Mycophenolate Mofetil Dose Reduction Research Articles

Mycophenolic acid agents: is enteric coating the answer?

Correspondence: Matthew Cooper Division of Transplantation, University of Maryland School of Medicine, Baltimore, MD, USA Tel +1 410 328 7336 Fax +1 410 328 6343 email mcooper@smail.umaryland.edu Abstract: Addition of mycophenolate mofetil (MMF) to calcineurin-based immunosuppressive therapy has led to a significant improvement in graft survival and reduction of acute rejection in renal transplant recipients. However, in clinical practice, MMF dose reduction, interruption, or discontinuation due to hematological and gastrointestinal (GI) side-effects occurred in up to 50% of the patients. Large retrospective analyses have demonstrated that patients requiring MMF dose manipulation due to adverse events experienced a higher rate of rejection and graft loss. Enteric-coated mycophenolate sodium (EC-MPS) was developed with the goal of improving upper GI side-effects. Here, we review the efficacy and safety of EC-MPS in de novo kidney transplant recipient, and in stable renal transplant patients who were converted from MMF. The changes in GI-related adverse events using patient-reported outcome instruments are also reviewed.

Mycophenolic Acid Dose Reductions Result in Poor Long-Term Renal Allograft Survival: Comparison Between Mycophenolate Sodium and Mycophenolate Mofetil

Mycophenolate acid (MPA) therapy is associated with a decrease in acute rejection rates and excellent renal allograft survival. Unfortunately, mycophenolate mofetil (MMF) is associated with significant adverse effects (AE), which, in many cases, preclude full-dose therapy. Previously, lower MMF drug exposure was significantly associated with a greater risk of rejection. Patients who had a ≥50% dose reduction of MMF experienced a lower graft survival compared to those who tolerated full-dose MMF. Mycophenolate sodium (MPS) was designed to lessen MPA-associated AE. In this retrospective study, we studied the tolerability and long-term outcomes in renal transplant recipients (RTR) treated with MPS versus MMF. Four hundred forty-nine RTRs who received MPS or MMF for more than 3 months were classified into three groups: group 1: MMF-treated; group 2: MPS-treated; and group 3; patients who converted from MMF to MPS due to AE. Donor and recipient demographics as well as induction and maintenance immunosuppressive therapies were similar in all groups. Patient survival was not different in all groups. However, long-term graft survival was lower in patients whose dose of either MPS or MMF was reduced by ≥50%. Moreover, a ≥50% MPA dose reduction was associated with a higher rate of rejection compared to full dose (38% vs 21%, respectively, P < .01). Compared to patients treated initially with MMF, fewer MPS-treated recipients required dose reductions (65% vs 42%, respectively, P < .001). Furthermore, 38% of patients in group 3 tolerated full-dose MPS despite previous intolerance to MMF. Finally, the long-term graft survival was best in MPS-treated RTR and worst in those who converted from MMF to MPS due to AE. We conclude that MPS is better tolerated than MMF, which may explain the superior graft outcome in RTR who were treated with MPS from the onset.

Impact of Mycophenolate Mofetil Dose Reduction on Allograft Outcomes in Kidney Transplant Recipients on Tacrolimus-Based Regimens: A Systematic Review

To systematically evaluate the clinical consequences of mycophenolate dose reduction in renal transplant recipients on tacrolimus-based regimens. PubMed (1949-July 2010), EMBASE (1980-July 2010), Cochrane Database of Systematic Reviews, International Pharmaceutical Abstracts, and Web of Science were searched using the terms mycophenolate mofetil, tacrolimus, dose reduction, and kidney and/or renal transplant. References from publications identified were reviewed. Studies reporting on rejection rate, allograft survival, or renal function were included and ranked according to the US Preventive Services Task Force classification; excluded were studies that were dose-finding or used cyclosporine only, involved patients on enteric-coated mycophenolate sodium or those with multiorgan transplant, or provided no information on concomitant immunosuppressants. Data extracted were study design, sample size, immunosuppression regimen, type of transplant, and allograft outcomes. Of 13 studies included, 1 was level I evidence, 3 were level II-2, 6 were level II-3, and 3 were level III evidence. Three focused on tacrolimus-based regimens, whereas 7 included either cyclosporine or tacrolimus. The only prospective, randomized, multicenter trial demonstrated that early taper of mycophenolate dosage to 1 g/day can be utilized without increased risk of rejection, compared with late tapering, but the rejection rate was high (30-40%). Overall, we found conflicting evidence regarding the impact of mycophenolate dose reduction on rejection rate and allograft loss and that discontinuing mycophenolate led to an increased risk of graft loss as high as 8 fold. Allograft survival was lowest in patients with gastrointestinal complications and those in whom mycophenolate was discontinued, compared with patients with neither gastrointestinal complications nor mycophenolate discontinuation. Weak evidence suggests that mycophenolate dose modifications, either reduction or discontinuation, may increase rejection rate and graft loss; however, this is more apparent in cyclosporine-based regimens. Prospective, well-designed trials are necessary to definitively determine the impact of dose reduction in renal transplant recipients on tacrolimus-based regimens.

Sustained Renal Response to Mycophenolate Mofetil and CNI Taper Promotes Survival in Liver Transplant Patients with CNI-Related Renal Dysfunction

The aim of this trial was to evaluate the impact of conversion from a calcineurin-inhibitor (CNI)-based immunosuppressive regimen to mycophenolate mofetil (MMF) and reduced-dose CNI on long-term renal function and survival in a series of 63 liver transplant patients with CNI-induced renal dysfunction. CNI dosage was significantly tapered after introduction of 2,000 mg MMF per day. Renal function was assessed by determination of serum creatinine levels and calculated creatinine clearance (CCl). The impact of relevant clinical parameters on renal function and survival post-conversion was analyzed by univariate and multivariate analysis. At 60 months post-conversion, mean creatinine level had significantly declined from 197.2±58.3 μmol/l at baseline to 160.0±76.5 μmol/l, and mean CCl has significantly increased from 38.4±13.4 ml/min at baseline to 47.9±21.1 ml/min (p<0.001), respectively. Forty-six patients (73.1%) demonstrated sustained renal response to modified immunosuppression. Full-dose MMF medication (p=0.006) and the early conversion (p=0.02) were identified as independent predictors of persistent renal function improvement. Sustained renal response to MMF plus reduced-dose CNI was identified as the most relevant independent promoter of long-term survival (hazard ratio 6.9). Five-year survival rate post-conversion was 93.9% in renal responders and 64.3% in renal non-responders (log rank<0.001). Sustained renal response to MMF and CNI dose reduction promotes long-term survival in liver transplant patients with CNI-induced renal dysfunction.

Rapid resolution of persistent mycophenolate mofetil-induced diarrhoea with a single dose of infliximab

Background Diarrhoea is a common complication seen in renal transplant recipients. Post-transplantation diarrhoea may result from infectious agents, drug-specific effects or metabolic conditions. Although infections are the major cause of diarrhoea after transplantation, almost a quarter of the cases are related to medication. Approximately 50% of the drug-induced diarrhoea is caused by mycophenolate mofetil (MMF) [1]. MMF is a commonly used immunosuppressive agent that can induce ulcerating colitis [2,3]. MMF-induced ulceratingcolitis isadiagnosisbyexclusion. The pathological diagnosis is difficult because of the similarities with other causes of diarrhoea such as inflammatory bowel disease [4]. Although MMF-induced colitis usually resolves after dose reduction or cessation of MMF, persistent cases havebeen reported [5]. We present a case in which MMF-induced ulcerating colitis persisted after withdrawal of MMF but was successfully treated with tumour necrosis factor-alpha (TNF-α) inhibition.

Posttransplant Lymphoproliferative Disorders of the Central Nervous System After Kidney Transplantation: Single Center Experience Over 40 Years -Two Case Reports-

Posttransplant lymphoproliferative disorder (PTLD) is one of the life-threatening complications of organ transplantation. PTLD sometimes involves the central nervous system (CNS), but the clinical characteristics are not well recognized. A total of 631 patients received kidney transplantation at Osaka University Hospital between March 1965 and December 2008. Two of the 631 patients (0.32%) developed CNS PTLD. A 40-year-old Japanese woman suffered onset of CNS PTLD 5 years after renal transplantation. After diagnosis based on histological examination by open biopsy, she obtained remission with dose increase of steroid and dose reduction of mycophenolate mofetil. She experienced relapse 20 months after first remission. She underwent second biopsy and the diagnosis was recurrent CNS PTLD. Further reduction of mycophenolate mofetil and increase of steroid led to second remission. The disease remained in complete remission at 60 months after first onset. A 61-year-old woman suffered onset of CNS PTLD 19 years after renal transplantation. After tumor removal, whole brain irradiation was performed. The disease remained in remission at 54 months after onset. Histological examination showed polymorphic-type PTLD in both cases. The first case of polymorphic CNS PTLD was successfully treated by modulation of immunosuppressants without radiation therapy even at recurrence. PTLD should be included in the differential diagnosis of brain tumors in recipients of solid organ transplantation, and histological subtype should be carefully identified to establish the correct treatment strategy.

Mycophenolate Mofetil Versus Enteric-Coated Mycophenolate Sodium After Simultaneous Pancreas-Kidney Transplantation

Introduction Adverse gastrointestinal events are frequent after mycophenolate use. The objectives of the present study were to report the incidence of acute noninfectious diarrhea, to determine the risk factors, and to compare the severity of reactions between mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) after simultaneous pancreas kidney transplantation (SPKT). Methods We included 165 SPKT patients from December 2000 to May 2007. Uni- and multivariate analyses were performed, using acute noninfectious diarrhea as the dependent variable. P < .05 was considered significant. Results Mean age and duration of dialysis and of diabetes were 34.9 ± 8.2 years, 27.3 ± 18.3 months, and 21.9 ± 16.2 years, respectively. Sixty-three percent used MMF, 36.4% used EC-MPS, and 0.6% used azathioprine. Multivariate analysis showed that the duration of diabetes ( P = .049, confidence interval [CI] 1.0– 1.13) and MMF use ( P = .013, 95% CI 0.2–0.82) were the main determinants of acute diarrhea after SPKT. MMF dose reduction (79.2% vs 62.3%, P = .024) and severity of diarrhea associated with orthostatic hypotension were more pronounced among MMF than EC-MPS patients (42.4% vs 15.1%, P = .001). There was no difference between MMF and EC-MPS after dose reduction in relation to the occurrence of acute kidney rejection (30.8% vs 26.7%, P = .53). Conclusions Acute noninfectious diarrhea after SPKT was related to the duration of diabetes and to prescription of MMF. Preferential use of EC-MPS was associated with a lower necessity of dose reduction and less severe episodes of acute diarrhea compared with MMF, although dose reduction was equally associated with acute episodes of kidney rejection.

Mycophenolate Mofetil Dose Reduction in Renal Transplant Recipients: A 5-Year Follow-up Study

Mycophenolate mofetil (MMF), an immunosuppressant that is widely used in renal transplantation, is associated with several dose-dependent hematologic and gastrointestinal side effects that may require dose reduction or even discontinuation. The aim of this study was to compare renal allograft function and acute rejection episodes among kidney allograft recipients who were on 2 regimens of MMF for at least 5 years. This prospective cohort of 55 kidney allograft recipients was followed for deterioration of allograft function, evidence of acute rejection, and allograft survival. Twenty-two patients (40%) underwent MMF dose reduction to 1.35 to 0.23 g/d due to perceived side effects or economic reasons (group 1). The mean time for this change was 4.2 +/- 2.1 months after kidney transplantation. The remaining patients (group 2, n = 33) were continued on MMF (2 g/d). All patients were followed for at least 5 years after transplantation. Renal function tests (blood urea and serum creatinine) were measured monthly for 2 years and then every 2 months. Statistical analysis was performed using SPSS 11.0 (Student t test). P <or= .05 was considered significant. The 2 groups were comparable regarding age, gender, and immunosuppressive medications. The renal function tests were comparable at the end of the study. Mean blood urea values were 44.8 +/- 5.8 and 46.8 +/- 6.8 mg/dL in groups 1 and 2 (P > .05); mean serum creatinine values were 1.32 +/- 0.14 and 1.38 +/- 0.21 mg/dL, respectively (P > .05). There were 2 graft losses and 1 patient loss in group 2. There were also 2 graft losses among group 1 patients. Our study showed that MMF dose reduction was not associated with an increased risk of acute renal allograft rejection or impaired allograft function at 5 years.

UGT Genotype May Contribute to Adverse Events Following Medication With Mycophenolate Mofetil in Pediatric Kidney Transplant Recipients

Leukopenia and diarrhea are the predominant adverse events associated with mycophenolate mofetil (MMF), leading to dose reduction or discontinuation in children. Polymorphisms of the drug's main metabolizing enzyme, uridine diphosphate-glucuronosyl transferase (UGT), confer alteration in drug exposure. We studied the incidence of these polymorphisms in pediatric kidney transplant recipients experiencing MMF-associated leukopenia and diarrhea. UGT genotypes of 16 affected children who recovered after MMF dose reduction or discontinuation were compared with those of 22 children who tolerated the drug at standard doses. DNA was extracted and sequenced using standard procedures to detect polymorphisms associated with increased (e.g., UGT1A9 -331T>C) or decreased drug exposure. All three patients who were homozygous for UGT1A9 -331T>C developed leukopenia, and heterozygotes also had significantly more toxicity (P = 0.04). A weaker association (P = 0.08) existed in UGT2B7 -900G>A carriers. Our data implicate UGT polymorphisms associated with altered drug exposure as potential predictors of MMF adverse events.

Impact of gastrointestinal‐related side effects on mycophenolate mofetil dosing and potential therapeutic strategies

In renal transplant patients receiving mycophenolate mofetil (MMF), maintaining an adequate dosing regimen has been shown to maximize short- and long-term outcomes. Gastrointestinal (GI) adverse events associated with MMF are frequent, and lead to MMF dose reduction or withdrawal in 40-50% of cases. Among MMF-treated patients experiencing GI complications, one analysis has reported MMF discontinuation to be associated with almost a threefold increase in risk of graft loss, while a dose reduction > or = 50% carried over a twofold increase in risk. If GI symptoms improve and the pre-reduction MMF dose is resumed the increased risk of graft loss may be reversed, but continuing intolerance can make this difficult to achieve. Investigation of contributing factors is important and may alleviate symptoms. Conversion to enteric-coated mycophenolate sodium (EC-MPS) may be an effective option. Two open-label studies using patient-reported outcomes data have shown a significant and clinically relevant benefit in GI-related symptom burden after conversion from MMF to EC-MPS. In conclusion, monitoring of GI complications is essential following renal transplantation, and maintaining adequate mycophenolic acid exposure should be a priority when considering treatment options.

Mycophenolate Mofetil Dose Reduction for Gastrointestinal Intolerance is Associated With Increased Rates of Rejection in Heart Transplant Patients

Gastrointestinal (GI) intolerance to mycophenolate mofetil (MMF) is a frequent problem. We conducted a retrospective analysis of all the heart transplant patients followed up at the Toronto General Hospital from the years 1999 to 2006 to determine the impact of dose reductions for GI intolerance on rejection rates. The charts of all patients followed up in the heart transplant clinic at the Toronto General Hospital from the years 1999 to 2006 were reviewed. Sustained significant rejection was defined as an International Society of Heart and Lung Transplantation grade 2 or higher on 2 successive biopsies. The Student's t-test was used to compare rates of rejection between populations. Mycophenolate mofetil was part of the anti-rejection regimen in 182 of 189 patients (98%), and the medication dose in 71% of these patients had to be reduced at some point because of intolerance or toxicity. The prevalence of sustained significant rejection was significantly higher in the group of patients with GI intolerance to MMF compared with patients maintained on target doses (66% vs 35%, p = 0.002) or patients with non-GI related toxicities necessitating dose reduction (67% vs 35%, p = 0.003). Gastrointestinal intolerance is a common reason for MMF dose reduction in heart transplant patients and was associated with a significantly increased rate of sustained rejection, suggesting that these individuals need to have particularly close follow-up.

466: First-year mycophenolate mofetil dose reductions: Do they portend poor outcome?

Purpose: Mycophenolate mofetil (MMF) is known to cause gastrointestinal (GI) side effects (ie nausea, abdominal discomfort, diarrhea) which limits dosing. Reduction of MMF doses is common to reduce these reported adverse effects. In a recent multicenter randomized trial of MMF vs the enteric-coated mycophenolate sodium (EC-MPS), two or more dose reductions were significantly greater in the MMF group vs the EC-MPS group. It is not known whether these dose reductions are clinically relevant or lead to poor outcomes.

Mycophenolate Mofetil Tolerability and Dose Changes in Tacrolimus-Treated Renal Allograft Recipients

Mycophenolate mofetil (MMF) reduces acute rejection episodes (AREs) and may be associated with better renal graft survival than azathioprine. However, MMF-related adverse events are frequent; dose reduction or even withdrawal are quite common. Between 1999 and 2003, 115 renal transplantation patients were treated with tacrolimus, MMF, and steroids. An observational study was undertaken until graft loss ( n = 7), death with a functioning graft ( n = 2), or October 31, 2005 (mean follow-up-50 months). We assessed MMF dose reductions due to adverse events with the possible consequences on AREs and graft function. Treated acute ARE occurred in 11.3% of recipients, all of which were steroid-responsive. The median MMF initial daily dose was 1000 mg. In 44 patients (38.3%), the MMF dose was not changed; in 48 (41.7%) it was reduced; and in 23 (20%), withdrawn. The causes for dose modification were diarrhea ( n = 33, 28.7% of all patients), leukopenia ( n = 22, 19.1%), both of these ( n = 7, 6.1%), or other events ( n = 9, 7.8%). No AREs were attributed to MMF dose changes. Tacrolimus blood levels were higher at 3 years and serum creatinine values at 4 years among patients with dose changes (8.43 ± 2.42 vs 7.37 ± 2.23 ng/mL; P = .051 and 1.75 ± 0.71 vs 1.48 ± 0.38 mg/dL; P = .038, respectively). The need for MMF dose reduction or withdrawal was frequent in our patients with diarrhea or leukopenia during treatment with tacrolimus, MMF, and steroids. These adverse event-related changes were not associated with AREs, but produced deleterious effects on long-term graft function.

Comparison of Transplanted Kidney Function in Patients on Two Different Doses of Mycophenolate Mofetil

Introduction Mycophenolate mofetil (MMF), an immunosuppressant that is widely used in renal transplant recipients, is associated with several dose-dependent hematologic and gastrointestinal side effects that lead to drug dose reduction or even discontinuation. The aim of this study was to compare the renal function and acute rejection rates of kidney allograft recipients who were on two different mycophenolate mofetil doses. Methods In a prospective study, 59 allograft kidney recipients who were on MMF 2 g/d were randomly selected and followed for evidences of acute rejection or drug side effects. Four patients were excluded from the study due to noncompliance, graft loss, and patient loss from opportunistic infection. Of the remaining 55 patients, 22 patients (40%) underwent MMF dose reduction to 1.35 ± 0.23 g/d due to perceived side effects or economic reasons (group 1). The mean time for this change was 4.2 ± 2.1 months after the kidney transplantation. The remaining patients (group 2, n = 33, 60%) had no change in MMF 2 g/d drug dosage. All patients were followed for at least 30 months after transplantation. Renal function tests (blood urea and serum cratinine) were measured monthly. Statistical analysis was performed using SPSS 11.0 (Student t test). A P value < .05 was considered significant. Results The two groups were comparable regarding age, gender, other immunosuppressive medications, and the time after transplantation. There were no episodes of acute rejection in group 1 after MMF dose reduction. The renal function (blood urea or serum creatinine levels) was comparable between the two groups at the end of study ( P = .846 and .610, respectively). Conclusion MMF dose reduction was not associated with an increased risk of acute renal allograft rejection or impaired graft function.

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.

Improvement in Social Functioning in Kidney Transplant Patients after Conversion from Mycophenolate Mofetil to Enteric-coated Mycophenolate Sodium (myfortic??): Three Case Studies

The patient was a 61-year-old Caucasian woman who had suffered from Wegener’s granulomatosis for 4 years, requiring haemodialysis for 3 years. As a result of her condition, she experienced constant tiredness, weakness, depression and lack of motivation, and was unable to work. After receiving a kidney transplant from a 69-year-old female deceased donor, five antigen mismatch, cold ischaemia time of 25 h, she received thymoglobulin induction and maintenance immunosuppression consisting of prednisone 5mg/day, tacrolimus 1mg twice a day, and mycophenolate mofetil (MMF) 750mg three times a day. This dose was chosen as the patient received an extended criteria donor kidney, and it was felt that to maintain good graft function the dose of calcineurin inhibitor should be maintained as low as practicable and the MMF dose should be maximized. Her serum creatinine improved from 406mmol/l on day 2 posttransplant to 150mmol/l at one week posttransplant. The patient then started to experience severe abdominal pain, bloating, diarrhoea, nausea and vomiting, within 2 weeks of transplantation, which were present for 3 days before her next hospital visit, although kidney function was unaffected and tacrolimus trough levels were 12.3 ng/ml. As a result of the severity of the symptoms, she felt unable to leave the house and became increasingly depressed; antidepressant therapy was prescribed. In an attempt to ameliorate the severe gastrointestinal symptoms MMF was reduced to a dose of 500mg three times a day, but the symptoms did not reduce and she was readmitted to hospital. At this point it was decided that, because of the severity of her symptoms, conversion to enteric-coated mycophenolate sodium (EC-MPS; myfortic) would be attempted instead of a further MMF dose reduction or dose splitting. The patient converted from MMF to EC-MPS at a dose of 360mg three times a day. After conversion, her gastrointestinal symptoms resolved. Serum creatinine levels remain stable at 97mmol/l. The patient has now been receiving EC-MPS 360mg three times a day for 10 months with no recurrence of gastrointestinal complaints. She now feels able to leave the house each day because her diarrhoea has resolved, and she has discontinued antidepressant medication.

Clinical Application of Population Pharmacokinetic Methods Developed for Immunosuppressive Drugs

After a brief overview of the relevant exposure indices for cyclosporine (CsA) and mycophenolate mofetil (MMF), as well as of the different steps necessary to develop maximum a posteriori Bayesian estimators (MAP-BE), this paper presents applications of MAP-BE for CsA or MMF to clinical cases and clinical trials. Ina renal transplant patient under CsA, grade I chronic allograft nephropathy was found at the sixth month posttransplantation, with CsA CO slightly above the target range and C2 markedly below; the AUCO0-12 h Bayesian estimate was quite high, at 5.6 mg h/L, as compared with a mean value of 4.3+0.9 mg.h/L in stable renal transplants at this period; the inconsistent C2 level found could be explained by delayed absorption of CsA in this patient, in which case C2 no longer represents the major part of the AUC. The patient was switched to sirolimus, which resulted in a slow and significant improvement of graft function with no acute rejection. In a 50-year-old female renal transplant recipient administered MMF and CsA and with a very favorable outcome otherwise, progressive anemia appeared 8 months posttransplantation. Clinical investigations were negative,but Bayesian estimation showed a rather high MPA AUCO0-12 h (69.8 mg h/L). After MMF dose reduction, hemoglobin level progressively returned to normal, without erythropoietin injection or blood transfusion. Finally, the feasibility of accurate dose adjustment using these MAP-BE is shown through preliminary results from 2 ongoing multicenter clinical trials, 1 evaluating an AUC-controlled cyclosporine-sparing strategy in stable renal transplants, the second evaluating the benefit of MMF therapeutic drug monitoring based on MPA AUCO0-12 h in de novo renal transplant recipients.

Pilot Study of Rapid Steroid Elimination With Alemtuzumab Induction Therapy in Kidney and Pancreas Transplantation

This study evaluates our initial experience using alemtuzumab induction with rapid corticosteroid elimination in kidney (KTX) and pancreas transplant (PTX) patients. Data were collected retrospectively for all patients who received single-dose alemtuzumab (30 mg IV intraoperatively) with steroid pretreatment and a control group who received alternate day rabbit antithymocyte globulin (rATG) induction with a steroid-based regimen. Patients in both groups received tacrolimus (TAC) and mycophenolate mofetil (MMF). There were 16 patients in each group, including 9 deceased donor KTXs, 5 living donor KTXs, 1 simultaneous K-PTX, and 1 sequential PTX after KTX. Demographic, immunologic, and transplant characteristics were similar between groups. Nine patients (56%) in the alemtuzumab group compared to five (25%) in the control group developed neutropenia requiring MMF or valganciclovir dose reduction (or both). Absolute lymphocyte counts at 3 months were 340 ± 200/mm 3 and 890 ± 544/ mm 3 in the alemtuzumab and control groups, respectively ( P = .001). There were two biopsy-proven acute rejection episodes (12.5%) in each group, and no difference in the incidence of infection. Creatinine clearance at 6 months was 58 mL/min in each group. Patient and kidney graft survival rates were both 94% in the alemtuzumab group (one death from cardiac arrest), compared with 100% patient and kidney graft survival rates in the control group ( P = NS), with a mean follow-up of 9 and 11 months, respectively. The results of this pilot study suggest that similar short-term outcomes can be achieved using a rapid steroid elimination protocol with alemtuzumab induction therapy compared to rATG with steroids in patients receiving TAC and MMF maintenance therapy.

Pre-Transplant Inosine Monophosphate Dehydrogenase Activity is Associated with Clinical Outcome After Renal Transplantation

Mycophenolate mofetil (MMF), an inhibitor of inosine monophosphate dehydrogenase (IMPDH) activity, is usually administered as a standard dose of 1 g b.i.d. after renal transplantation. Because MMF dose reductions are associated with inferior outcome, we investigated pre-transplant IMPDH activity, MMF dose reductions and outcome. IMPDH activity was determined in isolated peripheral mononuclear cells immediately prior to renal transplantation. We observed considerable inter-individual variability in pre-transplant IMPDH activity (9.35 +/- 4.22 nmol/mg/h). Thirty of 48 patients (62.5%) with standard MMF dose (1 g b.i.d.) had dose reductions within 3 years post-transplant; these patients also had significantly lower IMPDH activity. The area under the receiver-operating characteristics curve (AUC-ROC) for prediction of dose reduction within 6 months post-transplant was 0.75 (95% CI, 0.61-0.89; p < 0.004). IMPDH activity above the cut-off value, MMF dose reduction and age of recipient were significant contributors for the occurrence of acute rejection in the multivariate logistic regression. Patients with high IMPDH activity and MMF dose reduction had the highest rejection rate (81.8% vs. 36.4%; p < 0.01). Patients with low IMPDH activity experienced more complications of MMF therapy. High pre-transplant IMPDH activity and MMF dose reductions were associated with rejection. Determination of IMPDH activity prior to transplantation may help to improve MMF therapy after renal transplantation.

MYCOPHENOLATE INTOLERANCE INCREASES THE RISK OF REJECTION IN KIDNEY TRANSPLANT PATIENTS ON CYCLOSPORINE BUT NOT ON TACROLIMUS TRIPLE THERAPY

O289 Aims: We analysed mycophenolate mofetil (MMF) safety profile and the effect of MMF dosing changes on early results of kidney transplantation. Methods: Between September 1, 1992 and October 1, 2003, 407 cadaveric kidney transplantations were performed using triple immunosuppression with cyclosporine (CyA, N=264) or tacrolimus (Tac, N=143) and MMF plus steroids. The initial dosage of MMF was usually 1000 mg b.i.d. in CyA-patients and 500 mg b.i.d. in Tac-patients. We evaluated the safety profile and efficacy of these regimens. Original patient documents were examined and adverse events (AE), MMF dose changes and rejections during the first 100 posttransplant days were recorded. For this analysis, laboratory limits for AEs were set as follows: platelet count <100 x 109, WBC count <3,0 x 109, and liver toxicity was defined as alanine aminotransferase (ALAT) >60 U/l. Results: Liver toxicity was found in 49.6% of patients, thrombocytopenia in 9.1%, leukopenia in 6.4%, diarrhoea in 20.9%, other gastrointestinal (GI) AEs in 23.1% and infections in 25.8%. CyA patients had significantly more liver toxicity (55.3 % vs. 39.2 %, p<0.005) and thrombocytopenia (11.4 % vs. 4.9 %, p< 0.05), whereas Tac patients had more diarrhoea (32.9 % vs. 14.4 %, p<0.001) and other GI AEs (30.8 % vs. 18.9 %, p<0.01). Patients with delayed graft function had significantly more diarrhoea (29.6% vs 16.3%, p<0.005), other GI symptoms (31.9% vs 17.5%, p<0.005), and thrombocytopenia (15.6% vs 6.1%, p<0.005). MMF dose reductions or discontinuations had been done according to clinical judgement in 136/407 cases (33.4%), and 77% of them had been done before day 21 post TX. The indications were liver toxicity in 90 (22.1% of all patients), thrombocytopenia in 8 (2.0%), leukopenia in 15 (3.7%), anaemia in 4 (1.0%), diarrhoea in 7 (1.7%), other GI AEs in 8 (2.0%) and infection in 4 patients (1.0%). Dose reductions had been done in 39.8% of all CyA patients and in 24.5% of all Tac patients (p=0.001). The overall rejection rate was 11.5% (CyA 11.4%, Tac 11.9%). With full MMF throughout, the rejection rate was 8.3% compared to 17.6% with MMF dose reductions (p=0.005). In CyA patients, reduction of MMF within the first three weeks increased the rejection rate during the subsequent three-week period, from 0.6% to 10 % (Chi-square: p<0.001). In Tac patients no increase could be seen. Conclusions: MMF intolerance, especially liver toxicity, occurred in a high proportion of our patients, more often in CyA patients with the higher MMF dosage. In one third of all patients, MMF reduction was deemed necessary. These results demonstrate that if an adequate MMF dose can not be maintained, patients on CyA-MMF-steroid immunosuppression carry a highly increased risk of rejection during a vulnerable post transplant time period.