrointestinal trouble (8 patients; 22.2%), oral ulcer (3 patients; 8.3%), and peripheral edema (4 patients; 11.1%). Graft rejection, morbidity, and mortality did not occur within the study period.
RESULTS
The mean age of the 36 patients was 41.7 10.3 years (50.0% were male). The mean time from transplantation to the conversion to Advagraf and sirolimus was 25.8 15.0 months and the mean Advagraf level after conversion was 3.00 0.51 ng/mL. The mean sirolimus level was 6.64 2.01 ng/mL. Serum creatinine and GFR showed a tendency to decrease after the conversion, however, the change was statistically significant at 3 months (P ¼ .024 and P < .001, respectively) and insignificant after 6 months (P ¼ .296 and P ¼ .119, respectively). Lipid profiles, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride, increased significantly at 3 and 6 months. Fasting serum glucose level and proteinuria increased significantly at 6 months (P ¼ .016 and P ¼ .030, respectively). MAP decreased significantly at 6 months (P < .001; Table 2). The impact of time after conversion at 3 months was significantly related to the increase in postoperative eGFR (Table3).
DISCUSSION
CNI minimization was very important and necessary. Nephrotoxicity is the most significant side effect associated with tacrolimus, occurring primarily as a result of intrarenal vasoconstriction [5]. This causes progressive fibrosis and renal insufficiency in the long run [6]. CNI treatment for 10 years will cause nephrotoxicity in the majority of the patients [7]. There are other side effects of CNI, such as neurotoxicity, impaired glucose metabolism with DM, arterial hypertension, and gastrointestinal dysfunction. CNI twice-daily administration places a burden on patients whose general health status has been weakened [8,9]. In a renal disease, specific inhibitors of the mammalian target of rapamycin (mTOR) play an important role in preventing renal graft dysfunction by reducing glomerular hypertrophy, proinflammatory and profibrotic cytokine production, interstitial inflammation, and fibroblast production [10]. In addition, recently there have been many reports on the benefits of sirolimus, such as decreasing the
Table 2. Laboratory and Clinical Outcomes on the Conversion From Tacrolimus-Based Regimen to Once-Daily Advagraf-Sirolimus Regimen After 3 and 6 Months Preconversion Mean SD
Serum creatinine (mg/dL) eGFR (mL/min/1.73 m2) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglyceride (mg/dL) Hemoglobin (g/dL) WBC (x103/mL) Platelet count (x103/mL) Potassium (mmol/L) Phosphate (mg/dL) Fasting glucose (mg/dL) Proteinuria Pyuria MAP (mm Hg)
1.14 67.59 152.31 70.83 107.50 13.46 7.94 214.92K 4.24 3.08 91.89 þ 0.14 þ 0.61 97.74
0.33 14.87 27.58 19.55 40.22 1.61 2.08 54.77 0.47 0.57 10.75 0.35 1.18 7.76
3 mo Mean SD
1.09 72.33 184.19 91.14 147.86 13.21 7.20 212.56K 4.14 2.99 93.89 þ 0.36 þ 0.56 96.65
0.30 15.16 28.86 22.52 69.43 1.70 1.80 56.13 0.46 0.59 9.83 0.54 1.03 11.93
P
.024 <.001 <.001 <.001 <.001 .073 .001 .712 .172 .308 .060 .058 .782 .572
Abbreviations: eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; WBC, white blood cell.
6 mo Mean SD
1.11 70.59 178.11 101.08 151.33 13.42 7.49 205.06K 4.13 2.96 97.67 þ 0.36 þ 0.50 90.35
0.37 15.36 19.18 21.41 67.22 1.45 1.96 55.28 0.44 0.50 15.46 0.49 1.19 10.41
P
.296 .119 <.001 <.001 <.001 .860 .123 .194 .210 .300 .016 .030 .513 <.001
402
JUN, JUNG, KIM ET AL Table 3. Multivariate Mixed Regression Analysis for Postconversion Increase in eGFR
Intercept Time after conversion, mo 0 (referent) 3 6 Female gender Age Total cholesterol Fasting glucose
b
Standard Error
65.481
14.692
0 4.227 2.899 2.550 0.114 0.021 0.077
2.054 1.984 4.873 0.241 0.039 0.089
95% CI
P
36.240e94.722 .000
0.133e8.320 1.055e6.854 7.366e12.466 0.375e0.604 0.058e0.100 0.255e0.099
.043 .148 .604 .638 .597 .384
Abbreviation: CI, confidence interval.
rate of malignancy in a transplant recipient [11] and having potential antiviral effect on cytomegalovirus [12]. Tacrolimus and mTOR inhibitors are structurally similar and bind to FK506 binding proteins to form immunosuppressive complexes [5]. Based on the similar structure of tacrolimus and sirolimus, synergic effect can be expected, which is an important basis of combination therapy [13]. The use of sirolimus can decrease CNI administration, which in turn decreases chronic CNI toxicity and improves graft survival [14]. In a recent study, Gralla et al reported, that although combination with reducing tacrolimus and sirolimus brings an increase in hyperlipidemia and newonset diabetes, 3-year patient and graft survival rates were significantly higher [15]. In this study as well, there was a statistically significant increase in lipid profiles and fasting serum glucose level after the conversion. In studies on medical adherence, nonadherence to prescribed medical regimens has been proven to be associated with the risk of acute rejection and allograft failure in renal transplant recipients [16] and it is clear that a lower dose frequency will play an important role in improving medical adherence and long-term graft outcome [17]. More studies on the potential benefit and risk of converting to Advagraf and sirolimus are necessary for stable kidney recipients. In conclusion, a once-daily Advagraf and sirolimus regimen can be a novel standard regimen in stable kidney recipients due to its effects in improving renal function and convenience for patients. A further randomized, controlled study and long-term follow-up data are the requisites for safety and efficacy of this conversion. REFERENCES [1] Kahan BD, Welsh M, Urbauer DL, Mosheim MB, Beusterien KM, Wood MR, et al. Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care costs. J Am Soc Nephrol 2000;11:1122e31.
[2] Wu SW, Tsai HC, Tsai PY, Hung TW, Chang HR, Lian JD. Conversion to prolonged release tacrolimus formulation in stable kidney transplant recipients. Swiss Med Wkly 2013;143:w13850. [3] Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562e75. [4] Perrakis A, Schwarz K, Yedibela S, Croner RS, Hohenberger W, Muller V. Impact of the conversion of the immunosuppressive regimen from prograf to advagraf or to sirolimus in long-term stable liver transplant recipients: indications, safety, and outcome. Transplant Proc 2011;43:3702e7. [5] Perry I, Neuberger J. Immunosuppression: towards a logical approach in liver transplantation. Clin Exp Immunol 2005;139: 2e10. [6] Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol 2003;23:465e76. [7] 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;349:2326e33. [8] van Hooff JP, Alloway RR, Trunecka P, Mourad M. Fouryear 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. [9] Marin-Gomez LM, Gomez-Bravo MA, Alamo-Martinez JA, Barrera-Pulido L, Bernal Bellido C, Suarez Artacho G, et al. Evaluation of clinical safety of conversion to Advagraf therapy in liver transplant recipients: observational study. Transplant Proc 2009;41:2184e6. [10] Lieberthal W, Levine JS. The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol 2009;20: 2493e502. [11] Alberu J, Pascoe MD, Campistol JM, Schena FP, Rial Mdel C, Polinsky M, et al. Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation 2011;92:303e10. [12] Nashan B, Gaston R, Emery V, Saemann MD, Mueller NJ, Couzi L, et al. Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation 2012;93:1075e85. [13] De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, Saliba F, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 2012;12: 3008e20. [14] Vu MD, Qi S, Xu D, Wu J, Fitzsimmons WE, Sehgal SN, et al. Tacrolimus (FK506) and sirolimus (rapamycin) in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the rat. Transplantation 1997;64: 1853e6. [15] Gralla J, Wiseman AC. Tacrolimus/sirolimus versus tacrolimus/mycophenolate in kidney transplantation: improved 3-year graft and patient survival in recent era. Transplantation 2009;87: 1712e9. [16] Prendergast MB, Gaston RS. Optimizing medication adherence: an ongoing opportunity to improve outcomes after kidney transplantation. Clin J Am Soc Nephrol 2010;5:1305e11. [17] Weng FL, Israni AK, Joffe MM, Hoy T, Gaughan CA, Newman M, et al. Race and electronically measured adherence to immunosuppressive medications after deceased donor renal transplantation. J Am Soc Nephrol 2005;16:1839e48.
T
HE MAIN concerns of stable kidney recipients are the function of the transplanted kidney and the adherence to immunosuppressants. Medications for kidney transplant recipients are often somewhat complex and a high incidence of medication nonadherence results in late rejection and graft loss [1]. Following tacrolimus, Advagraf (Astellas Pharma Inc., Tokyo, Japan) was recently developed to promote once-daily prescription. Unlike the traditional twice-daily formulation, Advagraf is expected to improve medical adherence [2]. Henrik et al reported that reduction in calcineurin inhibitor (CNI) dose decreases CNI toxicity, bringing improved renal function, improved allograft survival, and decreased allograft rejection [3]. The purpose of this study was to report the efficacy and safety of conversion from tacrolimus to a once-daily Advagraf and sirolimus regimen in stable kidney recipients. METHODS Out of stable kidney recipients, a few were selected according to the inclusion and exclusion criteria based on a few studies [4] (Table 1). The patients were evaluated prior to conversion to Advagraf and sirolimus with physical examination, chest X-ray, and laboratory tests to exclude wound, infection, pneumonia, and so on. The conversion to Advagraf followed the same procedure as the previous daily tacrolimus dosage. The patients were followed up on 1, 3, 0041-1345/14/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2014.01.004 400
and 6 months after conversion. The target trough level (C0) of Advagraf was 2e4 ng/mL and the target of sirolimus was 6e10 ng/mL. Within the study period, 4 of 40 patients (10.0%) were excluded. Two (5.0%) were excluded due to worsened diabetes mellitus (DM), 1 (2.5%) due to recurrent urinary tract infection, and 1 (2.5%) due to aggravated proteinuria. Thirty-six patients of mean age 41.7 10.3 years who underwent conversion to the once-daily Advagraft and sirolimus combination at Korea University Anam Hospital from September 2011 to March 2013 were retrospectively reviewed at 3 and 6 months for renal function, lipid profile, proteinuria, mean arterial pressure (MAP), and so on (Table 2). With the statistical software (SPSS for Windows version 17.0; SPSS Inc., Chicago, Ill, United States), statistical analysis was performed by using c2 testing for categorical variables and t test for continuous variables. Results were reported as mean standard deviation (SD). The independent prognostic value of significant
From the Department of Transplantation and Vascular Surgery (H.J., C.-W.J., K.-T.P.), Nephrology (M.-G.K.), Korea University Anam Hospital, Korea University College of Medicine, Seoul, Korea. Address reprint request to Kwan-Tae Park, MD, PhD, Department of Transplantation and Vascular Surgery, Korea University College of Medicine, Inchon-ro 73, Seoungbuk-gu, Seoul 136705, Korea. E-mail: [email protected] ª 2014 by Elsevier Inc. All rights reserved. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 46, 400e402 (2014)
CONVERSION TO ONCE-DAILY ADVAGRAF AND SIROLIMUS
401
Table 1. The Inclusion and Exclusion Criteria of Conversion to Once-Daily Advagraf and Sirolimus Combination in Korea University Anam Hospital Inclusion Criteria
Exclusion Criteria
More than 6 mo after KT Serum creatinine <1.5 mg/dL Glomerular filtration rate <60 mL/min Creatinine variance <30% within 3 mo 24-h urine protein <400 mg
Any types of infection, including recurrent lymphadenitis and urinary tract infection Uncontrollable hyperlipidemia Uncontrollable hypertension History of diabetes mellitus Any types of malignancies, including lymphoma Chronic wound with impaired healing History of recurrent BK or cytomegalovirus infection Chronic gastrointestinal trouble, including diarrhea and abdominal pain
Abbreviation: KT, kidney transplantation.
clinical factors on the increase in estimated glomerular filtration rate (eGFR) was ascertained by multivariate mixed regression model. All P values were 2-sided, and P < .05 was considered statistically significant.
Adverse effects after conversion included gastrointestinal trouble (8 patients; 22.2%), oral ulcer (3 patients; 8.3%), and peripheral edema (4 patients; 11.1%). Graft rejection, morbidity, and mortality did not occur within the study period.
RESULTS
The mean age of the 36 patients was 41.7 10.3 years (50.0% were male). The mean time from transplantation to the conversion to Advagraf and sirolimus was 25.8 15.0 months and the mean Advagraf level after conversion was 3.00 0.51 ng/mL. The mean sirolimus level was 6.64 2.01 ng/mL. Serum creatinine and GFR showed a tendency to decrease after the conversion, however, the change was statistically significant at 3 months (P ¼ .024 and P < .001, respectively) and insignificant after 6 months (P ¼ .296 and P ¼ .119, respectively). Lipid profiles, including total cholesterol, low-density lipoprotein (LDL) cholesterol, and triglyceride, increased significantly at 3 and 6 months. Fasting serum glucose level and proteinuria increased significantly at 6 months (P ¼ .016 and P ¼ .030, respectively). MAP decreased significantly at 6 months (P < .001; Table 2). The impact of time after conversion at 3 months was significantly related to the increase in postoperative eGFR (Table3).
DISCUSSION
CNI minimization was very important and necessary. Nephrotoxicity is the most significant side effect associated with tacrolimus, occurring primarily as a result of intrarenal vasoconstriction [5]. This causes progressive fibrosis and renal insufficiency in the long run [6]. CNI treatment for 10 years will cause nephrotoxicity in the majority of the patients [7]. There are other side effects of CNI, such as neurotoxicity, impaired glucose metabolism with DM, arterial hypertension, and gastrointestinal dysfunction. CNI twice-daily administration places a burden on patients whose general health status has been weakened [8,9]. In a renal disease, specific inhibitors of the mammalian target of rapamycin (mTOR) play an important role in preventing renal graft dysfunction by reducing glomerular hypertrophy, proinflammatory and profibrotic cytokine production, interstitial inflammation, and fibroblast production [10]. In addition, recently there have been many reports on the benefits of sirolimus, such as decreasing the
Table 2. Laboratory and Clinical Outcomes on the Conversion From Tacrolimus-Based Regimen to Once-Daily Advagraf-Sirolimus Regimen After 3 and 6 Months Preconversion Mean SD
Serum creatinine (mg/dL) eGFR (mL/min/1.73 m2) Total cholesterol (mg/dL) LDL cholesterol (mg/dL) Triglyceride (mg/dL) Hemoglobin (g/dL) WBC (x103/mL) Platelet count (x103/mL) Potassium (mmol/L) Phosphate (mg/dL) Fasting glucose (mg/dL) Proteinuria Pyuria MAP (mm Hg)
1.14 67.59 152.31 70.83 107.50 13.46 7.94 214.92K 4.24 3.08 91.89 þ 0.14 þ 0.61 97.74
0.33 14.87 27.58 19.55 40.22 1.61 2.08 54.77 0.47 0.57 10.75 0.35 1.18 7.76
3 mo Mean SD
1.09 72.33 184.19 91.14 147.86 13.21 7.20 212.56K 4.14 2.99 93.89 þ 0.36 þ 0.56 96.65
0.30 15.16 28.86 22.52 69.43 1.70 1.80 56.13 0.46 0.59 9.83 0.54 1.03 11.93
P
.024 <.001 <.001 <.001 <.001 .073 .001 .712 .172 .308 .060 .058 .782 .572
Abbreviations: eGFR, estimated glomerular filtration rate; LDL, low-density lipoprotein; WBC, white blood cell.
6 mo Mean SD
1.11 70.59 178.11 101.08 151.33 13.42 7.49 205.06K 4.13 2.96 97.67 þ 0.36 þ 0.50 90.35
0.37 15.36 19.18 21.41 67.22 1.45 1.96 55.28 0.44 0.50 15.46 0.49 1.19 10.41
P
.296 .119 <.001 <.001 <.001 .860 .123 .194 .210 .300 .016 .030 .513 <.001
402
JUN, JUNG, KIM ET AL Table 3. Multivariate Mixed Regression Analysis for Postconversion Increase in eGFR
Intercept Time after conversion, mo 0 (referent) 3 6 Female gender Age Total cholesterol Fasting glucose
b
Standard Error
65.481
14.692
0 4.227 2.899 2.550 0.114 0.021 0.077
2.054 1.984 4.873 0.241 0.039 0.089
95% CI
P
36.240e94.722 .000
0.133e8.320 1.055e6.854 7.366e12.466 0.375e0.604 0.058e0.100 0.255e0.099
.043 .148 .604 .638 .597 .384
Abbreviation: CI, confidence interval.
rate of malignancy in a transplant recipient [11] and having potential antiviral effect on cytomegalovirus [12]. Tacrolimus and mTOR inhibitors are structurally similar and bind to FK506 binding proteins to form immunosuppressive complexes [5]. Based on the similar structure of tacrolimus and sirolimus, synergic effect can be expected, which is an important basis of combination therapy [13]. The use of sirolimus can decrease CNI administration, which in turn decreases chronic CNI toxicity and improves graft survival [14]. In a recent study, Gralla et al reported, that although combination with reducing tacrolimus and sirolimus brings an increase in hyperlipidemia and newonset diabetes, 3-year patient and graft survival rates were significantly higher [15]. In this study as well, there was a statistically significant increase in lipid profiles and fasting serum glucose level after the conversion. In studies on medical adherence, nonadherence to prescribed medical regimens has been proven to be associated with the risk of acute rejection and allograft failure in renal transplant recipients [16] and it is clear that a lower dose frequency will play an important role in improving medical adherence and long-term graft outcome [17]. More studies on the potential benefit and risk of converting to Advagraf and sirolimus are necessary for stable kidney recipients. In conclusion, a once-daily Advagraf and sirolimus regimen can be a novel standard regimen in stable kidney recipients due to its effects in improving renal function and convenience for patients. A further randomized, controlled study and long-term follow-up data are the requisites for safety and efficacy of this conversion. REFERENCES [1] Kahan BD, Welsh M, Urbauer DL, Mosheim MB, Beusterien KM, Wood MR, et al. Low intraindividual variability of cyclosporin A exposure reduces chronic rejection incidence and health care costs. J Am Soc Nephrol 2000;11:1122e31.
[2] Wu SW, Tsai HC, Tsai PY, Hung TW, Chang HR, Lian JD. Conversion to prolonged release tacrolimus formulation in stable kidney transplant recipients. Swiss Med Wkly 2013;143:w13850. [3] Ekberg H, Tedesco-Silva H, Demirbas A, Vitko S, Nashan B, Gurkan A, et al. Reduced exposure to calcineurin inhibitors in renal transplantation. N Engl J Med 2007;357:2562e75. [4] Perrakis A, Schwarz K, Yedibela S, Croner RS, Hohenberger W, Muller V. Impact of the conversion of the immunosuppressive regimen from prograf to advagraf or to sirolimus in long-term stable liver transplant recipients: indications, safety, and outcome. Transplant Proc 2011;43:3702e7. [5] Perry I, Neuberger J. Immunosuppression: towards a logical approach in liver transplantation. Clin Exp Immunol 2005;139: 2e10. [6] Burdmann EA, Andoh TF, Yu L, Bennett WM. Cyclosporine nephrotoxicity. Semin Nephrol 2003;23:465e76. [7] 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;349:2326e33. [8] van Hooff JP, Alloway RR, Trunecka P, Mourad M. Fouryear 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. [9] Marin-Gomez LM, Gomez-Bravo MA, Alamo-Martinez JA, Barrera-Pulido L, Bernal Bellido C, Suarez Artacho G, et al. Evaluation of clinical safety of conversion to Advagraf therapy in liver transplant recipients: observational study. Transplant Proc 2009;41:2184e6. [10] Lieberthal W, Levine JS. The role of the mammalian target of rapamycin (mTOR) in renal disease. J Am Soc Nephrol 2009;20: 2493e502. [11] Alberu J, Pascoe MD, Campistol JM, Schena FP, Rial Mdel C, Polinsky M, et al. Lower malignancy rates in renal allograft recipients converted to sirolimus-based, calcineurin inhibitor-free immunotherapy: 24-month results from the CONVERT trial. Transplantation 2011;92:303e10. [12] Nashan B, Gaston R, Emery V, Saemann MD, Mueller NJ, Couzi L, et al. Review of cytomegalovirus infection findings with mammalian target of rapamycin inhibitor-based immunosuppressive therapy in de novo renal transplant recipients. Transplantation 2012;93:1075e85. [13] De Simone P, Nevens F, De Carlis L, Metselaar HJ, Beckebaum S, Saliba F, et al. Everolimus with reduced tacrolimus improves renal function in de novo liver transplant recipients: a randomized controlled trial. Am J Transplant 2012;12: 3008e20. [14] Vu MD, Qi S, Xu D, Wu J, Fitzsimmons WE, Sehgal SN, et al. Tacrolimus (FK506) and sirolimus (rapamycin) in combination are not antagonistic but produce extended graft survival in cardiac transplantation in the rat. Transplantation 1997;64: 1853e6. [15] Gralla J, Wiseman AC. Tacrolimus/sirolimus versus tacrolimus/mycophenolate in kidney transplantation: improved 3-year graft and patient survival in recent era. Transplantation 2009;87: 1712e9. [16] Prendergast MB, Gaston RS. Optimizing medication adherence: an ongoing opportunity to improve outcomes after kidney transplantation. Clin J Am Soc Nephrol 2010;5:1305e11. [17] Weng FL, Israni AK, Joffe MM, Hoy T, Gaughan CA, Newman M, et al. Race and electronically measured adherence to immunosuppressive medications after deceased donor renal transplantation. J Am Soc Nephrol 2005;16:1839e48.