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Kidney transplantation without calcineurin inhibitors using sirolimus
Kidney Transplantation Without Calcineurin Inhibitors Using Sirolimus M.D. Stegall, T.S. Larson, M. Prieto, J. Gloor, S. Textor, S. Nyberg, S. Sterioff, M. Ishitani, M. Griffin, W. Kremers, W. Lund, T. Schwab, F. Cosio, and J. Velosa ABSTRACT Introduction. With the introduction of new immunosuppressive medicines, it has become possible to determine the extent to which nephrotoxic medicines contribute to CAN. The aim of this study is to compare the safety and efficacy of calcineurin inhibitor (CI) free immunosuppression in a prospective, randomized trial comparing sirolimusmycophenolate mofetil (MMF)-prednisone to tacrolimus- MMF-prednisone. Methods. Patients are randomized at the time of transplant to receive either tacrolimus (target level 12 to 15 ng/mL in the first month) or sirolimus (target level 12 to 18 ng/mL in the first month). All patients also receive MMF (750 mg bid) and prednisone tapered to 10 mg/d by 3 months and thymoglobulin induction (1.5 mg/kg/d on days 0, 1, 2, 4 and 6). Results. At this point we have 4-month follow-up in 85 patients. The acute rejection rate is 7.5% (3/40) in the tacrolimus group and 6.7% (3/45) in the sirolimus group. We have discontinued sirolimus in eight patients so far, with wound complications being the most common indication. Renal function appears to be better in the sirolimus group at 1 month after transplantation, but the difference is not statistically significant. Conclusions. While longer follow-up is needed, these results demonstrate that total avoidance of CI can be achieved with extremely low acute cellular rejection rates using sirolimus-based immunosuppression in combination with thymoglobulin, MMF, and prednisone.
D
ESPITE IMPROVEMENTS in 1-year renal allograft survival, long-term graft loss to chronic allograft nephropathy (CAN) remains a major problem in clinical kidney transplantation. While there appear to be many contributors to CAN, one is chronic nephrotoxicity from immunosuppressive medicines. With the introduction of new immunosuppressive medicines, it has become possible to determine the extent to which nephrotoxic medicines contribute to CAN. Several studies of cacineurin inhibitor (CI)-free immunosuppression have been reported. Two early protocols that did not include antibody induction led to acute cellular rejection rates of greater than 30% including a combination of sirolimus-azathioprine-prednisone1 and a sirolimus-mycophenolate mofetil-prednisone.2 A protocol involving withdrawal of the CI at 3 months in patients without acute rejection,3 leaving patients on dual therapy of sirolimus and prednisone, had a cumulative acute rejection rate of greater than 20%. In this report, we describe the initial results of a prospective randomized trial using antibody induction in which one arm involves complete avoid© 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35 (Suppl 3A), 125S–127S (2003)
ance of CI using maintenance immunosuppression of sirolimus, mycophenolate mofetil, and prednisone. PATIENTS AND METHODS This study was conducted with informed consent using a protocol approved by the Institutional Review Board of the Mayo Foundation and Clinic. The aim of the study is to compare the safety and efficacy of CI-free immunosuppression in a prospective, randomized trial comparing sirolimus-mycophenolate mofetil-prednisone to tacrolimus-mycophenolate mofetil-prednisone. We included all cadaveric and living donor kidney transplants with the exception of pediatric patients, multiorgan recipients (simultaneous pancreaskidney, liver-kidney, etc), type I diabetic patients who are scheduled to receive a pancreas after kidney, patients with severe hyperlipidemia prior to transplantation (serum cholesterol level ⬎350 mg/dL or serum triglyceride level ⬎500 mg/dL), and patients From the Departments of Surgery and Medicine, Mayo Foundation and Clinic, Rochester, Minnesota. Address reprint requests to Mark D. Stegall, MD, Mayo Foundation and Clinic, 200 First St SW, Rochester, MN 55905. E-mail: [email protected] 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00226-4 125S
126S
STEGALL, LARSON, PRIETO ET AL Table 1. Acute Rejection
Tac-MMF-prednisone (n ⫽ 40) 37 no rejection (92.5%) 2 clinical rejections humoral/cellular 9 days posttransplant in a patient with a historically positive cross-match Banff IIa at 5 weeks, Rx with OKT3 1 subclinical during 45 DGF, Banff IIa, Rx with OKT3 Sirolimus-MMF-prednisone (n ⫽ 45) 42 no rejection (93.3%) 3 subclinical—all on 4-month surveillance biopsy including: borderline, Ia, IIb MMF, mycophenolate mofetil; TAC, tacrolimus.
with profound leukopenia pretransplant (total white blood cell count ⬍3000). Immunosuppression consisted of thymoglobulin induction in all patients (1.5 mg/kg/d on days 0, 1, 2, 4, and 6 with respect to transplantation). Patients are randomized at the time of transplant to receive either tacrolimus (target level 12 to 15 ng/mL in the first month) or sirolimus (target level 12 to 18 ng/mL in the first month). All patients also received mycophenolate mofetil (750 mg BID) and prednisone tapered to 10 mg/d by 3 months. Surveillance protocol renal allograft biopsies were performed in all patients at 4 and 12 months and evidence of subclinical rejection was treated with bolus corticosteroids. All clinical rejections were biopsy-proven. Renal function was assessed using iothalamate clearance in all patients at 1 month after transplant using a previously described technique.4 Briefly, this method includes the subcutaneous injection of iothalamate in nonisotopic form followed by a timed urine collection and two plasma samples for measurement of iothalamate by capillary electrophoresis and calculation of iothalamate clearance. The individual iothalamate clearance results are adjusted for body surface area.
RESULTS
As of September 1, 2002, we have 4-month follow-up in 85 patients. Eighty-five percent of the patients received living donor transplants. Median follow-up is 10 months (4 to 16 months). The acute rejection rate is 7.5% (3/40) in the tacrolimus group and 6.7% (3/45) in the sirolimus group (Table 1). All of the rejections in the sirolimus arm have been subclinical rejections diagnosed by protocol biopsy. Importantly, there have been no late acute cellular rejection episodes in either group. Graft losses have been
Table 3. Drug Discontinuation Tac-MMF-prednisone (n ⫽ 4) 1 2 Sirolimus-MMF-prednisone (n ⫽ 8) 1 1 2 3
thrombotic microangiopathy polyoma virus infection severed hyperlipidemia polyoma virus acute rejection delayed incisional healing
primarily secondary to nonimmunologic events, with only one patient with a historically positive cross-match in the tacrolimus arm experiencing a severe, irreversible mixed humoral and cellular rejection episode early after transplantation (Table 2). We have discontinued sirolimus in eight patients so far, with wound complications being the most common indication (Table 3). Overall, renal function appears to be better in the sirolimus group at 1 month after transplantation, but the difference is not statistically significant (Fig 1). CONCLUSIONS
These results demonstrate that total avoidance of CI can be achieved with extremely low acute cellular rejection rates using a combination of thymoglobulin induction and maintenance immunosuppression with sirolimus, mycophenolate mofetil, and prednisone. All of the rejection episodes in the sirolimus group were subclinical and no late rejection episodes occurred. No immunologic graft losses have occurred in the sirolimus group. Early renal function appears to be quite good in both arms of the study. The majority of the patients in the current study are relatively low-risk living donor recipients receiving goodquality kidneys. In this group, the impact of donor disease in the development of CAN is minimal. In this absence of acute rejection and the absence of donor disease, we believe
Table 2. Graft Losses Tac-MMF-prednisone (n ⫽ 5) 2 1 1 1 Sirolimus-MMF-prednisone 1
early graft thrombosis (randomized, but did not receive tacrolimus) refractory acute cellular and humoral rejection1 death with functioning graft recurrent thrombotic microangiopathy primary nonfunction of a cadaveric graft
Fig 1. Glomerular infiltration rate by iothalamate clearance at 1 month posttransplantation.
TRANSPLANTATION WITHOUT CALCINEURIN INHIBITORS
that this population of patients allows for the formal study of CI in the development of CAN. The use of protocol biopsies allows for both the diagnosis of subclinical rejection and for the morphometric analysis of the progression of fibrosis over time. While the low rate of acute rejection is encouraging, longer follow-up will be needed to determine if the total avoidance of CI will help to prevent the development of CAN in these patients.
127S
REFERENCES 1. Groth CG, Backman L, Morales J-M, et al: Transplantation 67:1036, 1999 2. Kreis H, Cisterne J-M, Land W, et al: Transplantation 69:1252, 2000 3. Johnson RWG, Kreis H, Oberbauer R, et al: Transplantation 72:777, 2001 4. Wilson DM, Bergert JH, Larson TS, et al: Am J Kid Dis 30:646, 1997
D
ESPITE IMPROVEMENTS in 1-year renal allograft survival, long-term graft loss to chronic allograft nephropathy (CAN) remains a major problem in clinical kidney transplantation. While there appear to be many contributors to CAN, one is chronic nephrotoxicity from immunosuppressive medicines. With the introduction of new immunosuppressive medicines, it has become possible to determine the extent to which nephrotoxic medicines contribute to CAN. Several studies of cacineurin inhibitor (CI)-free immunosuppression have been reported. Two early protocols that did not include antibody induction led to acute cellular rejection rates of greater than 30% including a combination of sirolimus-azathioprine-prednisone1 and a sirolimus-mycophenolate mofetil-prednisone.2 A protocol involving withdrawal of the CI at 3 months in patients without acute rejection,3 leaving patients on dual therapy of sirolimus and prednisone, had a cumulative acute rejection rate of greater than 20%. In this report, we describe the initial results of a prospective randomized trial using antibody induction in which one arm involves complete avoid© 2003 by Elsevier Science Inc. 360 Park Avenue South, New York, NY 10010-1710 Transplantation Proceedings, 35 (Suppl 3A), 125S–127S (2003)
ance of CI using maintenance immunosuppression of sirolimus, mycophenolate mofetil, and prednisone. PATIENTS AND METHODS This study was conducted with informed consent using a protocol approved by the Institutional Review Board of the Mayo Foundation and Clinic. The aim of the study is to compare the safety and efficacy of CI-free immunosuppression in a prospective, randomized trial comparing sirolimus-mycophenolate mofetil-prednisone to tacrolimus-mycophenolate mofetil-prednisone. We included all cadaveric and living donor kidney transplants with the exception of pediatric patients, multiorgan recipients (simultaneous pancreaskidney, liver-kidney, etc), type I diabetic patients who are scheduled to receive a pancreas after kidney, patients with severe hyperlipidemia prior to transplantation (serum cholesterol level ⬎350 mg/dL or serum triglyceride level ⬎500 mg/dL), and patients From the Departments of Surgery and Medicine, Mayo Foundation and Clinic, Rochester, Minnesota. Address reprint requests to Mark D. Stegall, MD, Mayo Foundation and Clinic, 200 First St SW, Rochester, MN 55905. E-mail: [email protected] 0041-1345/03/$–see front matter doi:10.1016/S0041-1345(03)00226-4 125S
126S
STEGALL, LARSON, PRIETO ET AL Table 1. Acute Rejection
Tac-MMF-prednisone (n ⫽ 40) 37 no rejection (92.5%) 2 clinical rejections humoral/cellular 9 days posttransplant in a patient with a historically positive cross-match Banff IIa at 5 weeks, Rx with OKT3 1 subclinical during 45 DGF, Banff IIa, Rx with OKT3 Sirolimus-MMF-prednisone (n ⫽ 45) 42 no rejection (93.3%) 3 subclinical—all on 4-month surveillance biopsy including: borderline, Ia, IIb MMF, mycophenolate mofetil; TAC, tacrolimus.
with profound leukopenia pretransplant (total white blood cell count ⬍3000). Immunosuppression consisted of thymoglobulin induction in all patients (1.5 mg/kg/d on days 0, 1, 2, 4, and 6 with respect to transplantation). Patients are randomized at the time of transplant to receive either tacrolimus (target level 12 to 15 ng/mL in the first month) or sirolimus (target level 12 to 18 ng/mL in the first month). All patients also received mycophenolate mofetil (750 mg BID) and prednisone tapered to 10 mg/d by 3 months. Surveillance protocol renal allograft biopsies were performed in all patients at 4 and 12 months and evidence of subclinical rejection was treated with bolus corticosteroids. All clinical rejections were biopsy-proven. Renal function was assessed using iothalamate clearance in all patients at 1 month after transplant using a previously described technique.4 Briefly, this method includes the subcutaneous injection of iothalamate in nonisotopic form followed by a timed urine collection and two plasma samples for measurement of iothalamate by capillary electrophoresis and calculation of iothalamate clearance. The individual iothalamate clearance results are adjusted for body surface area.
RESULTS
As of September 1, 2002, we have 4-month follow-up in 85 patients. Eighty-five percent of the patients received living donor transplants. Median follow-up is 10 months (4 to 16 months). The acute rejection rate is 7.5% (3/40) in the tacrolimus group and 6.7% (3/45) in the sirolimus group (Table 1). All of the rejections in the sirolimus arm have been subclinical rejections diagnosed by protocol biopsy. Importantly, there have been no late acute cellular rejection episodes in either group. Graft losses have been
Table 3. Drug Discontinuation Tac-MMF-prednisone (n ⫽ 4) 1 2 Sirolimus-MMF-prednisone (n ⫽ 8) 1 1 2 3
thrombotic microangiopathy polyoma virus infection severed hyperlipidemia polyoma virus acute rejection delayed incisional healing
primarily secondary to nonimmunologic events, with only one patient with a historically positive cross-match in the tacrolimus arm experiencing a severe, irreversible mixed humoral and cellular rejection episode early after transplantation (Table 2). We have discontinued sirolimus in eight patients so far, with wound complications being the most common indication (Table 3). Overall, renal function appears to be better in the sirolimus group at 1 month after transplantation, but the difference is not statistically significant (Fig 1). CONCLUSIONS
These results demonstrate that total avoidance of CI can be achieved with extremely low acute cellular rejection rates using a combination of thymoglobulin induction and maintenance immunosuppression with sirolimus, mycophenolate mofetil, and prednisone. All of the rejection episodes in the sirolimus group were subclinical and no late rejection episodes occurred. No immunologic graft losses have occurred in the sirolimus group. Early renal function appears to be quite good in both arms of the study. The majority of the patients in the current study are relatively low-risk living donor recipients receiving goodquality kidneys. In this group, the impact of donor disease in the development of CAN is minimal. In this absence of acute rejection and the absence of donor disease, we believe
Table 2. Graft Losses Tac-MMF-prednisone (n ⫽ 5) 2 1 1 1 Sirolimus-MMF-prednisone 1
early graft thrombosis (randomized, but did not receive tacrolimus) refractory acute cellular and humoral rejection1 death with functioning graft recurrent thrombotic microangiopathy primary nonfunction of a cadaveric graft
Fig 1. Glomerular infiltration rate by iothalamate clearance at 1 month posttransplantation.
TRANSPLANTATION WITHOUT CALCINEURIN INHIBITORS
that this population of patients allows for the formal study of CI in the development of CAN. The use of protocol biopsies allows for both the diagnosis of subclinical rejection and for the morphometric analysis of the progression of fibrosis over time. While the low rate of acute rejection is encouraging, longer follow-up will be needed to determine if the total avoidance of CI will help to prevent the development of CAN in these patients.
127S
REFERENCES 1. Groth CG, Backman L, Morales J-M, et al: Transplantation 67:1036, 1999 2. Kreis H, Cisterne J-M, Land W, et al: Transplantation 69:1252, 2000 3. Johnson RWG, Kreis H, Oberbauer R, et al: Transplantation 72:777, 2001 4. Wilson DM, Bergert JH, Larson TS, et al: Am J Kid Dis 30:646, 1997