mycophenolic-acid and Diarrhea

The current standard of care immunosuppressive regimen in kidney transplantation (KT) includes a combination of mycophenolates (MMF/MPA) with a calcineurin inhibitor (CNI).. We designed a systematic review including all randomized clinical trials (RCTs) assessing the outcomes in KT recipients receiving mTORi + CNI compared with regimens containing MMF/MPA or azathioprine with CNI.. A total of 24 studies with 7356 participants were included. The comparison between mTORi-CNI and MMF/MPA-CNI did not show differences in acute rejection, mortality, or graft loss rates. Better graft function was observed using MMF/MPA-CNI than using mTORi + CNI, but this difference was not evident when the mTORi was associated with reduced dose CNI in more recent studies with everolimus. Dyslipidemia, lymphoceles, and impaired wound healing were more frequent with mTORi-CNI and diarrhea and leukopenia were more frequent with MMF/MPA-CNI. Viral infections at any time and malignant neoplasia beyond 2 years were less frequent with mTORi-CNI. Rates of discontinuation because of adverse effects in the mTORi groups varied between 17% and 46% compared to 0%-26.6% in MMF/MPA groups. The current use of lower mTORi dosage has decreased the discontinuation rates.. Efficacy is similar with mTORi + CNI and MMF/MPA-CNI. The safety profile is the predominant difference between the 2 regimens.

Topics: Calcineurin Inhibitors; Diarrhea; Drug Therapy, Combination; Dyslipidemias; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Mycophenolic Acid; Randomized Controlled Trials as Topic; Standard of Care; TOR Serine-Threonine Kinases; Treatment Outcome

We describe the first reported pediatric patient to our knowledge with a spindle cell pseudotumor caused by Mycobacterium genavense in a hematopoietic stem cell transplant recipient, and review the literature of such an entity in the transplant population.

Topics: Abdomen; Adolescent; Alemtuzumab; Antibiotic Prophylaxis; Antibiotics, Antitubercular; Antibodies, Monoclonal, Humanized; Bone Marrow Transplantation; Bronchoalveolar Lavage Fluid; Cyclosporine; Diabetes Mellitus, Type 1; Diarrhea; Genetic Diseases, X-Linked; Graft Rejection; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histiocytes; Humans; Immune System Diseases; Immunosuppressive Agents; Lymph Nodes; Male; Melphalan; Mycobacterium Infections, Nontuberculous; Mycophenolic Acid; Nontuberculous Mycobacteria; Photopheresis; Polymerase Chain Reaction; Transplantation Conditioning; Vidarabine

The success of organ transplantation allows many transplant recipients to return to life similar to nontransplant patients. Their need for regular health care, including preventive medicine, has switched the majority of responsibilities for their health care from transplant specialists to primary care physicians. To take care of transplant recipients, it is critical for primary care physicians to be familiar with immunosuppressive medications, their side effects, and common complications in transplant recipients. Ten subjects are reviewed here in order to assist primary care physicians in providing optimal care for transplant recipients.

Topics: Adrenal Cortex Hormones; Contraceptive Agents, Female; Cyclosporine; Diarrhea; Drug Interactions; Drug Monitoring; Elective Surgical Procedures; Female; Graft Rejection; Humans; Immunosuppressive Agents; Male; Medication Adherence; Mycophenolic Acid; Organ Transplantation; Osteonecrosis; Polycythemia; Pregnancy; Pregnancy Complications; Primary Health Care; Sirolimus; Tacrolimus; Transplant Recipients; Urinary Tract Infections

Immune checkpoint inhibition with the anti-CTLA-4 antibody ipilimumab and the anti-PD-1 antibodies nivolumab and pembrolizumab has improved survival in metastatic melanoma, lung cancer and renal cancer. Use of these agents holds promise in other malignancies. The augmented immune response enabled by these agents has led to a particular group of side effects called immune-related adverse events (irAEs). The main irAEs include diarrhea, colitis, hepatitis, skin toxicities and endocrinopathies such as hypophysitis and thyroid dysfunction. The anti-PD-1 antibodies have a different toxicity profile to ipilimumab with fewer high grade events. This article identifies the rates of common and uncommon irAEs associated with each immune checkpoint inhibitor (ICPI) and their timing of onset, focusing mainly on the experience in melanoma and lung cancer. An approach to management for each class of irAE is provided.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antilymphocyte Serum; Antineoplastic Agents; Carcinoma, Renal Cell; Chemical and Drug Induced Liver Injury; Colitis; CTLA-4 Antigen; Cyclosporine; Diarrhea; Drug Eruptions; Humans; Immunosuppressive Agents; Infliximab; Ipilimumab; Kidney Neoplasms; Lung Neoplasms; Melanoma; Mycophenolic Acid; Neoplasms; Nivolumab; Pituitary Diseases; Programmed Cell Death 1 Receptor; Skin Neoplasms; Tacrolimus; Thyroiditis

Topics: Adult; Arterioles; Blood Pressure; Cyclosporine; Diarrhea; Drug Resistance; Drug Therapy, Combination; Eye Diseases, Hereditary; Female; Fibrosis; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Glucocorticoids; Humans; Hyalin; Immunosuppressive Agents; Intestinal Diseases; Male; Mycophenolic Acid; Prednisolone; Prospective Studies; Proteinuria; Skin Abnormalities; Treatment Outcome; Vascular Diseases

Gastrointestinal (GI) symptoms in renal transplant recipients may be caused due to mycophenolic acid (MPA) toxicity. Using small bowel capsule endoscopy (SBCE) we examined the impact of conversion from Mycophenolate Mofetil (MMF) to enteric-coated formulation of Mycophenolate Sodium (EC-MPS) given to treat GI mucosal lesions.. Adult kidney-only recipients at least 30 days after transplant, presenting with GI symptoms while receiving MMF completed a Gastrointestinal Symptom Rating Scale (GSRS) questionnaire, underwent SBCE, and had MMF substituted by EC-MPS. After 30 days, GSRS and SBCE were repeated and findings were compared to baseline values. Patients who were still on EC-MPS 6-24 months post-conversion were contacted for completing a follow-up GSRS questionnaire and SBCE.. Eighteen out of 23 subjects completed the first part of the study. Subjects' median ages and post-transplant time were 47.5 years old and 4.5 months, respectively. Tacrolimus, MMF and prednisone was the main regimen (94%), with a median MMF dose of 750 mg BID. The average baseline GSRS was 2.99 ± 0.81; it significantly decreased to 2.19 ± 0.8 at 30 days post-conversion. At baseline, 50 had gastric and 89% had small bowel lesions. At 30 days, 29 and 62% of the SBCE were still showing gastric and small bowel lesions, respectively. Of 5 patients in the study extension, 4 had abnormal SBCE findings but have been reporting improvement in their symptoms.. Stomach and small bowel mucosal lesions are common in kidney recipients with GI symptoms when treated with MMF. Conversion to EC-MPS for 30 days significantly alleviated the GI symptoms; however, no evident correlation with SBCE findings was found.

Topics: Abdominal Pain; Adult; Aged; Capsule Endoscopy; Diarrhea; Drug Substitution; Dyspepsia; Follow-Up Studies; Heartburn; Humans; Immunosuppressive Agents; Intestine, Small; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Prospective Studies; Stomach; Surveys and Questionnaires; Tablets, Enteric-Coated

We investigated the association between genetic polymorphisms in ABCB1 and SLCO1B and mycophenolic acid (MPA) pharmacokinetics, and MPA-related diarrhea and leukopenia in 338 kidney transplant recipients.. A total of 338 patients participating in an international, randomized-controlled clinical trial were genotyped for ABCB1 and SLCO1B. Patients were all treated with mycophenolate mofetil and either cyclosporine or tacrolimus. MPA-area under the curve (AUCs), MPA-glucuronide AUCs and acylglucuronide-AUCs were measured on days 3 and 10, and months 1, 3, 6, and 12 after kidney transplantation.. The risk of developing diarrhea was 1.8-fold higher in patients cotreated with tacrolimus compared with patients cotreated with cyclosporine (95% confidence interval: 1.03-3.13; P=0.038). ABCB1 and SLCO1B SNPs were not associated with dose-adjusted exposure to MPA, MPA-glucuronide, nor acylglucuronide-MPA nor with the incidence of diarrhea or leukopenia.. Genotyping for ABCB1 or SLCO1B pretransplantation is unlikely to be of clinical value for individualization of MPA therapy.

Topics: Adolescent; Adult; Aged; Area Under Curve; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Child; Diarrhea; Dose-Response Relationship, Drug; Female; Genetic Association Studies; Genetic Predisposition to Disease; Humans; Incidence; Kidney Transplantation; Leukopenia; Liver-Specific Organic Anion Transporter 1; Male; Middle Aged; Mycophenolic Acid; Netherlands; Organic Anion Transporters; Organic Anion Transporters, Sodium-Independent; Solute Carrier Organic Anion Transporter Family Member 1B3

We conducted a multicenter randomized study in liver transplantation to compare standard-dose tacrolimus to reduced-dose tacrolimus with mycophenolate mofetil to reduce the occurrence of tacrolimus side effects. Two primary outcomes (censored criteria) were monitored during 48 weeks post-transplantation: occurrence of renal dysfunction or arterial hypertension or diabetes (evaluating benefit) and occurrence of acute graft rejection (evaluating risk). Interim analyses were performed every 40 patients to stop the study in the case of increased risk of graft rejection. One hundred and ninety-five patients (control: 100; experimental: 95) had been included when the study was stopped. Acute graft rejection occurred in 46 (46%) and 28 (30%) patients in control and experimental groups, respectively (HR = 0.59; 95% CI: [0.37-0.94]; p = 0.024). Renal dysfunction or arterial hypertension or diabetes occurred in 80 (80%) and 61 (64%) patients in control and experimental groups, respectively (HR = 0.68; 95% CI: [0.49-0.95]; p = 0.021). Renal dysfunction occurred in 42 (42%) and 23 (24%) patients in control and experimental groups, respectively (HR = 0.49; 95% CI: [0.29-0.81]; p = 0.004). Leucopoenia (p = 0.001), thrombocytopenia (p = 0.017) and diarrhea (p = 0.002) occurred more frequently in the experimental group. Reduced-dose tacrolimus with mycophenolate mofetil reduces the occurrence of renal dysfunction and the risk of graft rejection. This immunosuppressive regimen could replace full-dose tacrolimus in adult liver transplantation.

Topics: Adult; Diabetes Complications; Diarrhea; Dose-Response Relationship, Drug; Female; France; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Kidney; Leukopenia; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Thrombocytopenia; Treatment Outcome

In renal transplant (RT) recipients, treatment with enteric-coated mycophenolate sodium (EC-MPS) improves gastrointestinal (GI) tolerability compared with mycophenolate mofetil (MMF). The impact of conversion from MMF to EC-MPS on patient's health-related quality of life (HRQoL) using GI-specific instruments has been scarcely evaluated in randomized trials.. The present randomized, multicenter, open-labeled, 12-week study included RT recipients experiencing GI adverse events due to MMF treatment. Patients were randomized to continue with MMF (n=54) or change to EC-MPS (n=59). Patients were converted at equimolar doses, and dose was optimized between weeks 2 and 6 to achieve maximum tolerated dose.. Incidence of GI complications (particularly diarrhea) was significantly lower in the EC-MPS group (67.8% vs. 87.0%, P=0.015). The baseline-adjusted mean global scores at 12 weeks in GI quality of life index were significantly higher in the EC-MPS group versus MMF (P=0.014). Results at 12 weeks for all secondary scales indicated better HRQoL in the EC-MPS group compared with the MMF group (Gastrointestinal Symptom Rating Scale, Psychological General Well-Being Index, and overall treatment effect). In the EC-MPS group, a higher percentage of patients were receiving intermediate doses of mycophenolic acid (720 mg/day) at 12 weeks compared with MMF (55.4% vs. 27.4%, P=0.003), whereas no differences were observed for high doses (>720 mg/day).. In RT patients with GI undesirable effects due to MMF, switching from MMF to EC-MPS may enable an increase in the maximum tolerated dose of mycophenolic acid and reduce GI complications, thus enhancing patients' GI HRQoL.

Topics: Adult; Diarrhea; Female; Gastrointestinal Tract; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Quality of Life; Tablets, Enteric-Coated

Mycophenolic acid (MPA) is metabolized primarily by glucuronidation to form the biologically inactive 7-O-glucuronide conjugate (MPAG), which is the major urinary excretion product. MPA is also converted to acyl-glucuronide metabolite (AcylMPAG), which has been suggested to be involved in the generation of MPA-related adverse events such as diarrhea or leucopenia. This conversion of MPA to AcylMPAG is catalyzed by UDP-glucuronosyltransferase 2B7 (UGT2B7). We studied the impact of the -840G>A polymorphisms in the UGT2B7 gene on the pharmacokinetics of AcylMPAG. We also investigated whether the plasma concentrations of AcylMPAG are correlated with MPA-related toxicity to further evaluate its potential clinical significance. In a randomized, controlled trial, comparing fixed-dose mycophenolate mofetil (MMF) with concentration-controlled MMF therapy, patients undergoing renal transplantation were treated with a calcineurin inhibitor, MMF, and corticosteroids. Informed consent was obtained from 332 patients for genotyping. In all patients, blood samples were drawn (three samples within the first 2 hours after administration) on Day 3, Day 10, Week 4, and Months 3, 6, and 12 to measure MPA and AcylMPAG plasma concentrations. The pharmacokinetics of AcylMPAG were correlated with the -840G>A single nucleotide polymorphism (SNP) in the UGT2B7 gene. Heterozygosity for the -840G>A SNP in the UGT2B7 gene was found in 145 patients (145 of 332 [44%]) and 93 (93 of 332 [28%]) patients were homozygous for the -840G>A allele. No difference was found in the dose-normalized AcylMPAG trough (C0) levels and dose-normalized AcylMPAG areas under the concentration-time curve (AUCs) at each visit between carriers and noncarriers of the -840G>A SNP. Also, metabolic ratios, expressed as AcylMPAG/MPA and AcylMPAG/MPAG, were not related to UGT2B7 genotype. The dose-normalized AcylMPAG-C0 and AcylMPAG AUC were higher in the cyclosporine-treated group compared with the tacrolimus-treated patients at each visit. There was no difference in AcylMPAG concentrations (trough or AUC) or AcylMPAG/MPAG ratio between patients with compared with patients without diarrhea. None of the -840G>A UGT2B7 SNPs was disproportionately present among the patients with diarrhea. There was a higher incidence of diarrhea in tacrolimus-treated patients [26 of 163 (16.0%)] compared with cyclosporine-treated individuals [five of 51 (9.8%)], although AcylMPAG concentrations were lower in tacrolimus-treated patient

Topics: Adrenal Cortex Hormones; Calcineurin Inhibitors; Diarrhea; Dose-Response Relationship, Drug; Female; Glucuronides; Glucuronosyltransferase; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Polymorphism, Genetic; Prospective Studies

The aim of this study was to determine whether plasma concentrations of the acyl (AcMPAG) and phenolic (MPAG) glucuronide metabolites of mycophenolic acid (MPA) were related to diarrhoea in renal transplant patients on mycophenolate mofetil (MMF) with cyclosporine (CsA) or tacrolimus (TCL). Blood samples (0, 30, 120 min) were taken at days 3, 10, week 4, months 3, 6 and 12 for determination of MPA, MPAG and AcMPAG. MPA-AUC was estimated using validated algorithms. Two hour AUCs were calculated for MPAG and AcMPAG. Immunosuppressive therapy consisted of CsA/MMF (n= 110) and of TCL/MMF (n= 180). In 70/290 (24%) patients 86 episodes of diarrhoea were recorded during 12 months. Significantly more patients on TCL (31.1%) suffered from diarrhea compared to CsA (12.7%). MMF dose, MPA-AUC and the 2 h AUCs of MPAG and AcMPAG did not differ between patients with and without diarrhoea. Plasma AcMPAG and MPAG concentrations were substantially higher in patients on CsA compared with TCL, while MPA-AUC was lower in the former group. These data support the concept that CsA inhibits the biliary excretion of MPAG and AcMPAG, thereby potentially reducing the risk of intestinal injury through enterohepatic recycling of MPA and its metabolites.

Topics: Adrenal Cortex Hormones; Adult; Cyclosporine; Diarrhea; Dose-Response Relationship, Drug; Glucuronides; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Survival Analysis; Tacrolimus

There are data suggesting an association between mycophenolic acid (MPA) levels and acute rejection and toxicity in renal transplant recipients treated with mycophenolate mofetil (MMF), and therefore, knowledge of factors determining MPA levels may aid in accurate adjustment of MMF dosage. A total of 4970 samples taken 12 hours postdose were analyzed for MPA by immunoassay at regular intervals from the first week posttransplantation in 117 renal transplant patients immunosuppressed with MMF and tacrolimus in a steroid-sparing regimen (prednisolone for the first 7 days only). MPA levels rose in the first 3 months and stabilized thereafter; dose-normalized MPA levels rose throughout the first 12 months and subsequently stabilized. Multivariate analysis by means of a population-averaged linear regression showed positive associations between MPA level and total daily dose (P < 0.001) but not individual dose or total daily dose corrected for body weight. Positive associations were also seen with serum albumin (P = 0.01), tacrolimus trough level (P = 0.01), and female gender (P = 0.002). The association with tacrolimus levels diminished with time. Negative associations were seen between MPA level and higher estimated creatinine clearance (P < 0.001), and also with increasing alanine transaminase levels (P = 0.002), the use of oral antibiotics (P < 0.001), and infective diarrhea (P < 0.001). The latter findings may be related to changes in enterohepatic recirculation of MPA. Many clinical variables show associations with trough MPA levels. An understanding of these factors may aid therapeutic monitoring of MMF.

Topics: Adult; Alanine Transaminase; Amoxicillin-Potassium Clavulanate Combination; Biomarkers; Ciprofloxacin; Creatinine; Diarrhea; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metronidazole; Middle Aged; Mycophenolic Acid; Prodrugs; Serum Albumin; Tacrolimus; Time Factors; Treatment Outcome

The tolerance and pharmacokinetics (PK) of tacrolimus (T) by the addition of mycophenolate mofetil (MMF) in stable kidney transplant patients (6/group) on long-term tacrolimus-based therapy were investigated. Patients received combination T and MMF therapy at three MMF doses: 1, 1.5, and 2 g/day administered twice daily. A 12-hour blood PK profile for T was obtained prior to MMF dosing; concomitant 12-hour profiles for T, mycophenolic acid (MPA), and mycophenolic acid glucuronide (MPAG) were obtained after 2 weeks of administration. Tolerance was monitored through 3 months. The intra- and intergroup PK of T were variable. The mean AUC0-12 of T for each group was increased after 2 weeks of concomitant MMF administration, but the increase was not statistically significant. Both drugs were well tolerated. Gastrointestinal events were of interest as such have been attributed to both T and MMF. Events reported were diarrhea, nausea, dyspepsia, and vomiting. Other common adverse events were headache, hypomagnesemia, and tremors. Most were mild, although a few were considered to be moderate. There was no apparent relationship between the incidence of any adverse event and MMF treatment group. In the present study, the coadministration of T and MMF did not significantly alter T pharmacokinetics.

Topics: Adult; Area Under Curve; Diarrhea; Dose-Response Relationship, Drug; Drug Interactions; Dyspepsia; Female; Glucuronates; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Nausea; Prodrugs; Tacrolimus; Vomiting

Mycophenolate mofetil (MMF) is a new immunosuppressive drug that selectively inhibits de novo purine synthesis. It has been tested in three large double-blind controlled trials for the prevention of rejection in renal transplant patients. These studies indicate that the use of MMF dramatically decreases the incidence of biopsy-proven rejection, the use of multiple courses of steroids for rejection, and the use of antilymphocyte preparations for treatment of rejection. The drug was well tolerated with an acceptable safety profile. The main side effects were gastrointestinal (nausea, vomiting, diarrhea), but seldom resulted in the cessation of drug therapy. Hematologic side effects similar to those with azathioprine occurred and were reversible. There was a slight increase in CMV-invasive disease with the use of MMF, but no deaths. Rates of malignancy were within published ranges for transplant recipients. Mycophenolate mofetil is a safe and efficacious drug for prevention of rejection in kidney transplant recipients.

Topics: Antilymphocyte Serum; Azathioprine; Cytomegalovirus Infections; Diarrhea; Double-Blind Method; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Mycophenolic Acid; Nausea; Neoplasms; Opportunistic Infections; Placebos; Purines; Safety; Steroids; Vomiting

We report a case of mycophenolate mofetil-induced collagenous ileitis in a kidney transplant patient. A 38-year-old Chinese man who had received a kidney transplant 3 years earlier was admitted to our department for severe diarrhea and rapid weight loss. Infection studies were negative, and tumors were ruled out, so drug-induced factors were suspected. He had been taking mycophenolate mofetil for immunosuppression, which was then suspended, and he had a rapid resolution of diarrhea. Pathological findings of gastrointestinal endoscopy biopsy showed the presence of thickened collagen bands in the subepithelium of the terminal ileum. This is the first report of collagenous ileitis caused by mycophenolate mofetil in a patient with a kidney transplantation, adding another reversible cause to this rare condition. It is important for clinicians to recognize and treat it promptly.

Topics: Adult; Diarrhea; Graft Rejection; Humans; Ileitis; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid

Celiac-like disease and celiac sprue associated with widespread use of mycophenolic acid are among the most frequent complications of renal transplant. Most cases have been observed in patients receiving mycophenolate mofetil; however, there have been rare instance after administration of enteric-coated mycophenolate sodium. Here, we describe 4 renal transplant recipients with celiac-like duodenopathy that occurred in association with enteric-coated mycophenolate sodium treatment in a time period of 14 to 19 years after living donor kidney transplant. Three of 4 patients had diarrhea, and all 4 patients had marked loss of body weight. Esophago-gastroduodenoscopy was not diagnostically helpful; however, randomly performed duodenal biopsies showed mild villous atrophy and intraepithelial lymphocytosis. Replacement of enteric-coated mycophenolate sodium with azathioprine was successful with stopping diarrhea, allowing regained body weight, and stabilization of renal function. This potential complication in kidney transplant recipients can occur more than a decade after transplant. Diagnosis and treatment initiation are urgent to cure this disease.

Topics: Diarrhea; Duodenal Diseases; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney; Kidney Transplantation; Mycophenolic Acid; Transplant Recipients

Topics: alpha 1-Antitrypsin; Colonoscopy; Cryptosporidiosis; Diagnosis, Differential; Diarrhea; Feces; Humans; Hypoalbuminemia; Immunocompromised Host; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Nitro Compounds; Protein-Losing Enteropathies; Thiazoles; Travel

Immune dysregulation, polyendocrinopathy, enteropathy, and X-linked (IPEX) syndrome is a rare monogenic autoimmune disease, which is caused by mutations in the forkhead box protein 3 gene, can affect various systems. The typical clinical manifestations of IPEX are enteropathy, type 1 diabetes mellitus, and skin diseases. However, some atypical phenotypes can easily be misdiagnosed clinically.. A 9-year-and-7-month old patient suffered from recurrent wheezing, hematochezia, and eczematous dermatitis at the age of six months, but did not have any manifestations of autoimmune endocrinopathy. The patient was treated with glucocorticoids for more than six years, and he developed bronchiectasis.. Whole exome sequencing revealed a hemizygous pathogenic mutation c.1010G>A, p. (Arg337Gln) in Forkhead box protein 3 gene (NM_014009.3).. The patient was treated with oral mycophenolate mofetil combined with inhaled budesonide formoterol for six months after diagnosis.. The respiratory symptoms of the patient seemed to be controlled but eczematous dermatitis progressed, which led the patient to give up the treatment.. Early diagnosis and treatment of IPEX are crucial. Lung injury may be a major problem in the later stages of atypical IPEX, and mycophenolate mofetil seems to control the respiratory symptoms, but could induce significant skin side effects.

Topics: Budesonide, Formoterol Fumarate Drug Combination; Child; Delayed Diagnosis; Diabetes Mellitus, Type 1; Diarrhea; Forkhead Box Protein O3; Genetic Diseases, X-Linked; Humans; Immune System Diseases; Male; Mycophenolic Acid; Point Mutation; Respiratory System Agents

Diarrhea is a well-known side effect of mycophenolic acid (MPA) use in kidney transplant recipients (KTRs). It is unknown whether self-reported diarrhea using the Modified Transplant Symptom Occurrence and Symptom Distress Scale (MTSOSD-59R) corresponds to stool water content and how both relate to MPA usage.. MTSOSD-59R questionnaires filled out by 700 KTRs from the TransplantLines Biobank and Cohort Study (NCT03272841) were analyzed and compared with stool water content. Stool samples (N = 345) were freeze-dried, and a water content ≥80% was considered diarrhea.. Self-perceived diarrhea was reported by 46%, while stool water content ≥80% was present in 23% of KTRs. MPA use was not associated with self-perceived diarrhea (odds ratio(OR) 1.32; 95% confidence interval(CI), 0.87-1.99, p = .2), while it was associated with stool water content ≥80% (OR 2.88; 95%CI, 1.41-5.89, p = .004), independent of potential confounders. Adjustment for prior MPA discontinuation because of severe diarrhea, uncovered an association between MPA use and self-perceived diarrhea (OR 1.80; 95%CI, 1.13-2.89, p = .01).. These results suggest that reporting bias could add to the discrepancy between both methods for diarrhea assessment. We recommend use of objective biomarkers or more extensive questionnaires which assess information on stool frequency and stool consistency, to investigate post-transplantation diarrhea.

Topics: Cohort Studies; Diarrhea; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid

Topics: Caliciviridae Infections; Diabetes Mellitus, Type 1; Diagnosis, Differential; Diarrhea; Disease Progression; Drug Tapering; Feces; Fluid Therapy; Gastroenteritis; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Multiplex Polymerase Chain Reaction; Mycophenolic Acid; Pancreas Transplantation; Prednisone; Sapovirus; Tacrolimus

Topics: Adult; Aged; Aged, 80 and over; Antirheumatic Agents; Azathioprine; Betacoronavirus; Clinical Laboratory Techniques; Cohort Studies; Coronavirus Infections; Cough; COVID-19; COVID-19 Testing; Cyclosporine; Diarrhea; Dysgeusia; Dyspnea; Fatigue; Female; Fever; Glucocorticoids; Humans; Hydroxychloroquine; Immunosuppressive Agents; Incidence; Intensive Care Units; Italy; Lupus Erythematosus, Systemic; Male; Methotrexate; Middle Aged; Mycophenolic Acid; Olfaction Disorders; Pandemics; Pneumonia, Viral; Prednisone; Respiratory Distress Syndrome; SARS-CoV-2; Telemedicine

Chronic immunosuppression may increase the risk of post-transplant infection and medication-related injury and may also be responsible for the increased risk of gastrointestinal complications in kidney transplant recipients. Differentiating the various forms of post-transplant colitis is challenging, since most have similar clinical and histological features. This study evaluated the incidence of post-transplant gastrointestinal complications during screening colonoscopy. Kidney transplant recipients undergoing a colonoscopy for any reasons in the period 2014-2018 were included. Among the 134 patients completing the colonoscopy, 74 patients (56%) had an abnormal finding: an adenoma was found in 25 patients (18.6%), while 19 patients (14.1%) had colitis. Mycophenolic acid/related colitis was the most common colitis (6%), while 7 patients (5.2%) developed a

Topics: Adenoma; Age Distribution; Aged; Anemia; Colitis; Colonoscopy; Colorectal Neoplasms; Diarrhea; Diverticulosis, Colonic; Early Detection of Cancer; Female; Gastrointestinal Hemorrhage; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Inflammatory Bowel Diseases; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

Immunosuppressant drugs for renal transplant mycophenolate mofetil (MMF) and enteric-coated mycophenolate sodium (EC-MPS) cause gastrointestinal (GI) disorders. The specific site of GI tract targeted by MMF and EC-MPS remains unclear.. In this study, we investigated the effects of MMF and EC-MPS on stomach, duodenum, jejunum, ileum, colon and rectum using a rat model. Rats were randomized into five groups: control, MMF (100 mg/kg·d), mofetil (30 mg/kg·d), EC-MPS (72 mg/Kg·d), mofetil + EC-MPS. Each group was treated with drugs once a day for 7 days through intra-gastric gavage. Diarrhea grade of each rat were measured every day, as well as the body weight. Blood was collected by tail nick and Seven days later, the rats were sacrificed, GI tissues were collected for Histological research.. The results showed that diarrhea grade and weight loss were significantly higher in MMF group than other groups. The pathological score of MMF group was significantly higher than EC-MPS group and EC-MPS + mofetil group in jejunum and ileum tissues, but not other segments of GI tract. Absorption of EC-MPS is delayed, compared to that of MMF. MPAG concentration in duodenum, jejunum and ileum tissues of MMF group is higher than EC-MPS group. Mofetil may increase the magnitude of MPA absorption.. Our data suggested that MMF might target jejunum and ileum and induce GI injury. EC-MPS causes less injury in GI tract than MMF, probably due to its kinetic property.

Topics: Animals; Delayed-Action Preparations; Diarrhea; Gastrointestinal Tract; Immunosuppressive Agents; Male; Mycophenolic Acid; Rats; Rats, Sprague-Dawley

Topics: Adult; Biopsy; Colitis; Colon; Colonoscopy; Diarrhea; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Mycophenolic Acid; Pancreatitis

BACKGROUND Progressive familial intrahepatic cholestasis (PFIC) is an autosomal recessive inherited disease that disrupts the genes for bile formation. Liver transplantation (LT) is the only effective treatment for PFIC patients with end-stage liver disease. We describe our experience in terms of clinical characteristics, complications, and outcome of LT for PFIC. CASE REPORT The data of 5 pediatric PFIC patients recipients (3 PFIC1, 1 PFIC2, and 1 PFIC3) who received LT at our Liver Transplant Center from June 2013 to February 2017 were retrospectively analyzed. Four patients received liver transplantation from donation after cardiac death (DCD) donors. One patient received a living donor liver transplantation (LDLT). All the LT recipients received an immunosuppressive regimen of tacrolimus (FK 506) + methylprednisolone + mycophenolate mofetil (MMF). Diarrhea did not improve in 2 PFIC1 patients after LT, and they both developed steatohepatitis several months after LT. The other PFIC1 patient received ABO blood group incompatible LT and developed biliary complications and a severe Epstein-Barr virus infection; this patient underwent endoscopic retrograde cholangiopancreatography. She recovered after treatment with ganciclovir and reduction of tacrolimus dosage. The PFIC2 patient had abnormal liver function 19 months after LT, and recovered after administration of increased dosage of immunosuppressant agents. Liver function in the PFIC3 patient was normal during 2-year follow-up. CONCLUSIONS Liver transplantation is an effective treatment in PFIC patients. However, PFIC1 patients may develop aggravated diarrhea and steatohepatitis after LT. PFIC2 and PFIC3 patients have good outcomes after LT.

Topics: Child; Child, Preschool; Cholestasis, Intrahepatic; Diarrhea; Disease Progression; Fatty Liver; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Male; Methylprednisolone; Mycophenolic Acid; Postoperative Complications; Retrospective Studies; Tacrolimus; Treatment Outcome

Topics: Adult; Azathioprine; Diarrhea; Drug Substitution; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Time Factors

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is becoming increasingly popular as an alternative immunosuppressant in feline medicine. Pharmacokinetic information is not available for cats.. The purpose of this study was to determine whether MMF is biotransformed into the active metabolite MPA and to evaluate the disposition of MPA after a 2-hour constant rate intravenous (IV) infusion of MMF in healthy cats.. Healthy cats (n = 6).. This was a prospective pilot study. All cats were administered MMF at 20 mg/kg every 12 hours over a 2-hour constant rate infusion for 1 day. The concentrations of MPA and its derivatives in blood were determined using a validated UHPLC-UV method.. The disposition of MPA in plasma was highly variable, which could result in high interindividual variability in the safety and efficacy of treatment with MMF in cats.

Topics: Animals; Area Under Curve; Cats; Diarrhea; Female; Immunosuppressive Agents; Infusions, Intravenous; Male; Mycophenolic Acid; Pilot Projects; Prospective Studies

Chronic diarrhea after kidney transplantation is often attributed to mycophenolic acid (MPA) toxicity. We hypothesize that intestinal infections contribute to the pathogenesis of chronic MPA-associated diarrhea.. In this retrospective study, all patients (n = 726) receiving a kidney transplant between 2000 and 2010 at the University Hospital Zurich were followed until July 2014 for occurrence of chronic diarrhea (≥4 weeks). Infectious triggers at diarrhea onset were assessed by reviewing medical history, stool microbiology, and histology of colon biopsies.. In 46 patients (6.3% of the cohort), a total of 51 episodes of chronic diarrhea during MPA treatment were documented. The diarrhea episodes were often severe, as confirmed by significant weight loss. The cumulative incidence of chronic diarrhea was uniformly distributed throughout the post-transplant period, with 2.0%, 5.1%, and 9.6% at 1, 5, and 10 years, respectively. Evidence was found for intestinal infection at diarrhea onset in 38 episodes (74.5%). Occurrence of diarrhea onset showed a seasonal distribution with peaks in April and October/November. Specific antimicrobial treatment alone was associated with a 19% resolution rate only, whereas combination with dose reduction of MPA or switch from mycophenolate mofetil to enteric-coated mycophenolate sodium resulted in a 22.7% and 76.5% resolution rate, respectively. Change to an MPA-free regimen was associated with a 100% resolution rate.. These results provide first evidence for a contribution of intestinal infections in chronic post-transplant diarrhea associated with MPA treatment.

Topics: Adult; Area Under Curve; Chronic Disease; Colitis; Colon; Diarrhea; Feces; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Switzerland; Transplant Recipients; Transplantation, Homologous; Weight Loss

Topics: Child; Diarrhea; Enterocolitis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid

Diarrhoea following orthotopic liver transplantation (OLT) is a significant clinical problem associated with mycophenolic acid (MPA). The histological injury pattern associated with MPA in the large bowel is well documented in the literature; however, that in the duodenum is less extensively documented. The aim of this study was to investigate the histological spectrum of duodenal injury specifically in symptomatic OLT patients on MPA, and to compare this with the spectrum in patients with coeliac disease and in normal controls.. We reviewed our pathology database for all duodenal biopsies from patients on the OLT list over a period of 19 years. Medical records, anti-tissue transglutaminase IgA serology and histology were reviewed. Of the 667 patients who underwent endoscopy, 127 had duodenal biopsies (152 biopsies). Of these, 87.5% were normal. Sixteen showed abnormal histology, and seven (43.8%) of these were on MPA at the time of biopsy. Significant features included coeliac-like changes (shortened villi and increased intraepithelial lymphocyte counts), and novel findings included increased endocrine cell counts, apoptotic counts and lamina propria eosinophil counts in comparison with normal duodenal biopsies.. Pathologists should be aware of the features of MPA-associated duodenal injury, including coeliac-like changes and increased apoptotic counts. In those with abnormal histology, discontinuation or a reduction in the dose of MPA should be discussed.

Topics: Aged; Celiac Disease; Diarrhea; Duodenum; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies

Topics: Abdominal Pain; Child; Diarrhea; Humans; IgA Vasculitis; Immunosuppressive Agents; Male; Mycophenolic Acid; Recurrence; Treatment Outcome

Nodular lymphoid hyperplasia (NLH) of the gastrointestinal tract is a rare disease usually reported in patients with congenital or acquired immunodeficiency and chronic gastrointestinal infections. However, no case of NLH in a patient receiving immunosuppressive therapy has been reported to date. We describe the case of a woman who developed chronic diarrhea related to NLH 9 years after liver transplantation. Other causes of diarrhea and NLH were excluded. Her immunosuppressive regimen consisted on mycophenolate mofetil (MMF) and tacrolimus. Reduction of MMF dose improved symptoms but led to a rising aminotransferase level. Given the risk of graft rejection, MMF at full dose was resumed and she was started on symptomatic treatment for diarrhea. The role of immunosuppressive drugs in the pathogenesis of NLH may be related to the reduction of T- and B-lymphocyte proliferation and decreasing antibody production. NLH will further develop to compensate functionally inadequate lymphoid tissue, as reported in congenital immunodeficiency states.

Topics: Diarrhea; Duodenum; Female; Gastrointestinal Diseases; Graft Rejection; Humans; Hyperplasia; Immunosuppressive Agents; Intestinal Mucosa; Liver Transplantation; Lymph Nodes; Middle Aged; Mycophenolic Acid; Postoperative Complications; Tacrolimus

We report here on the clinical, histological and immunological findings regarding a patient with immunodysregulation polyendocrinopathy enteropathy X-linked syndrome who was treated for the first 21 years with a combination of immunosuppressant agents (IS). The potential modalities of care and treatment options in this rare and severe immune-mediated disorder are discussed. So, long-term outcome for IPEX patients can be obtained with immunosuppressive treatment, which is important since the outcome of haematopoietic stem cell transplantation for this population is variable.

Topics: Cyclosporine; Diabetes Mellitus, Type 1; Diarrhea; Drug Therapy, Combination; Endoscopy, Gastrointestinal; Follow-Up Studies; Genetic Diseases, X-Linked; Glomerular Filtration Rate; Glucocorticoids; Humans; Immune System Diseases; Immunoglobulin E; Immunosuppressive Agents; Infant, Newborn; Liver Cirrhosis; Male; Mycophenolic Acid; Prednisolone; Young Adult

To evaluate the efficacy and safety of enteric-coated mycophenolate sodium (EC-MPS) in renal transplant patients treated de novo and for maintenance.. The efficacy and safety data of EC-MPS in renal transplant patients treated de novo and for maintenance in our hospital from July 2009 to March 2013 were reviewed.. Thirty-one patients treated with EC-MPS de novo were included: there were 16 male and 15 female patients. The acute allograft rejection rate was 12.9% (4/31) and pneumonia occurred in 25.8% patients (8/31); the allograft survival rate was 96.7% (30/31) with a patient survival rate of 96.7% (30/31). Gastrointestinal side effects occurred in four patients (12.9%). Only one patient discontinued EC-MPS and treatment was converted to bredinin because of gastrointestinal intolerance. Thirty-nine patients receiving mycophenolate mofetil (MMF) de novo treatment served as a control group. Five (13.2%) of 38 patients developed serious acute rejection and 10 patients (26.3%) had pulmonary infection. Eight (21.1%) patients suffered abdominal distention, diarrhoea and other gastrointestinal adverse reactions; the symptoms improved significantly after treatment change to mizoribine. Compared with the MMF de novo group, the allograft function, blood cell counts and urine protein were similar in the EC-MPS de novo treatment group. The incidence of gastrointestinal side effects was obviously lower in the EC-MPS group than in the MMF group, and there was no difference in serious acute rejection and pulmonary infection between the groups. The study also included 23 renal transplantation maintenance patients who suffered from chronic diarrhoea and treatment was changed to EC-MPS treatment. This change to EC-MPS was at 77 months after transplantation. The gastrointestinal symptoms improved significantly in 21 patients after conversion. Compared with the results at 1 week, no obvious deterioration in serum creatinine, cystatin or estimated glomerular filtration rate was found at 1, 3 and 12 months after the change. In addition, there was no marked decline in blood cell counts and no significant increase in urine protein.. The outcome of EC-MPS treatment in clinical practice of de novo kidney transplant patients was good, with high patient and graft survivals. In maintenance patients it induced an improvement in gastrointestinal side effects and a stable allograft function.

Topics: Adult; Chronic Disease; Diarrhea; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney Transplantation; Male; Mycophenolic Acid; Retrospective Studies; Tablets, Enteric-Coated; Time Factors; Treatment Outcome

Mycophenolate (MF) is effective as induction and maintenance treatment in patients with lupus nephritis (LN). This study evaluates the efficacy and safety of MF in patients with refractory and relapsing LN.. Data were retrospectively obtained for 85 patients (35 refractory and 50 relapsing) from 11 nephrology departments in Spain. The primary endpoints were the incidence and cumulative number of renal responses and relapses and their relationship with baseline clinical and analytical data. The secondary endpoint was the appearance of side effects.. The main clinical and analytical variables were similar both in refractory and relapsing LN. Most of the patients had received cyclophosphamide, and all of them switched to MF. 74 patients (87%) achieved a response (69% partial, 31% complete). Age at starting MF, gender, pathological classification, body mass index, blood pressure, baseline renal function, and proteinuria were not associated with achieving response. After stopping MF, 3 of 19 patients (15.7%) relapsed, all at 6 months of follow-up. No differences were found between clinical and analytical variables and number of relapses. Side effects were unremarkable, except for 1 patient, who died of thrombocytopenia and ovarian hemorrhage.. Switching to MF from other immunosuppressive treatments is effective and safe in refractory and relapsing LN.

Topics: Adolescent; Adult; Aged; Cyclophosphamide; Diarrhea; Drug Substitution; Female; Follow-Up Studies; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Infections; Lupus Nephritis; Male; Middle Aged; Mycophenolic Acid; Recurrence; Retrospective Studies; Spain; Young Adult

Mycophenolate mofetil is a well-known immunosuppressive agent in transplantation medicine. The efficacy of enteric-coated mycophenolate sodium (EC-MPS) was confirmed in other inflammatory skin diseases, including atopic dermatitis and SCLE.. To investigate the efficacy and the tolerability/short-term safety of EC-MPS in patients with moderate to severe chronic plaque psoriasis.. An open-label pilot study in which 20 patients with a PASI >10 received EC-MPS 720 mg twice daily for 6 weeks followed by 360 mg twice daily for another 6 weeks. Patients who completed 12 weeks of treatment were followed-up for an additional 12 weeks. Treatment outcomes were assessed with PASI50% and PASI75%.. Eighteen men and two women (mean age 46 years) entered the study. Sixty-five percent (13/20) finished the treatment period. By week 6, no patient achieved PASI 75% and 8/20 patients achieved a PASI 50%. Compared to week 6, 4/13 showed a deterioration of their psoriasis at week 12. Twenty-five percent (2/8) achieved a PASI 75% in week 24. The most-reported adverse events were itching (30%), diarrhea (10%), and a reversible elevation of the triglycerides level.. EC-MPS does not seem effective as monotherapy for moderate to severe psoriasis, but might be used at a dosage of 1440 mg daily in well-selected patients with treatment-resistant psoriasis.

Topics: Adult; Aged; Diarrhea; Drug Administration Schedule; Female; Humans; Hypertriglyceridemia; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Pruritus; Psoriasis; Tablets, Enteric-Coated; Treatment Outcome

Diarrhea is considered to be a common side effect after renal transplantation, due to a number of infective or drug-related causes. Over the past decade the etiology has perhaps changed with the evolution of immunosuppression. In an attempt to minimize early acute rejection and potential steroid use, the recent introduction of mycophenolic acid-based therapies has increased the incidence of diarrheal symptoms. Histologic and macroscopic appearance of mycophenolate-induced colitis is not well documented.. Three patients with immunosuppression-induced colitis had received deceased-donor renal transplantations and presented with diarrhea and/or abdominal pain. All patients made a full recovery after decreasing the dose or withdrawing mycophenolate mofetil or myfortic with corticosteroid-free regimens.. Patients with immunosuppression-induced colitis require prompt intervention by dose reduction or withdrawal. Both myocophenolate mofetil and myfortic can induce a Crohn's-like colitis even after a long period of exposure. The symptoms may require 6 months to resolve, suggesting that surgery should be considered only as a last resort after a significant period off therapy.

Topics: Abdominal Pain; Adrenal Cortex Hormones; Biopsy; Crohn Disease; Diarrhea; Drug Substitution; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid

We report a case of a 52-year-old woman, on immunosuppressive treatment with mycophenolate due to a history of giant cell myocarditis (GCM), who presented with new-onset severe blood-tinged diarrhoea after a cytomegalovirus (CMV) primoinfection. An extensively prolonged mycophenolate-related colitis was seen after withdrawal of mycophenolate due to an intestinal Epstein-Barr virus (EBV) infection-a rarely seen event itself. We postulate that colonic toxicity was triggered by CMV infection and perpetuated by intestinal EBV replication/infection.

Topics: Colitis; Cytomegalovirus Infections; Diarrhea; Epstein-Barr Virus Infections; Female; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Severity of Illness Index

To compare short-term outcome and frequency of adverse events for dogs with idiopathic immune-mediated haemolytic anaemia treated with glucocorticoids and mycophenolate mofetil vs alternate immunosuppressive protocols.. A retrospective study of medical case records of dogs with immune-mediated haemolytic anaemia was conducted. Data collected included signalment, clinicopathological data, medications administered, duration of hospitalization, short-term survival and adverse events. Variables were compared between dogs treated with glucocorticoids and mycophenolate mofetil (mycophenolate mofetil group) vs dogs treated with other two-drug immunosuppressive protocols (combined group).. Sixty-four cases of idiopathic immune-mediated haemolytic anaemia were identified. Two dogs were euthanased without treatment, three received glucocorticoids alone, and seven received two additional drugs. Fifty-two dogs received glucocorticoids and additional immunosuppressive medications: 30 mycophenolate mofetil, 15 cyclosporine, 6 azathioprine and 1 human immunoglobulin. There was no significant difference between the discharge rate, 30-day or 60-day survival rates between the mycophenolate mofetil and the combined groups (Fisher's exact; P=0·272, 0·518, 1·000, respectively). The sole adverse event observed in the mycophenolate mofetil group was diarrhoea (n=5).. Administration of mycophenolate mofetil appears safe in dogs with idiopathic immune-mediated haemolytic anaemia. The combination of glucocorticoids and mycophenolate mofetil has similar efficacy to alternate immunosuppressive protocols used to treat this disease.

Topics: Anemia, Hemolytic, Autoimmune; Animals; Anti-Inflammatory Agents, Non-Steroidal; Azathioprine; Cyclosporine; Diarrhea; Dog Diseases; Dogs; Drug Therapy, Combination; Female; Glucocorticoids; Immunoglobulins; Immunosuppressive Agents; Male; Mycophenolic Acid; Retrospective Studies

Topics: Autoimmune Lymphoproliferative Syndrome; Diagnosis, Differential; Diarrhea; Exanthema; Fever; Flow Cytometry; Hematologic Tests; Humans; Immunosuppressive Agents; Infant; Lymphocyte Count; Male; Mycophenolic Acid; Thrombocytopenia

Diarrhea developing in patients under immunosuppression has a variety of underlying causes. A broad spectrum of histological findings can be found in intestinal biopsies taken for the diagnostic workup of diarrhea including a pathologically increased proportion of epithelial cell apoptosis in the colon, for which the descriptive term 'apoptotic colonopathy' was coined. In recent years, the immunosuppressive drug mycophenolate (mycophenolic acid, MPA) has been identified as a prototypical cause of apoptotic colonopathy, but other conditions may show similar or overlapping histological pictures.. Cases of likely or possible MPA colonopathy (n = 18) were retrospectively identified from the archive files. Clinical information on patient history, clinical presentation and endoscopic findings were recorded. All cases were routinely processed, i.e. stained by hematoxylin and eosin (HE) stain, optionally supplemented by special histochemical and immune stains.. Histopathological hallmarks of MPA treatment-related changes in the colon mucosa are reviewed with respect to the major histopathological differential diagnoses including normal and near-normal findings, infectious diseases, graft-versus-host disease and inflammatory bowel diseases. Furthermore, the challenge of multiple concomitant pathologies while on MPA treatment, in particular infectious diseases, is discussed, and some open questions concerning the effects of MPA on colon pathology are pointed out.

Topics: Apoptosis; Colon; Colonic Diseases; Diagnosis, Differential; Diarrhea; Enzyme Inhibitors; Epithelial Cells; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Middle Aged; Mycophenolic Acid; Retrospective Studies; Risk; Switzerland

The main purpose of this study was to define diagnostic histological characteristics of mycophenolate mofetil (MMF)-related colitis in association with crypt epithelial cell turnover.. The examined material included 43 colonic biopsies from renal transplant recipients with MMF administration and persistent diarrhoea. Thirty-three cases showed MMF-related colitis, while 10 showed no significant changes. The histological findings were scored and correlated with the apoptotic index (AI) and with the proliferation rate (PR) of the crypt epithelium examined by TUNEL assay and Ki-67 immunoexpression. Ten cases of Crohn disease and 10 of ulcerative colitis were used as comparative groups. Crypt distortion and loss as well as increased apoptosis constituted the main features, their degree and combination leading either to an inflammatory bowel disease (IBD)-like (82%) or to a graft-versus-host disease-like pattern (18%). A high AI was associated more frequently with moderate and severe crypt distortion, while the values were significantly higher compared with the control groups (P < 0.01). High PR was noted in 18 of 29 (62.1%) of the cases.. The diagnostic hallmark of MMF-related colitis is an IBD-like histological pattern in association with increased epithelial apoptosis, while apoptotic cell death seems to be a potential pathogenetic factor of mucosa injury.

Topics: Adult; Aged; Aged, 80 and over; Apoptosis; Cell Proliferation; Colitis; Colon; Diarrhea; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid

Topics: Antiviral Agents; Azathioprine; Colitis; Cytomegalovirus Infections; Diarrhea; Female; Ganciclovir; Humans; Immunosuppressive Agents; Middle Aged; Mycophenolic Acid; Treatment Outcome

To investigate the factors in association with colorectal disorders in adult renal transplant recipients.. A retrospective cohort study was carried out with clinical, microbiological and management data regarding diarrhea in 513 renal transplant recipients from Jan. 2007 to Dec. 2012.. Of the 513 patients, 118(23.00%) with no history of ulcerative colitis, were found to have diarrhea after kidney transplantation. In the 118 patients, diarrhea was probably caused by administration of immunosuppressive agents in 65 cases (55.08%), in 30 cases (25.42%) diarrhea was antibiotics associated, and in 23 cases (19.49%) it was due to infections, including bacterial, fungal and viral infections. Diarrhea occurred soon after transplantation in most cases. Of the 118 patients, the symptom of diarrhea occurred in the first 1 month in 84 cases (71.19%), and in the next 5 months in 16 cases (13.56%), and the other 18 cases (15.05%) occurred after 180 days after transplantation. Of the 118 patients, 84 cases (71.19%) were relieved or cured after proper diets, the symptomatic therapy or the adjust meat of the doses of immunosuppressive agents: 18 cases (15.25%) needed to use or adjust the antibiotics , 16 cases (13.56%) had to stop mycophenolate mofetil and convert to other drugs.. Immunosuppressive agents, antibiotics and infection are the common causes of diarrhea after kidney transplantation. The outcome is good with appropriate conservative management.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Bacterial Infections; Child; Cyclosporine; Cytomegalovirus Infections; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Mycoses; Retrospective Studies; Tacrolimus; Young Adult

Gastrointestinal adverse effects are common with mycophenolate mofetil administration, especially diarrhea. We report a case of mycophenolate mofetil-related colitis in a kidney transplant recipient. Colonoscopy revealed an ulcerative diffuse colitis. The colonoscopic biopsy specimen showed mild crypt distortion, accompanied by cryptitis and focal graft-versus-host disease like changes. The patient's symptoms improved after we discontinued the mycophenolate mofetil. A repeat colonoscopy 2 months after we discontinued the mycophenolate mofetil showed reparative changes. Mycophenolate mofetil is an important drug in organ transplant immune-suppression regimens; however, with its widespread use, additional adverse effects continue to be recognized.

Topics: Adult; Anti-Inflammatory Agents, Non-Steroidal; Colitis; Diarrhea; Graft Rejection; Humans; Kidney Transplantation; Male; Mycophenolic Acid

Topics: Adult; Chronic Disease; Colitis; Diarrhea; Female; Humans; Immunosuppressive Agents; Mixed Connective Tissue Disease; Mycophenolic Acid

Diarrhea is a frequent adverse event in patients treated with the combination of tacrolimus and mycophenolate mofetil (MMF). In case of severe diarrhea, the total exposure to tacrolimus can substantially increase, which is reflected in a rise of the predose trough level (C0). In mild diarrhea (two to three stools per day), an increased exposure might occur without trough levels exceeding the target range, resulting in "silent" chronic tacrolimus overexposure. The aim was to assess the degree of unnoticed tacrolimus overexposure in renal transplant patients with mild diarrhea while on treatment with tacrolimus and MMF.. A prospective pharmacokinetic study was performed in 12 recipients of a renal allograft using a combination of tacrolimus and MMF with mild diarrhea and in 12 controls. Tacrolimus levels were assessed by a validated dried blood spot method for sampling and measurement.. The C0 did not differ between patients with mild diarrhea and controls (mean [95% confidence interval], 9.6 µg/L [8.6-10.9 µg/L] and 8.3 µg/L [6.9-9.9 µg/L]). In addition, there was no significant difference in the 12-hr area under the curve between patients with mild diarrhea and controls (185.6 µg· h/L [153.6-224.2 µg·h/L] vs. 170.5 µg·h/L [137.2-221.8 µg·h/L]). As a result, the ratio between the 12-hr area under the curve and C0 was similar in both groups (19.2 [17.5-21.1] vs. 20.6 [19.0-22.4]). The intraindividual variability in tacrolimus exposure was limited and not affected by the presence of mild diarrhea.. We found no evidence for the presence of hidden tacrolimus overexposure in patients with mild diarrhea while on treatment with tacrolimus and MMF.

Topics: Adult; Aged; Biological Availability; Case-Control Studies; Diarrhea; Drug Monitoring; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Netherlands; Prospective Studies; Tacrolimus

Immunosuppressive drug (ISD)-associated gastrointestinal disorders are a relevant risk factor for graft loss or patient death. The pathomechanisms and the incidence of post-transplantation diarrhea remain to be fully understood. The aim of this study was to characterize the impact of cyclosporine A, tacrolimus (TAC), mycophenolate mofetil (MMF), enteric coated mycophenolic acid (EC-MPA), sirolimus, everolimus (EVE) and fingolimod (FTY 720) on small and large bowel transport and barrier function. Functions of the small bowel and distal colon of Wistar rats treated for 14 days with one of the drug were analyzed using Ussing chamber method. In detail, the glucose and sodium absorption, chloride secretion, and barrier function were compared. Bowel functions were investigated by inhibition or activation of the electrogenic epithelial transport, as well as by measuring transepithelial H(3) -lactulose flux. TAC altered glucose absorption; EVE glucose absorption, small bowel barrier function and chloride secretion; MMF small bowel barrier function; and EC-MPA glucose absorption and the small bowel barrier function. Drug effects were partially dose-dependent. In conclusion, different ISD, such as TAC, EVE, MMF, or EC-MPA lead to different and specific patterns of pathophysiologic changes of small and large bowel barrier and transport function.

Topics: Animals; Biological Transport; Cyclosporine; Diarrhea; Everolimus; Fingolimod Hydrochloride; Glucose; Immunosuppressive Agents; Intestinal Absorption; Intestine, Large; Intestine, Small; Male; Mycophenolic Acid; Propylene Glycols; Rats; Rats, Wistar; Sirolimus; Sphingosine; Tacrolimus

Persistent diarrhea is commonly observed after solid organ transplantation (SOT). A few cases of mycophenolate mofetil (MMF)-induced duodenal villous atrophy (DVA) have been previously reported in kidney-transplant patients with chronic diarrhea. Herein, we report on the incidence and characteristics of DVA in SOT patients with chronic diarrhea. One hundred thirty-two SOT patients with chronic diarrhea underwent an oesophago-gastroduodenoscopy (OGD) and a duodenal biopsy after classical causes of diarrhea have been ruled out. DVA was diagnosed in 21 patients (15.9%). It was attributed to mycophenolic acid (MPA) therapy in 18 patients (85.7%) (MMF [n = 14] and enteric-coated mycophenolate sodium [n = 4]). MPA withdrawal or dose reduction resulted in diarrhea cessation. The incidence of DVA was significantly higher in patients with chronic diarrhea receiving MPA compared to those who did not (24.6% vs. 5.1%, p = 0.003). DVA was attributed to a Giardia lamblia parasitic infection in two patients (9.5%) and the remaining case was attributed to azathioprine. In these three patients, diarrhea ceased after metronidazole therapy or azathioprine dose reduction. In conclusion, DVA is a frequent cause of chronic diarrhea in SOT recipients. MPA therapy is the most frequent cause of DVA. An OGD should be proposed to all transplant recipients who present with persistent diarrhea.

Topics: Adult; Aged; Atrophy; Diarrhea; Duodenum; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Treatment Outcome

Diarrhea of unspecified cause frequently occurs after renal transplantation and is usually ascribed to mycophenolic acid toxicity. Norovirus (NoV) and sapovirus (SaV) have been sporadically reported to cause chronic diarrhea in immunocompromised patients.. We undertook a retrospective study (2008-2009) to examine the clinical and epidemiologic significance of NoV and SaV infections in adult renal transplant recipients hospitalized for acute or chronic diarrhea.. Ninety-six renal transplant recipients were hospitalized for diarrhea at our institution during a 16-month period, 87 of whom were included in the study, including 46 patients with chronic diarrhea. Among 41 patients with unexplained diarrhea, 20 patients were screened for NoV/SaV, 16 of whom were positive. Fifteen of them (94%) had chronic diarrhea. When compared with bacterial and parasitic infections, NoV/SaV infections were associated with a greater weight loss at the time of admission, a 8.7-fold longer duration of symptoms and a more frequent need for mycophenolic acid dosage reduction. Eighty-one percent of patients hospitalized for NoV/SaV-associated diarrhea experienced acute renal failure. Five and one patients subsequently had biopsy-diagnosed active graft rejection and oxalate nephropathy, respectively. Ten of the 14 patients who underwent a longitudinal study of NoV/SaV stool's clearance exhibited a prolonged viral shedding period with a median time of 289 days (107-581 days).. Our study indicates that NoV/SaV infection causes posttransplant chronic diarrhea potentially complicated by severe kidney graft impairment.

Topics: Acute Kidney Injury; Adult; Aged; Algorithms; Caliciviridae Infections; Diarrhea; Gastroenteritis; Graft Rejection; Hospitalization; Humans; Kidney Transplantation; Longitudinal Studies; Middle Aged; Mycophenolic Acid; Norovirus; Retrospective Studies; Sapovirus; Virus Shedding; Young Adult

Diarrhea in a transplant recipient may be caused by infection, metabolic problems, or adverse drug effects. The immunosuppressive drug most frequently associated with diarrhea in transplant recipients is mycophenolate mofetil (MMF). We present the case of a patient with 2 potential explanations for diarrhea lasting several weeks, which occurred years after liver transplantation. Whereas stool samples were positive for cryptosporidia, the histopathological findings were compatible with MMF colitis. However, diarrhea resolved after treatment of cryptosporidial infection, despite continued MMF medication. This case shows that histopathological findings of MMF colitis may be misleading and do not prove that diarrhea is drug induced.

Topics: Adult; Animals; Cryptosporidiosis; Cryptosporidium; Diarrhea; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Mycophenolic Acid; Paromomycin; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Bronchoalveolar Lavage Fluid; Diagnosis, Differential; Diarrhea; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Metronidazole; Mycophenolic Acid; Pneumonia; Pneumonia, Bacterial; Pneumonia, Viral; Postoperative Complications; Sirolimus; Tacrolimus; Tomography, X-Ray Computed

Topics: Aged; Colitis; Crohn Disease; Cytomegalovirus Infections; Diagnosis, Differential; Diarrhea; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Mycophenolic Acid; Opportunistic Infections; Weight Loss

Mycophenolate mofetil (MMF) is a pro-drug that is hydrolyzed to release mycophenolic acid (MPA). Subsequently MPA is extensively metabolized to phenyl mycophenolic acid glucuronide (MPAG) and MPA acyl glucuronide (AcMPAG). It was presumed that the closest association is between plasma AcMPAG concentrations and the incidence of diarrhea. This study aimed to investigate the correlation between pharmacokinetics of MPA, MPAG, and AcMPAG and diarrhea in liver transplant recipients on MMF with tacrolimus.. Sixty-seven patients receiving liver transplantation were included. The pharmacokinetics of MPA and its metabolites were monitored repeatedly in the early stage (within 2 weeks) and in the late stage after transplant. The plasma concentrations of MPA, MPAG, and AcMPAG were determined by the HPLC method.. Twenty-two patients (32.8%) suffered from episodes of diarrhea. Compared with the data from the early stage, AUC(0-12h) of MPA, MPAG, and AcMPAG increased significantly in both groups in the later stage. AUC(0-12h) of MPA, MPAG, and AcMPAG were not different significantly between the group with diarrhea and the group without diarrhea, either in the early stage or in the late stage (P > 0.05).. These results suggest that systemic exposures to MPA and its metabolites are not associated with the incidence of diarrhea in liver transplant recipients.

Topics: Adult; Aged; Area Under Curve; Diarrhea; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus

In renal transplant patients given mycophenolate mofetil (MMF), we investigated the relationship between the digestive adverse events and polymorphisms in the UGT genes involved in mycophenolic acid (MPA) intestinal metabolism and biliary excretion of its phase II metabolites.. Clinical data and DNA from 256 patients transplanted between 1996 and 2006 and given MMF with cyclosporin (CsA, n = 185), tacrolimus (TAC, n = 49) or sirolimus (SIR, n = 22), were retrospectively analysed. The relationships between diarrhoea and polymorphisms in UGT1A8 (2; 518C>G, 3; 830G>A), UGT1A7 (622C>T), UGT1A9 (-275T>A), UGT2B7 (-840G>A) and ABCC2 (-24C>T, 3972C>T) or the co-administered immunosuppressant were investigated using the Cox proportional hazard model.. Multivariate analysis showed that patients on TAC or SIR had a 2.8 higher risk of diarrhoea than patients on CsA (HR = 2.809; 95%CI (1.730, 4.545); P < 0.0001) and that non-carriers of the UGT1A8 2 allele (CC518 genotype) had a higher risk of diarrhoea than carriers (C518G and 518GG genotypes) (HR = 1.876; 95%CI (1.109, 3.175); P = 0.0192). When patients were divided according to the immunosuppressive co-treatment, a significant effect of UGT1A8 2 was found in those co-treated with CsA (HR = 2.414; 95%CI (1.089, 5.354); P = 0.0301) but not TAC or SIR (P = 0.4331).. These results suggest that a possible inhibition of biliary excretion of MPA metabolites by CsA and a decreased intestinal production of these metabolites in UGT1A8 2 carriers may be protective factors against MMF-induced diarrhoea.

Topics: Adult; Cohort Studies; Cyclosporine; Diarrhea; Drug Combinations; Drug Interactions; Female; Genotype; Glucuronosyltransferase; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Multidrug Resistance-Associated Protein 2; Multivariate Analysis; Mycophenolic Acid; Polymorphism, Single Nucleotide; Proportional Hazards Models; Retrospective Studies; Risk; Sirolimus; Survival Analysis; Tacrolimus

Topics: Aged; Antibodies, Monoclonal; Colitis, Ulcerative; Diarrhea; Female; Humans; Immunosuppressive Agents; Infliximab; Mycophenolic Acid; Tumor Necrosis Factor-alpha

Mycophenolate (MMF) has arisen as an important addition in the immunosuppression armamentarium. GI disturbances (diarrhea) and bone marrow suppression are its main side effects requiring dose reduction or even withdrawal. The mechanism of diarrhoea is unknown, although some theories have been postulated. We evaluated three of our patients on MMF who came to us with chronic diarhoea. Their evaluation consisted of CBC, stool routine examination, stool culture, endoscopy and biopsy. Histopathologic examination in all three cases showed villous atrophy. All of them improved with discontinuation of MMF and addition of folic acid suggesting that diarrhoea was related to MMF. Since this complication is seen in only a few cases, we can hypothesize that it may be due to lower levels of the enzyme inosine monophosphate dehydrogenase (IMPDH)--the site of action of MMF.

Topics: Adult; Biopsy; Diarrhea; Female; Folic Acid; Humans; Immunosuppression Therapy; Immunosuppressive Agents; IMP Dehydrogenase; Male; Microvilli; Middle Aged; Mycophenolic Acid; Treatment Outcome

Mycophenolate mofetil (MMF) was introduced as a new immune-suppression drug in the mid-1990s. It is widely utilized in solid-organ transplantation immune-suppression regimens. Side effects include gastrointestinal (GI) toxicity in the form of nausea, vomiting, and diarrhea. Physicians tend to reduce the dose of MMF or switch their patients to an enterio-coated formula to overcome the side effects. Because GI side effects are well linked to MMF, colonoscopy is not utilized in most of the cases to investigate the diarrhea. However, Crohn's disease-like changes in the colon, erosive enterocolitis, and graft versus host disease-like colonic changes associated with the use of MMF have been reported. Colonic findings in five patients whose symptoms resolved after substituting another agent for MMF are described in the present report. Repeat colonoscopy 4 months following discontinuation of MMF showed reparative changes in one of our patients. MMF is an important drug in organ transplantation immune-suppression regimens; however, with its widespread usage, additional side effects continue to be recognized.

Topics: Adult; Colitis; Colon; Colonoscopy; Diarrhea; Drug Substitution; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Organ Transplantation; Time Factors

A 50-year-old woman with Beçhet's disease presented with episodic diarrhoea and generalised abdominal pain. She was on regular mycophenolate maintenance therapy, being intolerant of both ciclosporin and azathioprine. Previous rectal biopsy was consistent with colitis, probably associated with Beçhet's disease. During this admission, she began passing faecal matter per vaginam. Digital rectal examination confirmed the presence of a large rectovaginal fistula. She underwent urgent laparotomy for a subtotal colectomy with end ileostomy. Although there were no signs of septicaemia preoperatively, small perforations were identified in the caecum and at the splenic flexure on laparotomy. Histopathology confirmed the presence of multiple shallow ulcers throughout the colon with features suggestive of Beçhet's colitis.

Topics: Abdominal Abscess; Abdominal Pain; Behcet Syndrome; Colitis; Colitis, Ulcerative; Colon; Diarrhea; Female; Humans; Ileostomy; Immunosuppressive Agents; Intestinal Perforation; Middle Aged; Mycophenolic Acid; Rectovaginal Fistula

Mycophenolate mofetil (MMF) is licensed as a prophylaxis in combination therapy to prevent renal transplant rejection. Gastrointestinal side effects are fairly common and include diarrhoea, abdominal discomfort, nausea, vomiting, gastritis and constipation. This drug has recently been described as causing villous atrophy, nutrient malabsorption and colonic mucosal changes. We present a case of reversible steatorrhoea occurring in a patient treated with MMF following an episode of infections diarrhoea.

Topics: Campylobacter Infections; Diarrhea; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Malabsorption Syndromes; Male; Middle Aged; Mycophenolic Acid; Steatorrhea

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

Topics: Adolescent; Child; Child, Preschool; Diarrhea; Dose-Response Relationship, Drug; Female; Glucuronosyltransferase; Heterozygote; Homozygote; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Male; Mycophenolic Acid; Pilot Projects; Polymorphism, Genetic

Evaluation of: Machnicki G, Ricci JF, Brennan DC, Schnitzler MA. Economic impact and long-term graft outcomes of mycophenolate mofetil dosage modifications following gastrointestinal complications in renal transplant recipients. Pharmacoeconomics 26(11), 951-967 (2008). This commentary discusses findings from an observational study designed to determine the 3-year clinical and economic impact of dose reduction or discontinuation of mycophenolate mofetil after the first gastrointestinal complication in patients after kidney transplantation. The authors used data from the US Renal Data System to demonstrate that dosage reduction or discontinuation of mycophenolate mofetil in the first 6 months after diagnosis of gastrointestinal complications is associated with a significantly increased risk of graft failure and increased healthcare costs in adult renal transplant recipients. This article highlights the clinical significance as well as some of the shortcomings of the authors' findings. The introduction of mycophenolate mofetil has clearly improved renal transplant outcomes; however, there is a need for well-planned studies examining pharmacokinetics and pharmacodynamics of mycophenolate mofetil and strategies for reducing gastrointestinal side effects.

Topics: Chemistry, Pharmaceutical; Diarrhea; Gastrointestinal Diseases; Graft vs Host Disease; Health Care Costs; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Quality-Adjusted Life Years; Tablets, Enteric-Coated; Treatment Failure; United States

Diarrhoea in transplantation may be secondary to infectious agents and immunosuppressive drugs. The use of combined immunosuppressive drugs increases the incidence of infectious diarrhoea. We retrospectively collected all diarrhoea episodes during a 3-year period in 199 pediatric renal transplant recipients, including 47 patients receiving a kidney transplant during this period. We diagnosed 64 diarrhoea episodes (32% of the patients, 10.7% per year). Fourteen diarrhoea episodes could be attributed to the immunosuppressive treatment, and 12 remained without diagnosis. Nineteen patients (<10%) receiving mycophenolic acid (MPA) developed diarrhoea, 14 of whom had episodes attributable to the immunosuppressive treatment. Reducing the MPA dose or switching to another immunosuppressant did not induce graft rejection, if at all, for at least 6 months. Thirty-eight diarrhoea episodes were caused by infectious agents: viruses in 16 patients, bacterial agents in ten patients, Candida albicans in four cases and parasitic agents in eight cases (Giardia lambdia in one patient and Cryptosporidium in seven patients). In our cohort, Cryptosporidium was responsible for 18% of the infectious diarrhoea and 11% of all causes of diarrhoea, and it affected 3.5% of the newly transplanted patients during the 3-year study period. The clinical presentation of the disease was profuse and persistent diarrhoea with acute renal failure in all patients. We propose that oocysts be screened for in the stool during the early stages of tests for determining the origin of infectious diarrhoea. Disease treatment requires early specific treatment (nitazoxanide) for extended periods of time in conjunction with supportive rehydration.

Topics: Adolescent; Antiparasitic Agents; Biopsy; Child; Cohort Studies; Cryptosporidiosis; Diarrhea; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Nitro Compounds; Prednisone; Sirolimus; Tacrolimus; Thiazoles; Time Factors; Transplantation, Homologous; Treatment Outcome

The improvement of pre-existing inflammatory bowel disease after orthotopic liver transplant might be anticipated. However, both the exacerbation of inflammatory bowel disease and de novo inflammatory bowel disease after orthotopic liver transplant (despite sufficient allograft immunosuppressive therapy) have been described.. We present a case of ulcerative colitis in a pediatric liver transplant recipient.. A 13-year-old boy with cryptogenic liver cirrhosis received an orthotopic liver transplant from a deceased donor. Five months later, he presented with watery diarrhea and abdominal distention. He was treated with the immunosuppressive agents tacrolimus (0.15 mg/kg/d) and mycophenolate mofetil (20 mg/kg/d). A general physical examination revealed a boy with stable vital signs and without fever. The only positive finding was enlargement of the abdomen without tenderness. Many pus cells and a few red blood cells were detected in the patient's stool, but the results of a stool culture for bacteria were negative. Because of his chronic diarrhea, this patient underwent colonoscopy, which revealed diffuse erythematous mucosa, multiple ulcers, exudate, and pseudopolyps with a diffuse loss of vascularity. Those findings are indicators of colitis. The results of histopathologic examination of the colonic mucosa suggested ulcerative colitis. The patient was treated with mesalamine and prednisolone, and a repeat colonoscopy revealed an improvement in his bowel disease.. De novo inflammatory bowel disease should be considered in patients in whom chronic diarrhea develops after an orthotopic liver transplant. We suggest that colonoscopy and biopsy should always be performed if other causes of diarrhea have been excluded.

Topics: Adolescent; Anti-Inflammatory Agents; Biopsy; Chronic Disease; Colitis, Ulcerative; Colon; Colonoscopy; Diarrhea; Drug Therapy, Combination; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Intestinal Mucosa; Liver Cirrhosis; Liver Transplantation; Male; Mesalamine; Mycophenolic Acid; Prednisolone; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Mycophenolate mofetil (MMF) is a very powerful immunosuppressive drug used in preventing acute rejection in liver transplantation. However, MMF has some serious side effects, including hematologic and gastrointestinal disorders. This study was designed to investigate the relationship between the clinical events and the pharmacokinetics of mycophenolic acid (MPA) in Chinese liver transplant recipients. Sixty-three adult liver transplant recipients receiving 1.0 g of MMF twice daily in combination with tacrolimus were prospectively included. The MPA pharmacokinetic profiles (blood sampling time points: before the dose and 0.5, 1, 1.5, 2, 4, 6, 8, 10, and 12 hours after the dose) were monitored after transplantation. Every clinical event, including acute and MMF-related side effects, was monitored in all patients within 3 months. Two patients (3.2%) had an episode of acute rejection. Forty-two patients (66.7%) had 52 episodes of MMF-related side effects, including leukopenia, diarrhea, and infection. The 0-hour concentration (C(0h)), maximum (peak) concentration (C(max)), and area under the curve from 0 to 12 hours (AUC(0-12h)) in patients with side effects were significantly higher than those in patients without side effects (P < 0.05). The thresholds of side effects from receiver operating characteristic analysis were 2 mg/L (sensitivity, 52.4%; specificity, 90.5%) for C(0h), 10 mg/L (sensitivity, 45.2%; specificity, 85.7%) for C(max), and 40 mg h/L (sensitivity, 71.4%; specificity, 61.9%) for AUC(0-12h) (P < 0.05). Leukopenia was discriminated effectively in C(0h) and in C(max) (P < 0.05). These results demonstrate the close relationship between leukopenia and MPA pharmacokinetic parameters in the early period after liver transplantation. C(0h) and AUC(0-12h) of MPA could predict the subsequent occurrence of leukopenia. These values may be used in routine monitoring for MMF therapy.

Topics: Adult; Aged; Diarrhea; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Leukopenia; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; ROC Curve

The aim of this study was to describe the use of mycophenolate mofetil (MMF) in the treatment of patients with antineutrophil cytoplasmic antibody (ANCA)-associated vasculitis with ocular involvement.. A retrospective review was performed. Ocular and systemic manifestations, history of previous immunosuppressive drug therapy, concurrent therapy with MMF, response to treatment, side effects related to the use of MMF, and follow-up period were recorded.. Nine (9) eyes of 5 patients were evaluated. Ocular involvement included scleritis, choroidal and orbital granuloma, multifocal choroiditis, intermediate uveitis, and lacrimal gland involvement. Mycophenolate was started at 2 g daily. Mean follow-up after the initiation of MMF was 36 months. Mean prednisolone dose at onset of treatment with MMF was 27 mg daily and was reduced to 7 mg daily as disease control was achieved. Visual acuity was maintained or improved in all eyes, apart from 1 eye, which developed cataract formation. One (1) patient required a reduction in the dose of mycophenolate owing to diarrhea.. Our study suggests that mycophenolate mofetil may be a safe, effective therapeutic modality for ocular inflammation associated with ANCA-associated vasculitis.

Topics: Adult; Anti-Inflammatory Agents; Anti-Inflammatory Agents, Non-Steroidal; Antibodies, Antineutrophil Cytoplasmic; Cataract; Diarrhea; Eye Diseases; Female; Follow-Up Studies; Humans; Middle Aged; Mycophenolic Acid; Prednisolone; Retrospective Studies; Vasculitis; Visual Acuity

Mycophenolate mofetil (MMF) is an immunosuppressive prodrug approved for use in transplantation. Its active metabolite, mycophenolic acid, is mainly metabolized by UDP-glucuronosyltransferase (UGT) enzymes. In this study, we retrospectively analyzed 74 kidney transplant patients who had been prescribed MMF as part of their immunosuppression regimen. Polymorphisms in UGT1A8 (-999C > T, codon 255A > G, codon 277G > A) were correlated with the occurrence of side effects, such as diarrhea, blood disorders, and infections. The infectious episodes were more frequently observed among individuals receiving MMF (2 g/d) who carryied the variant UGT1A8 codon 277A (P = .031), the haplotype UGT1A8H5 (-999C/codon 55A/codon 277A; P = .02), and the diplotype UGT1A8H2/H5 (-999CC/codon 255AA/codon 277GA; P = .015). The molecular data from this study suggest that UGT polymorphisms may be a factor influencing clinical outcomes among patients receiving MMF for transplant therapy; however, larger studies are warranted.

Topics: Codon; Diarrhea; Glucuronosyltransferase; Hematologic Diseases; Humans; Infections; Kidney Transplantation; Mycophenolic Acid; Polymorphism, Single Nucleotide; Retrospective Studies

Mycophenolate mofetil (MMF), the prodrug of mycophenolic acid (MPA), is included in current combination immunosuppressive regimens following organ transplant. Treatment with MMF often results in dose-limiting gastrointestinal (GI) side effects. The underlying mechanisms responsible for these side effects are not fully understood, but exposure of the intestinal epithelia to MPA during enterohepatic recycling may be involved. The present study demonstrated that female rats are more susceptible to MMF-induced GI toxicity than male rats. Female Sprague-Dawley rats treated chronically with an oral dose of 50 mg of MPA equivalents/kg/day experienced greater GI toxicity than male rats, as measured by diarrhea grade and weight loss. Intestinal microsomes harvested from the upper jejunum of female rats had approximately 3-fold lower MPA glucuronidation rates compared with male rats. In the remaining areas of the small and large intestine, there was also a trend toward decreased glucuronidation in the female rats. The area under the plasma concentration-time curve (AUC) for MPA following an oral dose of 50 mg of MPA equivalents/kg was roughly similar between genders, whereas the AUC for mycophenolic acid phenolic glucuronide (MPAG) was significantly lower in female rats. Female rats also excreted half of the biliary MPAG as male rats. The greater susceptibility of female rats to MMF-induced gastrointestinal toxicity, despite diminished intestinal MPA exposure via reduced biliary excretion of MPAG, may result from reduced protection of enterocytes by in situ glucuronidation. Likewise, susceptibility to MMF-induced GI toxicity in humans may also result from variable intestinal glucuronidation due to UDP glucuronosyltransferase polymorphisms or differential expression.

Topics: Animals; Bile; Diarrhea; Female; Glucuronides; Immunosuppressive Agents; Intestinal Mucosa; Kidney; Liver; Male; Microsomes; Mycophenolic Acid; Rats; Rats, Sprague-Dawley; Sex Factors

After transplantation, diarrhea may be caused by infectious agents, drug-specific effects, metabolic conditions, or mechanical complications of surgery. Determining the cause helps to determine whether to initiate antimicrobial therapy and the duration of treatment. In this study we aimed to determine the causes of diarrhea in kidney or liver recipients. Fifty-two diarrhea episodes among 43 solid organ recipients were evaluated. The cause of diarrhea was detected in 43 patients (82.6%). Infectious etiologies accounted for 33 out of the 43 episodes (76.7%) in which a specific cause was determined: Giardia lamblia in 9, Cryptosporidium parvum in 7, cytomegalovirus (CMV) in 6, Clostridium difficile in 3, Campylobacter jejuni in 2, Shigella sonnei in 2, Salmonella enteritidis in 1, rotavirus in 1, Entamoeba histolytica in 1, and Blastocystis hominis in 1. Non-infectious etiologies were found for 10 episodes (23.3%): mycophenolate mofetil-associated diarrhea in 5, antibiotic-associated diarrhea in 2, colchicine-associated diarrhea in 2, and laxative drug-associated in 1. Non-infectious etiologies seem to be relatively common causes of diarrhea among transplant recipients. Therapy was adjusted in 5 patients because of mycophenolate mofetil-associated diarrhea. CMV and C. parvum, which are seldom seen in the normal population, were frequent causes of diarrhea in this group. Evaluating the transplant recipients for non-infectious causes of diarrhea is important in prompt diagnosis and treatment.

Topics: Adult; Anti-Bacterial Agents; Colchicine; Diarrhea; Feces; Humans; Immunosuppressive Agents; Kidney Transplantation; Laxatives; Liver Transplantation; Mycophenolic Acid

Studies of renal transplantation utilizing trough plasma level monitoring of mycophenolic acid (MPA) have shown inconsistent associations with toxicity and rejection. In this study, 5600 12-h trough MPA samples from 121 renal transplant recipients immunosuppressed with mycophenolate mofetil (MMF) and tacrolimus in a steroid sparing protocol (steroids for 7 days only) were sequentially analyzed. Higher MPA levels were associated with lower hemoglobin concentrations and anemia (hemoglobin <10 g/dL). Similarly, higher MPA levels were associated with lower total white cell counts and an increased incidence of leucopenia (total white cell count <4.0 x 10(9)/L). Hypoalbuminemia and renal impairment were also associated with hemotoxicity. MMF-associated diarrhea and viral infection were associated with higher MPA levels. Conversely, biopsy-proven acute rejection within the first month post-transplantation was associated with lower MPA levels. Anti-CD25 antibody induction was also associated with reduced rejection rates. No association was seen between MPA levels and platelet count, thrombocytopenia or bacterial infection. An MPA level of 1.60 mg/L early post-transplantation best discriminated patients with and without rejection, and an MPA level of 2.75 mg/L best discriminated patients with and without toxicity later post-transplantation.

Topics: Adult; Bacterial Infections; Bone Marrow; Diarrhea; Dose-Response Relationship, Drug; Drug Monitoring; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Leukocyte Count; Leukopenia; Male; Middle Aged; Monitoring, Physiologic; Mycophenolic Acid; Platelet Count; Tacrolimus; Thrombocytopenia; Virus Diseases

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

Mycophenolate mofetil (MMF) is used for prevention of allograft rejection in kidney transplant patients. A subset of patients suffers from chronic diarrhoea of unknown origin. The aim of the study was to investigate the effect of MMF on the colonic mucosa.. Colonic mucosal biopsies from 24 kidney transplant patients receiving MMF and presenting with chronic diarrhoea were analysed using routine stainings and immunohistochemistry for Ki67 and E-cadherin. Results were compared with a control group of 19 kidney transplant patients not receiving MMF. In all patients routine clinical and laboratory investigations were performed in order to explain the diarrhoea.. In 11 patients, the diarrhoea seemed to be of infectious origin. Furthermore, 19/24 of MMF-patients showed characteristic histological alterations of the mucosa that were Crohn's disease-like: discontinuous crypt architectural distortion, increased epithelial mucin secretion, mildly active inflammation and focal presence of dilated and inflamed crypts. Ki67 staining was abnormal in 6/24 MMF patients but also in 4/19 control patients. E-Cadherin staining was normal in most MMF and control patients.. Diarrhoea following MMF treatment is frequently infectious in origin and associated with morphological changes with a Crohn's-like pattern in the colonic mucosa in a subset of patients. MMF does not induce major alteration in the proliferative compartment of colonic epithelium. The diarrhoea is not associated with altered E-cadherin expression in the colonic epithelium.

Topics: Adolescent; Adult; Aged; Cadherins; Case-Control Studies; Chronic Disease; Colon; Diarrhea; Female; Humans; Immunosuppressive Agents; Intestinal Mucosa; Ki-67 Antigen; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid

To establish guidelines for avoiding the side effects of mycophenolate mofetil (MMF) in renal transplant recipients with tacrolimus (TAC)-based immunosuppression, the relationship between the daily dose of MMF and the occurrence of side effects was analyzed in this study. The frequency of side effects was investigated retrospectively in 28 renal transplant recipients treated with immunosuppression (men 14 : women 14, age: 33.0+/-12.4 years, weight: 50.9+/-10.7 kg). Cytomegalovirus (CMV) infection and diarrhea were the most frequent side effects in the early transplant phase (from transplantation to 3-month biopsy) in the recipients. In 18 recipients, excluding the recipients with risk factors for CMV infection (ABO-incompatible transplantation, donor (+)/recipient (-) CMV serostatus, etc.), no significant correlation was shown between the daily dose of MMF and the occurrence of CMV infection in the two-sample t-test. On the other hand, the daily dose in the diarrhea group (33.2+/-4.3 mg/kg/day, n = 5) was significantly higher than that in the no-diarrhea group at 30 days (28.4+/-3.7 mg/kg/day, n = 23, p < 0.05) and 90 days (25.7+/-4.4 mg/kg/day, n = 21, p < 0.005) after transplantation, respectively. The receiver-operating characteristic (ROC) curve also revealed that the risk of diarrhea increased with a daily MMF dose higher than 30 mg/kg/day. In conclusion, to decrease the risk of diarrhea in the early transplant phase in renal transplant recipients with TAC-based immunosuppression, the daily dose of MMF should not be more than 30 mg/kg/day.

Topics: Adolescent; Adult; Child; Cytomegalovirus Infections; Diarrhea; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; ROC Curve

Topics: Adult; Animals; Cryptosporidiosis; Cryptosporidium parvum; Diarrhea; Drug Therapy, Combination; Feces; Female; Humans; Kidney Transplantation; Mycophenolic Acid; Pancreas Transplantation; Parasite Egg Count; Rifamycins; Rifaximin

Gastrointestinal (GI) disorders are one of the main adverse events in patients treated by mycophenolic acid (MPA). The aim of our prospective questionnaire-based study was to assess GI side-effects in de novo renal-transplant patients receiving either mycophenolate mofetil (MMF) or enteric-coated mycophenolate sodium (EC-MPS).. Between January 2002 and April 2003, all patients receiving MPA with a functioning allograft at 1 month post-transplantation were enrolled in this study (n = 130). Ninety-three of them received MMF (group I), and 37 patients received EC-MPS (group II). Each month, every patient completed a questionnaire regarding GI disorders.. During the first year post-transplantation, GI disorders occurred in 31 patients from the MMF group (33.3%) and 12 patients from the EC-MPS group (32.4%) (not significant). The incidence of upper GI disorders was also similar in both groups. Diarrhoea was observed in 18 patients (19.3%) from group I, and in five patients from group II (13.5%) (not significant). Its frequency and severity were similar in both groups. Weight loss was observed in three patients receiving MMF. Diarrhoea resolved spontaneously in 10 patients from group I and in all patients from group II. For the other eight patients in group I, the diarrhoea required MMF discontinuation in three patients and dose reduction in five patients.. In conclusion, in this questionnaire-based evaluation, the incidence of GI disorders was similar in patients receiving either MMF or EC-MPS during the first year post-transplantation.

Topics: Adult; Diarrhea; Female; Gastrointestinal Diseases; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Surveys and Questionnaires; Tablets, Enteric-Coated; Time Factors

Diarrhea is the most frequently reported adverse event in mycophenolate mofetil (MMF)-treated transplant patients. The aim of this study was to explore the gastrointestinal tract in MMF-treated renal transplant recipients with persistent afebrile diarrhea to characterize its nature and etiology.. Renal transplant recipients with persistent afebrile diarrhea (daily fecal output >200 g) were prospectively investigated for infections, morphologic, and functional (gastrointestinal motility and intestinal absorptive capacity) integrity of the gastrointestinal tract; 26 patients met the inclusion criteria.. All but one patient had an erosive enterocolitis. Seventy percent of the patients had malabsorption of nutrients, contributing to the diarrhea. In +/-60%, an infectious origin was demonstrated and successfully treated with antimicrobial agents without changes in immunosuppressive regimen. In +/-40%, no infection occurred, but a Crohn's disease-like pattern of inflammation was noted. These patients also had a less pronounced bile-acid malabsorption but a significant faster colonic transit time, correlating with the trough level of mycophenolic acid (MPA). Cessation of MMF, however, was associated with allograft rejection in one third of these patients.. Persistent afebrile diarrhea in renal transplant recipients is characterized by erosive enterocolitis, which is of infectious origin in +/-60%. In +/-40%, a Crohn's disease-like (entero-)colitis was present. Because reduction or cessation of MMF was the only effective therapy, MPA or one of its metabolites may be suggested as a possible cause. However, reduction or cessation of MMF was associated with an increased risk for rejection.

Topics: Adult; Aged; Campylobacter Infections; Diarrhea; Enterocolitis; Female; Gastric Emptying; Humans; Immunosuppressive Agents; Kidney Transplantation; Malabsorption Syndromes; Male; Middle Aged; Mycophenolic Acid

Topics: Adult; Creatinine; Diarrhea; Female; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Octreotide

Mycophenolate mofetil (MMF) is widely used for maintenance immunosuppression in solid organ transplantation. Gastrointestinal toxicity, usually manifested as diarrhea, is the most common side effect of MMF. We evaluated colonic biopsies from 20 renal transplant patients with MMF-related diarrhea. The latter was defined by the absence of any other demonstrable etiology and improvement or resolution of symptoms by the discontinuation or reduction of the dose of MMF alone. These biopsies were compared with colon biopsies from patients with the following: acute graft-versus-host disease (GVHD, n=10), inflammatory bowel disease (IBD) or infectious colitis (n=10), and colon biopsies from renal transplant patients not receiving MMF (n=8). Normal colonic segments from surgical specimens served as normal controls (n=5). Colonic biopsies from patients with MMF-related diarrhea showed prominent crypt cell apoptosis and reactive/reparative changes including enterocyte cytologic atypia, increased neuroendocrine cells, and glandular architectural distortion. The changes were similar, although of milder degree to the ones seen in patients with acute intestinal GVHD. This pattern of injury was not seen in controls or in biopsies from transplant patients not receiving MMF, and it was markedly different from the one seen in idiopathic inflammatory or infectious colitis. The severity of histologic changes correlated significantly with the endoscopic degree of "colitis." There was no statistically significant correlation between histologic damage and the dose of MMF (corrected for body weight and renal function). MMF-related colitis is a distinct entity that displays histologic features remarkably similar to the ones associated with intestinal GVHD. This form of injury could be related to either direct toxicity or an "innocent by-stander" phenomenon secondary to the alteration of the immunologic microenvironment of the colon caused by the MMF.

Topics: Apoptosis; Colitis; Diarrhea; Dysentery; Graft vs Host Disease; Humans; Immunosuppressive Agents; Inflammatory Bowel Diseases; Kidney Transplantation; Mycophenolic Acid

Corticosteroids have been used traditionally for immunosuppression after solid organ transplantation. The variety of modern immunosuppressive agents offers the chance to replace drugs with an unfavorable risk-benefit ratio. The objective of this prospective pilot study was to investigate a novel steroid-free immunosuppressive regimen after clinical liver transplantation.. 30 adult liver graft recipients were included in an intent-to-treat analysis. Dual induction immunosuppression consisted of tacrolimus and mycophenolate mofetil. Prophylactic steroids were not given. Efficacy and safety parameters analyzed were patient and graft survival, incidence and severity of rejection, and adverse events in correlation to immunosuppressive drug levels.. Patient and graft survival at 2 years was 86.7 and 83.9%, respectively. Acute rejection occurred in 26.2%, and was associated with subtherapeutic tacrolimus blood levels and diarrhea. All rejections were completely reversible by temporary addition of steroids. Acute renal failure was seen in 10/30 patients, and was related to high tacrolimus blood levels together with primary liver graft dysfunction. 43% of all patients never received any steroids, and 73% were on a steroid-free maintenance regimen.. These results confirm that corticosteroids can be completely avoided from the beginning after liver transplantation. Double drug immunosuppression with tacrolimus and mycophenolate mofetil is effective and safe in terms of patient and graft survival as well as incidence and severity of rejection. In order to avoid under- or over-immunosuppression, which may be caused by impaired absorption or metabolism, close drug monitoring is advised.

Topics: Acute Disease; Adolescent; Adult; Aged; Diarrhea; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Severity of Illness Index; Survival Rate; Tacrolimus; Therapeutic Equivalency; Time Factors

Mycophenolate mofetil (MMF) is a prodrug that is hydrolyzed to the active immunosuppressant mycophenolic acid (MPA). The drug is now widely prescribed for adult renal transplant recipients and its use has been extended to pediatric patients, although pharmacological data in this age group are limited. Nine pediatric renal transplant recipients received MMF with corticosteroids and either cyclosporine or tacrolimus a median of 55 months (range 7.5-124 months) months after transplantation. The pharmacokinetic parameters of MPA and MPA glucuronide (MPAG) were determined at steady state by high-performance liquid chromatography after administration of MMF at the oral dose of 494+/-142 mg/m(2) twice daily. MPA was rapidly absorbed, with a peak concentration at 1.4 h. The mean plasma concentration of MPA at steady state was 4.7+/-1.3 microg/ml. The areas under the plasma concentration-time curves (AUCs) over 12 h (between two administrations) were 57.0+/-15.3 microg.h/ml for MPA and 1,515+/-722 microg.h/ml for MPAG, and the apparent oral clearance was 11.7+/-7.0 and 0.5+/-0.4 l/h for MPA and MPAG, respectively. Assuming that the pharmacokinetics of MPA was dose dependent, the mean concentration at steady state and the AUC for MPA were calculated for the recommended dosage schedule of 600 mg/m(2) every 12 h and were 6.3+/-2.7 microg/ml and 75.2+/-32.9 microg.h/ml, respectively. The tolerance of MMF was studied prospectively with a follow-up of 1.1+/-0.2 years. Gastrointestinal disorders requiring dosage reduction or discontinuation of therapy, observed in five of nine patients, occurred at an incidence higher than expected from adult data. Our results suggest that the dose of 600 mg/m(2) every 12 h extrapolated from adult data for use in pediatric patients would be associated with plasma levels and AUCs higher than expected and may be associated with a higher incidence of side-effects, primarily gastrointestinal.

Topics: Abdominal Pain; Adolescent; Child; Cyclosporine; Diarrhea; Glucuronates; Glucuronides; Humans; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Prospective Studies

Mycophenolate Mofetil (MMF) is a new immunosuppressive agent that selectively inhibits the proliferation of T and B lymphocytes. The use of MMF in renal transplantation significantly reduced the incidence of acute rejection episodes in the first year after transplantation. The main toxicities of MMF are the occurrence of diarrhea and leucopenia. This potent immunosuppressive agent is devoid of the nephrotoxicity of cyclosporin and of the multiple adverse effects of corticosteroids. Clinical trials are currently in progress to assess whether the use of MMF will allow the discontinuation of cyclosporine or corticosteroid therapy without leading to an increased risk of rejection. If results were positive, MMF would represent a significant advance in the field of renal transplantation.

Topics: Acute Disease; Adrenal Cortex Hormones; B-Lymphocytes; Cell Division; Clinical Trials as Topic; Cyclosporine; Diarrhea; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Leukopenia; Mycophenolic Acid; Risk Factors; T-Lymphocytes

PHARMACOKINETIC STUDIES. Eleven patients undergoing orthotopic liver transplantation (OLT) received mycophenolate mofetil (MMF) orally for prevention of rejection. Additional immunosuppressives used were cyclosporine (CsA) and steroids. Doses ranged from 3.5 to 4.5 g/d. Pharmacokinetic studies were performed between 11 d and 6 months after OLT. The Cmax and Tmax for mycophenolic acid (MPA) were 3.6-35.2 micrograms/mL and 0.5-4 h, respectively, and did not significantly change over 6 months. Oral clearance of MMF (dose of MMF/area under the curve for MPA) between d 11 and d 17 was significantly lower compared with d 21. Biliary diversion did not affect clearance. RESCUE THERAPY. Twenty-three patients with steroid- and OKT3-resistant acute rejection were converted to MMF (2-3.5 g/d) at a mean of 20 wk after OLT. Twenty-one patients responded, 14 with resolution of rejection and 7 with improvement. Sixteen patients remained on the drug. Eight patients had 14 infections, with cytomegalovirus (CMV) being the most common. The most common adverse events were diarrhea (4 patients) and leukopenia (3 patients). Four patients with chronic rejection all failed to improve after conversion to MMF. DOSE ESCALATION STUDIES--PRIMARY THERAPY. Seventeen patients received 3.5-5.0 g of MMF per d orally with reduced-dose CsA and prednisone as primary prophylaxis of rejection after OLT. Target CsA levels were 125-175 (whole-blood high-performance liquid chromatography). Two patients were terminated from the study for possible study drug-related reasons: pancreatitis in one and unsatisfactory response in the other. Gastrointestinal side effects were the most common (10 patients), including gastritis, esophagitis, and duodenal ulcer. Two patients developed leukopenia and/or pancytopenia. Of 5 culture-proven infections, 2 were CMV. After 3 months of follow-up, 7 of 17 patients had no rejection. Of 10 patients with rejection, 7 were treated with pulse steroids and 3 required OKT3. DUAL THERAPY WITH MMF AND STEROIDS. Four patients with rejection and unacceptable toxicity secondary to either CsA or FK-506 were treated with MMF 2-4 g/d and 20 mg of prednisone. After 325-500 d of follow-up, 3 had resolved their rejection episode and 1 had recurrent rejection and was restarted on low-dose CsA. CONCLUSION. MMF is a promising new immunosuppressive agent for both treatment of established rejection and primary rejection prophylaxis after OLT. More studies are needed to define its role furth

Topics: Administration, Oral; Adolescent; Adult; Cyclosporine; Cytomegalovirus Infections; Diarrhea; Female; Follow-Up Studies; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Leukopenia; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Recurrence

Topics: Clinical Trials as Topic; Costs and Cost Analysis; Cytomegalovirus Infections; Diarrhea; Drug Interactions; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Mycophenolic Acid; Organ Transplantation; Transplantation Immunology

Thirty five patients with psoriasis (plaque type 26, guttate 3, pustular 4, and erythrodermic 2) were treated with oral mycophenolic acid for a period ranging from 52 to 104 weeks. The average follow-up was 89 weeks, and the dose schedule ranged from 2,400 to 7,200 mg daily. Excellent response was noted in 20 patients, good in 13 patients, and poor in 2. The most common clinical side effects were in the gastrointestinal tract, namely, diarrhea, nausea, abdominal cramps, and soft stools. A high incidence of herpes simplex, herpes zoster, and a flu-like syndrome was noted. Laboratory abnormalities consisted of mild blood hemoglobin reduction, one case of leukopenia (3,9000 WBCs per cubic millimeter), two cases with thrombocytopenia and mild elevation of alkaline phosphatase. Mycophenolic acid appears as a promising drug for the treatment of severe psoriasis.

Topics: Adolescent; Adult; Aged; Diarrhea; Female; Humans; Male; Middle Aged; Mycophenolic Acid; Psoriasis; Virus Diseases