Primary immunosuppression with tacrolimus and low-dose mycophenolate mofetil in renal transplant recipients

Both tacrolimus and mycophenolate mofetil (MMF) are potent immunosuppressive agents used in combination for prevention of acute rejection in renal transplantation. We studied the efficacy and safety of tacrolimus/MMF-based primary immunosuppression as well as their pharmacokinetics (PK) in Chinese renal transplant recipients. Oral tacrolimus was initiated at about 0.2 mg/kg/d, dose which was adjusted to achieve target trough levels of 10 to 20 ng/mL at 3 months and 5 to 10 ng/mL thereafter. The patients also received MMF (0.5 g bid) and prednisolone. PK profiles were studied at 1 week, and 1, 3, and 6 months posttransplant. Blood samples were taken at 0 (predose), 20, 40, 60, 75, and 90 minutes and 2, 4, 6, 8, 10, and 12 hours postdose for each profile. Plasma MPA and whole blood tacrolimus levels were determined by HPLC and EMIT methods respectively. Eight patients were studied with mean follow-up of 16.1 +/- 2.4 months. One patient (12.5%) experienced a borderline acute rejection episode. Both 1-year graft and patient survival rates were 100%. Posttransplant diabetes, diarrhea, and hand tremor occurred in 12.5%, 12.5%, and 37.5%, respectively. No patient had an opportunistic infection. Tacrolimus trough concentrations showed a fair correlation with AUC(0-12h) (R(2) = 0.587). Mean MPA AUC values at 1, 3, and 6 months were 40.5 +/- 9.4, 44.4 +/- 17.3, and 57.2 +/- 20.7 mug*h/mL, respectively (P = .0486, n = 7). In conclusion, primary immunosuppression with tacrolimus, low-dose MMF (0.5 g bid), and prednisolone is effective and safe with adequate systemic MPA exposure in renal transplant recipients.     

Daclizumab induction as an immunosuppressive regimen for renal transplant recipients from non-heart-beating donors

BACKGROUND: Recent reports have demonstrated the efficacy of interleukin-2-receptor blockers in lowering the incidence of early acute rejection. The present study aimed to test the hypothesis that the use of daclizumab induction (DAC) plus low-dose tacrolimus, mycophenolate mofetil, and steroid diminishes the incidence of delayed graft function (DGF) in renal transplants from non-heart-beating donors (NHBD). METHODS: We compared the incidence of DGF and rejection in 185 renal transplants from NHBD treated as follows: Group-I: quadruple sequential therapy with antithymocyte globulin, cyclosporine, azathioprine, and steroids (n=22); Group-II: cyclosporine (8 mg/kg/d) plus azathioprine plus steroid (n=26); Group-III: low-dose cyclosporine (5 mg/kg/d) plus mycophenolate mofetil plus steroid (n=68); Group-IV: low-dose tacrolimus (0.1 mg/kg/d) plus mycophenolate mofetil plus steroid (n=17); and Group-V: DAC plus low-dose tacrolimus plus mycophenolate mofetil plus steroid (n=43). RESULTS: The incidences of DGF were 72.7% in Group-I, 73.1% in Group-II, 69.1% in Group-III, 76.5% in Group-IV, and 44.2% in Group-V. Acute rejection was higher in Group-IV. CONCLUSIONS: The combination of DAC, low-dose tacrolimus, mycophenolate mofetil, and steroids is effective in lowering the incidence of DSF in NHBD kidney transplant recipients without any increase in acute rejection.     

Daclizumab induction and maintenance steroid-free immunosuppression with mycophenolate mofetil and tacrolimus to prevent acute rejection of hepatic allografts

Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.     

Primary immunosuppression with mycophenolate mofetil and antithymocyte globulin for kidney transplant recipients of a suboptimal graft

Background. In renal transplantation the beneficial immunosuppressive effects of cyclosporin (CsA) may be curtailed by its nephrotoxicity, specially in patients receiving a cadaveric allograft from suboptimal donors or at risk of delayed graft function. Mycophenolate mofetil (MMF) and antithymocyte globulin (ATG) have each demonstrated to be potent immunosuppressants in renal transplantation. In a prospective analysis we have studied the results at 6 months of the combination of MMF, ATG and low-dose steroids in patients with low immunological risk receiving a first cadaveric renal allograft from a suboptimal donor or at risk of delayed graft function. Methods. Patients with preformed reactive antibodies <50% receiving a first graft from a suboptimal donor (age ⩾40years, non-heart-beating, acute renal failure, arterial hypertension) or at risk of delayed graft function (cold ischaemia time ⩾24 h) were eligible for this open single-arm pilot trial. From September 1996 to March 1997 we recruited 17 patients. They were treated with MMF 2 g p.o. preoperatively, and after transplantation at 3 g/day; rabbit ATG i.v. at 2 mg/kg preoperatively, and 1.5 mg/kg/day the first day after transplantation, followed by four doses of 1 mg/kg on alternate days; prednisone was given at 0.25 mg/kg/day and reduced progressively to 0.1 mg/kg/day at 3 months. Primary outcomes were incidence of biopsy-proven acute rejection, delayed graft function, opportunistic infections, graft and patient survival, and the need for introduction of CsA treatment. Results. Delayed graft function occurred in two cases (12%). Four of 17 patients (27%) had a biopsy-proven acute rejection (2 grade I and 2 grade II) within the first 3 months after transplantation. CsA was added in two cases with grade II biopsy-proven acute rejection, and in one with grade I biopsy-proven acute rejection. In one patient MMF was replaced by CsA because of gastrointestinal intolerance. Mean serum creatinine 6 months after transplantation was 159±59 &mgr;mol/l. Cytomegalovirus tissue invasive disease occurred in one patient (6%). At 6 months follow-up all patients are alive with functioning allografts. Conclusions. These preliminary results suggest that in low-immunological-risk patients who receive a suboptimal renal allograft or at risk of delayed graft function, the combination of MMF, ATG, and steroids is an efficient immunosuppressive regime that may avoid the use of CsA in 70% of the recipients.     

Safe conversion of mycophenolate mofetil to azathioprine in kidney transplant recipients with sirolimus-based immunosuppression

Aim:   Mycophenolate mofetil (MMF) is a powerful immunosuppressive drug with established efficacy and safety. The long-term use of MMF may bring increased risk of for infection and malignancy and also increased cost of transplantation. The search for minimization of immunosuppressive protocol has led to an open randomized clinical trial of conversion from MMF to azathioprine (AZA).
Methods:   A total of 50 kidney allograft recipients treated with prednisone, sirolimus and MMF were randomized into two groups: converted (AZA group) and continuing (MMF group). The average duration of MMF therapy prior to conversion was 43 months in each group. Inclusion criteria included: patients with serum creatinine levels of less than 200 µmol/L; no past history of acute vascular rejection or recent acute rejection 6 months before randomization; and normal liver function tests.
Results:   Baseline demographics were similar in the two groups. During the 12 month observation period, there were no acute rejection episodes in either group. There were no significant differences in overall patient or graft survival or function. AZA-treated patients had a lower incidence of gastrointestinal complications ( P  = 0.03). Daily cost reduction in the AZA group was more than $US8.79/day per patient.
Conclusion:   In general, replacing MMF with AZA in stable renal transplant recipients is well tolerated and was cost effective with no increased risk of rejection. As the this study was on relatively small samples, larger and longer follow-up studies will be needed to confirm these expected advantages for the long-term outcome and to assess the long-term safety of this minimization of immunosuppressive therapy.     

Effect of mycophenolate mofetil regimen on peripheral blood lymphocyte subsets in kidney transplant recipients

BACKGROUND AND AIMS: There is growing evidence of the effects of immunosuppressive agents on "immune targets" in renal transplantation. Immunological monitoring could indirectly measure the suppressive effect of these drugs and guide early preventive interventions in transplant recipients. Due to the selective antiproliferative effect of mycophenolate mofetil (MMF) on lymphocytes, our goal was to determine whether MMF modulates peripheral blood lymphocyte subsets (PBLS) in kidney allograft patients. METHODS: We assessed absolute CD3(+), CD3(+)CD4(+), CD3(+)CD8(+), CD19(+), CD16(+)CD3(-) PBLS counts and CD4/CD8 ratios for 12 months in three groups of kidney allograft patients stratified according to maintenance immunosuppressive regimen: group A (n = 31), which started MMF with prednisone (P) + cyclosporine A (CyA), and two control groups, B (n = 19) and C (n = 15) on P + CyA + azathioprine (Aza) and P + CyA regimens, respectively. We compared intra- and intergroup lymphocyte counts and ratios. RESULTS: Intergroup comparisons showed a significant reduction in all PBLS in group A (CD19(+) from 3 months and other subsets from 6 months), whereas there were no significant changes in PBLS in the other group analyses or comparisons. CONCLUSIONS: Our findings suggest that (1) MMF modulates all PBLS in kidney allograft patients, causing a progressive reduction occurring earlier in CD19(+), and (2) we can rule out that these changes were caused by the "natural immunological evolution" of the transplantation. These results could offer a new method for immunological monitoring of transplant patients.     

Corticosteroid-free immunosuppression with tacrolimus, mycophenolate mofetil, and daclizumab induction in renal transplantation

BACKGROUND: Corticosteroid-free maintenance immunosuppression after organ transplantation eliminates the well-known corticosteroid-related side effects and may help to improve long-term outcome. We investigated whether a corticosteroid-free tacrolimus (Tac)/mycophenolate mofetil (MMF) regimen, in combination with daclizumab (Dac) induction therapy, provides adequate immunosuppression after renal transplantation. METHODS: This 6-month, open-label, multicenter, parallel-group study involved 538 renal patients randomized (1:1) to a Dac/Tac/MMF regimen (n = 260) or a Tac/MMF/corticosteroids regimen (n = 278) as a control group. RESULTS: Of the patients who completed the study, 88.8% in the Dac/Tac/MMF group were free from corticosteroid therapy at month 6. The incidence of biopsy-proven acute rejection was 16.5% in both treatment groups; the incidence of biopsy-proven corticosteroid-resistant acute rejection was 4.3% and 5.0% with Tac/MMF/corticosteroids and Dac/Tac/MMF, respectively (P = NS for both comparisons). Renal function was also similar in both groups: median serum creatinine at month 6 was 125.0 micromol/L (Tac/MMF/corticosteroids) and 131.0 microml/L (Dac/Tac/MMF), P = 0.277. The overall safety profile was similar with both regimens. However, compared with the Tac/MMF/steroid regimen, a significantly reduced incidence of new-onset insulin-dependent diabetes mellitus (5.4% vs. 0.4%, P = 0.003) was found with steroid-free immunosuppression. Moreover, mean total cholesterol concentrations increased from baseline in the Tac/MMF/corticosteroids group by 0.19 mmol/L, whereas in the Dac/Tac/MMF group, levels decreased by 0.19 mmol/L, P = 0.005. CONCLUSIONS: Corticosteroid-free immunosuppression with a Dac/Tac/MMF regimen is as effective at preventing acute rejection after renal transplantation as a standard triple regimen of Tac/MMF/corticosteroids. Furthermore, the safety benefits reported with Dac/Tac/MMF treatment may help improve the long-term outcome for renal-transplant patients.     

The use of intravenous tacrolimus and mycophenolate mofetil as induction and maintenance immunosuppression in simultaneous pancreas--kidney recipients with previous transplants

Clinical trials using quadruple immunosuppression that include the combination of tacrolimus (TAC) and mycophenolate mofetil (MMF) have been shown to reduce the incidence of acute rejection episodes in simultaneous pancreas-kidney (SPK) transplantation. In attempting to obtain a low rejection rate without antibody induction therapy, we proceeded with the combination of TAC intravenous (i.v.), MMF, and steroids as induction therapy and as primary immunosuppression for recipients with previous transplants. In this study, we analyzed 10 patients who received previous transplants, treated with low-dose TAC i.v. as induction therapy. Group A consisted of 6 patients with previous transplants that underwent SPK and group B consisted of four recipients with previous SPK that underwent cadaveric kidney transplants. For group A, the previous transplants were: living related kidney (LRK) followed by islet cell (IC) transplant (n=2), LRK transplant (n=1), cadaver kidney (CAD) and IC transplant (n=1), SPK (n=1), and three previous CAD kidney transplants (n=1). In group A, all six kidneys were lost due to recurrent diabetic nephropathy, IC possibly to rejection, and the pancreas due to thrombosis. In group B with previous SPK transplants, three recipients lost their kidney to chronic rejection and one to long-term use of a nephrotoxic antibiotic. Currently, in all group A and B patients, the kidney and the pancreas are functioning, although 1 patient in group A developed type 2 diabetes (normal fasting C-peptide). Two patients in group A developed three rejection episodes that responded to steroid treatment. The results indicate the TAC i.v. in combination with oral TAC, MMF, and steroids offer effective induction therapy in patients with previous transplants.     

Two-dose daclizumab, tacrolimus, mycophenolate mofetil, and steroid-free regimen in de novo cardiac transplant recipients: early experience

BACKGROUND: Tacrolimus (TAC) with mycophenolate mofetil (MMF) and a steroid-free regimen seems to have good efficacy in preventing acute rejection in cardiac transplant recipients, although concern exists about nephrotoxicity. Induction therapy with Daclizumab seems to give protection without side effects. Data are lacking about the outcome of 2-dose Daclizumab+TAC+MMF and a steroid-free regimen. MATERIALS AND METHODS: We retrospectively reviewed 28 consecutive de novo heart transplantations performed at a single center between January 2001 and June 2006. Patients received induction therapy with 2-dose Daclizumab. Maintenance immunosuppression included TAC, MMF, and prednisone during the first 6 months. The endpoints were the incidence of acute rejection, patient and graft survival, and clinical tolerability. RESULTS: Among 28 patients of mean age 57 +/- 9 years, 2 subjects (7%) died in the perioperative period due to infections. The mean follow-up was 2.8 +/- 1.5 years. There were no late deaths. Six patients experienced acute rejection (International Society of Heart and Lung Transplantation [ISHLT] >or=3A) that required treatment during the first 3 months. At follow-up, only 3 patients (>or=3A) required treatment. Mean creatinine level increased from 1.08 +/- 0.37 at baseline to 1.08 +/- 0.41 at 1 year (n = 23; P = not significant [NS]) to 1.39 +/- 0.68 (n = 13; P < .05) at 4 years, 1.65 +/- 0.51 (n = 8; P < .05) at 5 years. No patient required replacement therapy. CONCLUSIONS: A steroid-free protocol with 2-dose Daclizumab induction therapy and maintenance with TAC and MMF seemed to be safe to prevent acute rejection. Creatinine levels were slightly but significantly increased.     

Improved renal function after conversion from tacrolimus/sirolimus to tacrolimus/mycophenolate mofetil in kidney transplant recipients

BACKGROUND: There is limited data on the potential nephrotoxicity of sirolimus (SRL) and tacrolimus (TAC) in combination. METHODS: We reviewed the course of 97 kidney transplant patients treated with SRL and reduced-dose TAC. Conversion from SRL to mycophenolate mofetil (MMF) was prescribed in a minority (n = 19) for various nonrenal side effects. We compared outcomes of converted patients to those remaining on TAC/SRL (n = 78). RESULTS: TAC levels were increased in converters (P = 0.009). Rejection rates were similar between groups over 18 months (21% vs. 16%, p = ns). Serum creatinine (Cr) and MDRD glomerular filtration rate (GFR) were similar between groups at nadir and six-months, but at 18 months the percent change from six-month Cr was +17% in non-converters vs. -10% in converters (P = 0.004 for the difference). The difference in GFR between groups at 18 months was also significant (P = 0.01). By multivariate analysis, only conversion to MMF was associated with a greater percent change in Cr from 6 to 18 months (P = 0.015). Conversion to MMF also correlated with higher GFR at 18 months independent of rejection, delayed graft function, and ethnicity. CONCLUSIONS: Conversion from TAC/SRL to TAC/MMF led to improved renal function despite increased TAC exposure after conversion.     

The pharmacokinetics of mycophenolate mofetil in Thai kidney transplant recipients

Mycophenolate mofetil, in addition to cyclosporine and prednisolone significantly reduces the rate of acute rejection. The original recommended dose of MMF is fixed at 2 g/day. However, Thai patients cannot tolerate this dose due to gastrointestinal adverse effects. So the majority of patients are maintained on MMF at doses ranging from 0.5 to 2 g/day, according to their tolerability with an acceptable rate of acute rejection episodes. This study sought to determine the steady state pharmacokinetics of MMF in Thai kidney transplant recipients on stable doses of MMF. Forty-six kidney transplant patients more than 3 months on a stable MMF dose of 0.5, 1, 1.5, and 2 g/day together with cyclosporine and prednisolone underwent a single pharmacokinetic blood sampling for 12 hours following the morning dose of MMF. The analysis of plasma concentrations of mycophenolic acid (MPA), the sole pharmacologically active metabolite of MMF, was performed by using an high performance liquid chromatography method. Sparse efficient sampling strategies were employed to optimize the blood sampling schedule. Hence, blood samples were collected at 0, 0.5, 2, 12 hours after the MMF dose. The sampling time was designed to best estimate AUC(0-tau) at steady state. The initial MPA-Bayesian estimator were used for MPA concentrations that would allow the best estimation of Vc, CLt, and Ka. In this study, there is a high interindividual variability in the AUC. The median MPA AUC was 34.3 ug.h/mL (range 14.1-65.4). Thirty-one of 45 (68.9%) patients had a MPA AUC within 20 to 40 ug.h/mL, which is the most reasonable risk: benefit ratio in terms of preventing acute rejection episodes. Forty-one of 45 (91.1%) patients had MPA AUC within 20 to 60 ug.h/mL, which is the MPA therapeutic range. The highest Pearson correlation coefficient of determination between MPA AUC and a single concentration was observed with MPA 2 hours (r = 0.622) Without a fixed dosing regimen, most Thai kidney transplant recipients who receive MMF as part of a maintenance immunosuppressive regimen have the MPA AUC within the therapeutic window. The single drug concentration that correlates well with the AUC is MPA at 2 hours postdose.     

Mycophenolate mofetil, microemulsion cyclosporine, and prednisone as primary immunosuppression for pediatric liver transplant recipients.

Triple immunosuppressive therapy using mycophenolate mofetil (MMF), microemulsion cyclosporine (me-CsA), and prednisone offers the potential for potent immunosuppression without intravenous drug therapy or anti-T-cell antibody induction therapy. This report describes the application of an immunosuppressive protocol (CNp) using MMF, me-CsA, and prednisone as primary immunosuppression for pediatric liver transplant recipients at the University of California at San Francisco. From August 1995 through December 1996, 26 children (17 boys, 9 girls) aged 1 month to 16 years (mean +/- standard deviation, 58 +/- 62 months; median, 31 months) underwent liver transplantation at our institution, receiving CNp as primary immunosuppression. Posttransplantation renal function, incidence of leukopenia, and drug tolerance within the group receiving CNp as primary immunosuppression were compared with those of 19 children who received primary immunosuppression consisting of azathioprine, oil-based gel-encapsulated cyclosporine, and prednisone with anti-T-cell antibody induction therapy at the same institution from October 1993 through July 1995. No significant difference was observed between immunosuppressive protocols in serum creatinine level or incidence of leukopenia requiring medical therapy during the first year posttransplantation. Whereas gastrointestinal symptoms were observed in approximately 30% of CNp recipients during initial immunotherapy, tolerance of CNp primary immunotherapy was routinely achieved by the dose reduction of MMF. At 1 year posttransplantation, 20 children (77%) remained on CNp primary immunotherapy, 5 children (19%) were receiving tacrolimus-based immunotherapy secondary to rejection, and 1 patient (4%) converted to tacrolimus-based immunotherapy secondary to persistent gastrointestinal intolerance. In conclusion, CNp provides an alternative immunosuppressive protocol that eliminates the necessity of intravenous and induction immunosuppressive therapy with no increased incidence of posttransplantation renal dysfunction or leukopenia and is well tolerated in children.