Increased incidence of allograft rejection in stable heart transplant recipients after late conversion from mycophenolate mofetil to azathioprine.

Mycophenolate mofetil (MMF) is a safe and effective immunosuppressive agent in kidney and liver transplantation. Preliminary studies also support its use in heart transplantation. However, the cost of MMF is substantially greater than azathioprine (AZA), the current alternative. Since the majority of rejection episodes occur within the first few months of transplantation, using MMF early after transplantation and subsequently converting to AZA, after the risk of rejection has diminished, might be cost-effective. In order to evaluate the safety of such a strategy in heart transplant recipients, we reviewed the rejection profiles of a group of patients who were converted from MMF to AZA late after transplantation. Forty-three stable patients on chronic MMF therapy as part of an open-label, long-term safety study were converted to either commercially available MMF (CellCept) or AZA, at the conclusion of the study. Demographic variables, rejection histories before and after conversion, and immunosuppressive regimens were examined. Twenty-three patients were continued on commercial MMF and 20 were converted to AZA therapy. The average duration of MMF therapy prior to conversion was 41 months in each group. Baseline demographics were similar in the two groups. Treated allograft rejection occurred in 10 of 20 patients converting to AZA, as compared to only 1 of 23 patients remaining on MMF; p = 0.002. Additionally, mean scores (1-5 scale) for the three biopsies before and after conversion favored continued MMF therapy (1.5+/-0.6 before and 1.2+/-0.4 after conversion in MMF group vs. 1.3+/-0.5 before and 1.7+/-0.9 after conversion to AZA; p = 0.02). No allograft loss occurred as a result of conversion. These data suggest that conversion from MMF to AZA, even late after transplantation, can be associated with allograft rejection. The costs associated with these rejection episodes (the additional immunosuppressive agents, endomyocardial biopsies, and physician visits) may exceed the potential cost savings of converting stable heart transplant recipients from MMF to AZA.     

Mycophenolate mofetil monotherapy in liver transplant recipients

Kriss M, Sotil EU, Abecassis M, Welti M, Levitsky J. Mycophenolate mofetil monotherapy in liver transplant recipients.
Clin Transplant 2011: 25: E639–E646. © 2011 John Wiley & Sons A/S. Abstract:  Introduction: Complete conversion of calcineurin inhibitor (CNI) immunosuppressant therapy to non‐nephrotoxic agents such as mycophenolate mofetil (MMF) is controversial, but may be safe in selected patients, although appropriate protocols and long‐term benefits of conversion are not well reported. Methods: We analyzed all liver transplant (LT) recipients at our institution who were converted from CNI‐based therapy to MMF monotherapy because of renal dysfunction (n = 23) and compared them with patients remaining on CNI‐based therapy (n = 23). Renal function, rejection episodes, and markers of CNI‐related comorbidities (lipid profile, blood pressure, and glycosylated hemoglobin) were noted. Results: Overall, serum creatinine (SCr) and calculated glomerular filtration rate improved on MMF monotherapy. This improvement was significant when compared with patients who remained on CNI‐based therapy. Improvement was most pronounced in patients with milder renal dysfunction (SCr <2.2 mg/dL prior to conversion) (n = 14) with decrease in SCr from 1.63 ± 0.29 to 1.34 ± 0.26 mg/dL (p = 0.02) at last follow‐up. Five patients on MMF monotherapy (21.7%) progressed to end‐stage renal disease (ESRD), while only two (8.7%) had rejection episodes following conversion. Clinical markers of CNI‐related comorbidities also improved. MMF monotherapy was well tolerated. Conclusion: In summary, our data support the safety and efficacy of CNI to MMF monotherapy conversion.     

Mycophenolate mofetil monotherapy in liver transplantation

Aim

Calcineurin inhibitors (CI) are associated with significant morbidity in transplant recipients. The aim of this study was to evaluate the effectiveness and safety of mycophenolate mofetil (MMF) monotherapy in liver transplantation (LT).

Methods

We analysed 32 patients (24 males, 8 female, of mean age 55.7 years) who underwent LT between 1994 and 2003. In 29 patients immunosuppressive therapy was cyclosporine; in three patients it was tacrolimus. Eleven patients were submitted for LT due to hepatitis B cirrhosis; eight for hepatitis C cirrhosis, six for alcoholic cirrhosis, and seven for other diseases. In these patients, MMF was added gradually, simultaneously reducing the dosage of CI up to complete withdrawal. We considered the efficacy (decrease in serum creatinine) and the incidence of complications (acute and chronic rejection, leukopenia, diarrhea).

Results

Patients were converted to MMF after a median of 50 months after LT. MMF monotherapy was started after a median of 9 months in association with CI. Indications for switch to MMF monotherapy were adverse effects of CI (renal disfunction in 30 patients) and de novo tumoral evidence after LT in two patients. Median dosage of MMF was 750 mg twice daily (500-1500 mg). There was a statistically significant decrease in serum creatinine levels (2.02-1.7 mg/dL; P = .0001). Side effects were: leukopenia in five of 32 patients (15.6%), diarrhea in four of 32 patients (12.5%), and one acute rejection.

Conclusion

MMF monotherapy improved renal function and was not associated with a significant risk of allograft rejection. Side effects were mild with dose regimens up to 750 mg twice daily.     

Mycophenolate Mofetil Monotherapy in Patients Who Underwent Liver Transplantation for Hepatitis C Cirrhosis

Introduction

Mycophenolate mofetil (MMF) monotherapy has recently been proposed for liver transplant recipients with adverse events (nephrotoxicity, hypertension) related to calcineurin inhibitors. We analyzed the influence of MMF on the clinical course of recurrent hepatitis C.

Methods

Among 1038 patients who underwent liver transplantation (OLT) from April 1986 to October 2006, we analyzed 48 adult recipients (4.6%) whose diagnosis was hepatitis C virus (HCV) cirrhosis and who were converted from calcineurin inhibitors to MMF monotherapy.

Results

The 36 men and 12 women, had a mean age at OLT of 52.9 ± 7.2 years; the time elapsed from OLT to the onset of MMF monotherapy was 72.5 ± 47.6 months (range = 11-210). The mean follow-up after monotherapy was 19 ± 16.1 months (range = 2-67). Indications for conversion were: chronic renal dysfunction with HCV in 45 patients; HCV recurrence in two; and hypertension plus HCV recurrence in one subject. When the indication was renal dysfunction (excluding three patients who underwent hemodialysis), the mean creatinine values decreased significantly from baseline to 6 months of monotherapy from 1.63 ± 0.61 mg/dL to 1.51 ± 0.78 mg/dL (P < .03). The creatinine clearance only improved significantly from the baseline value of 56.6 ± 16.8 mL/min to the value at 3 months of monotherapy—63.6 ± 18.4 mL/min (P < .001). At the last outpatient visit, creatinine and creatinine clearances had not changed significantly. The mean diastolic blood pressure did improve significantly at the end of the study. The mean glucose levels decreased but not significantly at the last outpatient visit. Liver function tests did not change significantly after conversion to MMF monotherapy. The acute rejection rate was 8.3%, and adverse events related to MMF monotherapy were present in 9 patients (18.7%).

Conclusions

Conversion from calcineurin inhibitors to MMF monotherapy in patients who underwent OLT for HCV transiently improved renal function and hypertension. The acute rejection rate was low, and adverse events were usually well tolerated.     

Conversion from cyclosporine to FK506 in adult liver transplant recipients: a combined North American and European experience

BACKGROUND: Although cyclosporine (CsA) made clinical liver transplantation possible, side effects and development of rejection have limited its use. In some patients, conversion to tacrolimus has been necessary to abrogate side effects and to preserve allograft function. METHODS: The results of conversion from CsA to tacrolimus were studied retrospectively in 94 liver allograft recipients from a North American and a European transplant center (Duke University Medical Center, Durham, NC, and Hopital Beaujon, Clichy, France). RESULTS: Forty-seven of 94 patients (50%) were converted for steroid-resistant acute rejection. Conversion was successful in 91% of these patients, whereas 9% of patients developed chronic rejection. A further nine patients were converted for chronic allograft rejection with positive results in eight of nine grafts. Mean serum bilirubin in these nine patients was 8.7 mg/dl before conversion and 2.1 mg/dl 6 months after conversion (P=0.02). Nine patients were converted due to inability to wean steroid. Of these, six patients remains steroid free 1 year after conversion. Twenty-three patients (24%) were converted for nephrotoxicity with a reduction in serum creatinine from 167+/-36 mmol/L to 119+/-28 mmol/L 1 year after conversion (P=0.006). Eight of 11 patients converted for neurotoxicity improved after conversion. Conversion to tacrolimus had no effect on seizure frequency or memory loss. CONCLUSIONS: These results suggest that conversion to tacrolimus from CsA is an appropriate paradigm for graft rescue and treatment of a variety of side effects after liver transplant. However, some situations such as memory loss and hypertension may require other strategies.     

Calcineurin-inhibitor related nephrotoxicity- reversibility in paediatric liver transplant recipients.

AIM: To study the efficacy of mycophenolate mofetil (MMF) as renal rescue in paediatric liver transplant recipients with calcineurin-inhibitor- (CI) related nephrotoxicity. METHODS: Pediatric liver transplant recipients with stable graft function and a glomerular filtration rate (GFR) <80 ml/min/1.73 m2 were enrolled. MMF was introduced at 20 mg/kg/day and increased to 40 mg/kg/day after 1 week. CI dose was then reduced 6 weeks to achieve blood levels 25% of baseline. GFR was reassessed after 6 and 12 months. RESULTS: Fourteen children with a median (range) interval from transplant of 57 (4-111) months were studied. Their median (range) GFR in ml/min/1.73 m2 increased from a baseline of 52 (31-71), to 69 (38-111) and 73 (35-98) at 6 and 12 months, respectively (P=0.00014). Side effects of MMF include leucopaenia in two and backache in one, two of whom discontinued MMF. Acute allograft rejection occurred in three children. All 14 are well with a median (range) follow-up of 24 (14-38) months from MMF introduction. CONCLUSION: MMF allows the recovery of renal function from CI related nephrotoxicity in more than 70% of paediatric liver transplant recipients with renal impairment.     

Tacrolimus as a rescue immunosuppressant after heart transplantation.

OBJECTIVE: The purpose of this retrospective study is to review our experience with tacrolimus as a rescue immunosuppressant for heart transplant recipients with refractory rejection or cyclosporine intolerance. METHODS: From June 1995 to November 1998, 15 cardiac transplant recipients were converted from our standard cyclosporine-based immunosuppressive regimen to a tacrolimus-based treatment. Each patient had been treated with cyclosporine, azathioprine and steroids. Six were switched to tacrolimus for persistent rejection, four for recurrent acute rejection and five for severe debilitating side-effects attributed to cyclosporine. All ten patients converted to tacrolimus because of rejection had been treated with high-dose methylprednisolone intravenously and four had also received anti-lymphocyte globulin (ALG; one patient) or anti-thymocyte globulin (ATG; three patients) preparations. RESULTS: The time between transplantation and conversion to tacrolimus ranged from 44 to 1866 (median, 380) days. The range of follow-up after conversion was 84-1379 (median, 806) days. Eleven patients are alive with a follow-up period of 764+/-435 (median, 820) days. Four patients died between 90 and 930 (median, 464) days after conversion. The average number of episodes of acute rejection/recipient decreased from 2.1+/-1.6 on the cyclosporine regimen to 0.2+/-0.4 on the tacrolimus regimen (P<0.001). When the incidence of acute rejection was normalized for follow-up times (episodes/100 patient-days), the results were 1.1+/-1.4 and 0.07+/-0.2, respectively (P<0.01). The persistent/recurrent rejection resolved in all ten patients who were converted to tacrolimus. None of the five cyclosporine intolerant patients converted to tacrolimus experienced rejection after the changeover. CONCLUSIONS: In our experience, conversion from a cyclosporine-based to a tacrolimus-based maintenance immunosuppression has been shown to be an effective and safe approach to the management of patients with persistent or recurrent cardiac allograft rejection or those with cyclosporine intolerance.     

Prospective, Pilot, Open-Label, Short-Term Study of Conversion to Leflunomide Reverses Chronic Renal Allograft Dysfunction

Leflunomide (LEF) is a synthetic isoxazole derivative with anti-inflammatory and antiviral properties, which has been reported to prevent acute rejection and delay progression of chronic allograft nephropathy (CAN) in animal models. We performed a pilot, crossover trial in 22 renal transplant recipients who were converted from azathioprine (AZA) or mycophenolate mofetil (MMF) to LEF in an effort to slow progression of renal dysfunction [deteriorating renal function (n = 5), cyclosporine (CyA) nephrotoxicity (n = 4) or biopsy-proven CAN (n = 13)]. Baseline maintenance immunosuppression consisted of CyA, AZA or MMF and prednisone. Six-month postconversion patient and graft survival was 100% and 91%, respectively. Mean serum creatinine 6months preconversion was 2.2 +/- 0.6mg/dL, at initiation was 3.0 +/- 1.1 mg/dL, and 6 months postconversion was 2.8 +/- 1.3 mg/dL. The rate of change in serum creatinine was 35 +/- 39%/6 months preconversion and -5 +/- 21%/6 months postconversion to LEF (p = 0.003). Two patients discontinued LEF for diarrhea and myalgia. No readmissions, increase in liver function tests, infections or acute rejection episodes occurred. Mean CyA levels did not change, 146 +/- 72 ng/ mL pre-LEF vs. 132 +/- 51 ng/mL post-LEF, p = NS. Conversion to LEF reversed progression of chronic renal allograft dysfunction with minimal toxicity.     

Tacrolimus with Mycophenolate Mofetil (MMF) or Sirolimus vs. Cyclosporine with MMF in Cardiac Transplant Patients: 1-Year Report

The most advantageous combination of immunosuppressive agents for cardiac transplant recipients has not yet been established. Between November 2001 and June 2003, 343 de novo cardiac transplant recipients were randomized to receive steroids and either tacrolimus (TAC) + sirolimus (SRL), TAC + mycophenolate mofetil (MMF) or cyclosporine (CYA) + MMF. Antilymphocyte induction therapy was allowed for up to 5 days. The primary endpoint of >/=3A rejection or hemodynamic compromise rejection requiring treatment showed no significant difference at 6 months (TAC/MMF 22.4%, TAC/SRL 24.3%, CYA/MMF 31.6%, p = 0.271) and 1 year (p = 0.056), but it was significantly lower in the TAC/MMF group when compared only to the CYA/MMF group at 1 year (23.4% vs. 36.8%; p = 0.029). Differences in the incidence of any treated rejection were significant (TAC/SRL = 35%, TAC/MMF = 42%, CYA/MMF = 59%; p < 0.001), as were median levels of serum creatinine (TAC/SRL = 1.5 mg/dL, TAC/MMF = 1.3 mg/dL, CYA/MMF = 1.5 mg/dL; p = 0.032) and triglycerides (TAC/SRL = 162 mg/dL, TAC/MMF = 126 mg/dL, CYA/MMF = 154 mg/dL; p = 0.028). The TAC/SRL group encountered fewer viral infections but more fungal infections and impaired wound healing. These secondary endpoints suggest that the TAC/MMF combination appears to offer more advantages than TAC/SRL or CYA/MMF in cardiac transplant patients, including fewer >/=3A rejections or hemodynamic compromise rejections and an improved side-effect profile.     

Sirolimus-based immunosuppressive therapy in liver transplant recipient with tacrolimus-related chronic renal insufficiency

BACKGROUND: While providing potent immunosuppression for liver transplant recipients, calcineurin inhibitors (CNI) exhibit nephrotoxicity as a major side effect. The purpose of this study was to evaluate the safety and efficacy of conversion from CNI to sirolimus (SRL) among liver transplant recipients with CNI-induced chronic nephrotoxicity. METHODS: Between January 2004 and June 2005, we performed conversion in 16 recipients after a median period of 8.5 months after liver transplantation. The indication for conversion was CNI-related nephrotoxicity with a serum creatinine (sCr) value >132.6 umol/L. Renal function was measured before and after conversion to SRL. Clinical and laboratory data related to the clinical course of the patients were recorded to investigate the safety and efficacy of conversion. RESULTS: Sixteen patients were converted to SRL after developing nephrotoxicity. Their renal function improved gradually after conversion. The levels of sCr decreased significantly within the first 30 days (164.1 +/- 12.48 micromol/L to 130.1 +/- 5.573 micromol/L), and over the next 60 days after conversion (97.86 +/- 11.69 micromol/L to 90.7 +/- 8.95 micromol/L) (P < .01). Similarly, the mean glomerular filtration rate (GFR) increased significantly during the same period. Four recipients experienced hypercholesterolemia, 1 with ankle edema, and 1 with acute rejection. The median follow-up was 2.4 years. No patient discontinued SRL due to side effects. No patient needed dialysis or kidney transplantation during the study period. CONCLUSIONS: SRL is a safe, effective replacement agent as primary immunosuppressive therapy following withdrawal of CNIs in liver transplant recipients with CNI-induced chronic nephrotoxicity.     

Cyclosporin withdrawal with concomitant conversion from azathioprine to mycophenolate mofetil in renal transplant recipients with chronic allograft nephropathy: a 2-year follow-up

Because recent large studies have demonstrated that mycophenolate mofetil (MMF) is superior to azathioprine (AZA) as a post-transplant immunosuppressant, it has been speculated that MMF could have a cyclosporin (CsA)-sparing effect in renal transplant recipients with chronic allograft dysfunction. Between April 1996 and October 1998, 31 patients with chronic allograft dysfunction were assigned to have conversion from AZA to MMF with concomitant CsA withdrawal. Patient and graft outcomes were analysed. Mean follow-up time after MMF conversion was 27+/-11 months. Serum creatinine concentration (sCt) significantly decreased after conversion and remained stable at the end of follow-up (227+/-31 micro mol/l vs. 185+/-50 micro mol/l; P<0.0005). Mean variation in sCt was -24% after conversion, whereas it was +20% in the year before conversion ( P<0.001). There was a significant inverse relationship between proteinuria at baseline and improvement in renal function (r=-0.35; P=0.01). Proteinuria increased during follow-up (0.79+/-0.6 vs. 1.79+/-1.08 g/day; P=0.04). Isolated CsA nephropathy was associated with the best outcome. Renal function significantly improved in patients with grade 1 chronic rejection and remained stable in patients with grade 2 chronic rejection. Two patients (6.5%) experienced late acute rejection, respectively 13 and 24 months after CsA withdrawal. Eight patients (29%) experienced systemic infections requiring hospitalization. Blood pressure control and lipid profile improved after conversion. CsA withdrawal with a concomitant switch from AZA to MMF allows a substantial and durable improvement in renal function. Both allograft histology and proteinuria at baseline are predictive of the evolution of renal function after conversion. Physicians should consider the risk of over-immunosuppression possibly associated with this therapeutic strategy.     

Mycophenolate Mofetil Can Be Used as Monotherapy Late After Liver Transplantation

We report our experience with calcineurin inhibitor (CNI) withdrawal and MMF monotherapy in 50 adult liver transplant (OLT) recipients with CNI-related toxicity. Thirty-four patients had chronic renal dysfunction (CRD) associated with arterial hypertension, 11 had only CRD and other five patients had hypertension. The mean time between OLT and introduction of MMF was 81 months. After the introduction of MMF, CNI was progressively reduced and withdrawn if possible. At the end of the follow up (mean time: 18 months) CNI was withdrawn in 39 patients (78%), and there was a significant decrease from baseline in serum creatinine (1.81-1.49 mg/dL; p < 0.0001), BUN (76.6-52.8 mg/dL; p < 0.0001) and uric acid (9-7.5 mg/dL; p < 0.0001) levels, and an increase in creatinine clearance (44.7-55.1 mL/min; p < 0.0001). Excluding patients who developed graft rejection and two patients who died, CRD improved in 32 of 40 patients (80%), and arterial hypertension improved in 22 of 29 patients (76%). Five patients (10%) developed acute rejection, and one patient (2%) chronic rejection. Twenty-six patients (52%) experienced side-effects, with asthenia, herpes virus infection, and diarrhea being the most common. Only eight patients (16%) required MMF dose reduction. In conclusion, MMF monotherapy late after OLT improves CRD and hypertension in most patients, is safe and well tolerated.     

Coadministration of the new macrolide immunosuppressant RAD and mycophenolate mofetil in experimental corneal transplantation

INTRODUCTION: The effect of RAD, a new macrolide immunosuppressant, was examined as mono- and combination therapy with mycophenolate mofetil (MMF) in prevention of acute allograft rejection in murine corneal transplantation. METHODS: Both drugs were administered orally for 18 days beginning at the day of transplantation. The inbred strains Fisher and Lewis were used as donors and recipients, respectively. Five groups were involved: syngeneic control, allogeneic control, 2.5 mg/kg RAD, 40 mg/kg MMF, and double drug therapy with 1.5 mg/kg RAD and 20 mg/kg MMF. RESULTS: The median transplant survival time in the allogeneic combination was 12 (+/-0.3) days. Monotherapy with 2.5 mg/kg RAD and 40 mg/kg MMF led to a statistically significant prolongation of transplant survival to 25.5 (+/-12.5, P=0.0001) days and 19.5 (+/-13.9, P=0.0053) days, respectively. Combination therapy was superior to both monotherapies (100+/-15.8 days, P=0.03). There was a significant reduction in the number of CD4+, CD8+, as well as CD45RA+ cells in the RAD- and double drug-treated animals when compared with the allogeneic control. This significant reduction in graft-infiltrating lymphocytes has not been found in the MMF monotherapy. CONCLUSIONS: The unique finding of this first study on the combination of RAD and MMF in murine corneal transplantation is that double drug therapy produces a highly synergistic effect in prevention of acute allograft rejection without a higher incidence of complications related to drug toxicity or overimmunosuppression.     

Four-year follow-up of mycophenolate mofetil for graft rescue in liver allograft recipients

BACKGROUND: Mycophenolate mofetil (MMF) has been shown to have promise in short-term liver transplantation graft rescue studies. The purpose of this study was to evaluate the long-term efficacy and safety of MMF in liver transplant patients who had failed cyclosporine (CsA)-based conventional immunosuppression. METHODS: Nineteen orthotopic liver allograft recipients were converted from azathioprine to MMF in combination with CsA and prednisone in this prospective, open-labeled, single-center, graft rescue, pilot study. Six patients were taken off CsA when MMF was initiated. A 4-year patient follow-up is reported here. Patients were considered to have failed CsA-based immunosuppression either for refractory rejection, chronic rejection, or severe CsA neurologic toxicity. RESULTS: Twelve patients had complete histologic resolution, two had partial resolution, and three had worsening of their rejection. Thirteen patients had a complete biochemical response; one had a partial response and four had worsening of their rejection. Two patients had no histologic and one no biochemical follow-up. Of the six patients treated with MMF and prednisone alone, four had complete resolution of rejection without recurrence. The majority of adverse reactions were gastrointestinal [nausea and/or vomiting (n=5); diarrhea (n=8); gastritis, duodenitis, or esophagitis (n=4); and ulcers (n=2)] or bone marrow suppressive [leukopenia (n=9), anemia (n=6), and thrombocytopenia (n=5)]. CONCLUSIONS: MMF seems to be an effective alternative immunosuppressive in patients failing CsA-based conventional therapy. MMF may be of particular benefit in patients who do not tolerate CsA or tacrolimus. The long-term safety profile is similar to that of other immunosuppressives.     

Mycophenolate mofetil and tacrolimus as primary maintenance immunosuppression in simultaneous pancreas-kidney transplantation: initial experience in 50 consecutive cases

BACKGROUND: The current study examines the use of mycophenolate mofetil (MMF) and tacrolimus as primary immunosuppression in simultaneous pancreas-kidney (SPK) transplantation. In addition, analyses of the rates of conversion from one immunosuppressive agent to another, and its subsequent consequences with respect to outcomes were determined. Quality of graft function, infections, and effect on preexisting essential hypertension are also described. METHODS: Immunosuppression consisted of quadruple therapy with antithymocyte globulin induction, tacrolimus, MMF, and prednisone. Patient and graft survival and rejection rates in 50 consecutive SPK recipients, followed for a minimum of 3 months and a mean of 14 months (range: 3-34 months), are described. RESULTS: Thirty-nine of 50 (78%) patients tolerated the MMF/tacrolimus combination long-term (mean duration of follow-up: 14+/-7 months). Nine of 50 patients (18%) were converted to Neoral, and 4 patients were converted to azathioprine as a substitute for MMF. The 2-year actuarial patient, kidney, and pancreas survival rates were 97.7%, 93.3%, and 90.0%, respectively. At 6 months after transplant, the overall incidence of acute rejection was 16%. There was a statistically significant (P< or =0.04, Cox-Mantel test) difference in the rate of rejection associated with conversion to Neoral. The incidence of rejection 6 months after transplant in the group maintained on MMF/tacrolimus was 10.2% vs. 44.4% in the group converted to Neoral (P< or =0.04, Cox-Mantel test). Overall, the 1-year actuarial cumulative incidence of tissue-invasive cytomegalovirus disease was 6.6%. There were no cases of fungal infections or post-transplant lymphoproliferative disorders. One patient developed Kaposi's sarcoma 10 months after transplant. With respect to hypertensive disease, 60% (12/20) of the patients who required pharmacologic control of blood pressure before transplant were off all antihypertensive medications at 1 year after transplant. An additional 20% (4/20) of patients had a reduction in the number of medications required to control blood pressure at 1 year after transplant. CONCLUSIONS: We conclude that the combination of MMF and tacrolimus as primary immunosuppression for SPK transplantation results in excellent patient and graft survival rates, a very low rate of acute rejection, and low rates of infection and malignancy.     

Randomised open clinical trial of conversion from mycophenolate mofetil to azathioprine in cadaveric renal transplantation

Abstract Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The search for a less expensive immunosuppressive protocol has led to an open randomised clinical trial of conversion from MMF to azathioprine (Aza). A total of 28 renal allograft recipients treated with prednisone, cyclosporine, and MMF was randomised into two groups: converted (early conversion) and control (late conversion). Conversion from MMF to Aza was conducted at the end of the 4th post‐transplant month in the converted group and after the 12th month in the control. During the 20‐month observation period, biopsy‐proven acute rejection occurred more frequently in the converted than in the control group, although the difference was not statistically significant. Early conversion from MMF to Aza increased the risk of subsequent rejection in those patients who underwent at least one episode of acute rejection prior to conversion.     

Efficacy and Safety of Mycophenolate Mofetil Monotherapy in Liver Transplant Patients With Renal Failure Induced by Calcineurin Inhibitors

Objective

To assess the efficacy and safety of mycophenolate mofetil (MMF) monotherapy in liver transplant recipients with renal failure secondary to the use of calcineurin inhibitors (CNIs).

Materials and methods

Thirty-one patients on MMF monotherapy with creatinine levels >1.3 mg/dL, previously immunosuppressed with CNIs and MMF, were analyzed. Conversion was started in patients with no acute or chronic rejection episodes and stable liver chemistry. CNI doses were reduced by 25% every 2 to 3 months, or to 50% if the dose was lower than 1 mg/d of tacrolimus or 50 mg/d of cyclosporine. Different variables were recorded from the time that conversion to monotherapy was decided, on the discontinuation day of the calcineurin inhibitor, and during the follow-up.

Results

Mean times from transplant to conversion ranged from 14 to 186 months. The minimum follow-up time in monotherapy was 12 months. Renal function improved at 6 months in 70% of cases and at 12 months in 69.6%. Patients with no renal function improvement maintained stable creatinine values. There were no rejection episodes, graft losses, or deaths. No leukopenia occurred, and triglyceride and uric acid values improved.

Conclusions

MMF monotherapy is a safe alternative in patients with posttransplant renal failure secondary to the use of CNIs. Renal function improvement was achieved in almost 70% of patients at 12 months, and creatinine values were maintained in all other patients. The risk of rejection due to the slow tapering of CNIs is minimum.     

Mycophenolate mofetil reduces late renal allograft loss independent of acute rejection

BACKGROUND: Mycophenolate Mofetil (MMF) has been shown to significantly decrease the number of acute rejection episodes in renal transplant recipients during the 1st year. A beneficial effect of MMF on long-term graft survival has been more difficult to demonstrate. This beneficial effect has not been detected, despite the impact of acute rejection on the development of chronic allograft nephropathy and experimental evidence that MMF may have a salutary effect on chronic allograft nephropathy independent of that of rejection. METHODS: Data on 66,774 renal transplant recipients from the U.S. renal transplant scientific registry were analyzed. Patients who received a solitary renal transplant between October 1, 1988 and June 30, 1997 were studied. The Cox proportional hazard regression was used to estimate relevant risk factors. Kaplan-Meier analysis was performed for censored graft survival. RESULTS: MMF decreased the relative risk for development of chronic allograft failure (CAF) by 27% (risk ratio [RR] 0.73, P<0.001). This effect was independent of its outcome on acute rejection. Censored graft survival using MMF versus azathioprine was significantly improved by Kaplan-Meier analysis at 4 years (85.61% v. 81.9%). The effect of an acute rejection episode on the risk of developing CAF seems to be increasing over time (RR=1.9, 1988-91; RR=2.9, 1992-94; RR=3.7, 1995-97). CONCLUSION: MMF therapy decreases the risk of developing CAF. This improvement is only partly caused by the decrease in the incidence of acute rejection observed with MMF; but, is also caused by an effect independent of acute rejection.     

Long-term results after conversion from cyclosporine to tacrolimus in pediatric liver transplantation for acute and chronic rejection

Tacrolimus is beneficial in liver transplantation for reversing steroid-resistant acute rejection, and for controlling the process of chronic rejection in allograft recipients receiving Cyclosporine- (CyA) based regimens. Very little is known about the long-term efficacy of tacrolimus in pediatric transplantation after conversion from CyA. Our study examines the long-term outcome after conversion to tacrolimus for acute or chronic rejection in pediatric liver transplant (LTx) recipients. METHOD: Seventy-three children (age < 18 years) receiving their primary LTx under CyA between August 1989 and April 1996 were converted to tacrolimus for ongoing acute rejection (n=22, group I) or chronic rejection (n=51, group II). Mean age at the time of conversion was 10.2+/-5.5 years with a mean interval from LTx to conversion of 3.5+/-2.9 (range 0.5-10.1 years). There were 33 boys and 40 girls. All patients were followed until June 1999. Mean follow-up was 97.3+/-17.4 months (range 62.4-118.9 months). RESULTS: Overall 5-year actual patient survival was 78.1% and 8-year actuarial survival was 74.6%. Patients converted to tacrolimus therapy to resolve acute rejection (group I) experience significantly better patient and graft survival at 5 and 8 years than those converted to resolve chronic rejection (group II). Eight-year patient survival and graft survival was 95.5 and 90.9% for group I compared to 74.6 and 53.5% for group II, respectively (long rank P=0.035 and 0.01, respectively). Nearly 75% of children were weaned off steroids after conversion. There was a marked improvement in hypertension, gum hyperplasia, hirsutism, and cushingoid appearance. One child in group I (4.5%) and four children in group II (7.8%) developed posttransplant lymphoproliferative disorder after conversion. There was an improvement in growth in children who were less than the age of 12 years at the time of conversion and who were weaned off steroids; more significantly girls responded more favorably than boys. CONCLUSION: The benefit of transplantation is maintained long-term after conversion to tacrolimus for acute or chronic rejection. The response rate was significantly better in group I as compared with group 11. Marked improvement in growth, hypertension, and reversal of the brutalizing effects of CyA was noted after conversion to tacrolimus. The results suggest that early conversion of pediatric liver transplant patients is warranted for the treatment of acute and chronic rejection, and for improvements in quality of life.     

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 creatinine) 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.