tacrolimus and Diarrhea

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 dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a severe autoimmune disease that is caused by regulatory T cell deficiency due to FOXP3 gene mutations. The long-term outcome can be variable depending on the extent of tissue damage caused by autoimmunity and infections, the use of immunosuppressive treatment or sequela of bone marrow transplantation.. We used immunohistochemical staining to analyze cell types infiltrating the tissue of affected organs from a classic IPEX patient with a splicing mutation (c.736-2A>C) in the FOXP3 gene. Expression of transcription factors that are critical for immune responses including T-bet, GATA-3, RORγt, and FOXP3 were evaluated in various tissue samples. For objective analysis of the distribution of different cell types in tissues, we used an automated microscope-based image acquiring system to assess quantitatively the different cell types by investigating the histopathological changes in the patient's biopsy samples obtained from the intestine and the kidneys before and after treatment.. The percentages of cells expressing the T. This study provides quantitative evidence that the inflamed intestinal and renal tissues of the IPEX patient contain T

Topics: Child; Diabetes Mellitus, Type 1; Diarrhea; Forkhead Transcription Factors; Gastrointestinal Tract; GATA3 Transcription Factor; Genetic Diseases, X-Linked; Humans; Immune System Diseases; Immunohistochemistry; Immunosuppression Therapy; Immunosuppressive Agents; Intestinal Mucosa; Kidney; Male; Nuclear Receptor Subfamily 1, Group F, Member 3; Rituximab; T-Box Domain Proteins; T-Lymphocytes, Regulatory; Tacrolimus; Th1 Cells; Th17 Cells; Th2 Cells

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

Diarrhea is a frequent but overlooked complication of kidney transplantation. Diarrhea is repeatedly neglected, often considered by patients and clinicians an unavoidable side effect of immunosuppressive regimens. It is, however, associated with a significant impairment in life quality. Severe and chronic posttransplant diarrhea may lead to dehydration, malabsorption, rehospitalization, immunosuppression, noncompliance, and a greater risk of graft loss and death. There is thus a need to optimize and standardize the management of posttransplant diarrhea with consistent diagnostic and therapeutic strategies. A recent study has suggested that the increased sensitivity of molecular tools might help in early pathogen identification and guidance of antimicrobial treatment. Most bacterial and protozoan infections are readily curable with appropriate antimicrobial agents; cryptosporidiosis and C. difficile infections may however be complicated by relapsing courses. In addition, identification of enteric viral genomes in stool has further reduced posttransplant diarrhea of unknown origin. Chronic norovirus-related posttransplant diarrhea, arising from the interplay of the virus and immunosuppressive drugs, has emerged as a new challenge in the field. Prospective and controlled studies are necessary to evaluate the efficacy and safety of innovative anti-norovirus therapeutics, as well as optimal immunosuppressive regimens, to enable viral clearance while preventing rejection and donor-specific antibody formation. This review seeks to provide a basis for the design of future clinical prospective studies.

Topics: Caliciviridae Infections; Clostridioides difficile; Cryptosporidiosis; Cytomegalovirus Infections; Diarrhea; Humans; Kidney Transplantation; Norovirus; Tacrolimus; TOR Serine-Threonine Kinases

Topics: Adult; Diarrhea; DNA, Ribosomal Spacer; Enterocytozoon; Female; Genotype; HIV Seronegativity; Humans; Immunocompromised Host; Liver Transplantation; Male; Microsporidiosis; Middle Aged; Polymerase Chain Reaction; Tacrolimus

Post-transplantation hypomagnesemia is common and predicts diabetes. Magnesium improves glycemic control in diabetics and insulin sensitivity in insulin resistant subjects. We aimed to assess the effectiveness of oral magnesium for improving glycemic control and insulin sensitivity at 3 months post-transplantation. We conducted a single-center, open-label, randomized parallel group study. We included adults with serum magnesium <1.7 mg/dl within 2 weeks after kidney transplantation. We randomized participants to 450 mg magnesium oxide up to three times daily or no treatment. The primary endpoint was the mean difference in fasting glycemia. Secondary endpoints were the mean difference in area under the curve (AUC) of glucose during an oral glucose tolerance test and insulin resistance measured by Homeostasis Model of Assessment-Insulin Resistance (HOMA-IR). Analyses were on intention-to-treat basis. In patients randomized to magnesium oxide (N = 27) versus no treatment (N = 27), fasting glycemia on average was 11.5 mg/dl lower (95% CI 1.7 to 21.3; P = 0.02). There was no difference between the two groups neither for 2 h AUC, where the mean value was 1164 mg/dl/min (95% CI -1884 to 4284; P = 0.45) lower in the treatment group nor for HOMA-IR. Magnesium supplements modestly improved fasting glycemia without effect on insulin resistance. Higher baseline glycemia among patients in the control group may have driven the positive outcome (ClinicalTrials.gov number: NCT01889576).

Topics: Adult; Aged; Area Under Curve; Blood Glucose; Calcineurin Inhibitors; Diabetes Mellitus, Type 2; Diarrhea; Female; Glucose Tolerance Test; Graft vs Host Disease; Humans; Insulin Resistance; Kidney Failure, Chronic; Kidney Transplantation; Magnesium; Magnesium Deficiency; Magnesium Oxide; Male; Middle Aged; Postoperative Complications; Prediabetic State; Receptor, Insulin; Severity of Illness Index; Tacrolimus

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

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 safety and efficacy of a 1% cream formulation of pimecrolimus, a selective, nonsteroid immunomodulator, was studied in infants with atopic dermatitis (AD).. During a 6-week double-blind phase, 186 infants with mild/moderate AD were randomly assigned to twice-daily pimecrolimus cream 1% or vehicle. All patients were subsequently treated with open-label pimecrolimus for 20 weeks.. At the end of the double-blind phase, 54.5% and 23.8% of patients in the pimecrolimus and vehicle groups, respectively, were clear or almost clear of AD (P <.001). Similar improvements were observed in the Eczema Area and Severity Index, pruritus assessment, and the care giver's assessment. By the first return visit, 69.9% and 36.5% of pimecrolimus and vehicle-treated patients, respectively, achieved absent or mild pruritus. Efficacy during the double-blind phase was maintained throughout the open-label phase. Vehicle-treated patients transferring to open-label pimecrolimus rapidly achieved disease control comparable to those receiving continuous pimecrolimus. There were no significant differences between groups in application site reactions or skin infections. Most adverse events were mild or moderate and unrelated to treatment.. Pimecrolimus was safe in infants with AD, with rapid and sustained efficacy. Pimecrolimus holds promise as a valuable new treatment option for the youngest patients with AD.

Topics: Administration, Cutaneous; Analysis of Variance; Anti-Inflammatory Agents, Non-Steroidal; Dermatitis, Atopic; Dermatologic Agents; Diarrhea; Double-Blind Method; Female; Fever; Humans; Infant; Male; Ointments; Pharyngitis; Respiratory Tract Infections; Safety; Severity of Illness Index; 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

Tacrolimus (FK506, Prograf) is marketed for the prophylaxis of organ rejection following allogenic liver or kidney transplantation. A previously conducted, randomized, 24-subject, crossover bioavailability study of 1 and 5 mg capsules (one period each) failed to demonstrate bioequivalence. A single-dose, four-period, four-sequence, randomized, crossover, replicate study (N = 32) was therefore used to evaluate the bioequivalence of the marketed 1 and 5 mg capsules in healthy volunteers. Tacrolimus blood concentrations were measured serially over 72 hours using a commercially available ELISA assay. Noncompartmental pharmacokinetic parameters were determined. Ninety percent CIs of log-transformed parameter ratios were 90.5-101.9, 87.1-101.7, and 89.7-103.8 for Cmax, AUC0-t, and AUC0-infinity, respectively. Since all values were within 80% to 125%, the capsules are bioequivalent. Based on %CVs, intersubject variability was approximately two to three times greater than intrasubject variability. The safety of single 5 mg oral tacrolimus doses administered to healthy volunteers at 7-day intervals was also ascertained.

Topics: Abdominal Pain; Adult; Area Under Curve; Arthralgia; Capsules; Cross-Over Studies; Diarrhea; Dose-Response Relationship, Drug; Female; Headache; Humans; Immunosuppressive Agents; Knee Joint; Male; Purpura; Tacrolimus; Therapeutic Equivalency

Topics: Adult; Aged; Anorexia; Diarrhea; Digestive System; Female; Humans; Liver Transplantation; Male; Nausea; Tacrolimus; Weight Loss

The oral dose recommendation for FK506 (Fujisawa Pharmaceutical, Deerfield, IL) after liver transplantation has, to date, made no distinction between adult and pediatric patients. Sixteen pediatric and 33 adult liver transplant patients treated long term with oral FK506 were studied. Initial FK506 doses were 0.3 mg/kg/day p.o. or 0.15 mg/kg/day i.v. Thereafter, doses were adjusted to achieve therapeutic FK506 serum levels (0.5-3.0 ng/ml, ELISA liquid/liquid separation) and to maintain an acceptable serum creatinine. FK506 (in mg/kg/day), FK506 levels, and liver function were assessed at monthly intervals on outpatient visits. The mean age of 16 pediatric patients was 5.3 +/- 3.5 years and of 33 adult patients was 49 +/- 12 years. Mean days of FK506 therapy were 284 +/- 136 for pediatric patients and 239 +/- 112 for adult patients. For each time period, pediatric patients required a significantly higher dose of FK506 compared to adult patients (P < 0.001). The overall mean pediatric dose for the first year was 0.46 +/- 0.4 mg/kg/day compared to the mean adult dose of 0.13 +/- 0.01 mg/kg/day. The ratio of pediatric to adult oral FK506 dose requirements ranged from 2.7 to 4.4 over the 1 year of followup. FK506 levels monitored at the same time points showed no significant differences at any month between pediatric and adult patients. We conclude that the oral dose per kilogram per day of FK506 required to maintain similar FK506 levels is significantly greater in pediatric patients compared to adult recipients during the first year of follow-up. Pediatric recipients require substantially more, and adult recipients substantially less, than the recommended oral FK506 dose to achieve a therapeutic effect.

Topics: Administration, Oral; Adult; Child; Child, Preschool; Diarrhea; Drug Interactions; Graft Rejection; Humans; Immunosuppression Therapy; Liver Transplantation; Middle Aged; Rifampin; Tacrolimus

Topics: Acute Disease; Adult; Bone Marrow Transplantation; Chronic Disease; Cyclosporine; Diarrhea; Drug Evaluation; Female; Graft vs Host Disease; Humans; Male; Tacrolimus; Transplantation, Homologous

Transplant recipients are at high risk of coronavirus disease 2019, and a timely supply of antivirals should be prioritized for those patients. Complicated drug‒drug interactions limit the use of Paxlovid (nirmatrelvir/ritonavir) coadministered with tacrolimus. Here, we report a patient with a kidney transplant who received Paxlovid and reduced-dose tacrolimus at the same time and suffered a severe tacrolimus toxicity.. We present a 56-year-old man of Han ethnicity with a kidney transplant who suffered from coronavirus disease 2019 twice. For the first infection, the immunosuppressants were substituted by dexamethasone when the patient used Paxlovid, and everything went well. For the second time, tacrolimus at a reduced dose concomitant with Paxlovid caused severe diarrhea, inducing combined diabetic ketoacidosis and a hyperglycemic hyperosmolar state.. This case challenges the dose-adjustment strategy of managing drug‒drug interactions. We suggest that tacrolimus should be stopped when Paxlovid is applied and that corticosteroids could be a good substitution.

Topics: COVID-19; Diabetes Mellitus; Diabetic Ketoacidosis; Diarrhea; Drug Interactions; Humans; Kidney Transplantation; Middle Aged; Tacrolimus

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

Acute nephrotoxicity is a common adverse reaction of tacrolimus therapy; however, its risk factors in pediatric nephrotic syndrome (NS) remain to be evaluated. The objective of this study was to investigate the risk factors and characteristics of tacrolimus-induced acute nephrotoxicity in children with NS.. Past records of children with NS admitted to our hospital from 2014 to 2018 were reviewed. The incidence and characteristics of nephrotoxicity were analyzed. Multivariate logistic regression analysis was used to identify the risk factors of nephrotoxicity. A clinically applicable risk score was developed and validated.. High trough concentration of tacrolimus and diarrhea can potentiate the risk of tacrolimus-induced acute nephrotoxicity in children with NS, while huaiqihuang granules can protect this condition.

Topics: Case-Control Studies; Child; Child, Preschool; Diarrhea; Drugs, Chinese Herbal; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Nephrotic Syndrome; Retrospective Studies; Risk Factors; Tacrolimus

Diarrhea in kidney transplant recipients influences outcome of transplantation. Data from India in this regard are sparse and do not address the differential outcome of infective and non-infective diarrhea. We studied the demographic data, laboratory findings, treatment response, disease duration, and outcome of diarrhea in kidney transplant recipients, and the differential outcome between infective and non-infective diarrhea, if any.. All kidney transplant recipients who were referred to the Division of Gastroenterology with diarrhea between June 2015 and February 2017 were prospectively included. Demographic, clinical and laboratory data, graft function, treatment administered, and outcome were noted, and the patients were followed up for 3 months.. Forty-seven patients (median age 45 years, range 16-78; 34 men) with 64 episodes of diarrhea were studied. Thirty-three (51.5%) episodes were attributed to infections. Eleven (17%) were immunosuppressant-induced (mycophenolate 8, tacrolimus 2, cyclosporine 1). Twenty (31%) were due to other causes (antibiotics 6, laxatives 3, irritable bowel syndrome 3, sepsis 8). Fifty-three episodes (82%) had graft dysfunction during the diarrheal episodes. Mean increase in serum creatinine was 45% in the infectious diarrhea group and 95% in the non-infectious diarrhea group (p < 0.05). Median time to resolution of diarrhea was 3 days. With improvement in diarrhea, return to pre-diarrhea creatinine levels occurred in 87% of episodes at 3 months.. One-half of episodes of diarrhea in kidney transplant recipients were non-infectious in origin. Seventeen percent were attributed to immunosuppressants, requiring dose modification. More than 80% were associated with worsening of graft function. Recovery of graft function to baseline was seen in a majority of cases with the resolution of diarrhea.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Diarrhea; Female; Humans; Immunosuppressive Agents; Irritable Bowel Syndrome; Kidney Transplantation; Laxatives; Male; Middle Aged; Primary Graft Dysfunction; Prognosis; Prospective Studies; Retrospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Tacrolimus, which bonds to an immunophilin, FK506 binding protein (FKBP) has emerged as one of the most widely used immunosuppressant post solid organ transplantation. It offers excellent patient survival rates post-transplantation and a lesser number of acute rejections as compared to cyclosporine. Tacrolimus has a narrow therapeutic window with overexposure leading to acute and chronic forms of nephrotoxicity. Remarkably few data have been published on the overexposure to tacrolimus following mild diarrhoea in post-transplant patients who received treatment with tacrolimus. We observed a post-liver transplant patient with increased trough level of tacrolimus during severe diarrhoea with no complications following a timely adjustment on the dose of tacrolimus.

Topics: Diarrhea; Humans; Immunosuppressive Agents; Liver Transplantation; Organ Transplantation; Tacrolimus

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

Exploration of fecal microbiota transplantation in the treatment of refractory diarrhea after renal transplantation.. Summarize the etiology of 120 cases with diarrhea after renal transplantation from 2014 to 2017 in our hospital. There were 4 recipients of refractory diarrhea who accepted fecal microbiota transplantation with informed consent, and we collected clinical data of stool and bacterial culture, gut microbiota analysis, graft function, electrolytes, immunosuppressant concentrations of prognostic evaluation of patients with fecal transplantation.. The absorption of electrolyte is slightly higher and concentration of tacrolimus and creatinine were not significantly changed compared with before.. Fecal microbiota transplantation provides a new choice to refractory diarrhea after renal transplantation as an innovative treatment, but the effectiveness of fecal microbiota transplantation needs long-term observation and further evaluation through large sample data.

Topics: Adult; Aged; Diarrhea; Fecal Microbiota Transplantation; Feces; Female; Gastrointestinal Microbiome; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Prognosis; Tacrolimus; Treatment Outcome; Young Adult

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

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

The bioavailability of oral tacrolimus is influenced by enterocyte metabolism, which involves CYP3A and P-glycoprotein. Viral infection-induced intestinal inflammation damages the enterocytes and causes unfavorable elevations in blood tacrolimus levels in transplant recipients, which may lead to nephrotoxicity.. From May 2000 to May 2011, 56 renal transplant recipients receiving tacrolimus at our hospital suffered from infectious enteritis with diarrhea. We investigated the tacrolimus trough levels before and after the onset of enteritis and evaluated the influence of elevated tacrolimus trough levels on the rate of changes in serum creatinine levels.. Elevated tacrolimus trough levels were observed in 52 recipients (93%) after the onset of diarrhea, and the mean value was 2.3 times higher than that before the onset of enteritis (P = .0175). Tacrolimus trough levels returned to their previous levels 2 weeks after the onset of enteritis, even in recipients with >2-fold increase, following dose adjustments. Serum creatinine levels did not significantly differ between recipients with >2-fold increase in tacrolimus trough levels and those with <2-fold increase in trough levels during a 6-month period after the onset of enteritis.. Elevations in the tacrolimus trough levels due to infectious enteritis with diarrhea can improve in ∼2 weeks by adjusting the tacrolimus dosage. Such temporary elevations in the tacrolimus trough levels may not produce serious nephrotoxicity even in recipients with remarkably elevated trough levels.

Topics: Adult; Diarrhea; Enteritis; Female; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Young Adult

Topics: Child; Child, Preschool; Diarrhea; Drug-Related Side Effects and Adverse Reactions; Humans; Immunosuppressive Agents; Nephrotic Syndrome; Tacrolimus

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

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

Tacrolimus is known to potentially lead to adverse events in recipients with diarrhoea and/or calcium channel blocker (CCB) co-administration. We report a renal transplant recipient who suffered from severe nephrotoxicity related to a toxic tacrolimus trough concentration in both conditions, diarrhoea and CCB co-administration, and with genotyped CYP3A system and P-glycoprotein (P-gp) polymorphisms. To our knowledge, this is the first case to be investigated for such polymorphisms. Clinicians should be reminded of the possibility of highly increased levels of tacrolimus in situations of diarrhoea and/or co-administration of CCBs. It also highlights the key role in tacrolimus pharmacokinetics of the CYP3A system and P-gp polymorphisms, and their influence in high-risk situations when enzyme activity is already affected by enterocyte damage due to diarrhoea and CCB competition.

Topics: Acute Kidney Injury; Adolescent; ATP Binding Cassette Transporter, Subfamily B; ATP Binding Cassette Transporter, Subfamily B, Member 1; Calcium Channel Blockers; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diarrhea; Drug Interactions; Drug Monitoring; Genetic Predisposition to Disease; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pharmacogenetics; Phenotype; Polymorphism, Single Nucleotide; Risk Factors; Tacrolimus

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

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

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

Topics: Acute Disease; Adult; Behcet Syndrome; Diarrhea; Glomerulonephritis, IGA; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Oral Ulcer; Recurrence; Tacrolimus

Malakoplakia is a rare inflammatory condition seen in transplant patients. There are two previously reported cases of malakoplakia involving the gastrointestinal tract in liver transplant patients. The present paper reports a case of colonic malakoplakia in a 58-year-old woman, a liver transplant recipient who was receiving immunosuppressive drugs. She presented with chronic diarrhea while on tacrolimus. There was no history of antecedent infection. Colonoscopy showed patchy mucosal edema, but no discrete yellow plaques or nodules. The diagnosis was made by colon biopsies, which showed chronic inflammation with many histiocytes containing Michaelis-Gutmann bodies. Although rare, malakoplakia is one of many potential causes of diarrhea in a transplant patient. The present case indicates that malakoplakia may be associated with chronic diarrhea, even if there are no macroscopic lesions seen during colonoscopy.

Topics: Diarrhea; Female; Humans; Immunosuppressive Agents; Liver Transplantation; Malacoplakia; Middle Aged; Tacrolimus

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

Renal transplant recipients suffering from persistent diarrhea have been repeatedly reported to have increased tacrolimus (Tac) trough levels. This study aimed to explore this phenomenon in detail in 15 renal transplant recipients with diarrhea, whose immunosuppression consisted of corticosteroids, mofetil mycophenolate and Tac. Both hepatic and intestinal CYP3A4 and PGP activity, important determinants of Tac bioavailability, were assessed, together with global CYP activity and investigations for gastrointestinal infection, function and morphology. Global CYP, CYP3A4, PGP and trough/dose levels of Tac were compared with diarrhea-free controls. In addition, a pharmacokinetic study of Tac was performed in 11 patients affected by diarrhea versus 9 controls. As expected, diarrhea was associated with increased Tac trough levels. An even stronger, significant increase of dose-normalized Tac levels was observed between 90 and 360 min after Tac intake. Time to peak concentration and drug half-life, however, were not altered. In addition, a concomitant decrease (+/-50%) of intestinal PGP activity was noticed in patients with diarrhea. For global CYP, CYP3A4 and hepatic PGP activity no such differences were noted. This pattern was not influenced by the specific cause of diarrhea. These data strongly suggest that persistent diarrhea is associated with an increased oral bioavailability of Tac.

Topics: ATP Binding Cassette Transporter, Subfamily B, Member 1; Biological Availability; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diarrhea; Feces; Female; Humans; Immunosuppressive Agents; Intestines; Kidney Transplantation; Liver; Male; Middle Aged; Postoperative Period; Prospective Studies; Tacrolimus

The rate of metabolism in the intestine of oral administered FK506 decreases as FK506 passes on to the lower intestine. In transplant recipients with diarrhea given oral FK506, the main areas for absorption of FK506 shift to the lower intestine, where the ability to metabolize FK506 is weaker. Therefore it is considered likely that when FK506 is administered to recipients with diarrhea, the blood concentration of FK506 will be higher.. Twenty recipients experiencing episodes of diarrhea were investigated to determine the trough level of FK506 and the time required for the FK506 trough level to return to the level that obtained before diarrhea. AUC0-4h and Cmax of FK506 were investigated in eight recipients. In cases with severe diarrhea, the daily fluctuations of FK506 blood concentration were also investigated.. The FK506 trough level (p < 0.0001), AUC (p = 0.0173), and Cmax (p = 0.0173) were found to be significantly higher during episodes of diarrhea. In almost all cases, it took between 2 and 4 wk for the elevated FK506 trough level to return to its previous level following a bout of diarrhea. In the daily fluctuations of FK506 concentration, Tmax was prolonged. In some cases, the concentration was highest just before administration of FK506, when it should have been at trough level.. Diarrhea caused significant elevations of trough level, AUC0-4h and Cmax of FK506, and the prolongation of Tmax in renal transplant recipients administered FK506.

Topics: Administration, Oral; Area Under Curve; Circadian Rhythm; Creatinine; Diarrhea; Follow-Up Studies; Humans; Immunosuppressive Agents; Intestinal Absorption; Kidney Transplantation; Tacrolimus

It is well known that during diarrhea episodes decreased cyclosporine and tacrolimus levels are often observed, usually requiring an increase in dose. An increase in tacrolimus trough levels is infrequently recognized as a potential cause of the adverse effect of severe diarrhea. Herein, we report the case of a renal transplant patient who displayed increased tacrolimus trough levels during an episode of gastroenteritis with severe diarrhea. The patient is 32-year-old male who received a renal transplant from his mother. Immunosuppression was initiated with tacrolimus in combination with mycophenolate mofetil and prednisone. The postoperative course was uneventful. The function of the transplanted kidney was normal. Eight months after transplantation he presented to our hospital with a history of high fever, abdominal pain, nausea and severe diarrhea. He was admitted with a diagnosis of enterocolitis of unknown etiology. The blood trough level of tacrolimus had increased from 6.7 ng/mL to 28.7 ng/mL after the onset of diarrhea. A therapeutic trough level of tacrolimus was reached 6 weeks after complete relief of diarrhea. Tacrolimus shows large variability in bioavailability after oral administration, both due to intestinal metabolism by cytochrome P450 (CYP3A4) and active secretion from enterocyte into intestinal lumen by P-glycoprotein. The epithelial cells of the intestine, may be destroyed abrogating P-glycoproteins during the course of enterocolitis, thereby increasing the levels of tacrolimus. It is recommended to monitor trough levels of tacrolimus during severe diarrhea of any nature to prevent tacrolimus-related complications.

Topics: Adult; Area Under Curve; Biological Availability; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diarrhea; Humans; Immunosuppressive Agents; Intestinal Mucosa; Kidney Transplantation; Male; Tacrolimus

We encountered 2 children with intractable diarrhea after allogeneic hematopoietic stem cell transplantation (SCT). In both cases, salazosulfapyridine (SASP) was administered to treat the diarrhea. One patient was a 14-year-old male with acute myelogenous leukemia who received SCT from a related HLA-identical donor. The leukemia recurred early, and a second SCT from the same donor was performed approximately half a year later. Because intestinal graft-versus-host disease (GVHD) was observed, steroids and octreotide were administered, but the symptoms were not improved. Thereafter, SASP was administered, and the symptoms remitted 9 days later. The other patient was a 12-year-old male with chronic myelogenous leukemia who received SCT from an unrelated HLA-identical donor. Diarrhea and abdominal pain developed early after engraftment and did not respond to either steroids or tacrolimus. Oral administration of SASP was initiated on day 236, and the diarrhea remitted 4 days later without recurrence thereafter. SASP may be effective in children for the digestive system symptoms of chronic GVHD.

Topics: Adolescent; Diarrhea; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Leukemia, Myeloid, Acute; Male; Steroids; Sulfasalazine; Tacrolimus

The diagnosis and treatment of diarrhea in liver transplant recipients often pose a challenge owing to the variety of infectious and non-infectious causes. However, diagnosis is principally focused on ruling out an infectious etiology. Tacrolimus, an immunosuppressive agent generally used after liver transplantation, is absorbed mainly from the duodenum through the upper jejunum. It can be assumed that metabolism of the drug will be influenced by diarrhea.. Four liver transplant recipients who developed an episode of acute gastroenteritis. Infectious etiology was confirmed; trough tacrolimus levels were measured before, during and after gastroenteritis.. All patients presented a two- to three-fold increase in blood tacrolimus levels after the onset of gastroenteritis.. Until the role played by the intestine in the metabolism of tacrolimus is fully understood, it is prudent to recommend early dose reduction of tacrolimus and careful monitoring of trough levels during diarrheal disorders of any nature in pediatric liver-transplanted patients.

Topics: Acute Disease; Child, Preschool; Diarrhea; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Infant; Intestinal Mucosa; Liver Transplantation; Male; Postoperative Complications; Tacrolimus

Topics: Child; Child, Preschool; Cyclosporine; Cytochrome P-450 Enzyme System; Diarrhea; Drug Monitoring; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Postoperative Complications; Tacrolimus

Diarrhea is the most frequently reported adverse event in patients treated with mycophenolate mofetil. Twenty-six renal transplant patients on a mycophenolate mofetil-based immunosuppressive regime with persistent afebrile diarrhea were examined. Diarrhea caused a significant rise in FK-506 trough levels despite intake of stable doses, necessitating FK-506 dose reductions of 30% to obtain pre-diarrhea trough levels. In contrast, trough levels of cyclosporine A remained stable without dose adjustments. This suggests that absorption and/or metabolism is differentially altered for FK506 compared with cyclosporine A in patients with diarrhea. In nine patients mycophenolate mofetil was reduced or stopped because of persistent diarrhea without identifiable cause. This resulted in end-stage renal disease because of chronic rejection in two patients, and in acute rejection in two patients, all taking FK506 and steroids. Therefore, dose adjustments of FK506 in patients with diarrhea must be carefully monitored, especially when doses of mycophenolate mofetil are also reduced.

Topics: Acute Disease; Cyclosporine; Diarrhea; Graft Rejection; Humans; Immunosuppressive Agents; Intestinal Absorption; Kidney Transplantation; Tacrolimus; Time Factors

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Autoimmune Diseases; Chronic Disease; Diarrhea; Follow-Up Studies; Gastrointestinal Agents; Humans; Immunosuppressive Agents; Infant; Infliximab; Intestinal Diseases; Male; Parenteral Nutrition; Tacrolimus

Topics: Animals; ATP Binding Cassette Transporter, Subfamily B, Member 1; Bone Marrow Transplantation; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Diarrhea; Dogs; Immunosuppression Therapy; Immunosuppressive Agents; Intestine, Small; Mixed Function Oxygenases; Models, Animal; Postoperative Complications; Tacrolimus; Time Factors; Transplantation, Autologous

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

Topics: Diarrhea; Drug Monitoring; Gastroenteritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Postoperative Complications; Rotavirus Infections; Tacrolimus; Transplantation

Rotavirus (RV) is the most common cause of diarrheal illness in children. We report three solid-organ-transplanted patients in whom RV infection caused increased trough levels of the immunosuppressive macrolide tacrolimus (TAC) by mechanisms that are still under investigation. The virus was detected for longer in the feces of these patients than in infants not receiving immunosuppressive therapy. In association with short-term monitoring of blood trough levels of TAC, the dosage should be reduced early if symptoms of an acute gastroenteritis are present.

Topics: Adult; Child; Diarrhea; Drug Monitoring; Feces; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Male; Postoperative Complications; Rotavirus Infections; Tacrolimus; Transplantation

While it is well known that diarrhea results in decreased trough levels of cyclosporin A, experience with levels of tacrolimus (FK506) and diarrhea is limited. We have therefore measured the tacrolimus trough levels of four male and two female recipients of solid organs before, during, and after gastroenteritis. The average age of these six patients was 31 (1-60) years. Four patients had received a kidney transplant, one patient had undergone simultaneous kidney-pancreas transplantation, and another patient had received a liver transplant. Rotavirus was identified in the feces specimen of a 1-year-old child that had undergone liver transplantation. All patients showed an elevated tacrolimus trough level (peak 20-60 ng/ml) after onset of gastroenteritis. Under symptomatic therapy and adequate adjustment of tacrolimus dose, the gastroenteritis stopped and tacrolimus levels returned to the therapeutic range. We recommend that FK506 levels be carefully monitored during diarrhea in order to prevent intoxication.

Topics: Adolescent; Adult; Child; Child, Preschool; Diarrhea; Female; Humans; Immunosuppressive Agents; Infant; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Pancreas Transplantation; Tacrolimus

Despite the beneficial immunosuppressive effects of FK506 during small intestine transplantation, FK506 appears to have direct toxic effects on the intestine. The mechanisms of FK506-induced intestinal damage is unclear, and whether nitric oxide (NO) is involved in the mechanism has not been well defined. This study was designed to evaluate the effects of NG-Nitro-L-arginine methyl ester (L-NAME), an inhibitor of NO synthase, on small intestinal damage in rats treated with FK506.. Wistar rats weighing 240-260 g, aged 11 weeks, were administered FK506 (5 mg/kg/day i.m) and/or L-NAME (5 mg/dl in drinking water) for 10 days. Body weight gain, diarrhoea and mortality were observed during experiment. At the end of experiment, the intestinal specimens were excised for histological evaluation. In addition, the effects of L-aginine treatment (1 g/dl in drinking water) were evaluated in this study.. L-NAME administration time-dependently induced diarrhoea and high mortality in the rats treated with FK506. At the end of 10 days treatment, 7 of 12 rats (58.3%) suffered from diarrhoea and 5 of 12 rats (41.7%) died in the FK506 + L-NAME group (vs. FK506 group, p = 0.05). A significant loss of body weight was also found in the rats treated with FK506 + L-NAME (-52.2 +/- 28.8 g, in FK506 + L-NAME group vs. -14.3 +/- 8.7 g in FK506 group, p = 0.001). In parallel with the severe diarrhoea and high mortality, the loss of villi, hemorrhage and necrosis (grade 5 of pathological damage) was seen in the small intestinal mucosa of rats treated with FK506 + L-NAME. L-arginine treatment in part prevented diarrhoea, mortality and pathological damage of small intestinal mucosa induced by L-NAME.. Inhibition of NOS induces intestinal mucosal damage and increases mortality in rats treated with FK506. L-arginine treatment can in part prevent the injury induced L-NAME. The present study suggests that NO, as an important protective factor, may be involved in the FK506-induced intestinal damage.

Topics: Administration, Oral; Animals; Body Weight; Diarrhea; Drinking; Drug Antagonism; Enzyme Inhibitors; Immunosuppressive Agents; Injections, Intramuscular; Intestinal Mucosa; Jejunum; Longevity; Male; NG-Nitroarginine Methyl Ester; Nitric Oxide Synthase; Rats; Rats, Wistar; Tacrolimus; Time Factors

Tacrolimus is an immunosuppressant used to prevent rejection of transplanted organs. It is metabolized in both the gut and the liver by the cytochrome P450 (CYP) 3A4 enzyme system and is a substrate for the P-glycoprotein (P-gp) drug efflux pump. As CYP3A4 enzymes and P-gp are present at differing concentrations throughout the gastrointestinal tract, the bioavailability of tacrolimus may be influenced by changes in gastrointestinal transit time in addition to changes in hepatic metabolism. We report the case of a pediatric renal transplant patient who experienced a three-fold increase in serum tacrolimus concentrations during an episode of gastroenteritis with chronic diarrhea.

Topics: Biological Availability; Child; Chronic Disease; Diarrhea; Female; Gastroenteritis; Humans; Immunosuppressive Agents; Kidney Transplantation; Tacrolimus

The use of cyclosporine for immunosuppression in renal transplantation allograft recipients is associated with hypertrichosis, gingival hyperplasia, and hypercholesterolemia. Conversion of patients to tacrolimus may lead to an improvement in these effects with minimal risk of rejection or allograft dysfunction.. Sixteen renal transplant recipients were prospectively converted from CsA to tacrolimus and followed for 1 year. Gingival hyperplasia index, total cholesterol, and blood pressure were recorded at the outset, 4-, 8-, and 12-month intervals. Glomerular filtration rate was checked before conversion and 1 year later. Photographs documenting hypertrichosis were taken before conversion and 1 year later. Adverse effects from tacrolimus were recorded at 4, 8, and 12 months.. Twelve patients with hypertrichosis noted rapid improvement. Mean gingival hyperplasia index decreased from 24 to 6; mean total cholesterol decreased from 237 to 195. Glomerular filtration rate was essentially unchanged (56 to 54). One episode of rejection occurred, three patients developed diarrhea, three noted headaches, and one had a tremor.. If carefully monitored, patients suffering adverse effects secondary to cyclosporine may be converted to tacrolimus with minimal risk of allograft dysfunction or rejection.

Topics: Adolescent; Adult; Cyclosporine; Diarrhea; Female; Gingival Hyperplasia; Humans; Hypercholesterolemia; Hypertrichosis; Immunosuppressive Agents; Male; Middle Aged; Tacrolimus; Time Factors

Topics: Adult; Clostridioides difficile; Diarrhea; Enterocolitis, Pseudomembranous; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney Transplantation; Male; Tacrolimus

Topics: Adolescent; Autoimmune Diseases; Biopsy; Chronic Disease; Colitis; Diarrhea; Duodenum; Gastroenteritis; Humans; Immunosuppressive Agents; Male; Rectum; Tacrolimus

Topics: Bronchiolitis, Viral; Cardiomyopathy, Hypertrophic; Child, Preschool; Diarrhea; Female; Humans; Immunosuppressive Agents; Intestine, Small; Parenteral Nutrition; Respiratory Syncytial Virus Infections; Selenium; Tacrolimus