- Email: [email protected]
mycophnolate mofetil immunosuppression: a single-center experience
Adverse Events in Renal Transplantation Under Tacrolimus/Mycophnolate Mofetil Immunosuppression: A Single-Center Experience K. Omoto, K. Tanabe, T. Tokumoto, H. Ishida, H. Shimmura, K. Makiyama, and H. Toma
T
ACROLIMUS (FK) and mycophenolate mofetil (MMF) are relatively new primary immunosuppressants used in solid organ transplantation. A recent randomized study shows that FK, a macrolide molecule that is a 10-fold to 100-fold more potent inhibitor of T-cell activation, than cyclosporine, is associated with a significant reduction in the rate of acute rejection and a similar safety profile.1 MMF, the morpholinoethyl ester of mycophenolic acid, is a noncompetitive inhibitor of inosine–monophosphate– dehydrogenase, an enzyme that influences the function of lymphocytes via inhibition of purine synthesis, and that in the first year after renal transplantation reduces the incidence of acute rejection by more than 50% compared with azathioprine.2,3 The immunosuppressive regimen of FK/MMF provides excellent outcomes in the cadaveric renal transplant patients.4 However, this strong immunosuppressant medication are associated with toxicity, and the careful observation is needed to obtain safety in the clinical management of transplant patients. In the present study, we investigate the short-term outcome and adverse events of renal transplant recipients treated with FK/MMF. MATERIALS AND METHODS Between 1999 and 2000 at our institute, 38 renal transplant patients were enrolled in this study. They underwent kidney transplantation under FK, MMF, and methylprednisolone (MP) immunosuppression. The mean age was 35 years, with 26 males and 12 females. Transplantation was living-related in 33 recipients or cadaveric in 5. The 13 recipients underwent ABO-incompatible transplants. Trough level targets for FK were 10 to 15 ng/mL during the first month, and 5 to 10 ng/mL at 3 months after the transplantation. MMF dosages of 2 g/d were administered orally beginning at 2 days prior to operation or on the day of the transplantation in patients who underwent living or cadaveric donor transplantation, respectively. The dose was continued unless severe adverse events of MMF intervened. MP (250 mg/d) was started on the day of the transplantatioin (day 0), then gradually decreased to 20 mg/d at day 5, and tapered to 6 mg/d at 3 months after transplantation. The diagnosis of CMV infection was based upon detection of CMV-antigen (the viral tegument protein pp56) in patient leukocytes. No patient was treated prophylacticly with oral administration of ganciclovir (GCV) to prevent CMV infection after the transplantation.
Fig 1. Graft survival in patients that underwent ABO-compatible or -incompatible renal transplantation.
RESULTS
Overall patient and graft survival rate was 100% and 96% at 1 year after the renal transplantation. The one-year graft survival rates in patients who underwent ABO-compatible and -incompatible transplantation were 97% and 93% respectively (Fig 1). Ten of 38 (26%) patients experienced acute rejection, OKT3 was administered to four patients. As shown in Table 1, the rate of MMF-associated adverse events was 42%, including CMV infection (n ⫽ 7), diarrhea (n ⫽ 4), leukopenia (n ⫽ 3), stomachache (n ⫽ 1), and pneumonia (n ⫽ 1). Three of 7 CMV infections, including two patients with CMV retinitis, were observed at 5 months after the transplantation. To manage MMF-associated adverse events, the drug was temporarily discontinued or reduced in dosage. Administration of GCV was necessary in all the CMV-infected patients. The existence of CMVantigenemia continued for 6 months in three patients, despite the appropriate administration of GCV. The detection of CMV-antigenemia finally had not been identifiable From The Department of Urology, Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan. Address reprint requests to Dr Kazunari Tanabe, Department of Urology, Kidney Center, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/02/$–see front matter PII S0041-1345(02)03090-7
Transplantation Proceedings, 34, 1821–1822 (2002)
1821
1822
OMOTO, TANABE, TOKUMOTO ET AL
Table 1. Management for MMF-Associated Adverse Events and the Number of Patients Discontinuation of MMF Adverse events
CMV infection Diarrhea Leukopenia Stomachache Pneumonia Total
Temporary*
Permanent
Reduction of MMF dosage
n (%)
6 0 1 0 1 8
0 0 0 1 0 1
1 4 2 0 0 7
7 (18%) 4 (11%) 3 (7.8%) 1 (2.6%) 1 (2.6%) 16 (42%)
*The temporary discontinuation of MMF followed by reduction of MMF dosage.
in all patients. The diarrhea, leukopenia, and pneumonia improved on temporary discontinuation or reduced dosage of MMF. However, permanent discontinuation of MMF was necessary in the patient with abdominal pain, since the symptom was difficult to control by reduction of the MMF dosage. DISCUSSION
Recent studies show that immunosuppressive therapy with FK/MMF in renal transplantation provides excellent efficacy.4,5 However, the safety of the immunosuppressant combinations regimen is not well known. In the present study, we observed that the incidence of observed MMF-associated adverse events is high (42%). Our results indicate that CMV infection is a major complication among MMF-associated adverse events. While recent studies suggest that the administration of MMF in renal transplantation increases CMV invasive organ disease, the mechanisms by which MMF increases the severity of CMV disease remains undefined and should be further investigated.6,7 MMF strongly inhibits both B and T cell function, thus impacting upon both humoral and cellular immunity that is specifically directed towards CMV. We experienced two cases of CMV retinitis, which developed at 5 months after the transplantation and required long-term treatment with GCV (4 to 6 weeks).
The incidence of adverse events of the gastrointestinal tract was 13% (5 of 38 patients). Diarrhea, a major complication of the gastrointestinal tract, developed at 2 weeks after the transplantation, and improved on temporary discontinuation or reduced dosages of MMF. However, the abdominal pain was difficult to control by temporary discontinuation of MMF. It is unclear why the management for this symptom in patients treated with MMF is difficult. Kaplan et al reported that the majority of patients on maintenance MMF therapy who presented with persistent midepigastric pain had evidence of active CMV infection which was confirmed by the existence of CMV in gastric or duodenal biopsy specimens.8 Unfortunately, our patient did not display CMV infection in the upper gastrointestinal tract. In summary, the CMV infection, including CMV retinitis, is a major adverse event in renal transplant patients treated with FK/MMF. It is important to achieve early detection and treatment of CMV-infection using GCV. Safe and Effective Immunosuppressive therapy with FK/MMF for renal transplant patients requires careful observation for infectious complications during at least the first year of therapy.
REFERENCES 1. Pirsh JD, Miller J, Deierhol MH, et al: Transplantation 63:977, 1997 2. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 3. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: Transplantation 61:1029, 1996 4. Squifflet J-P, Ba¨ckman L, Claesson K, et al: Transplantation 72:63, 2001 5. Ahsan N, Johnson C, Gonwa T, et al: Transplantation 72:245, 2001 6. Sarmiento JM, Dockrell DH, Schwab TR, et al: Clin Transplantation 14:136, 2000 7. Ter Meulen CG, Wetzels JFM, Hilbrands LB: Nephrol Dial Transplant 15:711, 2000 8. Kaplan B, Meier-Kriesche H-U, Jacobs MG, et al: Am J Kidney Dis 34:65, 1999
T
ACROLIMUS (FK) and mycophenolate mofetil (MMF) are relatively new primary immunosuppressants used in solid organ transplantation. A recent randomized study shows that FK, a macrolide molecule that is a 10-fold to 100-fold more potent inhibitor of T-cell activation, than cyclosporine, is associated with a significant reduction in the rate of acute rejection and a similar safety profile.1 MMF, the morpholinoethyl ester of mycophenolic acid, is a noncompetitive inhibitor of inosine–monophosphate– dehydrogenase, an enzyme that influences the function of lymphocytes via inhibition of purine synthesis, and that in the first year after renal transplantation reduces the incidence of acute rejection by more than 50% compared with azathioprine.2,3 The immunosuppressive regimen of FK/MMF provides excellent outcomes in the cadaveric renal transplant patients.4 However, this strong immunosuppressant medication are associated with toxicity, and the careful observation is needed to obtain safety in the clinical management of transplant patients. In the present study, we investigate the short-term outcome and adverse events of renal transplant recipients treated with FK/MMF. MATERIALS AND METHODS Between 1999 and 2000 at our institute, 38 renal transplant patients were enrolled in this study. They underwent kidney transplantation under FK, MMF, and methylprednisolone (MP) immunosuppression. The mean age was 35 years, with 26 males and 12 females. Transplantation was living-related in 33 recipients or cadaveric in 5. The 13 recipients underwent ABO-incompatible transplants. Trough level targets for FK were 10 to 15 ng/mL during the first month, and 5 to 10 ng/mL at 3 months after the transplantation. MMF dosages of 2 g/d were administered orally beginning at 2 days prior to operation or on the day of the transplantation in patients who underwent living or cadaveric donor transplantation, respectively. The dose was continued unless severe adverse events of MMF intervened. MP (250 mg/d) was started on the day of the transplantatioin (day 0), then gradually decreased to 20 mg/d at day 5, and tapered to 6 mg/d at 3 months after transplantation. The diagnosis of CMV infection was based upon detection of CMV-antigen (the viral tegument protein pp56) in patient leukocytes. No patient was treated prophylacticly with oral administration of ganciclovir (GCV) to prevent CMV infection after the transplantation.
Fig 1. Graft survival in patients that underwent ABO-compatible or -incompatible renal transplantation.
RESULTS
Overall patient and graft survival rate was 100% and 96% at 1 year after the renal transplantation. The one-year graft survival rates in patients who underwent ABO-compatible and -incompatible transplantation were 97% and 93% respectively (Fig 1). Ten of 38 (26%) patients experienced acute rejection, OKT3 was administered to four patients. As shown in Table 1, the rate of MMF-associated adverse events was 42%, including CMV infection (n ⫽ 7), diarrhea (n ⫽ 4), leukopenia (n ⫽ 3), stomachache (n ⫽ 1), and pneumonia (n ⫽ 1). Three of 7 CMV infections, including two patients with CMV retinitis, were observed at 5 months after the transplantation. To manage MMF-associated adverse events, the drug was temporarily discontinued or reduced in dosage. Administration of GCV was necessary in all the CMV-infected patients. The existence of CMVantigenemia continued for 6 months in three patients, despite the appropriate administration of GCV. The detection of CMV-antigenemia finally had not been identifiable From The Department of Urology, Kidney Center, Tokyo Women’s Medical University, Tokyo, Japan. Address reprint requests to Dr Kazunari Tanabe, Department of Urology, Kidney Center, Tokyo Women’s Medical University, 8-1 Kawada-cho, Shinjuku-ku, Tokyo 162-8666, Japan. E-mail: [email protected]
© 2002 by Elsevier Science Inc. 655 Avenue of the Americas, New York, NY 10010
0041-1345/02/$–see front matter PII S0041-1345(02)03090-7
Transplantation Proceedings, 34, 1821–1822 (2002)
1821
1822
OMOTO, TANABE, TOKUMOTO ET AL
Table 1. Management for MMF-Associated Adverse Events and the Number of Patients Discontinuation of MMF Adverse events
CMV infection Diarrhea Leukopenia Stomachache Pneumonia Total
Temporary*
Permanent
Reduction of MMF dosage
n (%)
6 0 1 0 1 8
0 0 0 1 0 1
1 4 2 0 0 7
7 (18%) 4 (11%) 3 (7.8%) 1 (2.6%) 1 (2.6%) 16 (42%)
*The temporary discontinuation of MMF followed by reduction of MMF dosage.
in all patients. The diarrhea, leukopenia, and pneumonia improved on temporary discontinuation or reduced dosage of MMF. However, permanent discontinuation of MMF was necessary in the patient with abdominal pain, since the symptom was difficult to control by reduction of the MMF dosage. DISCUSSION
Recent studies show that immunosuppressive therapy with FK/MMF in renal transplantation provides excellent efficacy.4,5 However, the safety of the immunosuppressant combinations regimen is not well known. In the present study, we observed that the incidence of observed MMF-associated adverse events is high (42%). Our results indicate that CMV infection is a major complication among MMF-associated adverse events. While recent studies suggest that the administration of MMF in renal transplantation increases CMV invasive organ disease, the mechanisms by which MMF increases the severity of CMV disease remains undefined and should be further investigated.6,7 MMF strongly inhibits both B and T cell function, thus impacting upon both humoral and cellular immunity that is specifically directed towards CMV. We experienced two cases of CMV retinitis, which developed at 5 months after the transplantation and required long-term treatment with GCV (4 to 6 weeks).
The incidence of adverse events of the gastrointestinal tract was 13% (5 of 38 patients). Diarrhea, a major complication of the gastrointestinal tract, developed at 2 weeks after the transplantation, and improved on temporary discontinuation or reduced dosages of MMF. However, the abdominal pain was difficult to control by temporary discontinuation of MMF. It is unclear why the management for this symptom in patients treated with MMF is difficult. Kaplan et al reported that the majority of patients on maintenance MMF therapy who presented with persistent midepigastric pain had evidence of active CMV infection which was confirmed by the existence of CMV in gastric or duodenal biopsy specimens.8 Unfortunately, our patient did not display CMV infection in the upper gastrointestinal tract. In summary, the CMV infection, including CMV retinitis, is a major adverse event in renal transplant patients treated with FK/MMF. It is important to achieve early detection and treatment of CMV-infection using GCV. Safe and Effective Immunosuppressive therapy with FK/MMF for renal transplant patients requires careful observation for infectious complications during at least the first year of therapy.
REFERENCES 1. Pirsh JD, Miller J, Deierhol MH, et al: Transplantation 63:977, 1997 2. European Mycophenolate Mofetil Cooperative Study Group: Lancet 345:1321, 1995 3. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group: Transplantation 61:1029, 1996 4. Squifflet J-P, Ba¨ckman L, Claesson K, et al: Transplantation 72:63, 2001 5. Ahsan N, Johnson C, Gonwa T, et al: Transplantation 72:245, 2001 6. Sarmiento JM, Dockrell DH, Schwab TR, et al: Clin Transplantation 14:136, 2000 7. Ter Meulen CG, Wetzels JFM, Hilbrands LB: Nephrol Dial Transplant 15:711, 2000 8. Kaplan B, Meier-Kriesche H-U, Jacobs MG, et al: Am J Kidney Dis 34:65, 1999