(1/1113) Mycophenolate mofetil prevents the progressive renal failure induced by 5/6 renal ablation in rats.
BACKGROUND: Extensive renal ablation is associated with progressive sclerosis of the remnant kidney. Because lymphocytes and monocytes accumulate in the remnant kidney, it is likely that they play a role in the renal scarring. Therefore, we treated rats with 5/6 nephrectomy (5/6Nx) with mycophenolate mofetil (MMF), a drug that has an antiproliferative effect and that suppresses the expression of intercellular adhesion molecules. METHODS: Sprague-Dawley rats with 5/6Nx received MMF (30 mg. kg-1. day-1 by daily gastric gavage, N = 15) or vehicle (N = 16). Ten additional rats were sham operated. All rats were fed a 30% protein diet. Body weight, serum creatinine, and urinary protein excretion were determined weekly. Lipid peroxidation, as a measure of oxidative stress observed by urinary malondialdehyde determinations, was performed every two weeks. Histologic studies were done in the remnant kidney four weeks (9 rats from the vehicle-treated group, 7 rats from the MMF group, and 5 sham-operated rats) and eight weeks after surgery (the remaining rats). Glomerular volume, sclerosis in glomeruli (segmental and global) and interstitium (semiquantitative scale), infiltrating lymphocytes and macrophages (CD43- and ED1-positive cells), and expression of adhesion molecules (CD54, CD18, and CD11b) were analyzed. RESULTS: MMF treatment prevented the progressive increment in serum creatinine and the proteinuria observed in the 5/6 nephrectomized rats during the eight weeks of observation (P < 0.01). Weight gain was comparable in the MMF-treated and sham-operated rats, whereas weight gain was decreased in untreated 5/6 nephrectomized rats. Excretion of malondialdehyde increased after surgery but returned sooner to control levels in the MMF-treated rats. Increments in glomerular size and mean arterial blood pressure induced by renal ablation were not modified by MMF treatment. Eight weeks after surgery, segmental sclerosis was present in 48.4 +/- 8.35% (+/- sd) glomeruli in the vehicle-treated group versus 25 +/- 10.5% in the MMF-treated group (P < 0.001). Interstitial fibrosis was reduced significantly with MMF treatment (P < 0.001). Infiltration with CD43- and ED1-positive cells in glomeruli and interstitium was two to five times lower in MMF-treated rats (P < 0.01). Expression of adhesion molecules CD18 and CD11b was similarly reduced. CONCLUSION: MMF ameliorates the progressive renal damage in the remnant kidney after 5/6Nx. This effect is associated with a reduction in the infiltration of lymphocytes and monocytes, whereas glomerular hypertrophy and systemic hypertension are unchanged. (+info)
(2/1113) A prospective, randomized trial of tacrolimus/prednisone versus tacrolimus/prednisone/mycophenolate mofetil in renal transplant recipients.
BACKGROUND: Between September 20, 1995 and September 20, 1997, 208 adult patients undergoing renal transplantation were randomized to receive tacrolimus/prednisone (n=106) or tacrolimus/prednisone/mycophenolate mofetil (n=102), with the goal of reducing the incidence of rejection. METHODS: The mean recipient age was 50.7+/-13.7 years. Sixty-three (30.3%) patients were 60 years of age or older at the time of transplantation. The mean donor age was 34.5+/-21.7 years. The mean cold ischemia time was 30.5+/-9.2 hr. The mean follow-up is 15+/-7 months. RESULTS: The overall 1-year actuarial patient survival was 94%; the overall 1-year actuarial graft survival was 87%. When the patient and graft survival data were stratified to recipients under the age of 60 who did not have delayed graft function, the overall 1-year actuarial patient survival was 97%, and the corresponding 1-year actuarial graft survival was 93%. There were no differences between the two groups. The overall incidence of rejection was 36%; in the double-therapy group, it was 44%, whereas in the triple therapy group, it was 27% (P=0.014). The mean serum creatinine was 1.6+/-0.8 mg/dl. A total of 36% of the successfully transplanted patients were taken off prednisone; 32% of the patients were taken off antihypertensive medications. The incidence of delayed graft function was 21%, the incidence of cytomegalovirus was 12.5%, and the initial and final incidences of posttransplant insulin-dependent diabetes mellitus were 7.0% and 2.9%; again, there was no difference between the two groups. CONCLUSIONS: This trial suggests that the combination of tacrolimus, steroids, and mycophenolate mofetil is associated with excellent patient and graft survival and a lower incidence of rejection than the combination of tacrolimus and steroids. (+info)
(3/1113) Mycophenolate mofetil inhibits rat and human mesangial cell proliferation by guanosine depletion.
BACKGROUND: Mycophenolate mofetil (MMF) is used for immunosuppression after renal transplantation because it reduces lymphocyte proliferation by inhibiting inosine monophosphate dehydrogenase (IMPDH) in lymphocytes and GTP biosynthesis. In the present study we asked if therapeutic concentrations of MMF might interfere with mesangial cell (MC) proliferation which is involved in inflammatory proliferative glomerular diseases. METHODS: Rat and human MCs were growth-arrested by withdrawal of fetal calf serum (FCS) and stimulated by addition of FCS, platelet-derived growth factor (PDGF) or lysophosphatidic acid (LPA). Different concentrations of MMF (0.019-10 microM) were added concomitantly in the presence or absence of guanosine. MC proliferation was determined by [3H]thymidine incorporation. Cell viability was assessed by trypan blue exclusion. Apoptotic nuclei were stained using the Hoechst dye H33258. Cytosolic free Ca2+ concentrations were determined with the fluorescent calcium chelator fura-2-AM. RESULTS: MMF inhibited mitogen-induced rat MC proliferation with an IC50 of 0.45 +/- 0.13 microM. Human MCs proved to be even more sensitive (IC50 0.19 +/- 0.06 microM). Inhibition of MC proliferation was reversible and not accompanied by cellular necrosis or apoptosis. Addition of guanosine prevented the antiproliferative effect of MMF, indicating that inhibition of IMPDH is responsible for decreased MC proliferation. Early signalling events of GTP-binding-protein-coupled receptors, such as changes in intracellular Ca2+ levels were not affected by MMF. CONCLUSIONS: The results show that MMF has a concentration-dependent antiproliferative effect on cultured MCs in the therapeutic range, which might be a rationale for the use of this drug in the treatment of mesangial proliferative glomerulonephritis. (+info)
(4/1113) Reduced kidney transplant rejection rate and pharmacoeconomic advantage of mycophenolate mofetil.
BACKGROUND: Several multinational controlled clinical trials have shown that triple therapy immunosuppressive regimens which include mycophenolate mofetil (MMF), cyclosporin A (CSA) and steroids (S) are superior compared with conventional regimens which include azathioprine (AZA), CSA and S, mainly because MMF reduces the rate of acute rejection episodes in the first 6 months after kidney transplantation. Post-marketing studies are useful to evaluate the general applicability and costs of MMF-based immunosuppressive regimens. METHODS: Based on the excellent results of the published controlled clinical trials, we have changed the standard triple therapy immunosuppressive protocol (AZA+CSA+S) to an MMF-based regimen (MMF+CSA+S) at our centre. To analyse the impact of this change in regimen, we have monitored 6-month patient and graft survival, rejection rate, serum creatinine and CSA levels, as well as the costs of the immunosuppressive and anti-rejection treatments, in 40 consecutive renal transplant recipients (MMF group) and have compared the data with 40 consecutive patients transplanted immediately prior to the change in regimen (AZA group). RESULTS: Recipient and donor characteristics were similar in the AZA and MMF groups. Patient survival (37/40; 92.5% in the AZA group vs 38/40; 95% in the MMF group), graft survival (36/40 vs 36/40; both 90%) and serum creatinine (137+/-56 vs 139+/-44 micromol/l) after 6 months were not significantly different. However, the rate of acute rejection episodes (defined as a rise in creatinine without other obvious cause and treated at least with pulse steroids) was significantly reduced with MMF from 60 to 20% (P=0.0005). The resulting cost for rejection treatment was lowered 8-fold (from sFr. 2113 to 259 averaged per patient) and the number of transplant biopsies was lowered > 3-fold in the MMF group. The cost for the immunosuppressive therapy was increased 1.5-fold with MMF (from sFr. 5906 to 9231 per patient for the first 6 months). CONCLUSIONS: The change from AZA to MMF resulted in a significant reduction in early rejection episodes, resulting in fewer diagnostic procedures and rehospitalizations. The optimal long-term regimen in terms of patient and pharmacoeconomic benefits remains to be defined. (+info)
(5/1113) Long-term results of pancreas transplantation under tacrolius immunosuppression.
BACKGROUND: The long-term safety and efficacy of tacrolimus in pancreas transplantation has not yet been demonstrated. The observation of prolonged pancreatic graft function under tacrolimus would indicate that any potential islet toxicity is short-lived and clinically insignificant. We report herein the results of pancreas transplantation in patients receiving primary tacrolimus immunosuppression for a minimum of 2 years. METHODS: From July 4, 1994 until April 18, 1996, 60 patients received either simultaneous pancreas-kidney transplant (n=55), pancreas transplant only (n=4), or pancreas after kidney transplantation (n=1). Baseline immunosuppression consisted of tacrolimus and steroids without antilymphocyte induction. Azathioprine was used as a third agent in 51 patients and mycophenolate mofetil in 9. Rejection episodes within the first 6 months occurred in 48 (80%) patients and were treated with high-dose corticosteroids. Antilymphocyte antibody was required in eight (13%) patients with steroid-resistant rejection. RESULTS: With a mean follow-up of 35.1+/-5.9 months (range: 24.3-45.7 months), 6-month and 1-, 2-, and 33-year graft survival is 88%, 82%, 80%, and 80% (pancreas) and 98%, 96%, 93%, and 91% (kidney), respectively. Six-month and 1-, 2-, and 3-year patient survival is 100%, 98%, 98%, and 96.5%. Mean fasting glucose is 91.6+/-13.8 mg/dl, and mean glycosylated hemoglobin is 5.1+/-0.7% (normal range: 4.3-6.1%). Mean tacrolimus dose is 6.5+/-2.6 mg/day and mean prednisone dose 2.0+/-2.9 mg/day at follow-up. Complete steroid withdrawal was possible in 31 (65%) of the 48 patients with functioning pancreases. CONCLUSIONS: These data show for the first time that tacrolimus is a safe and effective long-term primary agent in pancreas transplantation and provides excellent long-term islet function without evidence of toxicity while permitting steroid withdrawal in the majority of patients. (+info)
(6/1113) Mycophenolic acid plasma concentrations in kidney allograft recipients with or without cyclosporin: a cross-sectional study.
BACKGROUND: Combining cyclosporin (CsA) and prednisone with mycophenolate mofetil (MMF) results in a significant reduction in the rate of biopsy-proven acute rejection after kidney transplantation. This is achieved with a standard daily MMF dosage of 2 or 3 g. Whether monitoring of the pharmacologically active metabolite mycophenolic acid (MPA) will lead to improved safety and efficacy is unclear. METHODS: We monitored MPA trough levels in 18 kidney transplant recipients treated with CsA, prednisone, and MMF (63 samples) and in 11 patients (31 samples) treated with prednisone and MMF only, in a cross-sectional study. All patients were at least 3 months after transplantation with stable graft function. All patients were treated with 2 g MMF for at least 3 months and 10 mg prednisone. RESULTS: The MPA trough levels in the CsA-treated patients were significantly lower (P<0.0001; Mann-Whitney) than those in patients on MMF and prednisone only (mean MPA levels 1.98+/-0.12 vs 4.38+/-0.40 mg/l respectively). CONCLUSIONS: Although all patients were treated with an identical MMF dose, a significant difference was found in the MPA trough levels between CsA- vs non-CsA-treated patients. This suggests that CsA influences the MPA trough level. The level at which CsA affects the MPA trough levels is unclear. (+info)
(7/1113) Mycophenolate mofetil therapy in lupus nephritis: clinical observations.
Controlled clinical trials in renal transplantation have demonstrated that mycophenolate mofetil is well tolerated and has lower renal transplant rejection rates than azathioprine regimens. This study reports on the clinical experiences at two institutions with mycophenolate mofetil (MMF) for severe lupus nephritis. Twelve patients with relapsing or resistant nephritis previously treated with cyclophosphamide therapy and one patient who refused cyclophosphamide as initial therapy for diffuse proliferative nephritis but accepted MMF were included. During combined MMF/prednisone therapy, serum creatinine values remained normal or declined from elevated values: mean change in serum creatinine was -0.26+/-0.46 microM/L, P = 0.039. Proteinuria significantly decreased: mean change in urine protein-to-creatinine ratios was -2.53+/-3.76, P = 0.039. Decreased serum complement component C3 and elevated anti-double-stranded DNA antibody levels at baseline improved in some, but not all, patients. The mean initial dose of MMF was 0.92 g/d (range, 0.5 to 2 g/d). The mean duration of therapy was 12.9 mo (range, 3 to 24 mo). Adverse events included herpes simplex stomatitis associated with severe leukopenia (n = 1), asymptomatic leukopenia (n = 2), nausea/ diarrhea (n = 2), thinning of scalp hair (n = 1), pancreatitis (n = 1), and pneumonia without leukopenia (n = 1). Recurrence of the pancreatitis led to discontinuation of MMF in this patient; all other adverse events resolved with dose reduction. It is concluded that MMF is well tolerated and has possible efficacy in controlling major renal manifestations of systemic lupus erythematosus. Controlled clinical trials are needed to define the role of MMF in the management of lupus nephritis. (+info)
(8/1113) Identification of glucoside and carboxyl-linked glucuronide conjugates of mycophenolic acid in plasma of transplant recipients treated with mycophenolate mofetil.
1. Mycophenolic acid (MPA), is primarily metabolized in the liver to 7-O-MPA-beta-glucuronide (MPAG). Using RP-h.p.l.c. we observed three further MPA metabolites, M-1, M-2, M-3, in plasma of transplant recipients on MMF therapy. To obtain information on the structure and source of these metabolites: (A) h.p.l.c. fractions containing either metabolite or MPA were collected and analysed by tandem mass spectrometry; (B) the metabolism of MPA was studied in human liver microsomes in the presence of UDP-glucuronic acid, UDP-glucose or NADPH; (C) hydrolysis of metabolites was investigated using beta-glucosidase, beta-glucuronidase or NaOH; (D) cross-reactivity of each metabolite was tested in an immunoassay for MPA (EMIT). 2. Mass spectrometry of M-1, M-2, MPA and MPAG in the negative ion mode revealed molecular ions of m/z 481, m/z 495, m/z 319 and m/z 495 respectively. 3. Incubation of microsomes with MPA and UDP-glucose produced M-1, with MPA and UDP-glucuronic acid MPAG and M-2 were formed, while with MPA and NADPH, M-3 was observed. 4. Beta-Glucosidase hydrolysed M-1 completely. Beta-Glucuronidase treatment led to a complete disappearance of MPAG whereas the amount of M-2 was reduced by approximately 30%. Only M-2 was labile to alkaline treatment. 5. M-2 and MPA but not M-1 and MPAG cross-reacted in the EMIT assay. 6. These results suggest that: (i) M-1 is the 7-OH glucose conjugate of MPA; (ii) M-2 is the acyl glucuronide conjugate of MPA; (iii) M-3 is derived from the hepatic CYP450 system. (+info)