mycophenolic-acid and Body-Weight

Overall, the PK of MMF is reasonably straightforward and relatively unaffected by the complex pathophysiological changes involved in the management of renal transplant recipients. The ability to relate plasma MPA concentrations to efficacy through the PK/PD correlation implies that, unlike for many other drugs, plasma PK has direct relevance to the clinical outcome. These features should not only greatly help the exploration of immunosuppressive regiments using MMF but also the development of clinical use of MMF in situations other than renal transplantation.

Topics: Body Weight; Humans; Immunosuppressive Agents; Intestinal Absorption; Kidney Transplantation; Lymphocyte Activation; Mycophenolic Acid

We prospectively compared the effects of oral mycophenolate mofetil (MMF) or intravenous cyclophosphamide (IVC) combined with corticosteroids for induction therapy of microscopic polyangiitis (MPA) with renal involvement over a follow-up period of 6 months.. 41 MPA patients were randomly assigned to either the open-label MMF group or the IVC group. Patients in the MMF group (n = 19) received oral MMF 1.0 g/day (1.5 g/day for patients with a body weight >70 kg) and patients in the IVC group (n = 22) received IVC in monthly pulses of 1.0 g per pulse (0.8 g per pulse for patients with a body weight <50 kg). Both groups received intravenous methylprednisolone 360-500 mg/day for 3 days, followed by oral prednisone 0.6-0.8 mg/kg/day and gradual tapering.. There was no significant difference of estimated glomerular filtration rate (eGFR) level between the IVC and MMF groups at baseline. At 6 months, the eGFR level increased significantly in both groups, but there was no significant difference between the two. Three patients in the IVC group and 1 in the MMF group received maintenance dialysis within 6 months (p = 0.36). The remission rate was 63.6% in the IVC group and 78.9% in the MMF group (p = 0.23).. MMF is effective for inducing remission in Chinese MPA patients and may represent an alternative therapy to monthly impulses of IVC.

Topics: Administration, Oral; Adrenal Cortex Hormones; Adult; Aged; Body Weight; China; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Infusions, Intravenous; Male; Microscopic Polyangiitis; Middle Aged; Mycophenolic Acid; Prospective Studies; Remission Induction; Treatment Outcome

The objective was to develop a population pharmacokinetic-pharmacogenetic model of mycophenolic acid following administration of mycophenolate mofetil (MMF) in de novo pediatric renal-transplant patients and identify factors that explain variability. The pharmacokinetic samples were collected from 89 de novo pediatric renal-transplant patients treated with MMF and studied during the first 60 postoperative days. All patients were genotyped for UGT1A8-A9, UGT2B7, and ABCC2. Population pharmacokinetic analysis was performed with the NONMEM and was validated using bootstrap visual predictive check. The pharmacokinetic data were best described by a 2-compartment model with Erlang distribution to describe the absorption phase. The covariate analysis identified body weight as an individual factor influencing central volume of distribution and concomitant immunosuppressive medication and identified body weight and UGT2B7 802C>T genotype as individual factors influencing apparent oral clearance (CL/F) of MMF. CL/F in cyclosporine-MMF-treated patients was 33% higher than in tacrolimus-MMF-treated patients. The CL/F was significantly lower in patients with UGT2B7 802 C/C genotype compared with patients with UGT2B7 802 C/T and 802T/T genotypes, and this effect was independent of concomitant immunosuppressive medication or body weight. The population pharmacokinetic-pharmacogenetic model of mycophenolic acid was validated. Body weight, concomitant medication, and UGT2B7 genotype contribute significantly to the interindividual variability of MMF disposition in pediatric renal-transplant patients.

Topics: Adolescent; Body Weight; Child; Child, Preschool; Cyclosporine; Female; Genotype; Glucuronosyltransferase; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Models, Biological; Multidrug Resistance-Associated Protein 2; Mycophenolic Acid; Nonlinear Dynamics; Pharmacogenetics; Prospective Studies; Tacrolimus; Tissue Distribution

The Opticept trial was an open-label, randomized, multicenter trial involving 720 kidney recipients. Three immunosuppressant dosing regimens were evaluated, including both fixed and concentration-controlled dosing of mycophenolate mofetil in combination with standard and reduced calcineurin inhibitor levels. Mycophenolic acid (MPA) levels were measured, yielding one of the largest databases to assess the impact of variables on MPA exposure. The present subset analysis evaluated the effect of baseline body weight in three noncontiguous weight categories on MPA exposure at steady state (Day 90) in patients receiving tacrolimus. Multivariate linear regression models assessed the relationship between area under the concentration-time curve (AUC) and several variables. In all, 219 patients had baseline weights in the three categories and an MPA AUC at Day 90: 50 kg or less (n = 12, all female); 60 to 80 kg (n = 136); or 100 kg or greater (n = 71). In overall comparisons by weight class, clearance increased with increased weight, resulting in an inverse relationship between dose-corrected MPA AUCs and weight at Day 90 (P < 0.0001). In patients of extreme weight, wide disparities of MPA exposure were measured despite the mean mycophenolate mofetil dose, notably in those 50 kg or less who had comparatively high dose-corrected MPA AUCs. Patients at the extremes of weight might be at risk of over- or underimmunosuppression unless doses are adjusted.

Topics: Adult; Body Weight; Female; Humans; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Overweight; Prospective Studies; Thinness

A standard fixed dose of 2 g/day of mycophenolate mofetil (MMF), irrespective of total body weight (TBW), is recommended when used in combination with cyclosporine and corticosteroids in renal transplantation.. To determine the optimal MMF dose in a population with wide variation in TBW, steady-state pharmacokinetics of mycophenolic acid (MPA) was performed in 53 Asian (Chinese, Malay, Indian, Eurasian) renal transplant recipients (RTX) receiving MMF [250-1000 mg twice daily (BD)] for at least 3 months. Blood samples were collected at 0, 0.5, 1, 1.5, 2 and 6 h after the MMF dose and total MPA quantified using HPLC.. Drug exposure, as evaluated by AUC(ss, 0-12), demonstrated a significant positive correlation with TBW-adjusted MMF dose (outliers omitted: r(2) = 0.49, P < 0.0005). An AUC(ss, 0-12) of 45 mg h/l could be attained with an MMF dose of 12 mg/kg BD.. This study proposes that MMF should be dosed based on TBW rather than a fixed dose regimen in RTX.

Topics: Adrenal Cortex Hormones; Asian People; Body Weight; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Prospective Studies

Mycophenolic acid (MPA) pharmacokinetics exhibit large variability in transplant recipients and may be altered due to concurrent immunosuppressants. Little is known about the influence of sirolimus (SRL) on MPA pharmacokinetics in kidney transplant patients.. We studied the areas under concentration-time curves (AUC) for MPA in 15 patients receiving immunosuppression combining SRL with mycophenolate mofetil (MMF). The pharmacokinetic measurements were performed in all patients using three MMF dosing regimens (0.5 g twice a day, 0.75 g twice a day, 1 g twice a day). Similar blood AUC profiles were also sampled from 12 patients treated with a fixed dose of MMF 1 g twice a day and cyclosporine (CsA). MPA was measured using HPLC; the AUC0-12 of MPA was determined by the trapezoidal method using four sampling time points: C0, C1, C3, C5.. While patients on SRL were receiving 0.75 g MMF twice a day, mean AUC0-12 and C0 values of MPA were comparable to those of patients receiving CsA and 1 g MMF twice a day (54.1 +/- 17.6 and 3 +/- 1.87 vs 51.7 +/- 16.7 mg.h/L and 2.76 +/- 1.57 mg/L, respectively). On the other hand, 0.5 g MMF twice a day with SRL therapy resulted in AUC0-12 and C0 values of MPA of 32.3 +/- 12.6 mg.h/L and 2.32 +/- 1.72 mg/L, respectively, whereas, 1 g MMF twice a day with SRL resulted in AUC0-12 and C0 values of MPA of 70.9 +/- 19.3 mg.h/L and 4.7 +/- 2.44 mg/L, respectively.. These findings demonstrate that MPA exposure in the presence of SRL is higher than that with CsA. It appears that the MMF dose should be reduced to 0.75 g twice a day in patients receiving SRL to obtain AUC0-12 of MPA levels comparable to that in patients treated with CsA and MMF 1 g twice a day.

Topics: Area Under Curve; Body Weight; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Kinetics; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Sirolimus

Previous studies have shown poor absorption of enteric-coated mycophenolate sodium (E-MPS) during the initial post-kidney transplantation (KT) period. The percentage of patients with adequate therapeutic exposure (target AUC 30-60 microg.h/mL) of mycophenolic acid is 55%, 86%, and 100% at days 14, 90, and 180 postgrafting. To assess the adequacy of mycophenolic acid (MPA) delivery during the initial period, we prospectively studied the pharmacokinetics (AUC0-12 h of MPA (measured by high-performance liquid chromatography) in 12 patients after their first single dose of 720 mg of oral E-MPS and 3 to 8 months after 720 mg twice a day prescribed daily. Concomitant immunosuppression included CsA and prednisolone. Evaluation of the pharmacokinetic profiles was repeated at 2 weeks. The patients' mean +/- SD body weight was 48.1 +/- 8.8 kg; their mean (range) values of AUC0-12 h for MPA were 73.9 +/- 49.5 microg.h/ml (31.9-190) on day 1 and 74.3 +/- 44.3 (30.5-178) microg.h/ml on day 14. The mean nadir serum creatinine was 1.1 +/- 0.4 mg/dL. The patient and graft survival rates were 100%. Two patients (15%) developed significant diarrhea requiring E-MPS dose reduction. Other complications included urinary tract infections (n = 2), CMV syndrome (n = 1), borderline acute rejection (n = 1), and reversible CsA nephrotoxicity (n = 3). We conclude that the use of a standard dose of E-MPS results in immediate delivery of adequate therapeutic systemic MPA exposure in all patients. The absorption profile was better than that described previously.

Topics: Administration, Oral; Adult; Body Weight; Drug Monitoring; Glucuronates; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Tablets, Enteric-Coated

New-onset diabetes mellitus (NODM) is associated with increased risk of graft failure and death in renal transplant recipients. Some clinical studies have indicated that NODM risk is higher with tacrolimus than cyclosporine, but no comparative trial has used American Diabetic Association (ADA)/World Health Organization (WHO) criteria for diagnosis of diabetes mellitus. The Diabetes Incidence After Renal Transplantation, Neoral C2 Monitoring Versus Tacrolimus (DIRECT) study is a 6-month open-label, multicenter trial comparing the impact of tacrolimus and Neoral (cyclosporine microemulsion) on glucose metabolism in 700 de novo kidney transplant recipients, based on ADA/WHO criteria. Patients are randomized to tacrolimus (C0 monitoring) or Neoral (C2 monitoring), stratified by baseline diabetic status and ethnicity. All patients receive basiliximab, corticosteroids, and mycophenolate mofetil or enteric-coated mycophenolate acid (myfortic). Pooled interim 3-month results from a subset of 115 patients receiving either tacrolimus or Neoral showed that the primary efficacy end-point (biopsy-proven acute rejection [BPAR], graft loss or death) occurred in 11 patients (10%). There were four graft losses and only one death, which occurred after graft loss. Eight patients experienced BPAR (7.3%). Among 99 patients who were nondiabetic at baseline, 14 developed NODM by month 3, 17 developed impaired fasting glucose or impaired glucose tolerance, and another 5 patients received hypoglycemic treatment for at least 14 consecutive days or at the month 3 visit, resulting in a 36% incidence of impaired glucose metabolism. At 3 months, median GFR (Nankivell) was 63.7 mL/min; median serum creatinine was 137 micromol/L. Full complete results are expected in December 2005.

Topics: Adrenal Cortex Hormones; Adult; Body Weight; Cyclosporine; Diabetes Mellitus; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Reoperation; Tacrolimus; Tissue Donors; Treatment Failure; United States; White People

Weight gain is a known complication of corticosteroid maintenance therapy. The purpose of the present study was to compare patterns of weight gain under chronic corticosteroid therapy (CCST) with that observed under early (i.e., within 7 days posttransplant) corticosteroid withdrawal (CSWD) in renal-transplant recipients.. Renal-transplant recipients who underwent early CSWD under four prospective, institutional review board-approved clinical trials were compared with a historic control group of patients receiving maintenance CCST.. One hundred sixty-nine patients with early CSWD were compared with 132 patients who received CCST. Mean population weight gain was significantly higher in CCST patients at 3, 6, and 12 months posttransplant. Race influenced weight gain because white CSWD patients demonstrated greater reductions in weight gain compared with African-American patients. Sex also influenced weight gain: women demonstrated a greater benefit from CSWD than did men. Corticosteroid rejection therapy in CSWD patients completely restored weight gain because these patients showed weight gains similar to the CCST group. Finally, pretransplant body mass index (BMI) also influenced weight gain because patients who were overweight (BMI 25-30) or obese (BMI>30) demonstrated a greater reduction in weight gain with CSWD than did patients of normal weight (BMI<25).. Early CSWD minimizes weight gain in renal-transplant recipients. Women, whites, and patients with high pretransplant BMI had greater reductions in weight gain with early CSWD.

Topics: Adrenal Cortex Hormones; Body Mass Index; Body Weight; Drug Administration Schedule; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Sirolimus; Time Factors; Weight Gain

The purpose of this study was to characterize the pharmacokinetic parameters of mycophenolic acid (MPA) in Korean kidney transplant recipients. Plasma MPA concentrations of 10 Korean kidney transplant recipients administered a lower dose of mycophenolate mofetil (MMF; 750 mg twice a day) were measured at 2 weeks of MMF therapy by high-performance liquid chromatography (HPLC). The plasma MPA concentration-time curve pattern of patients taking lower doses of MPA was consistent with previously reported profiles of patients taking the fully recommended doses. The plasma MPA concentration-time curve was characterized by an early sharp peak within 1 hour and a small second peak in some patients at 4 to 12 hours postdose. The mean C(max) and AUC were 8.73 +/- 4.65 microg/mL and 18.45 +/- 4.25 microg*h/mL, respectively. The mean fraction of free MPA was 1.60% +/- 0.23%. Patients' age, weight, body surface area, and renal function did not influence the AUC. The free fraction of MPA appeared not to be affected by serum albumin and renal function when creatinine clearance was above 40 mL/min. Regression analysis between each plasma concentration and AUC for the limited sampling strategy of MMF therapeutic drug monitoring demonstrated that the concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC (r = 0.74545, p = 0.0133; r = 0.68485, p = 0.0289; and r = 0.63636, p = 0.0479, respectively). The pattern of the concentration-time profile of MPA in Korean kidney recipients was similar to the results of other studies performed in Caucasians, although there was interindividual variability of AUC, C(max), and t(max). MPA concentrations of predose and 1- and 8-hour postdose were positively correlated with AUC.

Topics: Adult; Age Factors; Area Under Curve; Asian People; Blood Specimen Collection; Body Weight; Chromatography, High Pressure Liquid; Female; Half-Life; Humans; Kidney Transplantation; Korea; Male; Mycophenolic Acid

Black American heart transplant recipients receiving cyclosporine-based primary immunoprophylaxis suffer higher rates of allograft rejection with hemodynamic compromise, infections, and posttransplant coronary artery disease. We examined the hypothesis that a combination of tacrolimus and mycophenolate mofetil "resurrects" clinical outcome of black Americans to those seen in white heart transplant recipients.. Sixty-three adult primary heart transplant recipients were included in this study. Twenty black American and 21 white patients who received tacrolimus-based primary immunoprophylaxis were enrolled in this prospective, observational parallel cohort investigation. A separate group of 22 black American patients were randomly allocated to receive cyclosporine-microemulsion-based primary prophylaxis and served as the control population for assessing outcomes in the black American group. Adjunctive immunosuppression included mycophenolate mofetil and corticosteroids. The primary end-point was the freedom from allograft rejection requiring treatment at 1 year. Secondary end-points included rejection with hemodynamic compromise, and patient or graft survival. Adverse events evaluated included development of infections requiring hospitalization and nonimmunological outcomes including hyperlipidemia, hypertension, and diabetes mellitus (new onset or worsened).. Tacrolimus-treated black American patients had greater freedom from allograft rejection requiring treatment at 1 year than those treated with cyclosporine (64% vs. 37%, P=0.01). No differences were noted between tacrolimus-treated black Americans and whites in the primary end point (64% and 67% respectively, P=nonsignificant [NS]). Tacrolimus-based immunosuppression was associated with better 1-year survival in black Americans compared with cyclosporine (95% vs. 73%, P=0.04), and this end point was similar to that achieved in tacrolimus-treated white heart transplant recipients (95%). No differences in infection rates were noted among either group. Cyclosporine-treated black Americans suffered more hyperlipidemia and worse hypertension than tacrolimus-treated patients.. Compared with cyclosporine, an immunosuppressive strategy using tacrolimus in black Americans achieves superior efficacy with regard to allograft rejection, higher allograft survival, and similar safety. Furthermore, tacrolimus-based immunosuppression is similar in immunological efficacy and safety in black Americans and in white heart transplant recipients.

Topics: Adult; Aged; Black or African American; Black People; Body Weight; Creatinine; Cytomegalovirus Infections; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Graft Rejection; Heart Transplantation; Hemodynamics; Humans; Hyperlipidemias; Hypertension; Immunosuppressive Agents; Incidence; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous; Treatment Outcome; White People

Topics: Body Weight; Double-Blind Method; Europe; Glucuronates; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Regression Analysis; Time Factors

Higher MMF dose can reduce acute GVHD risk after allogeneic hematopoietic cell transplantation (HCT). We examined the effect of MMF dose, relative to patient actual body weight (mg/kg/day), on outcomes of 680 adults after HCT.. MMF was combined with cyclosporine (n = 599) or sirolimus (n = 81). We divided MMF dose/kg/day in quartiles.. The median time to grade II-IV acute GVHD was 32 days. The incidence of grade II-IV acute GVHD at day 30 was 30% in 1st (<29), 20% in 2nd (29-34), 16% in 3rd (35-41), and 19% in 4th (≥42) quartile (P < .01). Corresponding relapse incidence at 1 year was 16%, 25%, 27%, and 31%, respectively (P = .01). In multivariate analysis, as compared to 1st quartile, higher dose of weight-based MMF reduced grade II-IV acute GVHD (HR = 0.64 for 2nd, HR = 0.48 for 3rd, and HR = 0.55 for 4th quartile), but increased the risk of relapse (HR = 1.63 for 2nd, HR = 1.75 for 3rd, and HR = 2.31 for 4th quartile).. Weight-based MMF dose had no significant impact on engraftment, chronic GVHD, or survival. These data suggest that higher weight-based MMF dose reduces the risk of acute GVHD at the expense of increased relapse and supports conducting prospective studies to optimize MMF dosing after HCT.

Topics: Acute Disease; Adolescent; Adult; Aged; Body Weight; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Prognosis; Recurrence; Severity of Illness Index; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Mycophenolate mofetil (MMF) is commonly prescribed and has proven advantages over other immunosuppressive drugs. However, frequent gastrointestinal side effects through an unknown mechanism limit its use. We have found that consumption of MMF alters the composition of the gut microbiota, selecting for bacteria expressing the enzyme β-glucuronidase (GUS) and leading to an up-regulation of GUS activity in the gut of mice and symptomatic humans. In the mouse, vancomycin eliminated GUS-expressing bacteria and prevented MMF-induced weight loss and colonic inflammation. Our work provides a mechanism for the toxicity associated with MMF and a future direction for the development of therapeutics.

Topics: Animals; Bacteria; Bacterial Proteins; Body Weight; Colitis; Disease Models, Animal; Female; Gastrointestinal Microbiome; Gastrointestinal Tract; Glucuronidase; Immunosuppressive Agents; Mice; Mice, Inbred C57BL; Mycophenolic Acid; Up-Regulation; Vancomycin

Background Mycophenolate mofetil has recently been reported to be effective against systemic lupus erythematosus. The influence of the pharmacokinetics of mycophenolic acid, the active form of mycophenolate mofetil and the major inactive mycophenolic acid phenolic glucuronide on the activity of the target enzyme inosine 5'-monophosphate dehydrogenase, is expected to be revealed. The aim of this study was to identify the factors associated with inosine 5'-monophosphate dehydrogenase activity in systemic lupus erythematosus patients. Methods Fifty systemic lupus erythematosus patients in remission maintenance phase (29 received mycophenolate mofetil [MMF+] and 21 did not [MMF-]) were enrolled. Median and interquartile range of dose of mycophenolate mofetil were 1500 and 1000-1500 mg/day, respectively. Stepwise multiple linear regression analysis was performed to assess the dependence between inosine 5'-monophosphate dehydrogenase activity and 25 predictor values including predose plasma concentrations of free mycophenolic acid and mycophenolic acid phenolic glucuronide. Results Median and interquartile range of predose total plasma concentrations of mycophenolic acid and mycophenolic acid phenolic glucuronide were 2.73 and 1.43-5.73 and 25.5 and 13.1-54.7  µg/mL, respectively. Predose inosine 5'-monophosphate dehydrogenase activity was significantly higher in MMF+ than MMF- patients (median 38.3 and 20.6 nmoL xanthosine 5'-monophosphate/g haemoglobin/h, P<0.01). The plasma concentration of free mycophenolic acid phenolic glucuronide, complement fraction C3 and body weight were significant predictors accounting for interindividual variability in the inosine 5'-monophosphate dehydrogenase activity (adjusted R

Topics: Adult; Body Weight; Complement C3; Cross-Sectional Studies; Drug Administration Schedule; Female; Glucuronides; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Lupus Erythematosus, Systemic; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Remission Induction; Ribonucleotides; Xanthine

This study investigates whether the intestinal toxicity of the immunosuppressive agent "mycophenolate mofetil (MMF)" varied according to the circadian dosing-time in rats. MMF (300 mg/kg) was acutely administered by i.p. route in rats at four different circadian stages (1, 7, 13 and 19 hours after light onset, HALO). The results obtained showed that MMF-induced intestinal toxicity depends on circadian dosing-time in rats. A severe toxicity in the duodenum and jejunum was observed when the drug was administered at 7 HALO compared to controls and to other circadian times. This toxicity appeared in the form of villous and Liberkhun gland atrophy and nodular inflammation. At this dosing-time, MMF induced a significant increase of phosphatase alkaline activity and a significant decrease of gut mucosa weight, protein content and disaccharidases activities. Conversely, MMF dosing at 19 HALO induced lower gut toxicity, irrespective of type of toxicity explored. These data suggest the existence of a circadian rhythm of gut toxicity for this immunosuppressive agent and the best time of gastrointestinal tolerance (chronotolerance) of this agent was observed in the middle of the dark-activity span of rats.

Topics: Animals; Body Weight; Circadian Rhythm; Drug Tolerance; Duodenum; Immunosuppressive Agents; Jejunum; Male; Mycophenolic Acid; Rats, Wistar; Time Factors

Topics: Adolescent; Antibodies, Monoclonal; Basiliximab; Body Weight; Child; Child, Preschool; Female; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Recombinant Fusion Proteins; Retrospective Studies; Tacrolimus; Treatment Outcome

To investigate the protective effects of rhein lysinate (RHL), a major bioactive constituent of the rhizome of rhubarb (Rheum palmatum Linn or Rheum tanguticum Maxim), against kidney impairment in senescence-prone inbred strain 10 (SAMP10) mice.. SAMP10 mice were orally administered RHL (25 or 50 mg/kg) daily until 50% of the mice died. Senescence-resistant inbred strain 1 (SAMR1) mice administered no drug were taken as control. The kidneys were harvested after animal death, and examined morphologically and with immunochemical assays. The levels of MAD, SOD and GSH-px in the kidneys were measured with a photometric method. The expression of inflammatory factors and related proteins in the kidneys was analyzed using Western blotting.. Treatment of SAMP10 mice with RHL had no effect on the body weight or phenotype. However, RHL significantly prolonged the median survival time of SAMP10 mice by approximately 25%, as compared to untreated SAMP10 mice. Compared SAMR1 mice, SAMP10 mice had a significantly lower level of SOD in the kidneys, but had no significant difference in the MDA or GSH-px levels. Treatment of SAMP10 mice with RHL significantly reduced the MAD level, and increased the SOD and GSH-px levels in the kidneys. Glomerulonephritis was observed in SAMP10 mice but not in SAMR1 mice. RHL decreased the incidence of glomerulonephritis, and significantly decreased the levels of TNF-α, IL-6, NF-κB, collagen types I and III in the kidneys.. Accelerated senescence is associated with glomerulonephritis in SAMP10 mice, and RHL prolongs their median survival time by reducing the severity of glomerulonephritis.

Topics: Adenine Nucleotides; Animals; Anthraquinones; Body Weight; Collagen Type I; Collagen Type III; Glomerulonephritis; Glutathione; Interleukin-6; Kidney Diseases; Macrophages; Male; Mice; Mycophenolic Acid; NF-kappa B; Rhizome; Superoxide Dismutase; Survival Rate; Tumor Necrosis Factor-alpha

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is characterized by autoantibody production and inflammatory disease involving multiple organs. Premature atherosclerosis is a common complication of SLE and results in substantial morbidity and mortality from cardiovascular disease (CVD). The reasons for the premature atherosclerosis in SLE are incompletely understood, although chronic inflammation is thought to play an important role. There is currently no known preventative treatment of premature atherosclerosis in SLE. Mycophenolate mofetil (MMF) is an immunosuppressive agent that is commonly used for treatment of patients with SLE. In order to study the impact of this drug on murine lupus disease including premature atherosclerosis development, we treated gld.apoE(-/-) mice, a model of SLE and accelerated atherosclerosis, with MMF. We maintained seven-week old gld.apoE(-/-) mice on a high cholesterol Western diet with or without MMF. After 12 weeks on diet, mice receiving MMF showed decreased atherosclerotic lesion area compared to the control group. MMF treatment also improved the lupus phenotype, indicated by a significant decrease circulating autoantibody levels and ameliorating lupus nephritis associated with this model. This data suggests that the effects of MMF on the immune system may not only be beneficial for lupus, but also for inflammation driving lupus-associated atherosclerosis.

Topics: Animals; Apolipoproteins E; Atherosclerosis; Autoantibodies; Body Weight; Disease Models, Animal; Disease Progression; Eating; Fas Ligand Protein; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lymphatic Diseases; Mice; Mycophenolic Acid; Nephritis; Splenomegaly

  TAC, MMF and MP are used in pediatric kidney tx. The cytochrome P450 (CYP)3A5 enzyme appears to play a role in TAC metabolism. The aims of this study were to investigate CYP3A5 polymorphism's effect on TAC dosing and the age dependency of TAC dosing by testing blood concentrations, and the interaction between steroids and TAC during the first year after tx. Genomic DNA was extracted and amplified with specific primers. CYP3A5 alleles were confirmed by direct sequencing of PCR products on an automated AB13100 capillary sequencer. We studied 48 renal transplant patients (age at tx 12±0.5yr, 22 boys) receiving TAC, MMF, MP. Of these, 79% were CYP3A5*3/*3 (non-expressers homozygotes) and 21% were CYP3A5*1/*3 (expressers). TAC trough levels were 7.1±0.4ng/mL in CYP3A5*3/*3 patients and 6.5±0.7ng/mL in CYP3A5*1/*3 group (p=0.03). CYP3A5*1/*3 patients had lower levels of dose-adjusted TAC (36.7±5.8ng/mL/mg/kg/day) to achieve target blood concentration and required higher daily dose per weight (0.21±0.03mg/kg/day) than CYP3A5*3/*3 patients, 72.4±8.0ng/mL/mg/kg/day and 0.13±0.01mg/kg/day (p<0.001). Prepubertal patients with different CYP3A5 polymorphisms required significant higher TAC doses and achieved lower dose-normalized concentration compared with pubertal patients. Both TAC dose and adjusted-dose correlated with daily MP dose in CYP3A5*1*3 (r: 0.4, p<0.03 and r: 0.4, p<0.03) and in CYP3A5*3*3 (r: 0.6, p<0.01 and r: 0.47, p<0.001) patients. CYP3A5 polymorphism performed before tx could contribute to a better individualization of TAC therapy. The higher TAC dose in prepubertal patients and the pharmacological interactions between MP and TAC may not be fully explained by different CYP3A5 polymorphisms.

Topics: Adolescent; Age Factors; Body Weight; Child; Cytochrome P-450 CYP3A; DNA Primers; Female; Homozygote; Humans; Kidney Transplantation; Male; Methylprednisolone; Mycophenolic Acid; Polymorphism, Genetic; Steroids; Tacrolimus; Treatment Outcome

The reasons for kidney allograft failure subsequent to pancreas after kidney (PAK) are multifactorial; therefore, we examined these factors to identify a meaningful risk assessment that could assist in patient selection.. Five transplant centers in New England collaborated for this multiinstitutional retrospective study of 126 PAK transplantation recipients who had a functioning pancreas allograft 7 days after transplantation. Host factors (age at pancreas transplant, gender, body weight, glomerular filtration rate at 3 months pre-PAK and at 3-, 6-, 9-, and 12-month post-PAK, presence of proteinuria, pre- or post-PAK kidney rejection, pancreas rejection, cytomegalovirus disease, and HbA1C at 6-month post-PAK) and transplant factors (time to PAK, use of induction antibody therapy, and combinations of immunosuppressive medications) were assessed in both univariate and multivariate analyses for the primary outcome of kidney allograft failure.. Of the variables assessed, factors associated with kidney allograft loss after PAK include impaired renal function in the 3 months before PAK, proteinuria, the occurrence of a post-PAK kidney rejection episode, and interval between kidney and pancreas transplantation more than 1 year.. In our analysis, post-PAK kidney allograft loss was strongly associated with glomerular filtration rate less than 45 mL/min pre-PAK, K to P interval of over 1 year, pre-PAK kidney rejection episode, and pre-PAK proteinuria. Diabetic candidates for PAK with any of these conditions should be counseled regarding the risk of post-PAK renal transplant failure.

Topics: Adult; Antilymphocyte Serum; Body Weight; Cytomegalovirus Infections; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Predictive Value of Tests; Proteinuria; Renal Replacement Therapy; Risk Assessment; Time Factors; Treatment Failure; Treatment Outcome

The aim of this study was to examine whether a limited sampling strategy (LSS) to allow the simultaneous estimation of the area under the concentration-time curves (AUCs) of tacrolimus and mycophenolic acid (MPA) calculated in the early stage after renal transplantation could be applied to maintenance phase pharmacokinetics. Seventy Japanese patients were enrolled. One year after transplantation, samples were collected just before and 1, 2, 3, 4, 6, 9, and 12 hours after tacrolimus and mycophenolate mofetil administration at 9:00 am and at 9:00 pm. The prediction formulas on day 28 (tacrolimus AUC 0-12 = 7.04 x C 0h + 1.71 x C 2h + 3.23 x C 4h + 15.19 and 2.25 x C 2h + 1.92 x C 4h + 7.27 x C 9h + 6.61, and MPA AUC 0-12 = 0.26 x C 0h + 2.06 x C 2h + 3.82 x C 4h + 20.38 and 1.77 x C 2h + 2.34 x C 4h + 4.76 x C 9h + 15.94) were applied to pharmacokinetic data obtained at 1 year. Three error indices [percent mean prediction error (ME), % mean absolute error, and percent root mean squared prediction error (RMSE)] were used to evaluate the predictive bias, accuracy, and precision. The predicted AUC 0-12 of tacrolimus and MPA at 3 time points, C 2h-C 4h-C 9h, showed higher correlation with the measured AUC 0-12 of tacrolimus and MPA (r2 = 0.817 and 0.789, respectively) in comparison with those at C 0h-C 2h-C 4h. The values for the prediction formulas for tacrolimus AUC at 1 year using the C 2h-C 4h-C 9h combination yielded less than 5% for %ME and 15% for %RMSE. The %ME and %RMSE values of the prediction formulas for tacrolimus AUC using the C 0h-C 2h-C 4h combination were 6.3% and 15.9%, respectively. The %ME and %RMSE values of the prediction formulas for MPA AUC at 1 year using the C 0h-C 2h-C 4h combination were 5.9% and 25.8%, respectively, and those for the C 2h-C 4h-C 9h combination were 4.9% and 21.2%, respectively. AUC 6-12/AUC 0-12 of MPA 1 year after transplantation was significantly lower than 28 days after transplantation. An LSS using C 2h-C 4h-C 9h seems to be applicable for predicting the AUC of tacrolimus and MPA at either posttransplantation stage. The enterohepatic circulation of MPA was significantly reduced 1 year after transplantation. Therefore, 1 year after transplantation, the estimation of the AUC 0-12 of MPA for the C 0h-C 2h-C 4h equations was imprecise. It is important that the LSS includes C 9h because it contains information on the secondary plasma peak of MPA.

Topics: Adult; Aged; Area Under Curve; Body Weight; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Regression Analysis; Tacrolimus; Young Adult

The purpose of the study was to assess the impact of age on the pharmacokinetics of immunosuppressive drugs.. One hundred and ten renal transplant recipients, including 12 elderly patients over 60 years of age, 57 middle-aged patients between 40 and 59 years and 41 young adult patients 20 to 39 years of age were studied. To evaluate dose-adjusted pharmacokinetics and cytochrome P450 (CYP) 3A5 pharmacogenetics, the concentrations of tacrolimus, mycophenolic acid (MPA), MPA glucuronide (MPAG) and prednisolone were measured at 1 month post-transplantation.. There were no differences in dose (D) and body weight (BW)-adjusted pharmacokinetic parameters of tacrolimus among the three groups. D/BW-adjusted C(max), C(0) and AUC(0-12) values of tacrolimus were significantly greater in patients with the CYP3A5*3/*3 genotype than in those with the CYP3A5*1 allele in young and middle-aged patients as previously reported, but not in the elderly. There were no significant differences in the D-adjusted pharmacokinetics of prednisolone and MPA among the three groups.. The aging process itself may have a small effect on the pharmacokinetics of tacrolimus, MPA, or prednisolone. However, a larger number of subjects need to be studied to confirm the impact of age on the CYP3A5 pharmacogenetics of tacrolimus in the elderly.

Topics: Adult; Age Factors; Aged; Aging; Analysis of Variance; Area Under Curve; Body Weight; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Enzyme Inhibitors; Female; Genotype; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Tacrolimus; Time Factors

Everolimus (EVL), an antagonist of mammalian target of rapamycin, has been recently introduced into solid organ transplantation either associated with low dose of anticalcineurins (CNI) or replacing them in an attempt to avoid nephrotoxicity and chronic allograft nephropathy. Due to the molecular similarities with sirolimus, it has been expected that there would be the same incidence of metabolic changes and adverse events. We retrospectively studied kidney allograft recipients converted from CNI to EVL during a 12-month period. Patients received a standard dose of EVL starting at 1.5 mg/d and thereafter titrating to achieve trough levels in the range of 3 to 5 ng/mL. Patients achieved mean EVL trough levels of 5.2, 4.0 and 4.5 ng/mL at 1, 6, and 12 months, respectively. One year following conversion, the calculated creatinine clearance increased from 57 to 63 mL/min and proteinuria did not change. Fasting blood glucose levels decreased significantly following conversion to EVL. During the same time, no significant changes were observed in body weight, body mass index, albumin, cholesterol, triglyceride, high-density lipoprotein cholesterol, low-density lipoprotein cholesterol, lipid-lowering medication requirements, blood magnesium, and uric acid. We concluded that EVL did not negatively influence various nutritional parameters.

Topics: Aged; Blood Pressure; Body Mass Index; Body Weight; Calcineurin Inhibitors; Cyclosporine; Everolimus; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Protein Kinases; Retrospective Studies; Sirolimus; TOR Serine-Threonine Kinases

Hypertension is a likely consequence of chronic lead exposure in humans, especially in association with reduced renal function and in high risk populations. Numerous studies have demonstrated that oxidative stress plays an important role in the pathogenesis of experimental lead-induced hypertension and we have shown recently that tubulointerstitial immune cell infiltration is a feature of chronic low-dose lead exposure. Since oxidative stress, renal inflammation, and angiotensin activity are closely linked characteristics in experimental models of hypertension, we decided to investigate whether lead-induced hypertension would be ameliorated by suppressing renal inflammation with the immunosuppressive drug mycophenolate mofetil (MMF). We studied rats exposed for 14 wk to lead acetate (100 ppm in the drinking water) that, in addition, received either MMF, 20 mg.kg(-1).day(-1) by gastric gavage (Pb.MMF group, n = 12) or vehicle (Pb group, n = 12). Control rats received MMF alone (n = 5) or neither lead nor MMF (n = 6). All rats were killed at the end of the experiment. Low-dose lead exposure resulted in mild to moderate tubular cell damage and a progressive increment in blood pressure, oxidative stress, interstitial accumulation of lymphocytes and macrophages, NF-kappaB activation, and increased renal angiotensin II level. The administration of MMF suppressed the tubulointerstitial accumulation of lymphocytes and macrophages and prevented the hypertension, oxidative stress, and NF-kappaB activation and reduced the heightened renal angiotensin content associated with chronic lead exposure. We conclude that interstitial inflammation plays an important role in lead-induced hypertension.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Creatinine; Hypertension; Immunosuppressive Agents; Inflammation; Kidney Diseases; Lead; Lymphocytes; Macrophages; Male; Malondialdehyde; Mycophenolic Acid; Oxidative Stress; Proteinuria; Rats; Rats, Sprague-Dawley; Superoxides; Transcription Factor RelA

Mycophenolate mofetil (MMF) is used for immunosuppression after organ transplantation, but gastrointestinal side effects including diarrhea are sometimes observed with this drug. We sought to construct on animal model of diarrhea with MMF in rodents.. BALB/Cj mice, weighing 25 g received 500 mg /kg of MMF, 60 mg/kg of levofloxacin (LVFX), 1000 mg/kg of Hangeshashin-to (HST), which is traditional Kampo medicine. This cocktail was administered orally to MMF, LVFX, HST, MMF+LVFX, and MMF+LVFX+HST groups for 21 days. We measured the water content fecal collected on days 1, 4, 8, 11, 14, 18, and 21. Feces on day 21 were cultured for identification of fecal flora. Mice were sacrificed on day 21, with blood samples collected to measure mycophenolic acid (MPA) concentrations by HPLC. Jejunum, cecum, and colon were taken for histological evaluation.. Significant weight loss of mice and increased fecal water content of were observed in MMF and MMF+LVFX but not in MMF+LVFX+HST groups. Serum MPA levels didn't differ in MMF-administered groups. Inflammatory changes in intestinal villi were observed in the cecum in MMF and MMF+LVFX groups. A change in fecal flora was observed in LVFX-administered groups.. Diarrhea induced by MMF in a rodent model produced inflammatory changes in the cecum. LVFX seemed to change the activity of beta-glucuronidase in the fecal flora. HST suppressed fecal softening induced by MMF in this animal model.

Topics: Animals; Body Weight; Diarrhea; Energy Intake; Feeding Behavior; Immunosuppressive Agents; Levofloxacin; Male; Mice; Mice, Inbred BALB C; Models, Animal; Mycophenolic Acid; Ofloxacin; Weight Loss

In order to evaluate whether immunosuppressive agents such as mycophenolate mofetil (MMF) and azathioprine would differently influence the outcome of the renal transplants, we prospectively analyzed the incidence of acute rejection episodes, cytomegalovirus infection within the first 6 months following renal transplantation and 5 yr graft survival rate after minimizing influences of donor factors by grafting the same cadaveric donor kidney. There was no significant difference in sex, HLA mismatch, cold ischemic time, and patients' weight between the two groups. Contrary to the previous studies which demonstrated that MMF could lower the incidence of acute rejection episodes and improved graft survival rate, the two groups showed no significant difference in the incidence of acute rejection episodes and 5-yr graft survival rate as well. This discrepancy in these results might explain that donor factors could be important to cadaveric renal transplantation. Thus, we suggest that the influences of donor factors should be considered in further clinical studies of cadaveric renal transplantation.

Topics: ABO Blood-Group System; Adult; Azathioprine; Body Weight; Cadaver; Cytomegalovirus; Cytomegalovirus Infections; Female; Graft Rejection; Graft Survival; Histocompatibility Testing; Humans; Immunophenotyping; Immunosuppressive Agents; Ischemia; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Time Factors; Tissue Donors; Treatment Outcome

Tubulointerstitial inflammation and fibrosis are hallmarks of chronic progressive renal diseases. To characterize the functional interaction between cell infiltration and matrix expansion, this study compared the immunosuppressant mycophenolate mofetil (MMF), intended as primarily anti-inflammatory intervention, the angiotensin-converting enzyme inhibitor enalapril, intended as primarily an anti-fibrotic drug, and a combination of both as anticipated anti-inflammatory/anti-fibrotic intervention. The model used was anti-thy1-induced chronic-progressive glomerulosclerosis (cGS) in the rat, where a brief anti-thy1-induced glomerular injury progresses spontaneously toward tubulointerstitial fibrosis and renal insufficiency. cGS was induced by injection of anti-thy1 antibody into uninephrectomized Wistar rats. One week after disease induction, animals were randomly assigned to the following groups: cGS, cGS plus MMF (20 mg.kg body wt(-1).day(-1)), cGS plus high-dose enalapril (12 mg.kg body wt(-1).day(-1)), and cGS plus both. At week 16 after disease induction, MMF or enalapril alone reduced signs of chronic renal disease significantly and similarly compared with the untreated cGS group. Variables measured included proteinuria, blood pressure, tubulointerstitial and glomerular matrix accumulation, expression of transforming growth factor-beta(1), fibronectin, and plasminogen activator inhibitor-1, infiltration of lymphocytes and macrophages, plasma creatinine and urea levels, and glomerular filtration rate. Combined MMF and enalapril treatment was not superior to single therapy. In conclusion, MMF slows the progression of chronic renal fibrosis and renal insufficiency as effectively as high-dose enalapril in the anti-thy1-induced chronic-progressive glomerulosclerosis model. The dual anti-inflammatory/anti-fibrotic intervention does not yield additive renoprotective effects, indicating that MMF and enalapril interfere with similar or very closely related pathways involved in progression of renal disease.

Topics: Angiotensin-Converting Enzyme Inhibitors; Animals; Blood Cell Count; Blood Pressure; Body Weight; Disease Progression; Drug Interactions; Eating; Enalapril; Fibronectins; Fibrosis; Glomerulosclerosis, Focal Segmental; Immunohistochemistry; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Male; Mycophenolic Acid; Nephrectomy; Plasminogen Activator Inhibitor 1; Proteinuria; Rats; Rats, Wistar; Thy-1 Antigens; Transforming Growth Factor beta; Transforming Growth Factor beta1

The authors have investigated whether cyclosporine decreases the serum concentration of mycophenolic acid, the active principle of the immunosuppressant mycophenolate mofetil, and increases that of the inactive metabolite 7-O-mycophenolic acid glucuronide by reducing their enterohepatic recirculation. Rats were treated daily with methylcellulose (1.66 mL/kg PO) plus 0.9% NaCl (6 mL/kg IP), mycophenolate mofetil (20 mg/kg PO) plus 0.9% NaCl (6 mL/kg IP), methylcellulose (1.66 mL/kg PO) plus cyclosporine (5 mg/kg IP), and mycophenolate mofetil (20 mg/kg PO) plus cyclosporine (5 mg/kg IP). After 14 days a bile fistula was installed to measure the biliary excretion of the immunosuppressants and their metabolites. After 90 minutes blood was taken to determine their concentrations in blood or serum by HPLC. Cyclosporine significantly decreased the serum concentration of mycophenolic acid by 39% and increased, not significantly, that of 7-O-mycophenolic acid glucuronide by 53%. The biliary excretion of 7-O-mycophenolic acid glucuronide was significantly reduced by cyclosporine by 57%, whereas that of mycophenolic acid was not affected. Mycophenolate mofetil did not show a significant effect on either the blood concentration or the biliary excretion of cyclosporine and its metabolites AM1, AM9, AM1c, and AM4N. Cyclosporine significantly decreased the serum concentration of active mycophenolate acid and increased, not significantly, the serum concentration of inactive 7-O-mycophenolic acid glucuronide, presumably by reducing the biliary excretion of this inactive metabolite.

Topics: Animals; Bile; Bile Acids and Salts; Biliary Fistula; Bilirubin; Body Weight; Cyclosporine; Disease Models, Animal; Drug Administration Schedule; Drug Therapy, Combination; Injections, Intraperitoneal; Male; Mycophenolic Acid; Organ Size; Rats; Rats, Wistar

In vitro and in vivo studies have shown that building-associated Penicillium spores and spore extracts can induce significant inflammatory responses in lung cells and animal models of lung disease. However, because spores and spore extracts comprise mixtures of bioactive constituents often including toxins, it is impossible to resolve which constituent mediates inflammatory responses. This study examined dose-response (0.5 nM, 2.5 nM, 5.0 nM, 12.5 nM/g body weight (BW) animal) and time-course (3, 6, 24 and 48 h post instillation (PI)) relationships associated with inflammatory and cytotoxic responses in mouse lungs intratracheally instilled with pure brevianamide A, mycophenolic acid, and roquefortine C. High doses (5.0 nM and/or 12.5 nM/g BW animal) of brevianamide A and mycophenolic acid, the dominant metabolites of P. brevicompactum, and roquefortine C, the dominant metabolite of P. chrysogenum, induced significant inflammatory responses within 6 h PI, expressed as differentially elevated macrophage, neutrophil, MIP-2, TNF, and IL-6 concentrations in the bronchioalveolar lavage fluid (BALF) of intratracheally exposed mice. Macrophage and neutrophil numbers were maximal at 24 h PI; responses of the other inflammatory markers were maximal at 6 h PI. Except for macrophage numbers in mycophenolic acid-treatment animals, cells exhibited significant dose-dependent-like responses; for the chemo-/cytokine markers, dose dependency was lacking except for MIP-2 concentration in brevianamide A-treatment animals. It was also found that brevianamide A induced cytotoxicity expressed as significantly increased LDH concentration in mouse BALF, at concentrations of 12.5 nM/g BW animal and at 6 and 24 h PI. Albumin concentrations, measured as a nonspecific marker of vascular leakage, were significantly elevated in the BALF of mice treated with 12.5 nM/g nM brevianamide A/animal from 6 to 24 h PI and in > or =5.0 nM/g mycophenolic acid-treated animals at 6 to 24 h PI. These results suggest that these three toxins from Penicillium species common on damp materials in residential housing provoke compound-specific toxic responses with different toxicokinetics. Moreover, that these toxins can stimulate significant inflammatory responses in vivo might help explain some of the indoor effects associated with Penicillium spore exposures in indoor environments.

Topics: Albumins; Alkaloids; Animals; Body Weight; Bronchoalveolar Lavage Fluid; Cytokines; Dose-Response Relationship, Drug; Heterocyclic Compounds, 4 or More Rings; Indoles; Inflammation; L-Lactate Dehydrogenase; Lung; Male; Mice; Mycophenolic Acid; Piperazines; Spiro Compounds

Experimental autoimmune myocarditis (EAM) is characterized by the appearance of multinucleated giant cells. EAM leads to severe myocardial damage and is a useful model of human giant cell myocarditis. We investigated whether mycophenolate mofetil (MMF), which is a potent immunosuppressant, prevents the development of myocarditis in a rat EAM model, and focused on the role of osteopontin (OPN) in the pathogenesis of this disorder. Adult Lewis rats were immunized with porcine cardiac myosin to establish EAM. The early MMF treatment completely prevented the development of EAM, and the late MMF treatment was also effective even against established EAM. Echocardiogram demonstrated that left ventricular function was also improved by the treatment with MMF. Real-time RT-PCR analysis showed that both early and late MMF treatments significantly inhibited myocarditis-induced OPN mRNA expression in the heart. Immunohistochemistry revealed that OPN expression was prominent in the myocardium on day 14, whereas expression was observed in the infiltrated macrophages on day 21. Mycophenolic acid (MPA) did inhibit agonist-induced OPN expression in cultured cardiomyocytes. These results show the therapeutic potential of MMF for autoimmune myocarditis and provide new insights into the pathogenesis of this disease.

Topics: Animals; Animals, Newborn; Autoimmune Diseases; Body Weight; Cells, Cultured; Disease Models, Animal; Echocardiography; Heart Ventricles; Immunohistochemistry; Immunosuppressive Agents; Male; Mycophenolic Acid; Myocarditis; Myocardium; Myocytes, Cardiac; Organ Size; Osteopontin; Rats; Rats, Inbred Lew; Rats, Sprague-Dawley; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Sialoglycoproteins; Time Factors

Cellophane wrapping of the kidneys (Page kidney) induces perinephrits and hypertension, assumed to be due to renal ischemia resulting from parenchymal compression by the fibrous hull surrounding the kidneys. We investigated if interstitial nephritis, rather than plasma angiotensin activity, played a role in the development of hypertension in the Page kidney model.. We followed for 7 weeks rats with bilateral cellophane wrapping of the kidneys that received 20 mg/kg/day of the immunosuppressive antiproliferative drug mycophenolate mofetil (MMF) (two-kidney wrap/MMF) (N = 10) or vehicle (two-kidney wrap) (N = 10), and sham-operated rats (N = 10).. The two-kidney wrap group had progressive increment in blood pressure, inflammatory damage occupying 25% to 50% of the renal tubulointerstitial region and increased number of angiotensin II-positive cells, angiotensin II content, and oxidative stress in the kidney. MMF treatment prevented the development of hypertension and renal inflammation without modifying the perinephritic hull or the increment it induced in the intrarenal pressure. The plasma levels of angiotensin II were similar in the two-kidney wrap group, the two-kidney wrap/MMF group and the sham-operated animals and unchanged from baseline, despite the blood pressure increase in the two-kidney wrap group.. Our results indicate that renal wrap hypertension is unrelated to plasma angiotensin II levels and related to the inflammatory damage caused by the external compression of the kidney.

Topics: Angiotensin II; Animals; Blood Pressure; Body Weight; Cellophane; Disease Models, Animal; Glutathione; Hypertension, Renal; Immunosuppressive Agents; Ischemia; Kidney; Kidney Function Tests; Male; Malondialdehyde; Mycophenolic Acid; Nephritis, Interstitial; Pressure; Rats; Rats, Sprague-Dawley

BACKGROUND.: Transplant arteriosclerosis is one of the main features of chronic graft failure in organ transplantation. In this article, the authors investigate mechanisms of mycophenolate mofetil (MMF) on prevention of transplant arteriosclerosis in a rat aortic allograft model.. Orthotopic rat abdominal aortic transplantation was performed from Brown Norway (RT1) to Lewis (RT1) rats. The recipients were divided into three oral treatment groups: (1). vehicle; (2). MMF40 (40 mg/kg); and (3). MMF20 (20 mg/kg). The authors histologically and immunohistochemically evaluated neointima formation; infiltration of macrophages and T cells; and expression of endothelin (ET)-1, platelet-derived growth factor (PDGF)-B, PDGF receptor-beta (Rbeta), transforming growth factor (TGF) beta 1, and osteopontin (OPN). Using cultured rat vascular smooth muscle cells (VSMC), effects of mycophenolic acid (MPA) on ET-1-induced proliferation and ERK1/2 activation were also examined in vitro.. In the vehicle group, marked neointima formation was observed, with massive macrophages and T-cell infiltration in neointima, media, and adventitia. Marked expression of ET-1, PDGF-B, PDGFR-beta, TGFbeta1, and OPN were also observed in neointima. In the MMF40 and MMF20 groups, neointima formation was halted, but macrophages and T cells were infiltrated in the adventitia and adhered to the endothelium. In the MMF40 group, medial infiltration by macrophages and T cells and intimal expression of ET-1, PDGF-B, PDGFR-beta, TGFbeta1, and OPN was inhibited compared with the vehicle and MMF20 groups. Furthermore, MPA inhibited ET-1-induced VSMC proliferation but failed to inhibit its ERK1/2 activation.. MMF treatment might have preventive potential in transplant patients with chronic vasculopathy through inhibition of VSMC proliferation.

Topics: Animals; Aorta, Abdominal; Aortic Diseases; Arteriosclerosis; Body Weight; Cell Division; Cells, Cultured; Endothelin-1; Growth Substances; Immunosuppressive Agents; Macrophages; Male; Muscle, Smooth, Vascular; Mycophenolic Acid; Myocytes, Smooth Muscle; Rats; Rats, Inbred BN; Rats, Inbred Lew; Rats, Sprague-Dawley; T-Lymphocytes; Tunica Intima

Chronic allograft nephropathy (CAN) is the most common cause of late graft loss. A beneficial effect of mycophenolate mofetil (MMF) on CAN was observed, although, due to the loss of body weight (BW) under MMF, serum creatinine (sCr) and reciprocal sCr may be unsuitable markers of graft function.. In 17 kidney transplant patients with CAN, azathioprine (Aza) was replaced by MMF. The remaining therapy was not changed; specifically, the cyclosporine (CsA) dose was not decreased. The mean values and regression coefficients of reciprocal sCr, CCr, urinary creatinine excretion (uCr x V), proteinuria, BW, blood pressure (BP), serum cholesterol (sChol), and serum triglycerides (sTG) versus time were analyzed 12 months before and after institution of MMF by a paired-comparison t test.. The mean regression coefficient of reciprocal sCr differed significantly before and after conversion to MMF (mean -0.01 +/- 0.01 vs +0.012 +/- 0.029 mg/dL per month), suggesting improved graft function. However, the mean values of BW (74 +/- 15 vs 71 +/- 15 kg, P <.001) and uCr x V (1152 +/- 321 vs 1065 +/- 266 mg per 24 hours, P=.0897) decreased, making the increase in CCr less significant (mean -1.16 +/- 2.69 vs 0.40 +/- 1.79 mL/min per month, P <.05). BP, sChol, sTG, and proteinuria before and after conversion did not differ significantly. Among patients with long-term stable graft function at 36.5 +/- 16.9 months after conversion to MMF there was an almost significant improvement in renal protein excretion.. MMF improved graft function, although this effect was overestimated using reciprocal sCr. Other risk factors, such as BP, sChol, and sTG, showed no significant differences, suggesting that MMF accounted for the improvement in CAN. The course of proteinuria under MMF seems to be of prognostic significance.

Topics: Albuminuria; Azathioprine; Body Weight; Creatinine; Cyclosporine; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Isoantigens; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Proteinuria

Combined treatments of mycophenolate mofetil (MMF) and losartan (LSRT) have synergistic effects on various renal diseases through their hemodynamic and anti-inflammatory effects. This study investigated whether MMF treatment is effective in inhibiting inflammatory processes in chronic cyclosporine A (CsA) nephrotoxicity, and whether combined treatment using MMF and LSRT affords superior protection compared with the respective monotherapies.. Rats on a low-salt diet were given vehicle (VH group, olive oil, 1 mg/kg per day), CsA (15 mg/kg per day), CsA and LSRT (CsA+LSRT group, 100 mg/L per day), CsA and MMF (CsA+MMF group; 40 mg/kg per day), or CsA, LSRT and MMF (CsA+LSRT MMF group). Control groups received each drug without CsA treatment. Renal function, histologic parameters (arteriolopathy, tubulointerstitial fibrosis, and inflammatory cell infiltration), and mediators of CsA-induced nephrotoxicity (angiotensin-II, osteopontin, and transforming growth factor [TGF]-beta1) were studied.. The CsA-treated rats showed decreased renal function and increased histologic parameters compared with the VH-treated rats. The CsA+MMF treatment significantly improved renal function and histopathologic parameters compared with the CsA group, and combined treatment with MMF and LSRT further improved those parameters compared with the CsA+LSRT and CsA+MMF groups. At a molecular level, increased expression of angiotensin II protein, osteopontin, and TGF-beta1 mRNAs in the CsA group were significantly decreased with MMF, and further decrease was observed with the combined treatment using MMF and LSRT.. MMF treatment decreases CsA-induced nephrotoxicity, and combined treatment with LSRT has a synergistic effect in preventing chronic CsA nephrotoxicity.

Topics: Angiotensin II; Animals; Antihypertensive Agents; Arterioles; Blood Pressure; Body Weight; Chronic Disease; Cyclosporine; Drug Synergism; Fibrosis; Gene Expression; Immunosuppressive Agents; Kidney; Kidney Diseases; Losartan; Macrophages; Male; Mycophenolic Acid; Osteopontin; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sialoglycoproteins; Transforming Growth Factor beta; Transforming Growth Factor beta1

Topics: Adolescent; Antilymphocyte Serum; Azathioprine; Body Weight; Cadaver; California; Child; Cyclosporine; Drug Therapy, Combination; Female; Humans; Kidney Transplantation; Living Donors; Male; Medical Records; Mycophenolic Acid; Racial Groups; Retrospective Studies; Tacrolimus; Tissue Donors

Topics: Area Under Curve; Body Weight; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Sex Characteristics; Tacrolimus

Recent evidence suggests that salt-sensitive hypertension develops as a consequence of renal infiltration with immunocompetent cells. We investigated whether proteinuria, which is known to induce interstitial nephritis, causes salt-sensitive hypertension. Female Lewis rats received 2 g of BSA intraperitoneally daily for 2 wk. After protein overload (PO), 6 wk of a high-salt diet induced hypertension [systolic blood pressure (SBP) = 156 +/- 11.8 mmHg], whereas rats that remained on a normal-salt diet and control rats (without PO) on a high-salt diet were normotensive. Administration of mycophenolate mofetil (20 mg. kg(-1). day(-1)) during PO resulted in prevention of proteinuria-related interstitial nephritis, reduction of renal angiotensin II-positive cells and oxidative stress (superoxide-positive cells and renal malondialdehyde content), and resistance to the hypertensive effect of the high-salt diet (SBP = 129 +/- 12.2 mmHg). The present studies support the participation of renal inflammatory infiltrate in the pathogenesis of salt-sensitive hypertension and provide a direct link between two risk factors of progressive renal damage: proteinuria and hypertension.

Topics: Animals; Body Weight; Dietary Proteins; Female; Hypertension, Renal; Immunosuppressive Agents; Kidney Glomerulus; Lymphocytes; Mycophenolic Acid; Nephritis, Interstitial; Oxidative Stress; Proteinuria; Rats; Rats, Inbred Lew; Sodium Chloride, Dietary

Recent clinical trials of mycophenolate mofetil (MMF) in chronic allograft nephropathy (CAN) demonstrated that the dose of cyclosporine A (CsA) is one of the critical factors in determining graft function in CAN, but the effect of MMF on chronic CsA nephropathy is undetermined. We undertook this study to evaluate the effect of MMF on CsA-induced nephrotoxicity in an animal model of chronic CsA nephropathy.. In the first experiment, Sprague-Dawley rats on a low-salt diet were treated with CsA (7.5 mg/kg per day) for 10 weeks, or were treated with CsA for five weeks and then MMF (20 mg/kg per day) was administered five weeks later. In the second experiment, rats were treated with CsA for five weeks, and CsA was then withdrawn for five weeks with or without MMF treatment. Renal function, histologic parameters (tubulointerstitial fibrosis, arteriolopathy, ED-1-positive cells, renin-positive glomeruli, TUNEL-positive cells) and the expression of osteopontin and transforming growth factor (TGF)-beta1 mRNA expressions were compared for different treatment groups.. CsA-treated rats showed decreased renal function and increased histologic parameters compared with the vehicle (VH)-treated rats. The addition of MMF did not improve these parameters compared with the CsA-treated rats. With CsA withdrawal, renal function and histologic parameters were significantly improved compared with the CsA-treated rats, and MMF treatment after CsA withdrawal further improved the histologic parameters. At the molecular level, the addition of MMF did not decrease the expression of osteopontin and transforming growth factor-beta1 (TGF-beta1) mRNAs, which were increased in the CsA-treated rat kidney. With CsA withdrawal, the expression of both mRNAs was significantly decreased compared with the CsA group, and a further decrease was observed with MMF treatment after CsA was withdrawn.. The combined treatment of CsA and MMF does not prevent the development of chronic CsA nephrotoxicity, but MMF treatment after CsA withdrawal does improve chronic CsA nephrotoxicity. This finding provides a rationale for MMF treatment in chronic CsA nephrotoxicity.

Topics: Animals; Apoptosis; Blood Pressure; Body Weight; Cyclosporine; Immunosuppressive Agents; Kidney; Macrophages; Male; Mycophenolic Acid; Osteopontin; Rats; Rats, Sprague-Dawley; Renin; RNA, Messenger; Sialoglycoproteins; Transforming Growth Factor beta; Transforming Growth Factor beta1

Interstitial mononuclear cell infiltration is a feature of experimental models of salt-sensitive hypertension (SSHTN). Since several products of these cells are capable of modifying local vascular reactivity and sodium reabsorption, we investigated whether mycophenolate mofetil (MMF), a drug known to inhibit infiltration and proliferation of immune cells, would modify the SSHTN induced by angiotensin II (Ang II) infusion.. Sprague-Dawley rats received Ang II for two weeks using subcutaneous minipumps. A high-sodium (4% NaCl) diet was started on the third week and was maintained until the eighth week. MMF (30 mg/kg, N = 15), an immunosuppressive drug, or vehicle (N = 15) was given daily by gastric gavage during the initial three weeks. Sham-operated rats (N = 9) were used as controls. Body weight, blood pressure (tail-cuff plethysmography), and serum creatinine were determined weekly. Urinary malondialdehyde (MDA) excretion, renal histology, and immunohistology, including the presence of Ang II and superoxide-producing cells, were analyzed at the end of Ang II infusion and at eight weeks.. MMF treatment did not modify hypertension induced during exogenous Ang II infusion, but prevented the subsequent SSHTN. Tubulointerstitial injury resulting from Ang II infusion was significantly reduced by MMF treatment, as were proliferative activity, T-cell infiltration and activation (interleukin-2 receptor expression), superoxide-producing cells, and urinary MDA excretion. Ang II-producing cells were present in the renal tubulointerstitium of rats with SSHTN (60 +/- 30 Ang II-positive cells/mm(2) at 8 weeks) and were reduced by two thirds in the MMF-treated group. Forty percent of lymphocytes infiltrating the tubulointerstitium stained positive for Ang II. The expression of Ang II receptors in the kidney was unmodified.. SSHTN resulting from Ang II infusion is associated with infiltration and activation of immune cells that produce Ang II. MMF treatment reduces these features and prevents the development of SSHTN.

Topics: Angiotensin II; Animals; Anti-Inflammatory Agents, Non-Steroidal; Blood Pressure; Body Weight; Cell Division; Creatinine; Disease Models, Animal; Fibronectins; Hypertension, Renal; Kidney; Leukocytes, Mononuclear; Lipid Peroxidation; Male; Malondialdehyde; Mycophenolic Acid; Osteopontin; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin; Sialoglycoproteins; Superoxides; Vasoconstrictor Agents

Recent studies have suggested that subtle microvascular and tubulointerstitial injury in the kidney can cause salt-sensitive hypertension. To test this hypothesis, we determined whether the mild renal disease induced by transient blockade of nitric oxide (NO) synthesis would result in salt-sensitive hypertension and whether prevention of the renal injury by coadministration of the immunosuppressive agent mycophenolate mofetil (MMF) would block the development of salt sensitivity. N(omega)-nitro-L-arginine-methyl ester (L-NAME; 70 mg/100 ml in the drinking water) was administered for 3 wk to rats with or without MMF (30 mg x kg(-1) x day(-1) by gastric gavage), followed by a 1-wk "washout" period in which the MMF was continued, which was followed in turn by placement on a high-salt (4% NaCl) diet for an additional 4 wk. Renal histology was examined at 3 and 8 wk, and blood pressure was measured serially. L-NAME treatment resulted in acute hypertension and the development of mild renal injury. During the washout period, blood pressure returned to normal, only to return to the hypertensive range on exposure of the animals to a high-salt diet. MMF treatment prevented the development of hypertension in response to a high-salt diet. This correlated with the ability of MMF to inhibit specific aspects of the renal injury, including the development of segmental glomerulosclerosis, the infiltration of T cells and ANG II-positive cells, and the thickening of afferent arterioles.

Topics: Animals; Blood Pressure; Body Weight; Glomerulosclerosis, Focal Segmental; Hypertension; Immunosuppressive Agents; Kidney; Lymphocytes; Macrophages; Male; Mycophenolic Acid; Nephritis, Interstitial; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Sprague-Dawley; Receptor, Angiotensin, Type 1; Receptor, Angiotensin, Type 2; Receptors, Angiotensin

Mycophenolate mofetil (MMF) is a new immunosuppressant drug used in association with cyclosporin and oral corticosteroids to prevent acute rejection following renal allograft transplantation. MMF is an ester pro-drug of mycophenolic acid (MFA), the true active species, into which it is completely transformed after oral administration. The recommended initial dose to prevent kidney transplant rejection is 2 g/day irrespective of body weight, 1 g twice daily. The goal of this study was to correlate dosage (fixed or by body weight) and toxic effects to some non-compartmental values such as peak level (Cmax), time to peak level (Tmax) and trough level (Cmin). In a small number of patients who had already reached the plasma steady state, we found a large inter-patient variability, while the same qualitative pharmacokinetic profile (as Tmax) was conserved. At plasma trough level > 4 microg/ml some serious toxic effects were observed, whereas at Cmin < 2 microg/ml, there were some cases of interstitial rejection. There was also a negative correlation between dosage and body weight, suggesting that dosages related to body weight might be better than fixed ones. Finally, monitoring plasma level of drug from transplantation to at least 12 months after surgery, at fixed MFA dosage, a small but significant decline of MFA plasma levels was found.

Topics: Administration, Oral; Body Weight; Dose-Response Relationship, Drug; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prodrugs; Time Factors

Prevention of rejection and preservation of graft function remain as obstacles to clinical small intestinal transplantation (SIT). This study evaluated the effects of combined immunosuppressive agents (FK506, Rapamycin, and Mycophenolate Mofetil) on intestinal function and animal well being.. Screening for additive toxicity was done in experiment one (D1, n = 10); doses were: FK506 0.3 mg/kg/d, Rapamycin 2 mg/kg/d, and Mycophenolate Mofetil 20 mg/kg/d, orally once daily. Control animals (C1, n = 10) received equivalent vehicle. In the second phase of the experiment, the effect of an additional parenteral treatment phase was investigated, with drug treated animals (D2, n = 6) received FK506 0.3 mg/kg, Rapamycin 1 mg/kg, and Mycophenolate Mofetil 10 mg/kg sq q12h for 1 week followed by FK506 3 mg/kg, Rapamycin 1 mg/kg, and Mycophenolate Mofetil 10 mg/kg p.o. q12h for 4 weeks. Control animals (C2, n = 6) received equivalent vehicle. Parameters followed were weight gain, nutrient absorption, drug levels and nutrient transport in vitro.. Controls grew normally, while weight gain was significantly reduced in drug treated animals: This was paralleled by a reduction in dietary fat absorption. Drug levels were low to therapeutic for all drugs in both experiments; FK506 appeared to affect Rapamycin and Mycophenolate Mofetil metabolism, increasing levels of both as FK506 doses increased. Nutrient transport was either not effected (D1) or increased (D2).. We conclude that low dose combination immunosuppressive therapy inhibits weight gain, without affecting absorption of dietary energy, or adversely affecting glucose transport. We postulate a systemic metabolic cause, which requires additional investigation at the cellular level; additional studies are also required to determine if the additive immunosuppression outweigh the side effects for SIT.

Topics: 3-O-Methylglucose; Animals; Body Weight; Drug Therapy, Combination; Glucose; Ileum; Immunosuppressive Agents; Intestinal Absorption; Intestine, Small; Jejunum; Male; Mycophenolic Acid; Rats; Sirolimus; Tacrolimus

Mycophenolate mofetil (MMF) is a new immunosuppressive drug used in combination with cyclosporin A (CsA) or tacrolimus and prednisone to prevent rejection of renal allografts in both adult and pediatric recipients. It has been shown in several large studies that MMF significantly decreases the incidence of acute rejection in adults and has acceptable adverse effects. In this retrospective study, we compare the incidence of adverse events between pediatric and adult renal allograft recipients. Twenty-two children and 37 adult renal allograft recipients were included in the study. The initial dose of MMF was 1.5 g b.i.d. for the adult patients and ranged from 15 to 30 mg/kg/d for the pediatric patients. All patients received p.o. acyclovir as prophylaxis for cytomegalovirus (CMV). The two groups were similar regarding gender distribution and graft source. Acute rejections occurred in 10 of the 22 pediatric patients (45%) and in nine of the 37 adults (24%), p = NS. The incidence of infections was similar in both groups except for the occurrence of CMV (n = 5), which was seen only in adults. The incidence of GI symptoms was significantly higher in the pediatric population (54.5% vs. 21.6%; p = 0.02). Significant weight loss was seen more often in the smaller pediatric patients (weight < or = 15 kg) compared to the larger pediatric patients, 60% vs. 11.7%, p = 0.05. Among the patients who had significant GI symptoms 50% of the adults and 75% of the pediatric recipients required either dose reduction or, most commonly, discontinuation of the MMF. The need to discontinue MMF was significantly higher in the pediatric patients, especially in those that weighed less than 15 kg. We suggest the possibility that the optimum dose, dosing interval or preparation of MMF has not yet been established for pediatric patients. One should therefore monitor pediatric patients closely, especially the small ones, to avoid significant nutritional problems and other adverse GI events.

Topics: Acute Disease; Acyclovir; Adolescent; Adult; Age Factors; Antiviral Agents; Body Weight; Child; Child, Preschool; Cytomegalovirus Infections; Data Interpretation, Statistical; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Male; Mycophenolic Acid

Classical immunosuppressants like cyclophosphamide give excellent results in human lupus nephritis. However, they augment malignancies and viral infections. Here we investigated the effect of the new immunosuppressant agent, mycophenolate mofetil (MMF), in New Zealand Black x New Zealand White (NZBxW) F1 hybrid mice, a model of genetically determined immune complex disease that mimics systemic lupus in humans. MMF has a selective antiproliferative effect on T- and B-lymphocytes, inhibits antibody formation and blocks the glycosylation of lymphocyte glycoproteins involved in the adhesion of leukocytes to endothelial cells. Two groups of NZBxW mice were used: group 1 (N = 20) given daily MMF (60 mg/kg p.o.) and group 2 (N = 15) given daily vehicle alone. Treatment started at three months of age and lasted until the death of the animals. Results showed that percentage of proteinuric mice was significantly reduced by MMF treatment and serum BUN levels were also lower than vehicle. MMF had a suppressive effect on autoantibody production and protected animals from leukopenia and anemia. Life survival of MMF treated lupus mice was significantly improved in respect to untreated animals. Thus, MMF delayed renal function deterioration and prolonged life survival in murine lupus nephritis. MMF has been already recognized as reasonably well tolerated in renal transplant patients and despite its gastrointestinal toxicity its overall safety profile appears superior to azathioprine. Human studies are needed to establish whether MMF may function as a steroid-sparing drug in lupus nephritis.

Topics: Animals; Antibodies, Antinuclear; Body Weight; DNA; Female; Immunosuppressive Agents; Kidney; Lupus Nephritis; Mice; Mice, Inbred NZB; Mycophenolic Acid; Proteinuria