tacrolimus and Leukopenia

Our objectives were to compare the clinical outcomes of mizoribine (12 mg/kg/d) and mycophenolate mofetil (2000 mg/d) in combination with tacrolimus, basiliximab, and corticosteroids.. We enrolled 83 recipients of living-donor renal transplant (performed between 2008 and 2013) in this study. This prospective multi-institutional randomized comparative study compared mizoribine (n = 41) and mycophenolate mofetil (n = 42) in combination with tacrolimus, basiliximab, and corticosteroids for living-donor renal transplant recipients. We compared the acute rejection and graft survival rates and adverse event rates within 1 year of renal transplant between the 2 groups using intention-to-treat analyses.. During the 1-year observation period, patient and graft survival rates were 100%. The acute rejection rate was 17.1% in the mizoribine group and 19% in the mycophenolate mofetil group. The incidence rate of cytomegalovirus infection seropositivity (recipient and donor with positive cytomegalovirus antibody status) was higher in the mycophenolate mofetil group than in the mizoribine group, although the difference in these rates was not statistically significant. The incidence of leukopenia was higher in the mizoribine group than in the mycophenolate mofetil group.. High-dose mizoribine at 12 mg/kg/day was a safe and efficacious immunosuppressive alternative to mycophenolate mofetil in living-donor renal transplant recipients. Leukopenia should be closely monitored in the initial period of insufficient kidney function after renal transplant.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Disease-Free Survival; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Intention to Treat Analysis; Japan; Kaplan-Meier Estimate; Kidney Transplantation; Leukopenia; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Ribonucleosides; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

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

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Azathioprine; Diabetes Mellitus, Type 1; Drug Therapy, Combination; Follow-Up Studies; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Middle Aged; Postoperative Complications; Spain; Tacrolimus; Time Factors; Treatment Outcome

Supplementation of immunosuppressive therapy with mycophenolate mofetil (MMF) has been found to reduce the rate of acute rejection in renal transplantation. We report a dose-finding study for MMF when administered in combination with low-dose tacrolimus and corticosteroid prophylaxis in cadaveric renal transplant recipients.. Two hundred thirty-two patients at 16 centers were enrolled in this randomized, parallel-group study. The three treatment groups were tacrolimus and corticosteroids (MMF-0 group, n=82); tacrolimus, corticosteroids, and 1 g of MMF daily (MMF-1 g group, n=79); and tacrolimus, corticosteroids, and 2 g of MMF daily (MMF-2 g group, n=71). Study duration was 6 months, and patients were followed up for patient and graft survival for 12 months.. At 6 months posttransplantation, daily doses of 1 g and 2 g of MMF were associated with significantly lower rates of acute rejection compared with tacrolimus alone. The Kaplan-Meier rates were 48.5%, 24.9%, and 22.9%, respectively, for the three treatment groups when acute rejection was determined by clinical criteria (P=0.007). At month 12, patient survival rates were 100%, 97.5%, and 97.2% and graft survival rates were 90.2%, 92.4%, and 93.0% for the MMF-0 group, MMF-1 g group, and the MMF-2 g group, respectively. Gastrointestinal adverse events and leukopenia were higher in the MMF groups, especially in the MMF-2 g group (P<0.05).. Low-dose tacrolimus combined with a MMF dose of 1 g daily and corticosteroids provided an optimized efficacy and safety profile. A higher dose of MMF (2 g) was associated with greater toxicity without a significant improvement in efficacy.

Topics: Adrenal Cortex Hormones; Adult; Cadaver; Dose-Response Relationship, Drug; Drug Therapy, Combination; Female; Gastrointestinal Diseases; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Survival Analysis; Tacrolimus; Time Factors; Treatment Outcome

The evidence supporting an initial mycophenolate mofetil (MMF) dose of 2 g daily in tacrolimus-treated renal transplant recipients is limited. In a non-contemporaneous single-centre cohort study we compared the incidence of leukopaenia, rejection and graft dysfunction in patients initiated on MMF 1.5 g and 2 g daily. Baseline characteristics and tacrolimus trough levels were similar by MMF group. MMF doses became equivalent between groups by 12-months post-transplant, driven by dose reductions in the 2 g group. Leukopaenia occurred in 42.4% of patients by 12-months post-transplant. MMF 2 g was associated with a 1.80-fold increased risk of leukopaenia compared to 1.5 g. Rejection occurred in 44.8% of patients by 12-months post-transplantation. MMF 2 g was associated with half the risk of rejection relative to MMF 1.5 g. Over the first 7-years post-transplantation there was no difference in renal function between groups. Additionally, the development of leukopaenia or rejection did not result in reduced renal function at 7-years post-transplant. Leukopaenia was not associated with an increased incidence of serious infections or rejection. This study demonstrates the initial MMF dose has implications for the incidence of leukopaenia and rejection. Since neither dose produced superior long-term graft function, clinical equipoise remains regarding the optimal initial mycophenolate dose in tacrolimus-treated renal transplant recipients.

Topics: Adult; Female; Follow-Up Studies; Graft Rejection; Humans; Kidney Transplantation; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Pregnancy; Retrospective Studies; Tacrolimus; Time Factors

The immunosuppressants tacrolimus and mycophenolate are important components to the success of organ transplantation, but are also associated with adverse effects, such as nephrotoxicity, anemia, leukopenia, and new-onset diabetes after transplantation. In this report, we attempted to identify genetic variants which are associated with these adverse outcomes.. We performed a genome-wide association study, using a genotyping array tailored specifically for transplantation outcomes containing 722 147 single nucleotide polymorphisms, and 2 cohorts of kidney allograft recipients-a discovery cohort and a confirmation cohort-to identify and then confirm genetic variants associated with immunosuppressant pharmacokinetics and adverse outcomes.. Several genetic variants were found to be associated with tacrolimus trough concentrations. We did not confirm variants associated with the other phenotypes tested although several suggestive variants were identified.. These results show that adverse effects associated with tacrolimus and mycophenolate are complex, and recipient risk is not determined by a few genetic variants with large effects with but most likely are due to many variants, each with small effect sizes, and clinical factors.

Topics: Adult; Aged; Anemia; Diabetes Mellitus; Female; Genome-Wide Association Study; Genotype; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Leukopenia; Male; Middle Aged; Mycophenolic Acid; Pharmacogenomic Variants; Polymorphism, Single Nucleotide; Risk Assessment; Risk Factors; Tacrolimus; United States; Young Adult

Ehrlichiosis in lung transplant (LT) recipients is associated with severe outcomes. Ehrlichia ewingii is a less frequent cause of symptomatic ehrlichiosis, characterized by cytoplasmic inclusions (morulae) within circulating neutrophils. We report a case of E. ewingii infection in an LT recipient diagnosed promptly by blood smear exam and confirmed with molecular studies.

Topics: Aged; Animals; Anti-Bacterial Agents; Cytodiagnosis; Disease Transmission, Infectious; DNA, Bacterial; Doxycycline; Early Diagnosis; Ehrlichia; Ehrlichiosis; Female; Fever; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Ixodidae; Leukopenia; Lung Transplantation; Mycophenolic Acid; Neutrophils; Polymerase Chain Reaction; Prednisone; Tacrolimus; Thoracentesis; Thrombocytopenia; Tomography, X-Ray Computed

Secondary acute myeloid leukemia is a very rare complication in patients with solid organ transplantation. We report a 62 years old female who received a right single lung allograft for idiopathic pulmonary fibrosis. Her immunosuppression scheme consisted in prednisone, azathioprine, and tacrolimus. Two years after the transplantation, she presented with progressive pancytopenia. Bone marrow aspiration was informed as a M4 acute myeloid leukemia, confirmed by flow cytometry. Cytogenetic study was complex, including alterations in chromosome 5. A secondary acute myeloid leukemia was diagnosed. The patient developed nosocomial pneumonia and died a few days after the diagnosis, without specific treatment. The pathogenesis of acute myeloid leukemia is probably related to the intensive exposure to immunosuppressant, especially azathioprine, in these patients.

Topics: Azathioprine; Bone Marrow; Chromosomes, Human, Pair 5; Fatal Outcome; Female; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Leukopenia; Lung Transplantation; Middle Aged; Pancytopenia; Tacrolimus

Although survival among heart recipients has increased, a limiting factor is chronic adverse effects of immunosuppression therapy.. We performed a retrospective analysis of 22 patients (19 men and 3 women) with a mean age of 48 ± 12 years who underwent orthotropic heart transplantation. There were 20 (91%) patients who received induction therapy (basiliximab, Simulect, Novartis Europharm Limited). All patients were treated with standard triple immunosuppressive regimen (tacrolimus, mycophenolate mofetil, and steroids).. Patients were divided into 2 groups according to postoperative peripheral cytopenia diagnosis. There were 16 (73%) in the cytopenic group and 6 (27%) in the non-cytopenic group. Mean time of peripheral leucopenia detection was 65 ± 13 days following surgery. The blood leucocyte count was 0.98 ± 0.2 × 10(3)/mm(3) vs. 5.85 ± 0.9 × 10(3)/mm(3) in patients with peripheral cytopenia compared to non-cytopenic patients (p<0.01). There was a statistically important difference in duration of intensive care unit stay between the 2 groups (p<0.01). A correlation between tacrolimus serum concentration and risk for leucopenia was also detected (p<0.05).. Basiliximab administration as induction therapy, tacrolimus serum concentration, and duration of intensive care unit stay are risk factors for leucopenia.

Topics: Adult; Antibodies, Monoclonal; Basiliximab; Critical Care; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Induction Chemotherapy; Length of Stay; Leukopenia; Male; Middle Aged; Recombinant Fusion Proteins; Retrospective Studies; Risk Factors; Tacrolimus

The dose of mycophenolate mofetil (MMF) has been reduced in Asia due to side effects associated with the conventional fixed dose of 2-3 g/day. We aimed to determine the pharmacokinetics of a reduced dose of MMF and to validate its feasibility in combination with tacrolimus in living-donor liver transplantation (LDLT).. Two sequential studies were performed in adult LDLT between October 2009 and 2011. First, we performed a prospective pharmacokinetic study in 15 recipients. We measured the area under the curve from 0 to 12 hours (AUC(0-12)) for mycophenolic acid at postoperative days 7 and 14, and we performed a protocol biopsy before discharge. Second, among 215 recipients, we reviewed 74 patients who were initially administered a reduced dose of MMF (1.0 g/day) with tacrolimus (trough, 8-12 ng/mL during the first month, and 5-8 ng/mL thereafter), with a 1-year follow-up. We performed protocol biopsies at 2 weeks and 1 year post-LDLT.. In the first part of study, AUC(0-12) was less than 30 mgh/L in 93.3% of cases. In the second, validating study, 41.9% of the recipients needed dose reduction or cessation due to side effects within the first year after LDLT. At 12 months post-LDLT, 17.6% of the recipients were administered a lower dose of MMF (0.5 g/day), and 16.2% needed permanent cessation due to side effects. The 1- and 12-month rejection-free survival rates were 98.6% and 97.3%, respectively.. A reduced dose of MMF was associated with low blood levels compared to the existing recommended therapeutic range. However, reducing the dose of MMF combined with a low level of tacrolimus was feasible clinically, with an excellent short-term outcome in LDLT.

Topics: Adult; Aged; Area Under Curve; Drug Therapy, Combination; Female; Follow-Up Studies; Gastrointestinal Diseases; Graft Rejection; Humans; Immunosuppressive Agents; Leukopenia; Liver; Liver Failure; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; ROC Curve; Tacrolimus; Tissue Donors

Diagnosis and management of acute renal allograft dysfunction often pose challenge to nephrologists during practice. Acute rejection is a major cause of acute graft dysfunction but is rare in patients with leucopenia. Acute rejection can have either humoral or cellular components or sometimes mixed components. Mixed acute cellular and humoral rejection often present as steroid resistant rejection. Here we report a patient with live related renal transplant recipient with acute graft dysfunction with leucopenia who was found to have mixed acute cellular and humoral rejection.

Topics: Adult; Antilymphocyte Serum; Biopsy; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Male; Mycophenolic Acid; Plasma Exchange; Prednisolone; Tacrolimus; Transplantation, Homologous; Treatment Outcome; Ultrasonography, Doppler

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 transplantation in children has traditionally required immunosuppression with multiple medications including glucocorticoids. Data collected over almost 30 yr suggest that although glucocorticoids are efficacious as part of a regimen to minimize the incidence of acute rejection episodes, their use is associated with increased risk for post-transplant hypertension, hyperlipidemia, and reduced growth rates. We desired to reduce these complications and thus used an immunosuppressive protocol including daclizumab, tacrolimus, and mycophenolate mofetil and study the efficacy of this protocol in a population with a high percentage of African-American recipients. No patient received glucocorticoids at any time post-transplant. Our results show that at 1 yr post-transplant, glomerular filtration rate, serum glucose, calcium and phosphorous metabolism, serum magnesium, and serum lipids were similar in patients receiving steroid-free and those receiving steroid-based immunosuppression. The incidence of acute rejection was similar in the two groups. Hematocrit and white blood count levels were lower 1 month after transplant in the steroid-free patients but these levels increased within several months. Systolic blood pressure was similar in the two groups, although this was achieved, in part, in the patients who received steroids by the administration of medications to lower blood pressure. Finally, tacrolimus levels were similar in the two groups, but patients receiving steroids required higher doses of tacrolimus at several time points studied during the first post-transplant year. Taken together, our data suggests that at one-year follow-up, steroid-free immunosuppression is safe, and efficacious in pediatric renal transplant recipients.

Topics: Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Blood Glucose; Blood Pressure; Calcium; Child; Daclizumab; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunoglobulin G; Immunosuppressive Agents; Kidney Transplantation; Leukopenia; Lipids; Male; Mycophenolic Acid; Phosphorus; Tacrolimus; Thrombocytopenia

Chronic actinic dermatitis (CAD) is a photosensitivity disorder marked by severe eczematous lesions on exposed areas. Although associations with contact dermatitis, atopic dermatitis, and human immunodeficiency virus (HIV) have been suggested, its pathogenesis remains unknown. CAD is often refractory, and systemic administration of cyclosporin A has been the treatment of choice. Recently, topical tacrolimus therapy has been reported to be effective. We report the efficacy of topical tacrolimus treatment in a CAD patient who also had the complication of idiopathic leukopenia. A phototest showed marked suppression of erythema formation in the skin pre-treated with tacrolimus before UVB radiation but not in the skin treated after the irradiation. Therefore, it is suggested that tacrolimus may prevent UV-B induced erythema by suppressing a very early phase of the inflammatory process in CAD.

Topics: Administration, Cutaneous; Aged; Diagnosis, Differential; Facial Dermatoses; Humans; Immunosuppressive Agents; Leukopenia; Male; Photosensitivity Disorders; Skin Tests; Tacrolimus