Mycophenolate Mofetil Withdrawal Research Articles

Mycophenolate Mofetil – Associated Pseudo-Crohn Colitis

Mycophenolate mofetil (MMF) was introduced in the pratice of clinical transplantation for more than 10 years. In live transplant patients, its use evolved from toxicity-sparing protocols to the most common regimen of maintenance immunosupression at hospital discharge. Gastrointestinal toxicity however, usually manifested as chronic diarrhea of unknown origin, is a common side effect, but only recently a pattern of injury described as Crohn's like changes has been defined. A male Caucasian 20 years old patient had OLT 6 years ago for isoflurane fulminant liver failure. For five year, on a double maintenance regimen of tracholymus and MMF, he was clinically stable through with insulin dependent diabetes mellitus from the 8th month post OLT. On his 5 year postop, he began to experience chronic diarrhea, progressively prolonged, with blood and night fever. We found mycrocytic anemia, ESR of 100 and hipokaliemia. He was admitted for 3 times, when several microbiologic, histologic and endoscopic studies were performed. After finding a Cohn's like pancolitis with patchy erithema, granularity and longitudinal serpiginous ulcers (with ileal and rectal sparring), several attempts were made to find CMV, tuberculosis or other mycobacteria, without success. Immunosupression was reduced and developed steroid sensitive rejection. After MMF withdrawal and rejection control, there was a clinical and endoscopic significative improvement. We present the endoscopic and histologic iconography, supporting the diagnosis of MMF Pseudo-Crohn's Colitis.

Mycophenolate Mofetil Dose Reductions and Discontinuations after Gastrointestinal Complications Are Associated with Renal Transplant Graft Failure

Mycophenolate mofetil (MMF) use in renal transplantation has steadily increased since 1995 because of its ability to lower the risks of rejection and chronic allograft nephropathy. However, significant gastrointestinal (GI) complications may lead to MMF dose reductions and discontinuations. Little is known of the association between MMF dose reductions and discontinuations following GI complications and graft survival. Using the United States Renal Data System, we identified 3,675 adult recipients (age >or=18) with a diagnosed GI complication who were prescribed MMF at the time of first GI diagnosis and had Medicare as their primary insurer. MMF doses were ascertained from Medicare payment records. We estimated risk of graft loss associated with MMF dose adjustments after GI diagnosis: dosage unchanged (reference), reduced <50%, reduced >or=50%, and MMF discontinued. Patients were followed until graft loss, death, last recorded immunosuppression prescription, or 3 years posttransplant. Compared to those with no MMF dose reductions or discontinuations, the risk of graft failure increased with MMF doses reduction >or=50% (HR=2.36, 95% CI 1.23-4.54) and those with MMF discontinuation (2.72, CI 1.60-4.64). Renal transplant recipients who underwent MMF dose reduction or withdrawal following GI diagnosis are associated with increased risk of graft failure.

Mycophenolate mofetil withdrawal

Mycophenolate mofetil withdrawal

Late Developing C4d-Positive Humoral Renal Allograft Rejection Associated With Withdrawal of Mycophenolate Mofetil

In renal transplantation, C4d-positive acute humoral rejection (AHR) usually develops in the early stage posttransplantation. It is clear C4d can be detected late after the operation, when it is associated with chronic renal allograft rejection. We report a case of a renal allograft recipient who experienced C4d-positive acute renal allograft rejection associated with withdrawal of mycophenolate mofetil (MMF) at 10 months after transplantation. This 21-year-old single male patient received his first cadaveric renal allograft under immunosuppression with cyclosporine, MMF, and prednisolone. The serum creatinine recovered to the normal range within 4 days. A protocol biopsy performed at 1 month after transplantation revealed no signs of rejection. The graft function was stable until 10 months postoperation, when MMF was converted to mizoribin. Three days later a biopsy showed a C4d-positive rejection. Patient had no response to the MMF combined with tacrolimus and steroid bolus therapy, which generally improves 85% of AHR among Chinese. He finally returned to dialysis. Our report suggested that C4d positive AHR may occur late after transplantation. MMF is important to suppress the body’s humoral response to allograft; when MMF was converted to a weaker immunosuppressant, the dose of the other immunosuppressants (cyclosporine for example) must be adjusted properly.

Primary CNS lymphoma complicating treatment of myasthenia gravis with mycophenolate mofetil

Mycophenolate mofetil (MM), an immunosuppressant used after organ transplantation, is also used for treatment of autoimmune myasthenia gravis (MG). A patient with generalized MG was effectively managed with MM but developed CNS lymphoma after 3 years of treatment. Primary CNS lymphoma regressed on withdrawal of MM. Despite minimal short-term side effects and apparent efficacy, chronic treatment of MG with MM may be associated with increased risk of lymphoproliferative disorders.

Mycophenolate mofetil in steroid/cyclosporine-dependent/resistant nephrotic syndrome

Attempts to minimize the effects of prolonged steroid use in steroid-dependent nephrotic syndrome (SDNS) and the need to overcome steroid resistance (SRNS) justifies immunosuppressant therapy. We report our experience in a cohort of patients with SD/SRNS during the administration of mycophenolate mofetil (MMF) in a prospective protocol initiated in January 2001. Twenty-six children with idiopathic nephrotic syndrome were included (21 steroid dependent and 5 steroid resistant), whose response did not change after sequential treatment with cyclophosphamide (CPM) and cyclosporine (CsA). Histopathologic patterns were: 11 minimal change disease (MCD), 1 diffuse mesangial proliferation (DMP), 13 focal segmental glomerulosclerosis (FSGS) and membranous 1 glomerulonephritis (MGN). The median age of onset of NS was 2.8 years (range 1.2-12.5), and treatment with MMF was performed at a median age of 11.4 years (range 5-17) with an initial dose of 600 mg/m(2)/12 h, adjusted to maintain levels of mycophenolic acid (MPA) at 2.5-5 mcg/ml. The planned duration of study to assess treatment efficacy was 6 months. The mean MMF dose required was 624 (SD=136) mg/m(2)/12 h (range 415-970), which maintained mean C(0)-MPA levels of 2.9 (SD=1.17) mcg/ml (range 1.2-5.9 mcg/ml). In the five patients with SRNS, only one achieved complete remission. In the patients with SDNS, steroid sparing was achieved in 15 and 9 remained in remission on MMF monotherapy. Withdrawal of MMF resulted in immediate relapse in 47%. In our study, MMF was a useful immunosuppressant due to its fewer undesirable effects and similar efficacy to other drugs used. It appears effective for the maintenance of remission in SDNS patients, with a response similar to that of CsA.

Uncommon Side Effect of MMF in Renal Transplant Recipients

Mycophenolate mofetil (MMF) is a potent immunosuppressive agent used in renal transplantation. Gastrointestinal and hematological side effects are commonly observed, but hepatotoxicity has not been reported. In this study, we assessed MMF-related hepatotoxicity in renal transplant recipients. A total of 124 renal transplantation recipients (RTRs) were evaluated for elevated liver enzymes associated with MMF, and 79 patients were enrolled to the study. Patients used MMF 2 g/day. The patients who had progressive increase in liver enzymes after renal transplantation and their AST, ALT, GGT, ALP, bilirubin levels, hepatitis, cytomegalovirus (CMV), abdominal ultrasonography, duration of hepatotoxicity, and decreased dosage or withdrawal of MMF were recorded. Also, we evaluated their liver enzymes while the patients were on the waiting list. Of the 79 patients, 11 patients (13.9%) had a progressive increase in liver enzymes. The median (min–max) age of the patients with MMF-hepatotoxicity was 29 (19–54) and 72.7% of them were male. None of the patients had hepatitis B or C, CMV infection, or other possible causes for elevated liver enzymes and their abdominal ultrasonography were normal. High liver enzyme levels regressed after the withdrawal (n = 6) or reduce dosage (n = 5) of MMF. The median time of the increase in liver enzymes was 28 (4–70) days and after 50% reduction or withdrawal of MMF, returned to normal values in 16 (4–210) days. The median levels of ALT in waiting list (I), before (II), and after (III) reduction dosage or withdrawal of MMF were 22.0 (3–22), 222.0 (51–508), and 33.0 (21–64) U/L, respectively (p I–II = 0.004, p I–II = 0.013, and p II–III = 0.005). There were no differences for ALP, GGT, total bilirubin, and direct bilirubin levels. Also, the correlation between recovery time of ALT and persistence time of ALT elevation before adjustment of MMF was significant (r = 0.739, p = 0.009). Consequently, after renal transplantation, hepatotoxicity can occur due to a lot of reason including MMF usage. If hepatotoxicity related to MMF is not considered, especially in the early period of renal transplantation, resolution of hepatotoxicity can be required long term.

Minimization of Immunosuppressive Therapy After Renal Transplantation: Results of a Randomized Controlled Trial

Modern immunosuppressive regimens reduce the acute rejection rate by combining a cornerstone immunosuppressant like tacrolimus or cyclosporine with adjunctive agents like corticosteroids, mycophenolate mofetil (MMF) or azathioprine, often associated with untoward side effects. A 6-month randomized study was conducted in 47 European centers. Triple therapy with tacrolimus (trough levels 5-15 ng/mL), corticosteroids (dosage 10 mg/day) and MMF (1 g/day) was administered for 3 months. From day 92, patients either continued with triple therapy (control, n = 277), or stopped steroids (n = 279), or stopped MMF (n = 277). Surrogate markers for long-term benefits were changes in lipid profiles and occurrence of hematological, gastrointestinal and infectious complications. The 6-month acute rejection incidence (biopsy-proven) was similar in all groups (17.0% vs. 15.1% vs. 14.8%, p = 0.744), although the incidence after month 3 was higher in the steroid stop group than in the two other groups. Mean reductions in total cholesterol (18.9 mg/dL [0.49 mmol/L]) and LDL-cholesterol (8.1 mg/dL [0.21 mmol/L]) between months 4 and 6 were greater in the steroid stop group (p < 0.001). Leukopenia (p = 0.0082), serious CMV infection (p = 0.024), anemia (p = NS) and diarrhea (p = NS) were less frequent in the MMF stop group. In a study population of immunologically low-risk patients' withdrawal of corticosteroids or MMF from a tacrolimus-based therapy at 3 months was feasible. A longer follow-up will be needed to confirm the expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.

Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil

Abstract This study examined consequences of gastrointestinal (GI) complications and mycophenolate mofetil (MMF) discontinuation on long-term outcomes in patients who received MMF at transplantation and had graft function 12 months post-transplantation. Data were obtained from the United States Renal Data System for cadaveric renal transplant recipients between 1995 and 1998. GI complications or MMF discontinuation occurred in 27.4% and 17.5% of patients, respectively. MMF was discontinued in 21.3% of patients with GI complications and 16.0% of patients without (P < 0.00001). Four-year graft survival was reduced from 87.1% to 82.3% (P= 0.091) with MMF discontinuation, to 83.0% (P= 0.001) with GI complications, and to 70.2% (P < 0.0001) with GI complications and MMF discontinuation. While the retrospective nature of this work cannot prove causality, which will require future prospective studies, both GI complications and MMF withdrawal are associated with increased risk of graft loss and may warrant further study in the management of transplant recipients.

Long-term outcome of gastrointestinal complications in renal transplant patients treated with mycophenolate mofetil

This study examined consequences of gastrointestinal (GI) complications and mycophenolate mofetil (MMF) discontinuation on long-term outcomes in patients who received MMF at transplantation and had graft function 12 months post-transplantation. Data were obtained from the United States Renal Data System for cadaveric renal transplant recipients between 1995 and 1998. GI complications or MMF discontinuation occurred in 27.4% and 17.5% of patients, respectively. MMF was discontinued in 21.3% of patients with GI complications and 16.0% of patients without (P<0.00001). Four-year graft survival was reduced from 87.1% to 82.3% (P=0.091) with MMF discontinuation, to 83.0% (P=0.001) with GI complications, and to 70.2% (P<0.0001) with GI complications and MMF discontinuation. While the retrospective nature of this work cannot prove causality, which will require future prospective studies, both GI complications and MMF withdrawal are associated with increased risk of graft loss and may warrant further study in the management of transplant recipients.

Conversion from mycophenolate mofetil to azathioprine in high-risk renal allograft recipients on cyclosporine-based immunosuppression

Objective. In a randomized control trial of mycophenolate mofetil (MMF) versus azathioprine (AZA) with cyclosporine and steroids, we demonstrated that MMF reduced acute rejection (AR) among renal allograft recipients (RTX) who were of low to moderate risk. However, 10% had AR when converted from MMF to AZA at 6 months, postrenal transplantation (RT). Two clinical markers, abnormal serum creatinine (SCr) and proteinuria at 6 months, post-RT, were associated with AR postconversion. The present study examined the safety of such conversion in selected high-risk RTX at 1 year of MMF therapy. Methods. Thirteen high-risk RTX receiving MMF for either high panel reactive antibody (n = 9) or following AR (n = 4), with normal SCr and no proteinuria at 1 year, were selected for conversion. The incidence of AR, adverse events, and renal parameters (SCr, creatinine clearance, proteinuria) at 6 months postconversion was evaluated. Eight high-risk RTX who did not meet these selection criteria were retrospectively reviewed and used as controls. Results. Renal parameters (SCr 123 ± 26 vs 129 ± 27 μmol/L; pre- vs postconversion) were not significantly different; no episodes of AR or proteinuria were documented. Azathioprine was discontinued in two patients due to leukopenia. In the control group, one patient had graft loss from chronic rejection, whereas one developed posttransplant lymphoproliferative disease necessitating MMF withdrawal. Conclusion. These results suggest that selective conversion from MMF to AZA after 1 year is safe, even in high-risk RTX. Normal SCr and absence of proteinuria are good screening parameters to identify patients at low risk for AR following such conversion.

Self-resolution of Epstein-Barr virus–associated B-cell lymphoma in a patient with dermatomyositis following withdrawal of mycophenolate mofetil and methotrexate

Self-resolving Epstein-Barr virus (EBV)–associated lymphomas have become more common with the use of immunosuppressive agents in both transplant patients and patients with connective tissue disorders. Immunosuppressive agents are often used for control of dermatomyositis, but their use has not been linked to subsequent malignancy. We present a 46-year-old woman with dermatomyositis, who developed an EBV-associated B-cell lymphoma of the brain while on oral methotrexate, mycophenolate mofetil and low-dose prednisone. The patient's lymphoma gradually resolved “spontaneously” upon discontinuation of the methotrexate and mycophenolate mofetil. The potential for EBV-associated B-cell lymphoma to self-resolve should be recognized by the clinician in order to prevent unnecessary and potentially toxic treatments including radiation therapy or multi-drug chemotherapy.

Effectiveness and safety of mycophenolate mofetil as monotherapy in liver transplantation

Introduction Calcineurin inhibitors (CIs) cause substantial long-term morbidity and mortality among orthotopic liver transplantation (OLT) patients. Our aim was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) among OLT patients with CI-related side effects. Patients Thirty three adult patients, including 29 men and 4 women of mean age 57 years, underwent OLT between 1986 and 2000 under treatment with CIs (28 cyclosporine and five tacrolimus). Mean follow-up after OLT was 59 months. Adverse effects were renal dysfunction in 26, hypertension in 23, and neurotoxicity in two. MMF was added gradually while simultaneously reducing the dosage of CI. Results After a mean 15-months follow-up of MMF treatment, CIs had been withdrawn in 28 patients (85%). The mean time from the initiation of MMF and CI withdrawal was 5 months. During the first year of follow-up chronic renal dysfunction improved in 16 of 26 patients (61.6%) accompanied by a decreased serum creatinine and urea and an increase in creatinine clearance. Among 13/23 (56.5%) hypertensive patients, there was a significant decrease in blood pressure or the number of antihypertensive drugs ( P < .05). One patient with neurotoxicity improved. Twenty-two patients (66%) displayed adverse events: five rejections (15%) including four acute episodes, controlled by CI re-introduction, and one chronic reaction. The most frequent adverse effects were herpes simplex infection in 10 patients (30%), asthenia in nine (27%), diarrhea in five (15%) and thrombocytopenia in four (12%). Nevertheless, only six patients (19%) required MMF dose reduction, namely, three patients with GI intolerance, two with repeated VHS infections, and one with anemia. Conclusions MMF monotherapy improves renal function and blood pressure levels in more than 50% of patients with chronic renal impairment and hypertension after OLT. Many of the side effects of MMF were mild; it was safe accompanied by a low incidence of rejection reactions.

Elective withdrawal of mycophenolate mofetil in renal transplant recipients treated with mycophenolate mofetil, cyclosporine, and prednisone.

In a retrospective study we investigated the risk of acute rejection after the withdrawal of mycophenolate mofetil (MMF) in 39 adult patients treated with cyclosporine (CyA), prednisone, and MMF for at least 6 months following renal transplantation. After reaching a stable renal graft function, MMF was withdrawn and CyA and prednisone were continued. Preceding the withdrawal of MMF, four patients experienced an acute rejection. During a median follow-up of 38 months after discontinuing MMF, no acute rejection occurred. The mean serum creatinine level did not change during the first 6 months after withdrawal of MMF. We conclude that elective withdrawal of MMF in stable renal transplant recipients at 6 months after transplantation bears no important risk of an occurrence of acute rejection.

Elective withdrawal of mycophenolate mofetil in renal transplant recipients treated with mycophenolate mofetil, cyclosporine, and prednisone

Abstract In a retrospective study we investigated the risk of acute rejection after the withdrawal of mycophenolate mofetil (MMF) in 39 adult patients treated with cyclosporine (CyA), prednisone, and MMF for at least 6 months following renal transplantation. After reaching a stable renal graft function, MMF was withdrawn and CyA and prednisone were continued. Preceding the withdrawal of MMF, four patients experienced an acute rejection. During a median follow-up of 38 months after discontinuing MMF, no acute rejection occurred. The mean serum creatinine level did not change during the first 6 months after withdrawal of MMF. We conclude that elective withdrawal of MMF in stable renal transplant recipients at 6 months after transplantation bears no important risk of an occurrence of acute rejection.

Adverse gastrointestinal effects of mycophenolate mofetil: aetiology, incidence and management.

Mycophenolate mofetil (MMF) is a relatively new immunosuppressive drug. It inhibits inosine monophosphate dehydrogenase, a key enzyme in the de novo pathway of purine synthesis, and thus causes lymphocyte-selective immunosuppression. Large clinical trials have revealed the efficacy of MMF in the prevention of allograft rejection when administered together with cyclosporin or tacrolimus and corticosteroids. Although the adverse effect profile of MMF is comparatively benign, gastrointestinal adverse effects are a major concern. These effects are partially explained by the increased immune suppression, by the mode of action and by interactions, particularly with other immunosuppressants. The aetiology of the rarest gastrointestinal adverse effects is still not completely clear. Therapy depends upon the clinical gravity of the adverse effects and is therefore a case of waiting and ob- serving. An adjustment of dosage of immunosuppressants according to the clinical situation and, particularly in the case of MMF, spreading the total dosage over more than 2 daily doses are often sufficient. Should adverse effects persist for a longer period of time and be of a more serious nature, a comprehensive invasive diagnostic process is necessary, including endoscopy and biopsy and the search for opportunistic infections. In this case, dosage reduction or the complete withdrawal of MMF seems to be unavoidable. Severe gastrointestinal complications with MMF are rare, but when they do occur they may require extensive diagnosis and treatment. In the future, therapeutic drug monitoring and, where necessary, pharmacological modifications of MMF could lead to a further reduction of adverse effects with an equal or even increased efficacy.

WITHDRAWAL OF MYCOPHENOLATE MOFETIL IN STABLE RENAL TRANSPLANT PATIENTS

440 Mycophenolate mofetil (MMF) has been shown to decrease episodes of acute rejection in renal transplant recipients during the first year. The utility of MMF after one year is less clear. We looked at withdrawal of MMF in stable renal transplant recipients after one year. Methods: 70 stable renal transplant patients who had not had an episode of acute rejection were screened. All patients were on Neoral, MMF (initially 1 gm bid) and Prednisone. Patients were assigned to be taken off MMF and to remain on dual therapy (35) or to remain on triple therapy (35). CsA 12 hour trough concentrations were maintained above 150 ng/ml and the Prednisone dose above 5mg/day. Results: A total of 35 patients were taken off MMF at 20.7 ± 9.2(range 5-56) months post tx, and followed up for 7.6 ± 5.3 (range 1-26) months post withdrawal. Of these 35 patients one patient suffered a rejection episode (borderline) 5 month after MMF withdrawal. As displayed in the table no differences in renal function as estimated by the calculated creatinine clearance (CrCl) and serum creatinine (Scr) were observed after as compared to before MMF withdrawal. There were also no changes in incidence of proteinuria, hyperlipidemia or hematological abnormalities. A general linear model for repeated measures did not show any significant differences over time of the above parameters in the MMF withdrawal group as compared to the control group over the total follow up period (28.3 ± 8.7 and 29.3 ± 7.2 months respectively). Conclusions: Our preliminary data would suggest that it may be safe to withdraw MMF at one year in stable renal transplant patients who had no previous acute rejection.Table

Incidence of leukopenia and cytomegalovirus disease in kidney transplants treated with mycophenolate mofetil combined with low cyclosporine and steroid doses

Mycophenolate mofetil (MMF) combined with conventional cyclosporine and steroids doses efficiently prevents acute rejection in kidney transplants. However, this regimen has been associated with an increased incidence of cytomegalovirus (CMV) disease and leukopenia, specially in patients receiving MMF at 3 g/d, suggesting that the combination of two powerful immunosuppressants carries the risk of overimmunosuppression. For this reason, we treated a group of patients with MMF 3 g/d combined with low cyclosporine and steroids doses. Eighty‐two kidney transplants performed at two centers and enrolled in the European Mycophenolate Mofetil Cooperative Study were randomized to receive: A) placebo (n = 27); B) MMF 2 g/d (n = 27); and C) MMF 3 g/d (n = 28). In this double blind study all patients received. cyclosporine and steroids at conventional doses. Fifteen kidney transplants enrolled in an MMF open pharmacokinetic study were treated with MMF 3 g/day combined with low cyclosporine and steroid doses. (group D). Efficacy was evaluated as the incidence of biopsy proven acute rejection, and safety focused on CMV disease and leukopenia. Patients receiving MMF showed a low incidence of biopsy proven rejection (B) 18.5%; C) 10.7%; and D) 13.3%). Patients of group C had a high incidence of CMV disease (35.7%) when compared with the other groups (lower than 8%). Incidence of leukopenia was higher in patients treated with MMF (B) 25.9%; C) 39.3%; and D) 40%) than in placebo treated patients (7.4%). Patients in group (C) displayed leukopenia mainly in the context of CMV disease, while patients of group (D) had leukopenia not related to CMV infection. All patients of group (D) who presented leukopenia recovered after MMF reduction dose, while in group (C) there were 5 out of 28 patients who required MMF withdrawal. We propose that a reasonable approach to take advantage of a powerful non‐nephrotoxic immunosuppressant such as MMF, could be the administration of this drug at 3 g/d from the time of transplantation combined with low CSA and steroid doses.

INCIDENCE AND MANAGEMENT OF MYCOPHENOLATE MOFETIL ADVERSE EFFECTS IN SIMULTANEOUS KIDNEY/PANCREAS TRANSPLANT RECIPIENTS

539 Mycophenolate mofetil (MMF) is a potent noncompetitive, reversible enzyme inhibitor of the de novo purine synthetic pathway which selectively blocks both T-and B-lymphocyte proliferation. MMF in combination with FK-506 or cyclosporine has been shown to decrease the incidence of rejection in simultaneous kidney/pancreas (SKP) transplant recipients. However, tolerability and serious adverse effects of MMF in combination with FK-506 are relatively unknown. The purpose of this study was to describe the incidence and management of adverse effects when used in combination with FK-506 in SKP transplantation. A cohort of 19 patients undergoing SKP transplantation between February 9, 1997 and September 22, 1997 received an immunosuppressive regimen consisting of FK-506, steroids, and MMF without antilymphocyte induction. Surgical technique performed included 10 (53%) with portal-enteric and 9 (47%) with systemic-bladder drainage. All patients were Caucasian and 12(63%) were male, with a mean age of 40.4 years. The incidence of acute rejection was 26%. Four patients had biopsy proven kidney rejection and one patient had biopsy proven pancreas rejection treated with ATGAM (n=3) and OKT3(n=2). One patient developed recurrent rejection responsive to steroid therapy alone. There was no graft loss due to rejection. Infectious complications included bacteremia in 10 (53%), UTI in 5 (26%), fungal infections in 3 (16%), CMV infection in 2 (11%), and other infections in 2 (11%). One patient developed post transplant lympho-proliferative disease (PTLD) 10 months post transplant. The initial dosing regimen for MMF was 1 gm BID in 9 (47%), 750 mg QID in 7 (37%), and 500 QID in 3 (16%). After these starting dosage regimens 18 (95%) patients required dosage reduction secondary to adverse effects. The reason for dosage reduction included: GI side effects in 12 (63%), leukopenia in 5 (26%), thrombocytopenia in 2 (11%), CMV in 2 (11%), and PTLD in 1 (5%). Four patients had temporary MMF withdrawal for viral infection (2 CMV, 1 EBV-lymphoma) or leukopenia for a mean of 15 days. After a mean follow-up of 6 months, 53% of patients were unable to tolerate a dose of 2 gms/day, and all patients required a QID rather than a BID dosing regimen to minimize GI toxicity. Patient and kidney/pancreas graft survival rates are 100%. Conclusion: This preliminary experience with MMF in combination with FK-506 shows efficacy in controlling rejection but dose limiting toxicity. However, the use of these agents in combination may result in additive GI side effects based on the fact that less than 50% of patients could tolerate goal doses of MMF.