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Mycophenolate mofetil with lower cyclosporine dose in high-risk renal transplant recipients
Mycophenolate Mofetil With Lower Cyclosporine Dose in High-Risk Renal Transplant Recipients R.M. Esmeraldo, M.O.R.C. Donadi, M.L. Oliveira, C.N. Ponte, and P.M.A. Pinheiro
R
ESULTS in kidney transplantation have improved over the last two decades due to better surgical care and improvements in immunosuppression. However, new strategies for dealing with high-risk recipients are required. In this category are paediatric patients, Black patients, sensitised patients, and recipients with delayed graft function (DGF).1 The use of biologic agents such as ATG or OKT3 as induction therapy is usually indicated because of the need for more potent and less nephrotoxic immunosuppression in this group of patients.2 Mycophenolate mofetil (MMF) is a new potent immunosuppressive agent that reduces the incidence of acute rejection episodes significantly when given in association with cyclosporine A (CsA) and steroids in renal transplantation.3,4 In this way, it may allow discontinuation or lowering the dosage of other immunosuppressants without increasing the risk of rejection.5 This open pilot clinical study was conducted to determine whether the use of MMF in higher doses could replace the need for ATG or OKT3 in high-risk renal transplant recipients. METHODS Our initial immunosuppression protocol is based on Neoral initiated at 10 mg/kg per day in addition to steroids and azathioprine with CsA dosage adjusted to maintain whole blood trough levels of 200 to 400 ng/mL during the first 6 months. Beginning in June 1996, we have gradually introduced MMF, 2 g/day, to the protocol. For high-risk patients we changed our protocol to MMF 3 g/day, given during the first 30 days posttransplant and afterward reduced to 2 g/day, in association with lower Neoral doses of 4 to 6 (mean 5.4) mg/kg per day, adjusted to target trough levels of 150 to 250 ng/mL. Initial prednisone dose was the same for all patients (1 mg/kg per day). From May 1997 to August 1998, 19 patients given cadaveric (n ⫽ 12) or living (n ⫽ 7) kidney transplants were enrolled. In 14 patients, MMF was begun between day 1 and day 5 as a substitute Table 1. Patients Characteristics and Reasons for Inclusion Age (Y) Sex (M/F) Donor (cadaver/living) Delayed graft function CsA toxicity Retransplant CIT ⬎ 24h
16 – 65 (42 ⫾ 12) 12/7 12/7 11 (58%) 4 (21%) 3 (16%) 1 (5%)
CIT ⫽ cold ischemia time.
Table 2. Overall Results in 19 Kidney Recipients n (%)
Adverse Events Diarrhoea Leukopenia Anaemia Abdominal pain Nausea and vomiting Thrombocytopenia Infection CMV Candida stomatitis/esophagitis Varicella virus infection Acute Rejection Graft Loss Deaths
6 (32) 5 (26) 4 (21) 3 (15) 2 (11) 1 (5) 4 (21) 4 (21) 3 (16) 2 (11) 1 (5) 1 (5)
for azathioprine. The other five patients received MMF from day 0. Clinical characteristics of these patients and reasons for inclusion are shown in Table 1. DGF was defined as the need for dialysis during the first posttransplant week. Severe CsA acute nephrotoxicity was considered as the cause of protracted acute renal failure,6 occurring between day 2 and 5 posttransplant, in four recipients of living kidney transplants with excellent previous function and whose biopsies showed no acute rejection. Graft failure was defined as the return of the recipient to chronic dialysis or recipient death. Follow-up period was 4 to 18 (mean 11) months.
RESULTS
The overall results are shown in Table 2. Adverse events were present in 53% of the patients. Among these, the most common were diarrhoea (32%) and leukopaenia (32%). Infectious complications were cytomegalovirus (CMV) disease in four (21%) patients, Candida stomatitis/esophagitis in four (21%), and varicella virus infection in three (16%). During this period both graft and patient survival were 95%—One patient (CMV status R⫺, D⫹) died due to CMV pneumonitis in the 2nd month posttransplant. BiopFrom the Transplant Unit, Hospital Geral de Fortaleza, Fortaleza, Brazil. Address reprint requests to R.M. Esmeraldo, Setor de Transplante Renal, Hospital Geral de Fortaleza, Rua Avila Goulart, 900, 5° Andar, 60.155-290, Fortaleza, CE, Brazil.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00644-2
Transplantation Proceedings, 31, 3007–3008 (1999)
3007
3008
ESMERALDO, DONADI, OLIVEIRA ET AL
Table 3. Mycophenolate Mofetil and Low Dose OKT3 Induction Therapy in High-Risk Renal Transplant Patients Group
n
GS (%)
PS (%)
AR (%)
CMV (%)
MMF (3g) OKT3
19 14
95 93
95 100
11 29
21 14
GS, graft survival; PS, patient survival; AR, acute rejection; CMV, cytomegalovirus.
sy-proven acute rejection occurred in two (11%) patients, both successfully treated with a 3-day course of intravenous methylprednisolone. A comparison of these results with our data on low dose OKT3, 2.5 mg/day, for 7 to 14 days as induction therapy for high-risk patients is shown in Table 3. DISCUSSION
The occurrence of DGF has long been recognised to be an important risk factor for short and long-term graft survival in both cadaveric and living renal transplantation.7–9 Its incidence was significantly higher in retransplants compared with primary transplants and acute rejection was more prevalent in patients with DGF,10 which resulted in lower graft survival. The aims of prophylactic immunosuppression in this group of patients are to minimise early cyclosporine nephrotoxicity and acute rejection during the time that the graft recovers from injuries. Although the
number of patients in this study is small, the overall results with this new immunosuppressive protocol are promising. In this selected and difficult group of patients (DGF, retransplant), the use of MMF, 3 g/day, in conjunction with lower doses of CsA may minimise the effect of kidney damage and offer a viable alternative to the need for using ATG or OKT3 as induction therapy. REFERENCES 1. Dyer PA, Johnson RWG, Martin S, et al: In Clinical Transplants. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1997, p 297 2. Danovitch GM: In Handbook of Kidney Transplantation. Boston: Little Brown; 1996, p 55 3. The Tricontinental Mycophenolate Mofetil Renal Transplant Study Group: Transplantation 61:1029, 1996 4. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 5. Grinyo JM, Gil-Vernet S, Sero ´n D, et al: Transplantation 63:1688, 1997 6. Perico N, Remuzzi G: Transplant Rev 5:63, 1991 7. Halloran PF, Aprille MA, Farewell V, et al: Transplantation 46:223, 1988 8. Shoskes DA, Halloran PF: J Urol 155:1831, 1996 9. Ghods AJ, Khosravani P: Transplant Proc 29:2773, 1997 10. Howard RJ, Pfaff WW, Brunson ME, et al: Transplant Proc 25:884, 1993
R
ESULTS in kidney transplantation have improved over the last two decades due to better surgical care and improvements in immunosuppression. However, new strategies for dealing with high-risk recipients are required. In this category are paediatric patients, Black patients, sensitised patients, and recipients with delayed graft function (DGF).1 The use of biologic agents such as ATG or OKT3 as induction therapy is usually indicated because of the need for more potent and less nephrotoxic immunosuppression in this group of patients.2 Mycophenolate mofetil (MMF) is a new potent immunosuppressive agent that reduces the incidence of acute rejection episodes significantly when given in association with cyclosporine A (CsA) and steroids in renal transplantation.3,4 In this way, it may allow discontinuation or lowering the dosage of other immunosuppressants without increasing the risk of rejection.5 This open pilot clinical study was conducted to determine whether the use of MMF in higher doses could replace the need for ATG or OKT3 in high-risk renal transplant recipients. METHODS Our initial immunosuppression protocol is based on Neoral initiated at 10 mg/kg per day in addition to steroids and azathioprine with CsA dosage adjusted to maintain whole blood trough levels of 200 to 400 ng/mL during the first 6 months. Beginning in June 1996, we have gradually introduced MMF, 2 g/day, to the protocol. For high-risk patients we changed our protocol to MMF 3 g/day, given during the first 30 days posttransplant and afterward reduced to 2 g/day, in association with lower Neoral doses of 4 to 6 (mean 5.4) mg/kg per day, adjusted to target trough levels of 150 to 250 ng/mL. Initial prednisone dose was the same for all patients (1 mg/kg per day). From May 1997 to August 1998, 19 patients given cadaveric (n ⫽ 12) or living (n ⫽ 7) kidney transplants were enrolled. In 14 patients, MMF was begun between day 1 and day 5 as a substitute Table 1. Patients Characteristics and Reasons for Inclusion Age (Y) Sex (M/F) Donor (cadaver/living) Delayed graft function CsA toxicity Retransplant CIT ⬎ 24h
16 – 65 (42 ⫾ 12) 12/7 12/7 11 (58%) 4 (21%) 3 (16%) 1 (5%)
CIT ⫽ cold ischemia time.
Table 2. Overall Results in 19 Kidney Recipients n (%)
Adverse Events Diarrhoea Leukopenia Anaemia Abdominal pain Nausea and vomiting Thrombocytopenia Infection CMV Candida stomatitis/esophagitis Varicella virus infection Acute Rejection Graft Loss Deaths
6 (32) 5 (26) 4 (21) 3 (15) 2 (11) 1 (5) 4 (21) 4 (21) 3 (16) 2 (11) 1 (5) 1 (5)
for azathioprine. The other five patients received MMF from day 0. Clinical characteristics of these patients and reasons for inclusion are shown in Table 1. DGF was defined as the need for dialysis during the first posttransplant week. Severe CsA acute nephrotoxicity was considered as the cause of protracted acute renal failure,6 occurring between day 2 and 5 posttransplant, in four recipients of living kidney transplants with excellent previous function and whose biopsies showed no acute rejection. Graft failure was defined as the return of the recipient to chronic dialysis or recipient death. Follow-up period was 4 to 18 (mean 11) months.
RESULTS
The overall results are shown in Table 2. Adverse events were present in 53% of the patients. Among these, the most common were diarrhoea (32%) and leukopaenia (32%). Infectious complications were cytomegalovirus (CMV) disease in four (21%) patients, Candida stomatitis/esophagitis in four (21%), and varicella virus infection in three (16%). During this period both graft and patient survival were 95%—One patient (CMV status R⫺, D⫹) died due to CMV pneumonitis in the 2nd month posttransplant. BiopFrom the Transplant Unit, Hospital Geral de Fortaleza, Fortaleza, Brazil. Address reprint requests to R.M. Esmeraldo, Setor de Transplante Renal, Hospital Geral de Fortaleza, Rua Avila Goulart, 900, 5° Andar, 60.155-290, Fortaleza, CE, Brazil.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00644-2
Transplantation Proceedings, 31, 3007–3008 (1999)
3007
3008
ESMERALDO, DONADI, OLIVEIRA ET AL
Table 3. Mycophenolate Mofetil and Low Dose OKT3 Induction Therapy in High-Risk Renal Transplant Patients Group
n
GS (%)
PS (%)
AR (%)
CMV (%)
MMF (3g) OKT3
19 14
95 93
95 100
11 29
21 14
GS, graft survival; PS, patient survival; AR, acute rejection; CMV, cytomegalovirus.
sy-proven acute rejection occurred in two (11%) patients, both successfully treated with a 3-day course of intravenous methylprednisolone. A comparison of these results with our data on low dose OKT3, 2.5 mg/day, for 7 to 14 days as induction therapy for high-risk patients is shown in Table 3. DISCUSSION
The occurrence of DGF has long been recognised to be an important risk factor for short and long-term graft survival in both cadaveric and living renal transplantation.7–9 Its incidence was significantly higher in retransplants compared with primary transplants and acute rejection was more prevalent in patients with DGF,10 which resulted in lower graft survival. The aims of prophylactic immunosuppression in this group of patients are to minimise early cyclosporine nephrotoxicity and acute rejection during the time that the graft recovers from injuries. Although the
number of patients in this study is small, the overall results with this new immunosuppressive protocol are promising. In this selected and difficult group of patients (DGF, retransplant), the use of MMF, 3 g/day, in conjunction with lower doses of CsA may minimise the effect of kidney damage and offer a viable alternative to the need for using ATG or OKT3 as induction therapy. REFERENCES 1. Dyer PA, Johnson RWG, Martin S, et al: In Clinical Transplants. Los Angeles, Calif: UCLA Tissue Typing Laboratory; 1997, p 297 2. Danovitch GM: In Handbook of Kidney Transplantation. Boston: Little Brown; 1996, p 55 3. The Tricontinental Mycophenolate Mofetil Renal Transplant Study Group: Transplantation 61:1029, 1996 4. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 5. Grinyo JM, Gil-Vernet S, Sero ´n D, et al: Transplantation 63:1688, 1997 6. Perico N, Remuzzi G: Transplant Rev 5:63, 1991 7. Halloran PF, Aprille MA, Farewell V, et al: Transplantation 46:223, 1988 8. Shoskes DA, Halloran PF: J Urol 155:1831, 1996 9. Ghods AJ, Khosravani P: Transplant Proc 29:2773, 1997 10. Howard RJ, Pfaff WW, Brunson ME, et al: Transplant Proc 25:884, 1993