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Mycophenolate mofetil, cyclosporine, and steroids after renal transplantation: five-year results at a single center
Mycophenolate Mofetil, Cyclosporine, and Steroids After Renal Transplantation: Five-Year Results at a Single Center J.C. Herrero, E. Morales, B. Dominguez-Gil, A. Carren˜o, A. Cubas, A. Andres, M. Praga, T. Ortun˜o, E. Hernandez, J.L. Rodicio, and J.M. Morales
I
T has been demonstrated that mycophenolate mofetil (MMF) associated with cyclosporine (CyA) and steroids (S) significantly reduced the rate of biopsy-proven acute rejection during the first 6 months after renal transplantation (RT).1–3 Also, the 2-g dose has been recommended.1 Nevertheless, there is not enough long-term experience with this new therapy after RT. The purpose of the present study was to show the efficacy and safety at 5 years of two oral doses of MMF associated with CyA and steroids compared with a protocol of double therapy.
PATIENTS AND METHODS All patients included in the European Mycophenolate Mofetil Cooperative Study performed in 1992 and 1993 in our hospital were analyzed and followed during 5 years. This was a multicenter, placebo-controlled study of MMF combined with CyA and steroids
From the Hospital 12 de Octubre, Madrid, Spain. Address reprint requests to J.M. Morales, Renal Transplant Unit, Nephrology Department, Hospital 12 de Octubre, Carretera de Andalucia Km 5.400, 28041 Madrid, Spain.
Table 1. Clinical Results at Five Years
Gender Age (years) Acute Rejection (%) Corticoresistant Acute Rejection Graft Survival Causes of graft lost Chronic rejection CyA nephrotoxicity Arterial thrombosis Obstructive uropathy Exitus Patient Survival Causes of death Severe infection Cardiorespiratory arrest Serum creatinine (mg/dL) CMV Infection Neoplasia Kaposi’s sarcoma Melanoma Basal cell carcinoma Bladder carcinoma Side effects Leukopenia Diarrhea
Group I (N ⫽ 12)
Group II (N ⫽ 11)
Group III (N ⫽ 11)
Group II ⫹ III (N ⫽ 22)
7M/5F 44 ⫾ 14 (20 – 62) 5/12 (42%) 2
7M/4F 51 ⫾ 10 (29 – 64) 1/11 (9%) 0
6M/5F 46 ⫾ 15 (24 – 68) 3/11 (27%) 0
13M/9F 48 ⫾ 13 (24 – 68) 4/22 (18%) 0
6/12 (50%)
7/11 (64%)
8/11 (73%)
15/22 (68%)
4 0 0 0 2 10/12 (83%)
0 1 1 1 1 10/11 (91%)
1 0 0 0 2 9/11 (82%)
1 1 1 1 3 19/22 (86%)
1 1 1.6 ⫾ 0.9 0
1 0 1.3 ⫾ 0.2 1*
1 1 1.3 ⫾ 0.4 1†
2 1 1.3 ⫾ 0.3 2
1 1 0 0
0 0 1 0
0 0 0 1
0 0 1 1
0 0
1 1
2 1
3 2
CMV, cytomegalovirus; CyA, cyclosporine. *Lung infection disease. † Infection with leukopenia.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00330-9
Transplantation Proceedings, 31, 2263–2264 (1999)
2263
2264 for prevention of acute rejection (AR). Inclusion and exclusion criteria have been published.1 Enrolled patients were equally and randomly assigned in our center to one of three treatments: group I: Placebo; group II: MMF 2 g; and group III: MMF 3 g. All groups also received CyA (10 mg/kg per day) and steroids (0.5 mg/kg initially, at 6 months 10 mg/d). First-line treatment for AR was high-dose intravenous corticosteroids. Corticoresistant (C) AR was treated with OKT3 for 7 to 10 days. All patients were followed in our center for 5 years. Incidence of acute rejection (biopsy-proven), incidence of (C)AR, graft and patient survival, causes of graft loss and causes of death, incidence of cytomegalovirus infection neoplasia, renal function (measured by serum creatinine, SCr), and the most relevant side effects of MMF were all recorded.
RESULTS
Thirty-four patients were selected randomly to receive the following: group I, N ⫽ 12, S ⫹ CyA ⫹ Placebo; Group II, N ⫽ 11, S ⫹ CyA ⫹ MMF 2 g; and group III, N ⫽ 11, S ⫹ CyA ⫹ MMF 3 g. Demographic data were similar in all groups. Table 1 shows the most important clinical results at 5 years. In an intention-to-treat analysis, patients with MMF showed less incidence (18% vs 42%) and severity of AR than did the control group. A tendency to present better survival rates was also observed in the MMF groups (86% vs 83% and 68% vs 50% patient and graft survival, respectively). Only one patient in the MMF groups lost a kidney by chronic rejection, whereas in the placebo group CR represented the most important cause of graft loss. Mortality was minor in the MMF 2-g group. There was a tendency to show better renal function in patients given MMF. Cytomegalovirus infection incidence was more frequent in the MMF groups, while neoplasia was quite similar. Diarrhea
HERRERO, MORALES, DOMINGUEZ-GIL ET AL
and leukopenia were more frequent in the MMF patients, but they were controlled with reduction of the dose. DISCUSSION
Our results indicate that patients with S, CyA, and MMF showed a clear reduction in the incidence of biopsy-proven AR compared with patients under a protocol of double therapy, S ⫹ CyA. Also, no patients with MMF experienced (C)AR. These results concerning AR are similar to those obtained for the entire European Study in the first 6 months.1 At 5 years, patient and graft survival rates were not significantly different in the various groups, although there was a tendency for better results in both MMF groups. This effect on graft survival can be explained by the diminution of AR incidence in the MMF groups. It will be very important to know if all patients included in the European Study this difference in graft survival will be statistically significant. Because there is no experience with MMF in the longterm, it is important to state that there was no difference between groups in the incidence of severe infections and neoplasia at 5 years. Also, the safety profile was similar between MMF groups, although it is important to consider that after 2 years the patients given MMF 3 g had their dose reduced once we knew the results at 6 months. In summary, long-term therapy with S ⫹ CyA Neoral ⫹ MMF 2 or 3 g is well tolerated and offers good survival rates at 5 years after RT. REFERENCES 1. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 2. Sollinger HW, Belzer FD, Deierhoi MH, et al: Ann Surg 216:513, 1992 3. Deierhoi MH, Kaufmann RS, Hudson SL, et al: Ann Surg 217:476, 1993
I
T has been demonstrated that mycophenolate mofetil (MMF) associated with cyclosporine (CyA) and steroids (S) significantly reduced the rate of biopsy-proven acute rejection during the first 6 months after renal transplantation (RT).1–3 Also, the 2-g dose has been recommended.1 Nevertheless, there is not enough long-term experience with this new therapy after RT. The purpose of the present study was to show the efficacy and safety at 5 years of two oral doses of MMF associated with CyA and steroids compared with a protocol of double therapy.
PATIENTS AND METHODS All patients included in the European Mycophenolate Mofetil Cooperative Study performed in 1992 and 1993 in our hospital were analyzed and followed during 5 years. This was a multicenter, placebo-controlled study of MMF combined with CyA and steroids
From the Hospital 12 de Octubre, Madrid, Spain. Address reprint requests to J.M. Morales, Renal Transplant Unit, Nephrology Department, Hospital 12 de Octubre, Carretera de Andalucia Km 5.400, 28041 Madrid, Spain.
Table 1. Clinical Results at Five Years
Gender Age (years) Acute Rejection (%) Corticoresistant Acute Rejection Graft Survival Causes of graft lost Chronic rejection CyA nephrotoxicity Arterial thrombosis Obstructive uropathy Exitus Patient Survival Causes of death Severe infection Cardiorespiratory arrest Serum creatinine (mg/dL) CMV Infection Neoplasia Kaposi’s sarcoma Melanoma Basal cell carcinoma Bladder carcinoma Side effects Leukopenia Diarrhea
Group I (N ⫽ 12)
Group II (N ⫽ 11)
Group III (N ⫽ 11)
Group II ⫹ III (N ⫽ 22)
7M/5F 44 ⫾ 14 (20 – 62) 5/12 (42%) 2
7M/4F 51 ⫾ 10 (29 – 64) 1/11 (9%) 0
6M/5F 46 ⫾ 15 (24 – 68) 3/11 (27%) 0
13M/9F 48 ⫾ 13 (24 – 68) 4/22 (18%) 0
6/12 (50%)
7/11 (64%)
8/11 (73%)
15/22 (68%)
4 0 0 0 2 10/12 (83%)
0 1 1 1 1 10/11 (91%)
1 0 0 0 2 9/11 (82%)
1 1 1 1 3 19/22 (86%)
1 1 1.6 ⫾ 0.9 0
1 0 1.3 ⫾ 0.2 1*
1 1 1.3 ⫾ 0.4 1†
2 1 1.3 ⫾ 0.3 2
1 1 0 0
0 0 1 0
0 0 0 1
0 0 1 1
0 0
1 1
2 1
3 2
CMV, cytomegalovirus; CyA, cyclosporine. *Lung infection disease. † Infection with leukopenia.
© 1999 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/99/$–see front matter PII S0041-1345(99)00330-9
Transplantation Proceedings, 31, 2263–2264 (1999)
2263
2264 for prevention of acute rejection (AR). Inclusion and exclusion criteria have been published.1 Enrolled patients were equally and randomly assigned in our center to one of three treatments: group I: Placebo; group II: MMF 2 g; and group III: MMF 3 g. All groups also received CyA (10 mg/kg per day) and steroids (0.5 mg/kg initially, at 6 months 10 mg/d). First-line treatment for AR was high-dose intravenous corticosteroids. Corticoresistant (C) AR was treated with OKT3 for 7 to 10 days. All patients were followed in our center for 5 years. Incidence of acute rejection (biopsy-proven), incidence of (C)AR, graft and patient survival, causes of graft loss and causes of death, incidence of cytomegalovirus infection neoplasia, renal function (measured by serum creatinine, SCr), and the most relevant side effects of MMF were all recorded.
RESULTS
Thirty-four patients were selected randomly to receive the following: group I, N ⫽ 12, S ⫹ CyA ⫹ Placebo; Group II, N ⫽ 11, S ⫹ CyA ⫹ MMF 2 g; and group III, N ⫽ 11, S ⫹ CyA ⫹ MMF 3 g. Demographic data were similar in all groups. Table 1 shows the most important clinical results at 5 years. In an intention-to-treat analysis, patients with MMF showed less incidence (18% vs 42%) and severity of AR than did the control group. A tendency to present better survival rates was also observed in the MMF groups (86% vs 83% and 68% vs 50% patient and graft survival, respectively). Only one patient in the MMF groups lost a kidney by chronic rejection, whereas in the placebo group CR represented the most important cause of graft loss. Mortality was minor in the MMF 2-g group. There was a tendency to show better renal function in patients given MMF. Cytomegalovirus infection incidence was more frequent in the MMF groups, while neoplasia was quite similar. Diarrhea
HERRERO, MORALES, DOMINGUEZ-GIL ET AL
and leukopenia were more frequent in the MMF patients, but they were controlled with reduction of the dose. DISCUSSION
Our results indicate that patients with S, CyA, and MMF showed a clear reduction in the incidence of biopsy-proven AR compared with patients under a protocol of double therapy, S ⫹ CyA. Also, no patients with MMF experienced (C)AR. These results concerning AR are similar to those obtained for the entire European Study in the first 6 months.1 At 5 years, patient and graft survival rates were not significantly different in the various groups, although there was a tendency for better results in both MMF groups. This effect on graft survival can be explained by the diminution of AR incidence in the MMF groups. It will be very important to know if all patients included in the European Study this difference in graft survival will be statistically significant. Because there is no experience with MMF in the longterm, it is important to state that there was no difference between groups in the incidence of severe infections and neoplasia at 5 years. Also, the safety profile was similar between MMF groups, although it is important to consider that after 2 years the patients given MMF 3 g had their dose reduced once we knew the results at 6 months. In summary, long-term therapy with S ⫹ CyA Neoral ⫹ MMF 2 or 3 g is well tolerated and offers good survival rates at 5 years after RT. REFERENCES 1. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 2. Sollinger HW, Belzer FD, Deierhoi MH, et al: Ann Surg 216:513, 1992 3. Deierhoi MH, Kaufmann RS, Hudson SL, et al: Ann Surg 217:476, 1993