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Sirolimus: A Switch Option for Mycophenolate Mofetil–Induced Leukopenia in Renal Transplant Recipients
Sirolimus: A Switch Option for Mycophenolate MofetileInduced Leukopenia in Renal Transplant Recipients B.C. Shin, J.H. Chung, and H.L. Kim ABSTRACT Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used to prevent acute and chronic rejection in kidney transplantation or for rescue therapy. One side effect of MMF is bone marrow toxicity, including leukopenia, which may necessitate drug withdrawal. We report 2 patients who underwent kidney transplantation and developed leukopenia while receiving MMF and safely switched to sirolimus. A 35-year-old woman underwent deceased donor kidney transplantation. She received basiliximab, tacrolimus, MMF, and a corticosteroid. On postoperative day (POD) 75, her white blood cell (WBC) count was 1800/mL. A 44-year-old women underwent deceased donor kidney transplantation and received basiliximab, tacrolimus, MMF, valganciclovir, and a corticosteroid. On POD 88, her WBC count was 1320/mL. MMF was switched to sirolimus, resulting in recovery of WBC count without rejection. Switch from MMF to sirolimus is safe and favorable in MMF-induced leukopenia in renal transplant recipient.
M
YCOPHENOLATE MOFETIL (MMF) is a potent immunosuppressive agent used to prevent acute and chronic rejection in kidney transplantation or for rescue therapy.1,2 The side effects of the drug include leukopenia, anemia, and thrombocytopenia, which may necessitate drug withdrawal.3,4 Sirolimus is a lipophilic microcyclic lactone and was isolated from a strain of fungus called Streptomyces hygroscopicus.5 Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) with rising expectations for immunosuppressive therapy without nephrotoxicity.6 Sirolimus also has antiangiogenic abilities that could prevent tumor growth.7 We report 2 renal transplant patients who developed marked leukopenia while receiving MMF and successfully switched to sirolimus without complications. Their progress is shown in Fig 1. CASE REPORTS Case 1 A 35-year-old woman underwent deceased kidney transplantation. She received basiliximab, tacrolimus, MMF (1.5 g/d), and a corticosteroid. On postoperative day (POD) 75, her white blood cell (WBC) count was 1800/mL; neutrophil 675/mL; platelet 158 103; and hemoglobin 9.7 g/dL. MMF was discontinued, and sirolimus (2 mg/d) was started. The neutrophil count returned to normal after 14 days (WBC count 4250/mL; neutrophil 2465/mL). She remains well at 15 months after transplantation.
Case 2 A 44-year-old women underwent deceased kidney transplantation and received basiliximab, tacrolimus, MMF (1.5 g/d), valganciclovir (450 mg/d) and a corticosteroid. On POD 88, her WBC count 1320/ mL; neutrophil 790/mL; platelet 204 103; and hemoglobin 8.0 g/dL. She was admitted to the hospital, and MMF and valganciclovir were discontinued and stitched to sirolimus (2 mg/d). Within 7 days the neutrophil level rose to normal (WBC count 4120/mL; neutrophil 1755/mL). Valganciclovir was started after 17 days. She remains well at 9 months after transplantation.
DISCUSSION
MMF is the prodrug of mycophenolic acid and inhibits inosine monophosphate dehydrogenase.3 Recognized adverse effects of MMF include leukopenia, anemia, and thrombocytopenia, which may need drug withdrawal, leukopenia affects at many as 5% to 11% of patients.4 Sirolimus, a lipophilic macrolide antibiotic, is the first in the class of mTOR inhibitor and is used as antifungal, antitumoral, and immunosuppressive therapy.5e7 Sirolimus has been found to be free from calcineurin inhibitor-induced nephrotoxicity, and a switch from cyclosporine-based to From the Department of Internal Medicine, Division of Nephrology, Chosun University Hospital, Gwangju, Korea. Address reprint requests to Hyun Lee Kim, MD, Department of Internal Medicine, Chosun University, College of Medicine, Gwangju, Republic of Korea. E-mail: [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.040
ª 2013 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
2968
Transplantation Proceedings, 45, 2968e2969 (2013)
SIROLIMUS SWITCH OPTION FOR MMF
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Fig 1. Progress notes of renal transplant patients with mycophenolate mofetil (MMF)-induced leukopenia. WBC, white blood cell; Hb, hemoglobin; KT, kidney transplantation.
sirolimus-based therapy has produced superior kidney function in kidney transplantation patients.8,9 Side effects include increased serum lipid levels, decreased hemoglobin, arthralgia, peripheral edema, gastrointestinal complaints, skin disorders, stomatitis, hypokalemia, hypophosphatemia, dyspnea, cough, infectious diseases, and a higher incidence of lymphocele.10 In this experiment, we have reported 2 cases of leukopenia in kidney transplant patients who successfully switched from MMF to sirolimus. Switch from MMF to sirolimus is safe and favorable in MMF-induced leukopenia in renal transplant recipient. REFERENCES 1. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation. 1995;60:225. 2. Offiemann G. Five-year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil. Clin Transplant. 2003;17:43.
3. Benerjee R, Halil O, Bain BJ, et al. Neutrophil dysplasia caused by mycophenolate mofetil. Transplantation. 2000;70: 1608. 4. Engelen W, Verpooten GA, Van der Plaken M, et al. Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients. Clin Nephrol. 2003;60:119. 5. Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003;80:7S. 6. Abraham RT, Wiederrecht GJ. Immunopharmacolgy of rapamycin. Annu Rev Immunol. 1996;14:483. 7. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8: 1228. 8. Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant. 2004;4:953. 9. Kreis H, Oberbauer R, Campistol JM, et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol. 2004;5:809. 10. Merkel S, Mogilevskaja N, Mengel M, et al. Side effects of sirolimus. Transplant Proc. 2006;28:714.
M
YCOPHENOLATE MOFETIL (MMF) is a potent immunosuppressive agent used to prevent acute and chronic rejection in kidney transplantation or for rescue therapy.1,2 The side effects of the drug include leukopenia, anemia, and thrombocytopenia, which may necessitate drug withdrawal.3,4 Sirolimus is a lipophilic microcyclic lactone and was isolated from a strain of fungus called Streptomyces hygroscopicus.5 Sirolimus is an inhibitor of the mammalian target of rapamycin (mTOR) with rising expectations for immunosuppressive therapy without nephrotoxicity.6 Sirolimus also has antiangiogenic abilities that could prevent tumor growth.7 We report 2 renal transplant patients who developed marked leukopenia while receiving MMF and successfully switched to sirolimus without complications. Their progress is shown in Fig 1. CASE REPORTS Case 1 A 35-year-old woman underwent deceased kidney transplantation. She received basiliximab, tacrolimus, MMF (1.5 g/d), and a corticosteroid. On postoperative day (POD) 75, her white blood cell (WBC) count was 1800/mL; neutrophil 675/mL; platelet 158 103; and hemoglobin 9.7 g/dL. MMF was discontinued, and sirolimus (2 mg/d) was started. The neutrophil count returned to normal after 14 days (WBC count 4250/mL; neutrophil 2465/mL). She remains well at 15 months after transplantation.
Case 2 A 44-year-old women underwent deceased kidney transplantation and received basiliximab, tacrolimus, MMF (1.5 g/d), valganciclovir (450 mg/d) and a corticosteroid. On POD 88, her WBC count 1320/ mL; neutrophil 790/mL; platelet 204 103; and hemoglobin 8.0 g/dL. She was admitted to the hospital, and MMF and valganciclovir were discontinued and stitched to sirolimus (2 mg/d). Within 7 days the neutrophil level rose to normal (WBC count 4120/mL; neutrophil 1755/mL). Valganciclovir was started after 17 days. She remains well at 9 months after transplantation.
DISCUSSION
MMF is the prodrug of mycophenolic acid and inhibits inosine monophosphate dehydrogenase.3 Recognized adverse effects of MMF include leukopenia, anemia, and thrombocytopenia, which may need drug withdrawal, leukopenia affects at many as 5% to 11% of patients.4 Sirolimus, a lipophilic macrolide antibiotic, is the first in the class of mTOR inhibitor and is used as antifungal, antitumoral, and immunosuppressive therapy.5e7 Sirolimus has been found to be free from calcineurin inhibitor-induced nephrotoxicity, and a switch from cyclosporine-based to From the Department of Internal Medicine, Division of Nephrology, Chosun University Hospital, Gwangju, Korea. Address reprint requests to Hyun Lee Kim, MD, Department of Internal Medicine, Chosun University, College of Medicine, Gwangju, Republic of Korea. E-mail: [email protected]
0041-1345/13/$esee front matter http://dx.doi.org/10.1016/j.transproceed.2013.08.040
ª 2013 Published by Elsevier Inc. 360 Park Avenue South, New York, NY 10010-1710
2968
Transplantation Proceedings, 45, 2968e2969 (2013)
SIROLIMUS SWITCH OPTION FOR MMF
2969
Fig 1. Progress notes of renal transplant patients with mycophenolate mofetil (MMF)-induced leukopenia. WBC, white blood cell; Hb, hemoglobin; KT, kidney transplantation.
sirolimus-based therapy has produced superior kidney function in kidney transplantation patients.8,9 Side effects include increased serum lipid levels, decreased hemoglobin, arthralgia, peripheral edema, gastrointestinal complaints, skin disorders, stomatitis, hypokalemia, hypophosphatemia, dyspnea, cough, infectious diseases, and a higher incidence of lymphocele.10 In this experiment, we have reported 2 cases of leukopenia in kidney transplant patients who successfully switched from MMF to sirolimus. Switch from MMF to sirolimus is safe and favorable in MMF-induced leukopenia in renal transplant recipient. REFERENCES 1. Sollinger HW. Mycophenolate mofetil for the prevention of acute rejection in primary cadaveric renal allograft recipients. U.S. Renal Transplant Mycophenolate Mofetil Study Group. Transplantation. 1995;60:225. 2. Offiemann G. Five-year results of renal transplantation on immunosuppressive triple therapy with mycophenolate mofetil. Clin Transplant. 2003;17:43.
3. Benerjee R, Halil O, Bain BJ, et al. Neutrophil dysplasia caused by mycophenolate mofetil. Transplantation. 2000;70: 1608. 4. Engelen W, Verpooten GA, Van der Plaken M, et al. Four cases of red blood cell aplasia in association with the use of mycophenolate mofetil in renal transplant patients. Clin Nephrol. 2003;60:119. 5. Sehgal SN. Sirolimus: its discovery, biological properties, and mechanism of action. Transplant Proc. 2003;80:7S. 6. Abraham RT, Wiederrecht GJ. Immunopharmacolgy of rapamycin. Annu Rev Immunol. 1996;14:483. 7. Guba M, von Breitenbuch P, Steinbauer M, et al. Rapamycin inhibits primary and metastatic tumor growth by antiangiogenesis: involvement of vascular endothelial growth factor. Nat Med. 2002;8: 1228. 8. Mota A, Arias M, Taskinen EI, et al. Sirolimus-based therapy following early cyclosporine withdrawal provides significantly improved renal histology and function at 3 years. Am J Transplant. 2004;4:953. 9. Kreis H, Oberbauer R, Campistol JM, et al. Long-term benefits with sirolimus-based therapy after early cyclosporine withdrawal. J Am Soc Nephrol. 2004;5:809. 10. Merkel S, Mogilevskaja N, Mengel M, et al. Side effects of sirolimus. Transplant Proc. 2006;28:714.