| Abstract|| |
A 35-year old male patient developed elevated transaminases about an year after cadaveric donor renal transplantation maintained on triple immunosuppression therapy. Azathioprine was discontinued and the liver enzymes normalized. Three years later, he showed evidence of cyclosporin (CyA) nephrotoxicity as well as sclerosing cholangitis. The dose of CyA was therefore reduced. This was followed shortly by deterioration of his renal function and mycophenolate mofetil (MMF) (3 gm daily) was therefore introduced. He developed intractable diarrhea, which improved on reducing the dose of MMF to 2 gm per day. Eventually, the patient seemed to stabilize on low dose CyA and prednisone (Pred) along with 2 gm of MMF. Four months later, the patient discontinued CyA on his own but continued with MMF and Pred. Over the following two years, his renal functions have remained stable with serum creatinine of around 120 µmol/L, despite the low immunosuppression being administered.
Keywords: Mycophenolate mofetil, Azathioprine, Prednisolone, Renal transplantation.
|How to cite this article:|
Iqbal A, Huraib S, Tanimu D. Successful Late Conversion to Mycophenolate Mofetil and Prednisone Immunosuppression Therapy in a Renal Transplant Recipient. Saudi J Kidney Dis Transpl 2000;11:197-200
|How to cite this URL:|
Iqbal A, Huraib S, Tanimu D. Successful Late Conversion to Mycophenolate Mofetil and Prednisone Immunosuppression Therapy in a Renal Transplant Recipient. Saudi J Kidney Dis Transpl [serial online] 2000 [cited 2019 Oct 14];11:197-200. Available from: http://www.sjkdt.org/text.asp?2000/11/2/197/36678
| Introduction|| |
Mycophenolate mofetil (MMF) (Cellcept® Roche Laboratories), is a new immunosuppressive drug that selectively inhibits de novo lymphocyte purine synthesis. [1, MMF has been developed as a replacement for azathioprine (Aza) for maintenance immunosuppression, and also as rescue therapy for refractory rejection episodes. , Use of MMF has been limited to combination therapy with cyclosporine (CyA). , We herewith present a case report of use of MMF (Pred) double therapy for immunosuppression in a renal transplant recipient.
| Case Report|| |
A 35-year-old Saudi male patient with end-stage renal failure (etiology unknown) received a cadaveric renal transplant on March 10, 1992. The allograft had a oneantigen match and came from a 27-year old male victim of a road traffic accident. The immediate post-transplant period was uneventful except for transient diabetes mellitus. The patient was maintained on triple immunosuppression with CyA, Aza and Pred and had stable graft function as evidenced by a serum creatinine (Se Cr) of 60-75 µmol/l. Mild elevation of hepatic transaminases was noted in January 1993 and he tested positive for HCV-RNA. Aza was discontinued following which there was normalization of liver enzymes. He was followed-up regularly in our renal transplant clinic and CyA blood level was maintained between 150-200 ng/ml by fluorescence polarization immuno-assay. In June 1996, the Se Cr was noted to have increased to 122 µmol/l accompanied by non-nephrotic range proteinuria. He underwent an allograft biopsy, which revealed striped interstitial fibrosis and tubular atrophy without lymphocytic inflammation. Occasional glomeruli showed ischemic collapse and the interlobular arteries were unremarkable. A diagnosis of chronic CyA toxicity was made. Also, at the same time, the patient developed mild hyperbilirubinemia and elevation of serum alkaline phosphatase levels to more than three times the upper limit of normal. The antimitochondrial antibodies were normal. Endoscopic retrograde cholangiopancreatography revealed focal areas of irregular ductal narrowing with intervening areas of dilatation. This beaded appearance was suggestive of sclerosing cholangitis. Liver biopsy showed enlargement, edema and scarring of the portal triads. There was also some mononuclear cell infiltration with piece-meal necrosis. There was no associated clinical evidence of enterocolitis or thyroiditis.
The dose of CyA was reduced in an effort to reduce the chronic toxicity and the levels were maintained between 80-120 ng/ml.
In August 1996, the patient had an episode of acute rejection, which was reversed successfully with pulse steroids as per our protocol. Option of use of FK506 as an alternative immunosuppressant was discussed with the patient, in view of the untoward effects of CyA. The patient refused the use of FK506 because of concerns of diabetes mellitus. After obtaining informed consent, it was decided to add MMF (3 g/day in two divided doses) to CyA and Pred in October 1996. The levels of CyA were aimed low, between 50-75 ng/ml and the patient remained stable with a Se Cr of 110-125 µmol/l. Intractable diarrhea necessitated reduction of MMF dose to 2 g/day by November 1996. The patient discontinued CyA on his own in December 1996 and he continued to use MMF 2 g/day and Pred 7.5 mg daily. A hepatic doppler performed in August 1998 showed evidence of portal hypertension. When last seen about two years after the use of MMF and Pred, the Se Cr was stable at around 120 µmol/l, inspite of the reduction in immunosuppression while the liver enzyme abnormalities have persisted.
| Discussion|| |
Mycophenolate mofetil, (Cellcept R) is the 2-(4)-morpholinoethylester of mycophenolic acid (MPA). It is rapidly converted to the active drug MPA after oral administration. MPA is a potent, selective, and noncompetitive inhibitor of inosine monophosphate dehydrogenase (IMPDH), particularly the type 11 isoform. Since this enzyme is required for the conversion of inosine monophosphate (IMP) to guanosine monophosphate (GMP), MMF administration decreases the metabolism of guanine nucleotides, via this de novo pathway. ,,
Compared with other cell types, lymphocytes rely on the de novo rather than the salvage pathway for the synthesis of GMP, guanosine disphosphate (GDP) and guanosine triphosphate (GTP). A deficiency of guanine nucleotides is known to inhibit allosterically many of the enzymes required for DNA synthesis and thereby inhibit cell proliferation.  MMF, therefore, functions as a potent inhibitor of lymphocyte proliferation and is effective in the arrest, as well as reversal of an ongoing allograft acute rejection episode. ,
In addition to inhibiting IMPDH, Allison et al have demonstrated that MMF blocks glycosylation of surface ligands, including VLA-4 on activated lymphocytes and adhesion molecules on lymphocyte target cells.  Thus, MMF interferes with the recruitment of lymphocytes and monocytes into sites of chronic rejection, blocking ongoing rejection at a time when clonal expansion has already taken place. 
MMF is a powerful and selective immunosuppressant for maintenance therapy following renal transplantation. It has been tested in three double-blind, placebocontrolled studies across three continents in renal transplant patients. These studies indicate that the use of MMF dramatically decreases the incidence of biopsy proven rejection, the use of multiple courses of steroids for rejection, and the use of antilymphocyte preparations for treatment of rejections. ,,
Additional work suggests that MMF may also be a valuable tool for arresting ongoing rejection episodes resulting in a clinically significant reduction in graft and patient loss in patients with acute refractory allograft rejection. One randomized, openlabel, multicenter study has compared the efficacy and safety of MMF, administered with CyA and low-dose corticosteroids, versus high-dose intravenous (i.v.) corticosteroids and conventional triple therapy, over a 6-month post-enrollment period, for the treatment of refractory acute cellular allograft rejection. Treatment with MMF resulted in a 45% reduction in graft loss by six months post enrollment. Use of MMF also significantly reduced the risks of experiencing a subsequent biopsy-proven rejection episode or treatment failure by 50%. The number of patients receiving one or more full courses of anti-lymphocyte therapy for a rejection episode subsequent to enrollment was more than two-fold greater in the i.v. steroid group compared with the MMF group. 
MMF is well tolerated with an acceptable safety profile. The common adverse effects are only infrequently reported as severe, and rarely result in discontinuation of therapy. Hematologic side effects are similar to those of Aza and result in reversible leukopenia. There is a slight increase in cytomegalovirus invasive disease, rarely, necessitating termination of therapy. ,
MMF has been used only in combination with CyA in different immunosuppressive regimens, as therapy for refractory rejection or as maintenance therapy. In our patient, we had to reduce CyA because of evidence of chronic CyA toxicity seen on allograft biopsy as well as hepatic dysfunction. Patient refused FK506 rescue because of family history of diabetes mellitus and prior evidence of glucose intolerance. After careful considerations and informed consent MMF was added to low-dose CyA and steroids for maintenance immunosuppressive therapy. Subsequently, CyA was discontinued by the patient. Stable renal function over the remaining follow-up period was observed despite the stoppage of CyA.
| Conclusion|| |
MMF is approved in the United States solely as a substitute for Aza, in maintenance immunosuppression for renal transplantation. Its use in recent years has been limited to combined use with CyA. We report a patient with CyA toxicity in whom only MMF and prednisone were used as double immunosuppression who maintained good allograft function despite the low immunosuppressive dosage.
| References|| |
|1.||Allison AC, Eugui EM, Sollinger HW. Mycophenolate mofetil (RS-61443): mechanisms of action and effects in transplantation. Transplant Rev 1993;7:129. |
|2.||Sollinger HW, Deierhoi MH, Belzer FO, et al. RS-61443: a phase 1 clinical trial and pilot rescue study. Transplantation 1992; 53:428-32. [PUBMED] |
|3.||Carter SB, Franklin TJ, Jones DF, et al. Mycophenolic acid: an anti-cancer compound with unusual properties. Nature 1969;223:848-50. [PUBMED] |
|4.||Franklin TJ, Cook JM. The inhibition of nucleic acid synthesis by mycophenolic acid. Biochem J 1969;113:515-24. [PUBMED] [FULLTEXT]|
|5.||Allison AC, Kowalski WJ, Muller CD, Eugui EM. Mechanism of action of mycophenolic acid. Ann NY Acad Sci 1993;696:63-87. [PUBMED] |
|6.||Allison AC, Eugui EM. The design of development of an immunosuppressive drug, Mycophenolate Mofetil. Springer Semin Immunopathol 1999;14:353-80. |
|7.||Morris RE, Hoyt EG, Murphy MP, Eugui EM, Allison AC. Mycophenolic acid morpholinoethylester (RS-61443) is a new immunosuppressant agent that prevents and halts heart allograft rejection by selective inhibition of T- and B-cell purine synthesis. Transplant Proc 1990;22:1659-62. [PUBMED] |
|8.||Platz KP, Bechstein WO, Eckhooff DE, Suzuki Y, Sollinger HW. RS-61443 reverses acute allograft rejection in dogs. Surg 1991;110(4):736-40. |
|9.||Allison AC, Almquist SJ, Muller CD, Eugui EM. In vitro immunosuppressive effects of mycophenolic acid and an ester prodrug, RS-61443. Transplant Proc 1991; 23:10-4. |
|10.||Gonwa TA. Mycophenolate mofetil for maintenance therapy in kidney transplantation. Clin Transplant 1996;10:128-30. [PUBMED] |
|11.||European Mycophenolate Mofetil Cooperative Study Group. Placebo-controlled study of mycophenolate mofetil combined with cyclosporine and corticosteroids for prevention of acute rejection. Lancet 1995; 345:1321-5. |
|12.||A blinded, randomized clinical trial of mycophenolate mofetil for the prevention of acute rejection in cadaveric renal transplantation. The Tricontinental Mycophenolate Mofetil Renal Transplantation Study Group. Transplantation 1996;61: 1029-37. [PUBMED] [FULLTEXT]|
|13.||The Mycophenolate Mofetil Renal Refractory Rejection Study Group. Rescue therapy with Mycophenolate mofetil. Clin Transplant 1996;10:131-5. |
|14.||Pirsch JD, Sollinger HW. Mycophenolate mofetil-clinical and experimental experience. Ther Drug Monit 1996;18:357-61. [PUBMED] [FULLTEXT]|
Department of Medicine, King Fahd National Guard Hospital, P.O. Box 22490, Riyadh 11426