tacrolimus and Infections

This study evaluated the relative efficacy and safety of tacrolimus, tacrolimus+mycophenolate mofetil (MMF), and cyclophosphamide (CYC) for lupus nephritis.. Randomized controlled trials (RCTs) were included to investigate the effectiveness and safety of tacrolimus, tacrolimus+MMF, and CYC as a lupus induction therapy. We performed a Bayesian network meta-analysis of the random effects to incorporate direct and indirect data from RCTs.. Four RCTs met the inclusion criteria, giving a sample size of 543 patients. Tacrolimus+MMF had a significantly higher overall response rate (complete plus partial remission) than CYC (OR 4.22, 95% credible interval (CrI) 11.02 - 29.23) and was more efficacious than tacrolimus (OR 2.02, 95% CrI 0.24 - 28.51). Tacrolimus had higher overall response than CYC (OR 2.14, 95% CrI 0.38 - 12.33). Ranking the treatments based on the surface under the cumulative ranking curve (SUCRA) suggested that tacrolimus+MMF was the best treatment by the overall response (SUCRA = 0.876), followed by tacrolimus (SUCRA = 0.533) and CYC (SUCRA = 0.091). Tacrolimus was the least likely to cause serious infections (-SUCRA = 0.758), followed by CYC (SUCRA = 0.398) and tacrolimus+MMF (SUCRA = 0.345).. Tacrolimus+MMF was the most effective induction treatment for patients with lupus nephritis, and tacrolimus was the least likely to cause severe infections.

Topics: Bayes Theorem; Cyclophosphamide; Humans; Immunosuppressive Agents; Infections; Lupus Nephritis; Mycophenolic Acid; Remission Induction; Tacrolimus; Treatment Outcome

The purpose of this study was to determine efficacy and safety of cyclosporine A (CsA) for patients with steroid-resistant nephrotic syndrome (SRNS).. The Cochrane Library and PubMed were searched to extract the associated studies on Oct 10, 2018, and the meta-analysis method was used to pool and analyze the applicable investigations included in this study. The P(opulation) I(ntervention) C(omparison) O(utcome) of the study were defined as follows: P: Patients with SRNS; I: treated with CsA, cyclophosphamide (CYC), tacrolimus (TAC) or placebo/not treatment (P/NT); C: CsA vs. placebo/nontreatment (P/NT), CsA vs. CYC, CsA vs. TAC; O: complete remission (CR), total remission (TR; complete or partial remission (PR)), urine erythrocyte number, proteinuria levels, albumin, proteinuria, serum creatinine, and plasma cholesterol, etc. Data were extracted and pooled using RevMan 5.3.. In the therapeutic regimen of CsA vs. placebo/nontreatment (P/NT), the results indicated that the CsA group had high values of CR, TR, and low values of proteinuria, serum creatinine, and plasma cholesterol when compared with those in the placebo group. In comparing CsA vs. cyclophosphamide (CYC), the results indicated that the CsA group had higher TR than the CYC group. In comparing CsA vs. tacrolimus (TAC), the results revealed insignificant differences in CR, and TR between the CsA and TAC groups. The safety of CsA was also assessed. The incidence of gum hyperplasia in CsA group was higher than that in the P/NT group, with no differences in incidence of infections or hypertension between CsA and P/NT groups. There was no difference in the incidence of hypertension between the CsA and TAC groups.. CsA is an effective and safe agent in the therapy of patients with SRNS.

Topics: Cholesterol; Creatinine; Cyclophosphamide; Cyclosporine; Drug Resistance; Gingiva; Humans; Hyperplasia; Hypertension; Immunosuppressive Agents; Infections; Nephrotic Syndrome; Proteinuria; Steroids; Tacrolimus

Infection is an important concern in lupus nephritis treatment, but few studies have focused on this complication. Available data suggest marked variation in occurrence and outcome. This meta-analysis and review aims to provide an overview of infective complications, focusing on the risk factors and outcomes.. Original articles on lupus nephritis Class III/IV/V published in the period January 1980 to December 2016 were identified from the Pubmed/Medline electronic database. Meta-analysis of randomized controlled trials was performed to investigate total and serious infections at different phases of treatment and their associated factors. A descriptive review that included all studies was also performed, providing details on the types of infection, infection-related mortality, and potential impact of different eras on infection rates.. A total of 56 studies (32 randomized controlled trials) were included. The incidence rates of overall and serious infections were higher during the induction than maintenance phase of therapy, with serious infections occurring at 8.2-50 and 3.5 per 100 patient-years, respectively. Recent data, predominantly from Asia, suggested lower rates of overall infections with induction regimens that included tacrolimus compared with mycophenolate (risk ratio 0.50, 95% confidence interval 0.33-0.76, p = 0.001). Mycophenolate as induction treatment was associated with lower overall infection risks than cyclophosphamide in non-Asians (risk ratio 0.60, 95% confidence interval 0.48-0.75, p < 0.001). The rates of serious infections were 4.1-25% in Asian and 4.4-8.5% in non-Asian countries; with infection-related mortality rates of 0-6.7% in Asian, compared to 0-2.1% in non-Asian locations.. Infection remains a serious complication during treatment of lupus nephritis, but the reported rates and outcomes varied markedly. Mycophenolate was associated with lower infection risk than cyclophosphamide in non-Asians. Infection-related deaths appeared more common in Asian patients.

Topics: Cyclophosphamide; Humans; Immunosuppressive Agents; Infections; Lupus Nephritis; Mycophenolic Acid; Randomized Controlled Trials as Topic; Risk Factors; Tacrolimus

Idiopathic membranous nephropathy (IMN) is a common cause of nephrotic syndrome in adults and one of the leading causes of end-stage renal disease (ESRD). During recent years, the incidence of IMN has been increasing. The main treatment option for IMN is the use of immunosuppressive (IS) drugs combined with glucocorticoids (GC). However, the infection risk with different IS drug treatments has not been systematically compared. Therefore, a network meta-analysis was performed to compare the risk of infection of different IS drug treatments for IMN.. Randomized controlled trials (RCTs) that assessed the risk of infection in patients with IMN treated with different IS drugs combined with GC were included in the network meta-analysis. Risk ratios for dichotomous data with 95% confidence intervals (CI) were calculated and the data were pooled with a random-effects model. The surface under the cumulative ranking area (SUCRA) was calculated to rank the risk of infection with different interventions.. A total of 38 RCTs with 2066 participants were included for comparison of nine interventions. Tacrolimus combined with GC (TAC + GC) was associated with a significantly lower risk of infection than that with intravenous cyclophosphamide (IVCTX) + GC with a risk ratio (95% CI) of 0.52 (0.34-0.79). IVCTX + GC was associated with a significantly higher risk of infection than that with TAC + GC, cyclosporin (CSA) + GC, and oral cyclophosphamide (POCTX) + GC. A sensitivity analysis, excluding studies with a very long follow-up period, revealed minimal differences in the estimates. The SUCRA showed that CSA + GC had the lowest risk of infection (SUCRA 86.0%), and the second best treatment was POCTX + GC (SUCRA 78.6%). Conversely, IVCTX + GC (SUCRA 16.2%) had a higher risk of infection than that with the other IS drugs.. CSA + GC and POCTX+ GC were associated with a lower risk of infection than that with other IS drugs combined with GC for IMN. Combined with comparative efficacy data, these results can help patients make informed decisions about treatment options for IMN. PROSPERO registration: CRD42018104849.

Topics: China; Cyclophosphamide; Cyclosporine; Drug Therapy, Combination; Drug-Related Side Effects and Adverse Reactions; Glomerulonephritis, Membranous; Glucocorticoids; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Randomized Controlled Trials as Topic; Risk; Tacrolimus

Tacrolimus and cyclosporine are the 2 major immunosuppressants for lung transplantation. Several studies have compared these 2 drugs, but the outcomes were not consistent. The aim of this meta-analysis of randomized controlled trials (RCTs) was to compare the beneficial and harmful effects of tacrolimus and cyclosporine as the primary immunosuppressant for lung transplant recipients.. We conducted searches of electronic databases and manual bibliographies. We performed a meta-analysis of all RCTs comparing tacrolimus with cyclosporine as primary immunosuppression for lung transplant recipients. Extracted, pooled data for mortality, acute rejection, withdrawals, and adverse events were analyzed using Mantel-Haenszel tests with a random effects model.. Three RCTs including 297 patients were assessed in this study. Mortality at 1 year or more was comparable between lung recipients treated with tacrolimus and cyclosporine (odds ratio [OR], 0.94; 95% confidence interval [CI], 0.42-2.10; P = .88). Tacrolimus-treated patients experienced fewer incidences of acute rejection (MD = -0.14; 95% CI, -0.28 to -0.01; P = .04). Pooled analysis showed a trend toward a lower risk of bronchiolitis obliterans syndrome (BOS) among tacrolimus-treated patients, although it did not reach significances (OR, 0.53; 95% CI, 0.25-1.12; P = .10). Fewer patients stopped tacrolimus than cyclosporine (OR, 0.12; 95% CI, 0.03-0.48; P = .003). The rate of new-onset diabetes was higher among the tacrolimus group (OR, 3.69; 95% CI, 1.17-11.62; P = .03). The incidence of hypertension and renal dysfunction were comparable in these 2 groups (OR, 0.24; 95% CI, 0.03-1.70; P = .15; and OR, 1.67; 95% CI, 0.70-3.96; P = .25, respectively). There was a trend toward lower risk of malignancy in tacrolimus-treated patients, although it did not reach significance either (OR, 0.19; 95% CI, 0.03-1.13; P = .07). The incidence of infection was comparable in these 2 groups (MD = -0.29, 95% CI, -0.68 to 0.11; P = .16).. Using tacrolimus as primary immunosuppressant for lung transplant recipient resulted in comparable survival and reduction in acute rejection episodes when compared with cyclosporine.

Topics: Adult; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infections; Lung Transplantation; Odds Ratio; Postoperative Complications; Randomized Controlled Trials as Topic; Registries; Survival Rate; Tacrolimus; Treatment Outcome

Atopic eczema is predominantly a disease of children and infants, and is often a significant burden for both the sufferer and the family. Pimecrolimus cream 1% (Elidel) is a topical calcineurin inhibitor that has been developed for the treatment of inflammatory skin diseases. When applied twice daily, pimecrolimus has been shown to be effective and well tolerated in paediatric patients with mild to moderate atopic eczema, and appears to be particularly suitable for use on the face, the neck and skin folds. Reduction of pruritus or erythema can be seen within 48 hours of initiating treatment, and when used at the first signs or symptoms of recurrence, pimecrolimus can significantly reduce the incidence of flares and the amount of topical corticosteroid used. Long-term pimecrolimus therapy shows that the initial reduction of disease severity (Eczema Area and Severity Index) is sustained and that most patients have minimal residual disease at 2 years. The most common application-site reaction is a mild to moderate, transient, warm/burning sensation occurring in approximately 10% of patients. Blood concentrations of pimecrolimus following topical administration remain low in all patients. Currently there is no evidence for systemic adverse events, immune suppression or alterations in the vaccine response, after short-term or prolonged treatment. In conclusion, pimecrolimus is an effective treatment option for the short-term treatment and long-term control of atopic eczema in paediatric patients.

Topics: Administration, Cutaneous; Adolescent; Animals; Body Size; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Humans; Immunosuppressive Agents; Infant; Infections; Severity of Illness Index; Skin; Skin Diseases, Infectious; Tacrolimus

To determine how well tacrolimus (FK506) and cyclosporin A (CsA) are tolerated after HLA-identical blood stem cell transplantation, we performed a retrospective review of 87 adults transplanted consecutively who received FK506 (n = 40) or CsA (n = 47) in a nonrandomized fashion in combination with methylprednisolone for graft-versus-host disease (GVHD) prophylaxis and compared the incidences of complications potentially related to the immunosuppressive agents. Pre-transplant demographic characteristics, drug compliance and rates of acute GVHD were comparable for the two groups. Following first discharge, fewer patients in the FK506 group required antihypertensive therapy (32 vs 59%, P = 0.022), but more required insulin (34 vs 10%, P = 0.014). There was also a trend for more hyperkalemia and less moderate-to-severe venoocclusive disease in the FK506 group. However, nephrotoxicity, neurotoxicity, hemolytic-uremic syndrome, and cytomegaloviral or fungal infections through the first 100 days post-transplant did not differ significantly between the two groups. We conclude that for allogeneic blood stem cell transplant recipients, the incidence of complications related to FK506 and CsA in equally effective dose schedules in combination with methylprednisolone are similar with the exception of the risks of hypertension and hyperglycemia.

Topics: Acute Kidney Injury; Adolescent; Adult; Chemical and Drug Induced Liver Injury; Cyclosporine; Female; Hematopoietic Stem Cell Transplantation; Hepatic Veno-Occlusive Disease; Humans; Hyperglycemia; Hyperkalemia; Hypertension; Immunosuppressive Agents; Incidence; Infections; Male; Methylprednisolone; Middle Aged; Patient Compliance; Retrospective Studies; Seizures; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

Currently, expected 10-year first graft survival rates for kidneys from HLA-identical sibling, 1-haplotype-matched relative, and cadaver donors are 74, 51, and 40%, respectively. Histocompatibility, immunological conditioning with blood products, and immunosuppression with glucocorticoids, azathioprine, cyclosporin, and the antithymocyte (antilymphocyte) antibody preparations have been significant factors in the gradual improvement of kidney graft survival rates. Nearly all immunosuppression regimens are cyclosporin-based. Antithymocyte antibody induction therapy with delayed administration of cyclosporin is widely practised to avoid cyclosporin nephrotoxicity while the kidney graft is recovering from preservation injury. Late cyclosporin withdrawal results in inferior cadaver kidney transplant survival rates. Rejection crises usually respond to high dose glucocorticoid therapy. Glucocorticoid-resistant rejection usually responds to treatment with antithymocyte antibody. FK-506 is a promising new immunosuppressant that has properties similar to cyclosporin. Prophylaxis against viral, bacterial and fungal infections is necessary to reduce the morbidity of immunosuppression. The incidence of malignant conditions associated with viral infections is significantly increased with immunosuppression. New immunopharmacological agents and advances in genetic procedures may allow the induction of specific transplantation tolerance and successful xenotransplantation within the next decade.

Topics: Antilymphocyte Serum; Azathioprine; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Kidney Transplantation; Neoplasms; Prednisolone; Tacrolimus

The discovery and clinical use of the immunosuppressants cyclosporin A, FK506, and rapamycin have greatly advanced solid organ and bone marrow transplantation. Though active as antibiotics against a variety of pathogens, their utility has been severely limited by toxicity. Research on the immunophilins, the major binding proteins of these drugs, has given new insights into protein folding and transport as well as mediators of signal transduction in mammalian cells. Microbial immunophilins may also have direct relevance to the intracellular survival of important human pathogens. Defining the mechanisms of enhanced virulence generated by these proteins holds great promise for understanding both the fundamental pathogenesis of these organisms and the immune response generated against them. Such an understanding may provide novel targets for the design of anti-infective agents as well as assist in the development of future immunosuppressives.

Topics: Amino Acid Isomerases; Animals; Anti-Bacterial Agents; Carrier Proteins; Cyclosporine; DNA-Binding Proteins; Heat-Shock Proteins; Humans; Immunity; Immunosuppressive Agents; Infections; Lymphocyte Activation; Peptidylprolyl Isomerase; Polyenes; Sirolimus; Tacrolimus; Tacrolimus Binding Proteins; Virulence

In a phase 2 study, kidney transplant recipients of low immunologic risk who switched from a calcineurin inhibitor (CNI) to belatacept had improved kidney function at 12 months postconversion versus those continuing CNI therapy, with a low rate of acute rejection and no transplant loss.. 36-month follow-up of the intention-to-treat population.. CNI-treated adult kidney transplant recipients with stable transplant function (estimated glomerular filtration rate [eGFR], 35-75mL/min/1.73m. At 6 to 36 months posttransplantation, patients were randomly assigned to switch to belatacept-based immunosuppression (n=84) or continue CNI-based therapy (n=89).. Safety was the primary outcome. eGFR, acute rejection, transplant loss, and death were also assessed.. Treatment exposure-adjusted incidence rates for safety, repeated-measures modeling for eGFR, Kaplan-Meier analyses for efficacy.. Exploratory post hoc analysis with a small sample size.. Switching patients from a CNI to belatacept may represent a safe approach to immunosuppression and is being further explored in an ongoing phase 3b trial.

Topics: Abatacept; Adult; Calcineurin Inhibitors; Cyclosporine; Drug Substitution; Female; Graft Rejection; Graft Survival; Humans; Immunocompromised Host; Immunosuppressive Agents; Infections; Kidney Transplantation; Lymphoproliferative Disorders; Male; Middle Aged; Mortality; Neoplasms; Tacrolimus; Treatment Outcome

Different types of graft-versus-host disease prophylaxis have been proposed in the setting of reduced intensity and non-myeloablative allogeneic stem cell transplantation. An alternative combination with sirolimus and tacrolimus has recently been tested although comparative studies against the classical combination of a calcineurin inhibitor and mycophenolate mofetil or methotrexate are lacking. We describe the results of a prospective, multicenter trial using sirolimus + tacrolimus as immunoprophylaxis, and compare this approach with our previous experience using cyclosporine + mycophenolate in the setting of unrelated donor transplantation setting after reduced-intensity conditioning. Forty-five patients received cyclosporine + mycophenolate between 2002 and mid-2007, while the subsequent 50 patients, who were transplanted from late 2007, were given sirolimus + tacrolimus. No significant differences were observed in terms of hematopoietic recovery or acute graft-versus-host disease overall, although gastrointestinal acute graft-versus-host disease grade ≥ 2 was more common in the cyclosporine + mycophenolate group (55% versus 21%, respectively, P=0.003). The 1-year cumulative incidence of chronic graft-versus-host disease was 50% versus 90% for the patients treated with the sirolimus- versus cyclosporine-based regimen, respectively (P<0.001), while the incidence of extensive chronic disease was 27% versus 49%, respectively (P=0.043). The 2-year non-relapse mortality rate was 18% versus 38% for patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively (P=0.02). The event-free survival and overall survival at 2 years were 53% versus 29% (P=0.028) and 70% versus 45% (P=0.018) among patients receiving the sirolimus- versus the cyclosporine-based regimen, respectively. In conclusion, in the setting of reduced intensity transplantation from an unrelated donor, promising results can be achieved with the combination of sirolimus + tacrolimus, due to a lower risk of chronic graft-versus-host disease and non-relapse mortality, which translates into better event-free and overall survival rates, in comparison with those achieved with cyclosporine + mycophenolate.

Topics: Adult; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Cyclosporine; Disease-Free Survival; Female; Gastrointestinal Diseases; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Infections; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Sirolimus; Survival Rate; Tacrolimus; Time Factors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Unrelated Donors; Young Adult

Pharmacokinetic monitoring of CNI is unsatisfactory, because at comparable CNI blood concentrations frequency and severity of adverse effects vary considerably among individual patients. Determining the RGE of NFAT-regulated genes in leukocytes is a new pharmacodynamic approach to measure directly the functional consequences of calcineurin inhibition in T-lymphocytes. We compared clinical outcome parameters and RGE of activated T-cells after pLtx. We measured prospectively RGE of NFAT regulated genes in 33 pLTX recipients in the maintenance period after pLTX. CsA-treated patients with recurrent infections had significantly lower RGE rates (27%) than children without recurrent infections (50%; p = 0.04), whereas pharmacokinetic parameters of CsA and the concomitant immunosuppressive therapy were comparable between both groups. In patients on tacrolimus-based IS therapy NFAT RGE was only slightly reduced (90%). Pharmacodynamic monitoring of CsA by measurement of RGE in T-lymphocytes has the potential to identify over-immunosuppressed pediatric liver transplant recipients on a CsA-based IS therapy, while in children on low-dose tacrolimus therapy, RGE measurement does not provide additional clinically useful information.

Topics: Adolescent; Biomarkers; Child; Child, Preschool; Cyclosporine; Drug Monitoring; Female; Gene Expression Regulation; Granulocyte-Macrophage Colony-Stimulating Factor; Humans; Immunosuppressive Agents; Infections; Interferon-gamma; Interleukin-2; Liver Transplantation; Male; NFATC Transcription Factors; Prospective Studies; Real-Time Polymerase Chain Reaction; T-Lymphocytes; Tacrolimus; Young Adult

Reducing side effects of immunosuppressive regimens has become a priority in transplantation medicine because of the large number of patients and grafts that succumb to infection in the short term and cardiovascular disease in the long term. The Symphony study was a 12-month prospective, randomized, open-label, multi-centre, four parallel arm study that aimed to evaluate the safety and efficacy of low-dose immunosuppressive regimens compared with a standard-dose regimen in renal transplant recipients. This sub-analysis focuses on specific toxicities observed with the low-dose regimens.. Adult patients (n = 1645) scheduled to undergo renal transplantation received low-dose cyclosporine (CsA), tacrolimus (Tac) or sirolimus (SRL) in addition to daclizumab induction or standard-dose cyclosporine without induction. All patients received mycophenolate mofetil and corticosteroids. We evaluated the incidence of adverse events (AEs), tested specific group differences and assessed the relationship of selected AEs with drug levels.. The four arms had similar incidences of AEs, but serious AEs were more common with low-dose SRL and led to more discontinuations. Infections were the most common AEs, with the highest incidence in the standard-dose CsA group, in particular, cytomegalovirus (CMV) infections. Low-dose Tac had the most reports of new-onset diabetes, leucopenia and diarrhoea. Low-dose SRL negatively influenced triglycerides, wound healing, lymphocele and anaemia. We found only weak relationships between specific AEs and drug levels.. Despite the low doses, CsA, Tac and SRL retained distinct and different toxicity profiles. These findings may be of relevance for tailoring specific immunosuppressive regimens to patients with particular needs.

Topics: Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Calcineurin Inhibitors; Cyclosporine; Daclizumab; Delayed Graft Function; Female; Humans; Immunoglobulin G; Immunosuppressive Agents; Infections; Kidney Transplantation; Lipid Metabolism; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Sirolimus; Tacrolimus; Treatment Outcome

We sought to reduce the risk of infectious complications and nonrelapse mortality (NRM) associated with the use of antithymocyte globulin (ATG) without compromising control of acute graft-versus-host disease (aGVHD) in patients undergoing reduced-intensity conditioning (RIC) transplantation. As part of an ongoing quality improvement effort, we lowered the dose of rabbit ATG from 7.5 mg/kg of ATG (R-ATG) (n = 39) to 6.0 mg/kg of ATG (r-ATG) (n = 33) in association with fludarabine (Flu) and busulfan (BU) RIC transplantation and then monitored patients for adverse events, relapse, and survival. Of the 72 mostly high risk (82%) patients studied, 89% received unrelated donor allografts, 25% of which were HLA-mismatched. No differences in posttransplantation full donor-cell chimerism rates were observed between the 2 ATG-dose groups (P > .05). When R-ATG versus r-ATG patients were compared, we observed no significant difference in the cumulative incidence of grade II-IV aGVHD (32% versus 27%; P = .73) or grade III-IV aGVHD (23% versus 11%; P = .28). However, the r-ATG group had significantly less cytomegalovirus (CMV) reactivation (64% versus 30%; P = .005) and bacterial infections (56% versus 18%; P = .001), a better 1-year cumulative incidence of NRM (18% versus 3%; P = .03), and a trend for better 1-year overall survival (OS) (64% versus 84%; P = .07) compared to R-ATG patients. A seemingly modest reduction in the dose of rabbit ATG did not compromise control of aGVHD or achievement of donor chimerism, but led to a significant decrease in the risk of serious infections and NRM in high-risk RIC allograft recipients.

Topics: Adult; Aged; Animals; Anti-Infective Agents; Antilymphocyte Serum; Busulfan; Disease Susceptibility; Female; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunocompromised Host; Immunosuppressive Agents; Infection Control; Infections; Male; Medical Audit; Methotrexate; Middle Aged; Myeloablative Agonists; Patient Isolation; Postoperative Complications; Rabbits; T-Lymphocytes; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Vidarabine; Young Adult

Atopic dermatitis often requires long-term treatment. This European, multicentre, non-comparative, 24-month, follow-up study investigated the efficacy and safety of 0.1% tacrolimus ointment applied to adults with atopic dermatitis. Patients (n=672) applied a thin layer of 0.1% tacrolimus ointment twice daily for 3 weeks to all affected body areas. After 3 weeks, ointment was applied once daily. Clinical improvement became apparent after 2 weeks of treatment and 65.5% of patients had a rating of clearance, excellent or marked improvement by month 3. Skin burning (31.7%) was the most common causally-related adverse event, followed by pruritus (11.3%) folliculitis (6.4%), alcohol intolerance (5.7%), herpes simplex (5.7%), skin infection (4.6%), skin erythema (3.3%) and hyperaesthesia (2.4%). The most commonly reported infections were flu syndrome (12.9%), skin infection (9.8%), folliculitis (7.4%) and herpes simplex (7.0%). Long-term treatment up to 24 months with 0.1% tacrolimus ointment is safe and efficacious in adults with atopic dermatitis.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Dermatitis, Atopic; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Infections; Male; Middle Aged; Ointments; Patient Satisfaction; Quality of Life; Tacrolimus; Treatment Outcome

Steroids have occupied a major role in renal transplantation for more than 4 decades. However, chronic use of steroids is associated with numerous comorbidities. We sought to elucidate the safety and efficacy of a steroid-free immunosuppression regimen in live-donor renal transplant recipients.. One hundred patients were randomized to receive tacrolimus, mycophenolate mofetil, basiliximab induction, and steroids only for 3 days (experimental group, n=50 patients) or tacrolimus, mycophenolate mofetil, basiliximab induction, and steroid maintenance (control group, n=50 patients,). The median follow-up was 12 months.. Patient and graft survival rates were 100% in both groups. The rate of biopsy-proven acute rejection was 16% in both groups. For patients in the control group, the mean serum creatinine level was 111.22 micromol /L compared with 110.39 micromol/L in patients in the experimental group. Posttransplant hypertension was encountered in 4% of the patients in the experimental group compared with 24% of the patients in the control group (P = .0009). Posttransplant diabetes mellitus was detected in 4% of the patients in the experimental group compared with 16% of the patients in the control group (P = .037). Posttransplant weight gain was reported in 6% of the patients in the experimental group compared with 15% of the patients in the control group (P = .001). The chronic allograft damage indexes of biopsy specimens at 1-year follow-up were comparable in both groups (2.48 vs 2.28, respectively) (P = .16).. In living-donor renal transplant recipients with low immunologic risk, steroid avoidance (using basiliximab induction, tacrolimus, mycophenolate mofetil maintenance, and 3 days' steroid treatment) is feasible, safe, and carries with it fewer morbidities compared with the same immunosuppressive protocol with steroid maintenance. Longer follow-ups are required to prove the safety of this regimen.

Topics: Adolescent; Adult; Antibodies, Monoclonal; Basiliximab; Child; Child, Preschool; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Living Donors; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Recombinant Fusion Proteins; Steroids; Tacrolimus; Treatment Outcome

Steroid-free immunosuppressive regimens reduce corticosteroid-related side effects in liver transplant recipients although their efficacy is very variable. We evaluated the efficacy and safety of a steroid-free regimen in a 6-month, open-label, multicenter, pilot study, which involved 102 liver transplant patients treated with daclizumab (2 mg/kg within 6 h following transplant and 1 mg/kg on day 7), mycophenolate mofetil (MMF, 1 g b.i.d) and tacrolimus (trough levels of 5-15 ng/ml in the first month and 5-10 ng/ml thereafter). One intra-operative dose of methylprednisolone was administered. At 6 months, the acute rejection rate was 9.8%, and patient and graft survival rates were 96% and 95%, respectively. Acute rejection rates were similar for hepatitis C-positive patients (8.6%) and hepatitis C-negative patients (10.4%). Infections occurred in 22% of patients; most cases were considered mild or moderate. Post-transplantation hypertension and diabetes mellitus developed in 37% and 14% of patients, respectively, during the study period, but were markedly less frequent (8% and 6%, respectively) at 6 months. Hypercholesterolemia was observed in only 2% of patients. In conclusion, the steroid-free immunosuppressive regimen of daclizumab, MMF, and tacrolimus effectively prevents acute rejection after liver transplantation without decreasing safety.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Daclizumab; Female; Graft Rejection; Humans; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Infections; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Safety; Tacrolimus

This study presents the first prospective multicenter study assessing sirolimus-based immunosuppression with early (4-day) corticosteroid withdrawal (CSWD) in renal transplantation. Immunosuppression included: anti-IL-2 receptor antibody and tacrolimus/sirolimus. Inclusion criteria included adult primary recipients. Exclusion criteria included: (i) African Americans, (ii) current PRA >50%, (iii) multiple organ transplants, (iv) WBC < 3000 cells/microL and (v) fasting hypercholesterolemia/hypertriglyceridemia. The primary endpoints were acute rejection and the proportion of patients off corticosteroids. Seventy-seven patients were enrolled: mean age of 49.7 +/- 12 years. Transplants included: cadaveric (26%) and living donor (74%). Patient and graft survival were 100%. Biopsy proven acute rejection occurred in 13%; presumptive rejection in 10.5%. Banff grades included: IA (seven patients), IB (one patient), IIA (one patient) and IIB (one patient). Renal function at 1 year: serum creatinine (1.18 +/- 0.06 mg/dL). Mean weight gain was minimal at 1 year: 3 +/- 2 kg/patient. Mild increases in total, LDL and HDL cholesterol were observed and new antilipid agent use occurred in 26 patients. In conclusion, early CSWD under tacrolimus/sirolimus-based immunosuppression in selected, low-risk renal transplant recipients provides: (i) excellent patient and graft survival, (ii) good renal function, (iii) reduced hyperlipidemia and antilipid agent use and (iv) low acute rejection rates.

Topics: Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Biopsy; Blood Pressure; Body Weight; Cadaver; Cardiovascular System; Cholesterol, HDL; Cholesterol, LDL; Creatinine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Living Donors; Male; Middle Aged; Pilot Projects; Recombinant Fusion Proteins; Risk Factors; Sirolimus; Steroids; Tacrolimus; Time Factors; Treatment Outcome

Topics: Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infections; Japan; Kidney Function Tests; Kidney Transplantation; Living Donors; Postoperative Complications; Ribonucleosides; Survival Analysis; Tacrolimus; Time Factors

Between September 2002 and February 2004, 40 kidney transplant (27 from deceased and 13 from living donors) recipients (25 male and 15 female, aged 50.3 +/- 15.1 years) were treated with Campath 1H (C 1H; 30 mg/dose IV) for biopsy-proven steroid-resistant rejection (SRR) or rejections equal to or worse than Banff 1B. All transplantations occurred between August 2001 and May 2003. All patients had received antibody preconditioning (RATG 5 mg/kg, n = 34; C 1H 60 mg, n = 4; C 1H 30 mg, n = 2) preoperatively and were treated with Tacrolimus monotherapy (target level 10 ng/ml) postoperatively and subsequent spaced weaning. Elevated creatinine levels at follow-up were evaluated by renal transplant biopsy. Rejection was treated with steroids, reversal of weaning, addition of sirolimus, and/or antibody treatment, depending on grade of rejection. The mean duration of follow-up was 453 +/- 163 days after C 1H administration. Twenty-nine patients received C 1H for SRR and 11 patients for Banff 1B or worse rejections; 26 patients received more than 1 dose of C 1H. Graft survival was 62.5% (25 patients); 6 of the 15 allografts (40%) that failed had presented with rejections because of noncompliance. Graft survival in compliant patients with SRR or rejections equal to or worse than Banff 1B was 73.5% (25 of 34). Fourteen patients (35%) had infectious complications, of whom 2 patients (5%) died. C 1H is an effective agent for SRR and Banff 1B or worse rejections, with 95% patient survival and 73.5% graft survival (in compliant patients). The number of doses of 30 mg C 1H should be restricted to two, as there is a high incidence of potentially fatal infectious complications.

Topics: Acute Disease; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Biopsy; Creatinine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus

Blockade of costimulation and adhesion signaling is an attractive approach to interfere with graft rejection. Between January 1997 and May 1999, forty adults having benign liver diseases were included in a prospective, randomized study comparing tacrolimus plus low-dose short-term steroids without (n=20, TAC group) or with a 10-day course of antihuman CD2 monoclonal antibody (n=20, BTI group).. At day 7, histological rejection expressed by mean Banff scores (2.3+/-1.6 vs. 5.4+/-1.6 in the TAC group; P<0.0001) and incidence of moderate to severe rejection (score>or=6) (0 vs. 10 [50%] in the TAC group; P<0.001) were significantly lower in the BTI group. Rejection was treated in 10% (two patients) of BTI patients during the first 3 months and in 15% during the whole follow-up and in 25% (five patients) of TAC patients (P=NS). None of the BTI-patients presented with an adverse event. Three-month, 1-year, and 5-year actual patient survival rates were 100%, 95%, and 95% in the BTI group and 100%, 100%, and 85% in the TAC group. Graft survival rates were 100%, 90%, and 90% in the BTI group and 95%, 95%, and 80% in the TAC group (P=NS). The mAb had no negative impact on infectious or tumor events.. Antihuman CD2 monoclonal antibody is a safe immunosuppressive drug which has a favorable impact on early immunological follow-up of liver transplanted patients. The antibody had no impact on late patient and graft survival.

Topics: Adult; Aged; Antibodies, Monoclonal; CD2 Antigens; Dose-Response Relationship, Drug; Drug Administration Schedule; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infections; Liver Failure; Liver Transplantation; Lymphocyte Count; Middle Aged; Neoplasms; Postoperative Period; Steroids; Survival Analysis; Tacrolimus

Topics: Adrenal Cortex Hormones; Adult; Azathioprine; Brazil; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Postoperative Complications; Protozoan Infections; Tacrolimus; Time Factors

With tacrolimus-based immunosuppression, it appears safe to withdraw steroids 3 to 6 months after renal transplantation. We hypothesized whether steroids could also be safely withdrawn early after transplantation.. Sixty-two patients (first or second transplant, with no previous immunological failure, and current panel reactive human leucocyte antigen [HLA] antibodies [PRA]<50%), treated with tacrolimus, were prospectively randomized to stop steroids (10 mg prednisolone) after day 7 posttransplantation (stop group [STOP], n=28) or to gradually wean off steroids in 3 to 6 months (tapering group [TAP], n=34). Analyses were performed on an intention-to-treat basis.. After a median follow-up of 2.7 years, patient and graft survival were 97 and 90% and comparable between both groups (P =0.11 and P=0.13, respectively). The incidence of acute rejection was 29 (STOP) versus 33% (TAP) ( P=0.30). The time to the first rejection was a median of 35 days (STOP) versus 11 days (TAP) ( =0.19). The severity of the rejections (1997 Banff classification) was comparable (P =0.57). Creatinine clearance and proteinuria were similar (P >0.70). The incidence of infections was comparable ( P>0.10). The incidence of new-onset diabetes mellitus, defined as the use of antidiabetic medication, was 8.0 (STOP) versus 30.3% (TAP) (P =0.04). All cases occurred in the STOP group after 1 year, while all cases occurred in TAP in the first 4 months ( P<0.001).. Compared with tapering in 3 to 6 months, stopping steroids 1 week posttransplantation results in comparable patient and graft survival and in a similar incidence of acute rejections. The incidence of new-onset diabetes may be reduced. The immunosuppressive benefit of adding 10 mg prednisolone to tacrolimus seems to be limited.

Topics: Acute Disease; Adult; Aged; Anti-Inflammatory Agents; Creatinine; Diabetes Mellitus; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Incidence; Infections; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Postoperative Complications; Prednisolone; Prospective Studies; Proteinuria; Risk Factors; Tacrolimus

The need for better immunosuppressive protocols after lung transplantation led us to investigate tacrolimus (Tac) in combination with mycophenolate mofetil (MMF) and steroids or cyclosporine (CsA) in combination with MMF and steroids in a prospective, open, randomized trial after lung transplantation.. Between September 1997 and April 1999, 50 lung transplant recipients were randomized to receive either Tac (n = 26) or CsA (n = 24) in combination with MMF and steroids. All patients underwent induction therapy with rabbit antithymocyte globulin (ATG) for 3 days. Freedom from acute rejection (AR), patient survival, infection episodes, and side effects were monitored.. There was no difference in patient demographics between the two groups. Six-month and 1-year survival was similar (84.6% and 73.1% in the Tac group vs 83.3% and 79.2% in the CsA group). Freedom from AR at 6 months and 1 year after lung transplantation was slightly higher in the Tac group (57.7% and 50% vs 45.8% and 33.3%, p = not significant [n.s.]), whereas the number of treated rejection episodes per 100 patient days in the Tac group was significantly lower (0.225 vs 0.426, p < .05). Four patients in the CsA group had to be switched to Tac. Two patients in the CsA group had to be retransplanted. Incidence of infections was similar in both groups with a trend toward more fungal infections in the Tac group (n = 7 vs n = 1, p = n.s.).. The combination of Tac and MMF seems to have slightly higher immunosuppressive potential compared with CsA and MMF. The effectiveness of Tac as a rescue agent is not paralleled with undue signs of overimmunosuppression.

Topics: Acute Disease; Adult; Aged; Bronchiolitis Obliterans; Chronic Disease; Creatinine; Cyclosporine; Drug Combinations; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infections; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adult; Analysis of Variance; Azathioprine; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Lung Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prednisone; Tacrolimus; Time Factors

Topics: Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Infections; Liver Transplantation; Methylprednisolone; Mycophenolic Acid; Pilot Projects; Safety; Survival Rate; Tacrolimus; Time Factors; Treatment Failure

Eighty-four adult patients were recruited from four centres in Spain to evaluate the efficacy and safety of low-dose (0.1 mg/kg per day) oral tacrolimus plus corticosteroid immunosuppression in liver transplantation. The median daily dose of tacrolimus was increased during the first 3 weeks of therapy from an initial dose of 0.1 mg/kg per day to a maximum of 0.145 mg/kg per day and was subsequently decreased gradually to a minimum of 0.076 mg/kg per day at 1 year. At 7 days posttransplantation, 87.7% of patients had trough whole blood levels of tacrolimus within the therapeutic range (5-20 ng/ml), and the median levels remained fairly constant during the rest of the year (10.1-11.8 ng/ml). None of the patients required intravenous administration of tacrolimus. At 1 year, Kaplan-Meier estimates showed that 73.8% of the patients were receiving tacrolimus monotherapy without the need for corticosteroids. One-year patient and graft survival were 75.9% and 72.3%, respectively. The incidence of acute rejection was 51.2%; 9.5% of cases resolved spontaneously without antirejection therapy and 10.7% were corticosteroid resistant. Only 1 patient (1.2%) developed chronic rejection. The most important adverse events were hypertension (45.2%), tremor (44.0%), diabetes mellitus (33.3%), diarrhoea (31%) and nephrotoxicity (29.8%). Severe neurotoxicity-like convulsions (4.8%), dysarthria (9.5%), delirium (1.2%), coma (1.2%) and the need for haemodialysis (3 patients) were uncommon. In conclusion, low-dose oral tacrolimus immunosuppression is associated with low toxicity without compromising efficacy.

Topics: Administration, Oral; Adrenal Cortex Hormones; Adult; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infections; Liver Transplantation; Male; Middle Aged; Survival Rate; Tacrolimus

Tacrolimus (FK506) is an effective and relatively safe novel immunosuppressant able to revert refractory rejection after pediatric liver transplantation (LTx). Between April 1993 and October 1996, 20 pediatric patients were converted to tacrolimus for biopsy-proven, steroid-resistant liver rejection. The mean follow-up was 18 months. The median time from LTx to switch was 20 days. Tacrolimus was administered per os at a mean dosage of 0.23 mg/kg per day to maintain median blood levels of 10.8 ng/ml at 1 week and 9.2 ng/ml at 1 year from the switch. Of the 20 patients, 15 are alive and they all recovered from rejection without the need of OKT3 after conversion. The major causes of death were: one multiorgan failure, two infections (cytomegalovirus Aspergillus), one bowel perforation, and one posttransplant lymphoproliferative disease. One patient experienced late side effects and was reconverted to cyclosporine when she was already rescued from hepatic allograft rejection. The results confirm that an earlier conversion to tacrolimus should be recommended after pediatric liver transplantation in order to revert hepatic allograft rejection with the best safety profile.

Topics: Child, Preschool; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Liver Transplantation; Postoperative Complications; Tacrolimus

Mycophenolate mofetil (MMF) is a new immunosuppressive agent that is gaining widespread use in solid organ transplantation recipients. A comprehensive assessment of infectious complications after its use after liver transplantation has never been assessed.. Bacterial, fungal, and viral infections occurring after transplantation were compared for a cohort of consecutive liver transplant recipients who received MMF (because of suspected tacrolimus-related nephrotoxicity or neurotoxicity) and a cohort who did not receive the drug. All patients received a tacrolimus-based primary immunosuppressive protocol.. Biopsy-proven acute rejection episodes within the first 6 months after transplant occurred in 6% of MMF-treated patients but in 30% of those who did not receive MMF (P=0.07). No significant differences were found in occurrence of cytomegalovirus infection or disease, Pneumocystis carinii, Aspergillus, or other fungal infection and hepatitis C virus recurrence between MMF-treated and untreated patients. Bacterial infections were more common in MMF-treated patients, but this cohort had a prolonged intensive care unit stay compared with patients who did not receive MMF. None of the MMF-treated patients with bacterial infection had leukopenia.. MMF use does not appear to be associated with an significantly increased risk of infection occurring after liver transplantation and is associated with fewer episodes of acute rejection.

Topics: Cohort Studies; Humans; Immunosuppressive Agents; Incidence; Infections; Liver Transplantation; Mycophenolic Acid; Pennsylvania; Prospective Studies; Tacrolimus

Initial studies of FK506 combined with methotrexate (MTX) in patients receiving unrelated donor BMT have demonstrated a possible-decrease in the incidence of severe GVHD but high rates of severe stomatitis and nephrotoxicity. With this background, we undertook a pilot study evaluating FK506 in combination with a lower than usual dose of MTX in an attempt to improve the tolerability of this immunoprophylaxis regimen. Between July 1993 and October 1994, 26 consecutive adults receiving unrelated donor BMT at Emory University Hospital were enrolled on this study. All patients received FK506 intravenously at an initial dose of 0.03 mg/kg/day beginning day -1 and continuing until oral FK506 was tolerated. Patients also received MTX intravenously at 5 mg/m2 on days 1, 3, 6, and 11. The preparative regimen administered to all but one patient included cyclophosphamide at 200 mg/kg over 4 days followed by total body irradiation (TBI) at 1400 cGy in twice daily fractions over 4 days. The median age of patients was 31 years (range: 19 to 52). Sixteen donor/recipient pairs were matched for HLA-A, -B, and -DR by serology and molecular typing. Ten paris were minor mismatches at either class I or class II. Twenty-two of 26 patients (85%) completed four doses of MTX on schedule. Nephrotoxicity was the most common adverse event associated with the administration of FK506: 88% of patients experienced a doubling of their serum creatinine. One patient died of central nervous system hemorrhage prior to engraftment. Twenty-four of the remaining 25 patients (96%) engrafted. Fourteen of 24 patients (50%) evaluable developed grades 2-4 acute GVHD. The rate of severe (grades 3-4) acute GVHD was 25%. Chronic GVHD developed in 11 of 20 (55%) evaluable patients. At a median follow-up of 461 days, 14 patients (54%) are alive. All are relapse-free with a median Karnofsky performance status of 90% (range: 70-100%). The cumulative probability of 2-year disease-free survival is 50% (95% confidence interval [CI]: 0.33 to 0.77); for low risk patients 67% (95% CI: 0.47 to 0.95) and for high risk patients 23% (95% CI: 0.049 to 1.00). These preliminary data indicate that FK506-based immunosuppression following unrelated donor BMT is effective in preventing severe acute GVHD and warrants comparison to CSA-based regimens.

Topics: Adult; Bone Marrow Transplantation; Disease-Free Survival; Drug Therapy, Combination; Female; Graft Survival; Graft vs Host Disease; Hematologic Neoplasms; Histocompatibility; Humans; Hyperglycemia; Hypertension; Immunosuppressive Agents; Infections; Kidney Diseases; Life Tables; Liver Diseases; Male; Methotrexate; Middle Aged; Pilot Projects; Safety; Survival Analysis; Tacrolimus; Transplantation, Homologous; Treatment Outcome

To evaluate the efficacy and safety of oral tacrolimus-based immunosuppressive induction therapy, 130 primary orthotopic liver transplant (OLT) recipients were randomised to treatment in an open, parallel-group, European multicentre trial. Following OLT, patients were immediately administered either tacrolimus (0.10 mg/kg) and prednisolone (dual therapy group) or tacrolimus (0.06 mg/kg) in conjunction with prednisolone and azathioprine (triple therapy group) both orally. Patient survival at 1 year was 79.4% for the dual therapy group and 88.7% for the triple therapy group (P = 0.194); 1-year graft survival rates were 76.5% in the dual therapy group and 80.6% in the group receiving triple therapy (P = 0.615). The frequencies of rejection (dual therapy 42.6%, triple therapy 50.0%; P = 0.482), infection, and other complications (renal, neurological and glucose metabolic disorders) were similar in both groups. Tacrolimus whole blood trough concentrations were detectable on days 1 and 2, respectively, in the dual and triple therapy treatment groups whilst median tacrolimus blood concentrations in the triple therapy group reached levels similar to those in the dual therapy group on postoperative day 11 following a steady increase in dose. After 1 year, 54.4% of the patients randomised to dual therapy were receiving tacrolimus monotherapy and only 56.4% of the patients randomised to triple therapy continued to receive azathioprine. In conclusion, oral tacrolimus-based immunosuppression is both potent and safe when administered as induction therapy after OLT. Treatment may commence at either 0.06 or 0.10 mg/ kg per day, but doses may need to be increased to the latter value within the first 10 days to maintain effective immunosuppression.

Topics: Administration, Oral; Adult; Aged; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infections; Kidney; Liver Transplantation; Male; Middle Aged; Tacrolimus

Topics: Adolescent; Bilirubin; Child; Child, Preschool; Cyclosporine; Female; Graft Survival; Humans; Hyperkalemia; Immunosuppression Therapy; Infant; Infections; Liver Transplantation; Lymphoproliferative Disorders; Male; Safety; Tacrolimus

Neurotoxicity represents a serious complication following orthotopic liver transplantation. Neurotoxicity may be evoked by various perioperative factors or develop due to drug-specific toxicity of immunosuppression. We evaluated the incidence of neurotoxicity in 121 patients, 61 randomly assigned to FK506 and 60 to CsA-based immunosuppression. The incidence of moderate or severe neurotoxicity was markedly higher in patients treated with FK506 in the early postoperative period (21.3% vs. 11.7% in patients receiving CsA), after retransplantation (100% vs. 0% in patients receiving CsA), and late (8 of 10 patients; P < or = 0.05 vs. CsA). Furthermore late neurotoxicity was highly associated with severe infections and MOFS, which had a lethal outcome in more than 50% of the patients. Patients who subsequently died developed neurologic symptoms in 67% of the cases. These patients also experienced moderate or severe neurotoxicity significantly more often in the early postoperative period compared with patients with a successful outcome (50% vs. 17.3%; P < or = 0.01). However, various blood and serum parameters, including ALT, bilirubin, urea, creatinine and glucose, when analyzed alone or in multivariate fashion, also correlated significantly with the incidence and severity of early postoperative neurotoxicity, indicating that neurotoxicity following LTX may be caused by various factors and is not exclusively a drug-specific side effect of immunosuppression.

Topics: Adolescent; Adult; Aged; Blood Chemical Analysis; Brain; Brain Diseases; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Infections; Liver Transplantation; Male; Middle Aged; Multiple Organ Failure; Reoperation; Tacrolimus

Nephrotoxicity represents a serious side effect of immunosuppression following liver transplantation. In order to compare the nephrotoxic action of CsA and FK506 in a clinical setting, we evaluated the incidence of early and late nephrotoxicity in 121 patients, 60 of whom were randomly assigned to CsA- and 61 to FK506-based immunosuppression. Early postoperative renal insufficiency (between PODs 0 and 30; SCr 1.5-3 mg/dl) was observed to a similar extent in patients treated with CsA (38.3%) and FK506 (42.6%). Early postoperative acute renal failure (ARF) (SCr > 3 mg/dl) was observed in 18.0% of patients in the FK506 treatment group and 18.3% of patients receiving CsA therapy. Approximately half the patients with ARF required hemodialysis (CsA: 11.7%; and FK506: 8.2%). All patients with early postoperative ARF requiring hemodialysis survived for more than one year. New onset of late ARF (between PODs 30 and 365) was observed in 6.6% of patients receiving FK506 therapy and in 1.7% in the CsA treatment group as a result of severe infection with multiple organ failure syndrome (MOFS). There was 100% mortality in patients with late ARF requiring hemodialysis. Etiology and prognosis of early and late ARF seem to be completely different. Early ARF was associated with severe coagulopathy and a rise in bilirubin and free hemoglobin, and was accompanied by impaired liver function. Mean onset of hemodialysis in CsA-treated patients was POD 1 and in FK506-treated patients POD 6, which disclosed a different time course of drug-specific nephrotoxicity of CsA and FK506 in early ARF. In contrast, late ARF occurred in both treatment groups only as a part of the MOFS in association with severe infections, an observation consistent with the assumption of overimmunosuppression rather than a primary nephrotoxic effect. Late renal insufficiency appeared in 23.3% of CsA- and in 29.4% of FK506-treated patients, and represented a slowly progressing form of drug-specific nephrotoxicity of CsA and FK506. These preliminary results demonstrate a similar outcome in terms of both early and late nephrotoxicity, but longer follow-up will delineate the overall efficacy and toxicity in humans.

Topics: Acute Kidney Injury; Adolescent; Adult; Aged; Cyclosporine; Female; Graft Rejection; Humans; Infections; Kidney Function Tests; Liver Transplantation; Male; Middle Aged; Multiple Organ Failure; Renal Dialysis; Tacrolimus

Studies in the USA and Japan have shown that tacrolimus (FK506) is a potent immunosuppressant. To compare the efficacy and safety of tacrolimus-based and conventional cyclosporin-based immunosuppressive regimens we recruited 545 liver transplant recipients from eight European centres into a randomised open trial. Analysis of the data at 12 months post-transplant showed that tacrolimus was associated with a significant reduction in acute, refractory acute, and chronic rejection episodes. The rates were, for acute rejection, tacrolimus 40.5% vs 49.8% cyclosporin (p = 0.040; absolute difference 9.3% [95% CI 0.9-17.8%]). For refractory acute and chronic rejections the comparisons were 0.8% vs 5.3% (p = 0.005) and 1.5% vs 5.3% (p = 0.032). There results were seen despite significantly lower corticosteroid usage. The incidence of infection was also lower in patients receiving tacrolimus. Patient and graft survival rates were not significantly different (tacrolimus 82.9% and 77.5%; cyclosporin 77.5% and 72.6%). Safety data were comparable--the most serious events being renal impairment, disturbances of glucose metabolism, and neurological complications--but these events were more common in the tacrolimus group. In this trial tacrolimus had advantages over cyclosporin in respect of lower rejection rates, even though less concurrent immunosuppression was administered.

Topics: Acute Disease; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Chronic Disease; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Incidence; Infections; Liver Transplantation; Male; Middle Aged; Survival Rate; Tacrolimus

A prospective randomised study was conducted to evaluate the efficacy and safety of FK 506 administered with corticosteroids compared with a cyclosporin A-based immunosuppressive regimen in patients undergoing primary liver transplantation. 545 patients were recruited in eight European centres, of whom 267 were randomised to FK 506 therapy and 273 to cyclosporin A-based therapy. The estimated Kaplan-Meier patient and graft survival figures of 82.9% and 77.5% respectively in the FK 506 group were higher than the comparable figures in the cyclosporin A group (77.5% and 72.6%, respectively). These differences did not reach statistical significance. Retransplantation rates, time to first rejection episode and number of rejection episodes were all lower (P < 0.001) in the FK 506 group. The infection rates were comparable between the two groups. During the study, the dose of FK 506 was reduced; this did not compromise efficacy and reduced the associated toxicity. FK 506 provides effective immunosuppression in patients undergoing primary liver transplantation and is associated with a lower incidence of rejection.

Topics: Adolescent; Adult; Aged; Anti-Bacterial Agents; Cyclosporine; Drug Therapy, Combination; Female; Graft Survival; Humans; Immunosuppressive Agents; Infections; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Survival Rate; Tacrolimus; Time Factors

The new immunosuppressive agent FK506 was used with steroids to treat 22 pediatric patients who received living-related partial liver transplantation. Seventeen recipients survived and 5 died between one and 16 months after transplantation. Three of the 5 patients who died had required intensive care preoperatively. Autopsy findings showed no evidence of rejection. There was no episode of rejection that required retransplantation in any of the patients. Liver allograft dysfunction, which was suspected to be a rejection response, was encountered in 2 recipients with ABO-nonidentical but compatible grafts. However, their clinical and biochemical findings were ameliorated upon steroid pulse therapy or upon augmented FK506 administration without additional potent immunosuppressive agents. Steroid treatment has been discontinued in all surviving patients at 1-9 months after transplantation. Infectious complications encountered in 9 patients included 2 bacterial, 5 viral, and 2 fungal infections. One recipient died of fungal pneumonia. Abnormal increase of serum creatinine level was confined to the complicated patients. Hypertension was a temporary adverse reaction in the early postoperative period, and only one patient needed an antihypertensive drug at 2 months after transplantation. Acute pancreatitis with hyperamylasemia was observed in one patient who was treated successfully with reduction of FK506 administration. Tremor was observed in 8 patients, itching in 4, insomnia in 2, and vomiting in one. Hirsutism, gingival hypertrophy, and lymphoma were not observed. FK506 was highly effective in living-related partial liver transplantation not only in terms of immunosuppressive potential but also because it produced fewer adverse effects.

Topics: Adolescent; Adrenal Cortex Hormones; Child; Child, Preschool; Female; Humans; Infant; Infections; Liver; Liver Transplantation; Male; Tacrolimus

The new immunosuppressive agent FK 506 was used as primary immunotherapy in conjunction with low-dose steroids and azathioprine in 72 patients subsequent to orthotopic cardiac transplantation. Overall patient survival at a mean follow-up of 360 days was 92%. The number of episodes of cardiac rejection (grade 3A or greater) within 90 days of transplantation was 0.95 per patient. The actuarial freedom from rejection at 90 days was 41%. Achievement of this level of immunosuppression is comparable with that of cyclosporine-based triple-drug therapy with OKT3 immunoprophylaxis. Thirty percent of patients were tapered off all steroids, and the average steroid dose in the group who received steroids was 8.6 mg of prednisone per day. The incidence of infection reflected the diminished necessity for steroids: seven major infections (10%) and 11 minor infections (16%). Renal dysfunction occurred during the perioperative period in most patients in this trial. However, the incidence of hypertension was 54% compared with 70% during the cyclosporine era. Ten adults underwent successful rescue therapy with FK 506 after cardiac rejection refractory to conventional immunotherapy. Side effects of FK 506 were notably few, and the results of the trial are encouraging for the future of the cardiac transplant recipient.

Topics: Adult; Female; Graft Rejection; Heart; Heart Transplantation; Humans; Immunosuppression Therapy; Infections; Kidney; Male; Methylprednisolone; Middle Aged; Postoperative Complications; Tacrolimus

To compare infectious risk between leflunomide versus TNF inhibitors (TNFi), and between tacrolimus versus TNFi among rheumatoid arthritis (RA) patients receiving methotrexate (MTX).. Using Korea National Health Insurance Service database, we conducted a cohort study on RA patients initiating TNFi, leflunomide, or tacrolimus. The primary outcome was any serious infections defined as a composite endpoint of serious bacterial, opportunistic, and herpes zoster infections. Secondary outcomes were individual components of the primary outcome. Propensity-score fine-stratification (PSS) and weighting were applied to adjust for confounding. Hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazard models comparing leflunomide versus TNFi, and tacrolimus versus TNFi.. Among 72,516 RA patients receiving MTX, we identified 3,336 TNFi initiators, 11,122 leflunomide initiators, and 5,136 tacrolimus initiators. Two study cohorts were 10,992 leflunomide initiators PSS-weighted on 1,623 TNFi initiators and 5,126 tacrolimus initiators PSS-weighted on 2,521 TNFi initiators. The incidence rate per 100 person-years of herpes zoster infection (3.70-4.27) was beyond 3-times that of serious bacterial infection (1.12-1.36), but opportunistic infection was relatively rare (0.11-0.23). The PSS-weighted HR [95% CI] for any serious infection was 1.03 [0.89-1.22] comparing leflunomide versus TNFi, and 0.91 [0.77-1.08] comparing tacrolimus versus TNFi. Analyses on the secondary outcomes showed consistent results.. In this nation-wide cohort study, we did not find a significant difference in the risk of serious infections (i.e., serious bacterial, opportunistic, and herpes zoster infections) between leflunomide versus TNFi, and between tacrolimus versus TNFi among RA patients receiving background MTX.

Topics: Antirheumatic Agents; Arthritis, Rheumatoid; Cohort Studies; Herpes Zoster; Humans; Infections; Leflunomide; Methotrexate; Tacrolimus; Tumor Necrosis Factor Inhibitors

A head-to-head comparison of outcomes of unrelated donor allogeneic peripheral blood stem cell transplantation for AML between reduced intensity conditioning (RIC) and myeloablative conditioning (MAC) regimens using thymoglobulin for GVHD prophylaxis is limited. We evaluated outcomes of 122 AML patients who received either busulfan (Bu)/fludarabine (Flu)/low-dose total body irradiation (TBI) as RIC (n = 64, 52%) or Bu/Flu as MAC (n = 58, 48%), and thymoglobulin 4.5 mg/kg total dose between day - 3 to - 1 for GVHD prophylaxis. Grades III-IV acute GVHD (aGVHD) was lower with Bu/Flu/TBI compared with Bu/Flu (6.2% vs 26.1%, p = 0.009). At 1 year, Bu/Flu/TBI was associated with similar chronic GVHD (41.2% vs 44.8%, p = 0.75), OS (61.9% vs 56.9%, p = 0.69), relapse rate (29.9% vs 20.7%, p = 0.24), relapse-free survival (52.8% vs 50%, p = 0.80), non-relapse mortality (17.4% vs 29.3%, p = 0.41), and GVHD-free relapse-free survival (24.2% vs 27.5%, p = 0.80) compared with Bu/Flu. Multivariable analysis did not reveal any difference in outcomes between both regimens. In summary, thymoglobulin at 4.5 mg/kg did not have any adverse impact on survival when used with RIC regimen. Both Bu/Flu/TBI and Bu/Flu conditioning regimens yielded similar survival.

Topics: Aged; Allografts; Antilymphocyte Serum; Busulfan; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infections; Leukemia, Myeloid, Acute; Lymphocyte Depletion; Male; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Peripheral Blood Stem Cell Transplantation; Progression-Free Survival; Retrospective Studies; T-Lymphocytes; Tacrolimus; Transplantation Conditioning; Treatment Outcome; Unrelated Donors; Vidarabine; Whole-Body Irradiation

Lung transplant immunosuppression regimens generally include the calcineurin inhibitor tacrolimus. We hypothesized that mean residual expression (MRE) of calcineurin-dependent genes assesses rejection and infection risk better than does tacrolimus trough. We prospectively followed 44 lung allograft recipients at 2 to 18 months posttransplant and measured changes in whole blood interleukin-2, interferon-γ, and granulocyte-macrophage colony-stimulating factor gene expression following a tacrolimus dose. Posttransplant duration, immunosuppressive medication levels, and bronchoscopic rejection and infection assessments were compared with MRE by using generalized-estimating equation-adjusted models. Prednisolone effect on MRE was assessed ex vivo in blood samples from nontransplanted controls. Tacrolimus concentration inhibiting 50% of cytokine production (IC

Topics: Allografts; Anti-Inflammatory Agents; Biomarkers; Calcineurin; Calcineurin Inhibitors; Case-Control Studies; Female; Follow-Up Studies; Gene Expression Profiling; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Prednisolone; Prognosis; Prospective Studies; Risk Factors; Tacrolimus

The aim of the study was to investigate the relationship between tacrolimus (TAC) immunosuppressive treatment and serum concentrations of immunoglobulin heavy/light chain pairs (sHLC) and free light chains (sFLC) in patients after heart transplantation (HTX) and to use these biomarkers to predict the risk of infection in these patients. A total of 88 patients with an immunosuppressive regimen involving tacrolimus who underwent HTX were analyzed over 24 months of follow-up. sFLC and sHLC levels were determined before and at three time points after HTX. TAC concentrations were determined at several time points after HTX, and mean TAC concentrations and areas under the curve (AUCs) of TAC concentration were calculated. Relevant clinical data were obtained from patients' medical records. A larger AUC of TAC was associated with decreases in the concentrations of IgG total (p < 0.05); similarly, cumulative AUC of TAC during 18 post-transplant months correlated inversely with sHLC IgG kappa (r = -0.228, p < 0.05) and IgG total (r = -0.352, p < 0.05). Concentrations of sFLC kappa, sFLC lambda, sHLC IgG kappa, and sHLC IgG total were significantly lower in infected patients (in the 9th month after HTX, all p < 0.05). Combined criteria for increased AUC (greater than the median of 12.9 mg·d/l) and decreased sFLC kappa (less than the median of 12.5 mg/l) correlated with the presence of infection (p < 0.03) in the 9th month after HTX. Ratio of concentration of TAC to sFLC kappa or lambda was significantly higher in infected patients (both p < 0.05). Intensive treatment with tacrolimus after HTX is possibly reflected by decreases in sFLC and sHLC (mainly sHLC IgG). Patients with decreased concentrations of these biomarkers are at increased risk for infection, primarily in the 9th month after HTX, when the concentrations of tacrolimus were the highest.

Topics: Adult; Aged; Biomarkers; Drug-Related Side Effects and Adverse Reactions; Female; Follow-Up Studies; Graft Rejection; Heart Transplantation; Humans; Immunoglobulin Heavy Chains; Immunoglobulin Light Chains; Immunosuppressive Agents; Infections; Male; Middle Aged; Predictive Value of Tests; Prognosis; Risk; Tacrolimus; Young Adult

Immunosuppression is a known risk for post-transplant infections. Little data exist on the risk contributions of specific agents for various infections.. A triply robust propensity score-adjusted analysis was performed in a renal transplant cohort between February 2006 and January 2014. The study was performed to identify the incidence and the risk factors for developing a post-transplant infection. After initial bivariate analysis, a triply robust propensity score-adjusted multivariate logistic regression was performed.. The mean age of the 717 renal transplant recipients was 50.0 ± 13.3 years, with the majority being male (61.6%) and 349 (48.7%) experiencing at least 1 post-transplant infection. Neither race, graft type, nor insurance status was associated with an increased incidence or risk of infection. In a fully adjusted regression model, the immunosuppressants mycophenolic acid mofetil (OR 0.38, 95% CI 0.21-0.71; P < .001) and alemtuzumab (OR 0.40, 95% CI 0.19-0.85; P = .020) were protective.. Alemtuzumab and mycophenolic acid mofetil as immunosuppressant agents in a multiagent protocol appear to decrease the incidence of infection. Cytomegalovirus antigenemia was the greatest risk for infection and mycophenolic acid mofetil possessed the greatest protective effect on viral infections.

Topics: Adult; Alemtuzumab; Case-Control Studies; Community-Acquired Infections; Cross Infection; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Opportunistic Infections; Propensity Score; Retrospective Studies; Risk Factors; Tacrolimus; Virus Diseases

Tacrolimus is metabolized by members of the cytochrome p450 3A subfamily, and its bioavailability depends also on P-glycoprotein. We have observed that some patients admitted for infection presented with increased tacrolimus trough levels (TLs). The aim of the study was to assess the impact of infection on tacrolimus TLs and to determine the factors involved in TL fluctuations.. This retrospective cohort study included patients transplanted with a kidney between 2009 and 2011 who were hospitalized for an acute infection. Tacrolimus TLs and dosages were recorded before hospitalization, at admission, and 1 month after discharge. Increased levels of tacolimus were defined as TL 25% higher on admission than those recorded at the last visit before hospitalization.. Seventy-seven patients were hospitalized 138 times for infection. More than two thirds of first hospitalizations occurred during the first post-transplant year. Causes of hospitalization were urinary (33%), cytomegalovirus (27%), digestive (15%), and pulmonary (12%) infections. Thirty-five percent of kidney transplant recipients had increased tacrolimus TLs (27/77 patients) in 24% of the hospitalizations (34/138). In 34 hospitalizations occurring in 27 patients, TL at admission was ≥25% compared with the last visit before admission. Comparing these 34 hospitalizations with the other 104, no significant differences were noted, except for a greater fraction of digestive infections in the group with elevated tacrolimus TLs, independent of diarrhea occurrence.. Up to 35% of kidney transplant recipients admitted for acute infection present with high tacrolimus TLs, requiring a dose reduction. How acute infection precisely affects metabolism and bioavailability of tacrolimus remains to be investigated.

Topics: Acute Disease; Adult; Aged; ATP Binding Cassette Transporter, Subfamily B, Member 1; Cytochrome P-450 CYP3A; Female; Hospitalization; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus

Tacrolimus (Tac) is one of the most commonly used immunosuppressive drugs after solid organ transplantation. Eight Tac metabolites have been described, but their clinical importance remains unclear. The aim of this study was quantification of the 2 major Tac metabolites, 13-O-demethyl (M-I) and 15-O-demethyl (M-III), in kidney transplant recipients and to link them with parameters of kidney and liver function, peripheral blood cell counts, and infection incidence.. In 81 kidney transplant recipients, concentrations of Tac, M-I, and M-III were measured with the use of liquid chromatography combined with tandem mass spectrometry (LC-MS-MS).. There was a negative correlation between M-III levels and estimated glomerular filtration rate (eGFR; r = -0.244; P < .05). Also, a negative correlation between M-III concentrations and red blood cell count (RBC) was found (r = -0.349; P < .05). Neither concentrations of Tac nor of M-I correlated with eGFR or RBC. M-I, M-III, and Tac were not related to alanine aminotransferase activity. Significantly higher Tac and M-III concentrations in the group with all types of infections in comparison with the group without infections were observed (6.95 ± 2.09 ng/mL vs 5.73 ± 2.43 ng/mL [P = .03] and 0.27 ± 0.17 ng/mL vs 0.20 ± 0.11 ng/mL [P = .04], respectively).. The results suggest that higher concentrations of M-III may have a nephrotoxic or myelotoxic effect and result in higher incidence of infections. Further studies are needed to confirm if monitoring of M-III could minimalize adverse effects such as nephrotoxicity or infections.

Topics: Adult; Chromatography, Liquid; Dydrogesterone; Female; Humans; Immunosuppressive Agents; Incidence; Infections; Kidney; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Tandem Mass Spectrometry; Transplant Recipients

Immunosuppressive therapy is associated with an increased risk of pregnancy complications and may have adverse effects for the newborn. The aim of this study was to determine the frequency and the type of early congenital infections and to assess typical markers of infections in neonates of liver and kidney recipients.. A retrospective analysis of 71 neonates born to either liver (39 cases) or kidney transplanted women (32 cases) was conducted. The rate and the type of newborns' infections as well as laboratory and bacteriologic markers of infections were analyzed.. There was no significant difference in the frequency of congenital infections between the LT and KT groups (8 vs 7 cases; P = .879).). The rate of infections was not significantly higher in both groups compared with the general population. Infections were detected in 23.9%, 13.6%, and 26.6% of neonates born to mothers using tacrolimus, cyclosporine, and azathioprine respectively. No significant differences in white blood count or levels of neutrocytes and lymphocytes were observed between the groups. No abnormalities in white blood smear, but 1 case of leukopenia in the kidney transplant group, were detected.. The rate of congenital infections in neonates of allograft recipients is not significantly higher than in the general population. Immunosuppressive regimens with azathioprine seem to carry the greatest risk, it is a little lower in the tacrolimus group, and cyclosporine-based regimens have the lowest risk of congenital infections. Differences were not statistically significant. Prenatal exposure to immunosuppressive agents seems not to be associated with any hematologic disturbances in white blood count and white blood smear.

Topics: Adult; Azathioprine; Cyclosporine; Female; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant, Newborn; Infections; Kidney Transplantation; Liver Transplantation; Male; Pregnancy; Pregnancy Complications; Retrospective Studies; Tacrolimus; Transplantation, Homologous

Because excessive or inadequate responses can be detrimental, immune responses to infection require appropriate regulation. Networks of signaling pathways establish versatility of immune responses. Drosophila melanogaster is a powerful model organism for dissecting conserved innate immune responses to infection. For example, the Toll pathway, which promotes activation of NF-κB transcription factors Dorsal/Dorsal-related immune factor (Dif), was first identified in Drosophila. Together with the IMD pathway, acting upstream of NF-κB transcription factor Relish, these pathways constitute a central immune signaling network. Inputs in these pathways contribute to specific and appropriate responses to microbial insults. Relish activity during infection is modulated by Ca(2+)-dependent serine/threonine phosphatase calcineurin, an important target of immunosuppressants in transplantation biology. Only one of the three Drosophila calcineurin isoforms, calcineurin A1, acts on Relish during infection. However, it is not known whether there is a role for calcineurin in Dorsal/Dif immune signaling. In this article, we demonstrate involvement of specific calcineurin isoforms, protein phosphatase at 14D (Pp2B-14D)/calcineurin A at 14F (CanA-14F), in Toll-mediated immune signaling. These isoforms do not affect IMD signaling. In cell culture, pharmacological inhibition of calcineurin or RNA interference against homologous calcineurin isoforms Pp2B-14D/CanA-14F, but not against isoform calcineurin A1, decreased Toll-dependent Dorsal/Dif activity. A Pp2B-14D gain-of-function transgene promoted Dorsal nuclear translocation and Dorsal/Dif activity. In vivo, Pp2B-14D/CanA-14F RNA interference attenuated the Dorsal/Dif-dependent response to infection without affecting the Relish-dependent response. Altogether, these data identify a novel input, calcineurin, in Toll immune signaling and demonstrate involvement of specific calcineurin isoforms in Drosophila NF-κB signaling.

Topics: Animals; Calcineurin; Cell Line; DNA-Binding Proteins; Drosophila melanogaster; Drosophila Proteins; Green Fluorescent Proteins; Infections; NF-kappa B; Nuclear Proteins; Phosphoproteins; Protein Isoforms; RNA Interference; RNA, Small Interfering; Signal Transduction; Tacrolimus; Toll-Like Receptors; Transcription Factors

Studying the possible influence of SNPs on efficacy and safety of calcineurin inhibitors upon heart transplantation.. In 60 heart transplant patients treated with tacrolimus or cyclosporine, we studied a panel of 36 SNPs correlated with a series of clinical parameters during the first post-transplantation year.. The presence of serious infections was correlated to ABCB1 rs1128503 (p = 0.012), CC genotype reduced the probability of infections being also associated with lower blood cyclosporine concentrations. Lower renal function levels were found in patients with rs9282564 AG (p = 0.003), related to higher blood cyclosporine blood levels. A tendency toward increased graft rejection (p = 0.05) was correlated to rs2066844 CC in NOD2/CARD15, a gene related to lymphocyte activation.. Pharmacogenetics can help identify patients at increased risk of clinical complications. Original submitted 30 January 2015; revision submitted 27 March 2015.

Topics: Adult; Aged; ATP Binding Cassette Transporter, Subfamily B; Cyclosporine; Female; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Infections; Kidney; Kidney Function Tests; Male; Middle Aged; Polymorphism, Single Nucleotide; Tacrolimus; Tissue Donors

Prospective, long-term data on corticosteroid withdrawal (CSW) versus corticosteroid continuation (CSC) following kidney transplantation are scarce.. The Mycophenolic Renal Transplant (MORE) Registry was a prospective, observational study of de novo kidney transplant patients receiving mycophenolic acid (MPA) and standard of care. Adult patients receiving tacrolimus and enteric-coated mycophenolate sodium (EC-MPS) or mycophenolate mofetil (MMF) at time of transplant were analyzed to 4 years according to CSW by month 3 (n=363) or CSC (n=509).. In the CSW and CSC groups, 3.3% and 13.0% had undergone retransplantation (p<0.001), 89.9% and 77.0% had panel reactive antibodies <30% (p<0.001), and 72.5% and 87.2% received pretransplant dialysis (p<0.001), respectively. Rabbit antithymocyte induction was used in 62.3% of CSW patients and 58.6% of CSC patients (p=0.015), and alemtuzumab in 23.7% and 4.7%, respectively (p=0.002). At all time points to 3 years post-transplant, significantly fewer CSW patients were maintained on the full recommended dose of MPA versus CSC patients. Biopsy-proven acute rejection occurred in 10.1% and 14.3% of CSW and CSC patients (p=0.12), graft survival was 96.9% versus 93.7% (p=0.030), and patient survival was 95.6% versus 95.0% (p=0.65), respectively. Adverse events were similar except for leukopenia (CSW 60.6%, CSC 29.9%; p<0.001) and neutropenia (CSW 17.4%, CSC 11.4%; p=0.013), with infections in 24.8% and 30.8% of CSW and CSC patients, respectively (p=0.057).. CSW patients were less likely to receive the full dose of MPA than CSC patients, possibly due to induction-related hematological toxicity. Graft survival to 4 years post-transplant was superior in CSW patients.

Topics: Abdomen, Acute; Adrenal Cortex Hormones; Adult; Aged; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infections; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Registries; Substance Withdrawal Syndrome; Tacrolimus; Treatment Outcome

Debate is increasing on whether mycophenolic acid (MPA) provides survival benefits comparable to azathioprine (AZA) after renal transplantation.. This retrospective cohort study compared safety and efficacy of AZA (n = 662) vs. MPA (n = 267) in low-immunologic-risk kidney transplant recipients (KTR) receiving tacrolimus (TAC) and steroids between 1998 and 2007. Primary outcomes were treatment discontinuation and infection. Secondary endpoints included survival free from biopsy-proven acute rejection, graft loss, death, and renal function.. The 5-year survival free of treatment discontinuation was higher in the MPA compared to the AZA group (74.1% vs. 60.3%, P < 0.001). MPA was discontinued exclusively because of adverse events (16.4%), while AZA was discontinued primarily for lack of efficacy (21.2%). In univariable analysis, MPA was associated with higher incidence of total (561.5 vs. 667.5 episodes/1000 person-year, P < 0.001), bacterial (167 vs. 158 episodes/1000 person-years, P = 0.001), and viral infections (83.2 vs. 100.4 episodes/1000 person-years, P = 0.001), but this association was not confirmed in multivariable analysis. Over 29% of viral infections in the AZA group occurred after conversion to MPA. A high incidence of tuberculosis was observed (2.9 episodes/1000 person-years) with a higher incidence (but not a statistically significant difference) in the AZA group. No significant differences were found in patient survival (90% vs. 89%, P = 0.78) or graft survival (81% vs. 77.7%, P = 0.08), but infection accounted for >50% of all deaths.. The type of antimetabolite, AZA or MPA, was not independently associated with any safety or efficacy outcome 5 years after transplantation, suggesting that AZA is still a viable option for low-risk KTR receiving TAC and steroids.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Aged; Azathioprine; Female; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infections; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Survival Analysis; Tacrolimus; Treatment Outcome; Young Adult

The aim of this study is to evaluate whether the combination of the ImmuKnow assay (IMK) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for identifying the risk of morbidity and mortality in living donor liver transplantation (LDLT) patients, and also to investigate the optimal cutoff value of IMK level of immune status.. Sixty six LDLT patients, who were randomly screened by using IMK between March 2002 and June 2011, were divided into 2 groups: patients in whom at least 1 IMK value was <175 ng/mL (Group A, n=16) and patients in whom all IMK values were >175 ng/mL (Group B, n=50). Both donors and recipients were evaluated for the CYP3A5 genotype.. The frequencies of cytomegalovirus and bacterial infection in Group A were significantly higher than those in Group B (P<0.001). The short term mortality was 4 (25.0%) in Group A and none in Group B, and the IMK level in all four cases became <100 ng/mL at least one time before death. The rate of CYP3A5*1 allele (expressors) among recipients was significantly higher in Group A than in Group B (63.6% vs. 22.2%, P=0.0147). The rates of CMV infection and bacterial infection, and the IMK levels was significantly higher in recipients with expressors (p=0.0216, p=0.0332, and p=0.0433, respectively).. The combination of the IMK and CYP3A5 genotype assay is useful for monitoring immune status after LDLT, and the IMK level <100 ng/ml might be the critical level to make a recovery from the severe immunesupressive condition.

Topics: Adolescent; Adult; Aged; Bacterial Infections; Child; Child, Preschool; Cytochrome P-450 CYP3A; Cytomegalovirus Infections; Female; Genotype; Humans; Immunoassay; Immunosuppressive Agents; Infant; Infections; Liver Transplantation; Living Donors; Male; Middle Aged; Morbidity; Polymorphism, Single Nucleotide; Risk Factors; Tacrolimus; Young Adult

Topics: Alemtuzumab; Antibodies, Monoclonal, Humanized; Female; Graft Survival; HLA Antigens; Humans; Immunosuppressive Agents; Infections; Inflammation; Intestinal Mucosa; Intestine, Small; Intestines; Mesenchymal Stem Cell Transplantation; Mesenchymal Stem Cells; Middle Aged; Neuromuscular Diseases; Postoperative Complications; Regeneration; Short Bowel Syndrome; Tacrolimus; Transplantation; Treatment Outcome

To evaluate whether the combination of the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (ImmuKnow assay: IMK assay) and cytochrome P450 3A5 (CYP3A5) genotype assay is useful for monitoring of immunological aspects in the patient followup of more than one year after living donor liver transplantation (LDLT).. Forty-nine patients, who underwent LDLT more than one year ago, were randomly screened by using IMK assay from January 2010 to December 2011, and the complete medical records of each patient were obtained. The CYP3A5 genotypes were examined in thirty-nine patients of them.. The mean ATP level of the IMK assay was significantly lower in the patients with infection including recurrence of hepatitis C (HCV) (n = 10) than in those without infection (n = 39): 185 versus 350 ng/mL (P < 0.001), while it was significantly higher in the patients with rejection (n = 4) than in those without rejection (n = 45): 663 versus 306 ng/mL (P < 0.001). The IMK assay showed favorable sensitivity/specificity for infection (0.909/0.842) as well as acute rejection (1.0/0.911). CYP3A5 genotypes in both recipient and donor did not affect incidence of infectious complications.. In the late phase of LDLT patients, the IMK assay is very useful for monitoring immunological aspects including bacterial infection, recurrence of HCV, and rejection.

Topics: Adenosine Triphosphate; Adult; Aged; CD4-Positive T-Lymphocytes; Cytochrome P-450 CYP3A; Female; Genotype; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Liver Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Transplantation Immunology; Young Adult

Seventy living donor liver transplantation (LDLT) and 39 kidney transplantation (KT) patients were randomly screened by using the peripheral blood CD4+ adenosine triphosphate activity (ATP) assay (IMK assay). The patients were divided into 2 groups in each organ transplantation with low IMK ATP level (<225 ng/mL) or high (>225) (LT-L: n = 23, KT-L: n = 19, LT-H: n = 47, and KT-H: n = 20, resp.). The incidence of bacterial and/or viral infection was significantly higher in LT-L group than in LT-H group (74.0 versus 8.5%: P < 0.001). Occurrence of total viral infection in KT-L was also significantly higher than that in KT-H (36.8 versus 10%: P = 0.046). The sensitivity and specificity of the IMK assay for identifying risk of infection was 0.810 and 0.878 in LDLT patients and 0.727 and 0.607 in KT patients. The percentage of LDLT patients with cytochrome P450 3A5 (CYP3A5) *1/*1 or *1/*3 genotype (expressors) was significantly higher in LT-L group than in LT-H group (53.8 versus 20.7%: P = 0.032). In both LDLT and KT patients, the IMK assay can be useful for monitoring immunological aspects of bacterial and/or viral infection. CYP3A5 expressors in LT-L group are related to postoperative infections.

Topics: Adenosine Triphosphate; Adolescent; Adult; Aged; CD4-Positive T-Lymphocytes; Child; Child, Preschool; Cytochrome P-450 CYP3A; Female; Genotype; Genotyping Techniques; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Infections; Kidney Transplantation; Liver Transplantation; Male; Middle Aged; Tacrolimus; Young Adult

To identify the levels of functional immunity measured by the ImmuKnow assay in Chinese liver transplantation recipients and its application in monitoring the risk of posttransplant infection.. Forty-five apparent healthy Chinese and 106 adult liver transplant (LT) recipients were under investigation. LTs were grouped in stable status or infection according to their clinical diagnosis. Whole blood samples were collected freshly and cultured within 6 hr, the CD4(+) T cells were selected, and their adenosine triphosphate (ATP) value was assayed the next day. Before stimulation, we also examined the percentage of T-helper (Th; CD3(+) CD4(+)) and T-suppress (Ts; CD3(+) CD8(+)) lymphocyte subpopulations and the ratio of Th/Ts.. The average ImmuKnow assay in infectious LT recipients was 128 + or - 84 ng/mL, significantly lower (P<0.05) than that in stable LTs (305 + or - 149 ng/mL) or in normal adults (301+ or - 101 ng/mL). The ImmuKnow values in LTs had a good negative correlation to infection clinically (r = -0.6217, P<0.001). Infectious risk was high when the ImmuKnow value was less than 130 ng/mL (odds ratio=13, 95% confidence interval 6.0-29.4, P<0.01). The sensitivity of low ImmuKnow values in posttransplant infection was 85.2%, significantly higher than those of Th/Ts ratio and immunosuppressant trough levels (P<0.01); specificity was 76.3%, comparable with that of Th/Ts ratio (75.5%), but greatly higher than immunosuppressant trough levels (P<0.01). ImmuKnow ATP values had no correlation with Th/Ts ratio or immunosuppressant trough levels.. ImmuKnow ATP levels are lower in LT recipients with infection, which provides a new tool in monitoring posttransplant infection, and an index of tailoring immunosuppression clinically.

Topics: Adult; Aged; Carcinoma, Hepatocellular; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Drug Therapy, Combination; Environmental Monitoring; Epidemiological Monitoring; Female; Humans; Immunosuppressive Agents; Infections; Liver Neoplasms; Liver Transplantation; Lymphocytes; Male; Middle Aged; Postoperative Complications; Retrospective Studies; T-Lymphocytes, Helper-Inducer; Tacrolimus; Young Adult

A pilot study was performed on eight consecutive renal-transplant (RT) patients presenting with acute humoral rejection (AHR) to assess the efficacy of monoclonal anti-B cell antibodies, such as rituximab (375 mg/m weekly) for 3 to 5 consecutive weeks, in addition to plasma exchange (PE), steroids, mycophenolate mofetil, and tacrolimus. AHR was associated with increased serum creatinine, the appearance of donor-specific alloantibodies (DSA), and the presence of C4d in a transplant biopsy. After a follow-up of 10 months (range 7-23), patient and graft survivals were 100% and 75%, respectively. Renal function improved in six cases in which serum creatinine decreased from 297+/-140 to 156+/-53 micromol/L (P=0.015); graft loss occurred in two cases; and four patients had infectious complications. At last follow-up, DSA had disappeared or decreased in four cases. Rituximab therapy, in addition to PE, might be of benefit for RT patients presenting with AHR.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Antibodies, Monoclonal, Murine-Derived; Antibody Formation; Creatine; Female; Graft Rejection; Humans; Immunologic Factors; Immunosuppressive Agents; Infections; Isoantibodies; Kidney; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Pilot Projects; Plasma Exchange; Rituximab; Steroids; Tacrolimus; Tissue Donors; Treatment Outcome

Heart transplant recipients treated with long-term calcineurin inhibitors (CNIs) experience significant nephrotoxicity and transplant vasculopathy. Signal proliferation inhibitors might prevent the development of transplant vasculopathy. In an open, prospective pilot study, 33 primary heart transplant recipients received tacrolimus (Tac) and sirolimus (rapamycin, Rapa) with steroids. To reduce both nephrotoxicity and transplant vasculopathy at the same time, both Tac and Rapa exposure was kept low (6 to 8 ng/ml). Steroids were withdrawn successfully from all patients within 6 months. Just one acute rejection occurred at 54 days post-transplant, resulting in 0.03 acute rejection episode per patient at 1-year (primary end-point) and 2-year follow-up. Transplant vasculopathy assessed by angiogram was absent at 2 years. Graft and patient survival were 100% at 1 and 2 years. Accordingly, the survival estimate for freedom from first acute rejection, transplant vasculopathy, graft loss or death was 0.97 at 1 and 2 years. The regimen was well tolerated with only 3 patients requiring a change of study medication. Mean serum creatinine increased during the first year but returned to baseline at 2 years.

Topics: Adrenal Cortex Hormones; Adult; Drug Administration Schedule; Female; Follow-Up Studies; Graft Rejection; Heart Failure; Heart Transplantation; Humans; Immunosuppressive Agents; Infections; Male; Middle Aged; Postoperative Complications; Prospective Studies; Sirolimus; Tacrolimus; Time Factors

Matched sibling donor (MSD) bone marrow transplantation is the treatment of choice for pediatric patients with severe aplastic anemia (SAA); however, only about 33% of patients will have an HLA-identical sibling. Alternative donor (AD) transplants may be an option for these patients, but such therapies have been associated with greater incidence of graft failure and graft-versus-host disease (GVHD). We retrospectively analyzed 36 pediatric patients who received 38 bone marrow or peripheral blood stem cell transplants (15 MSD and 23 AD) for SAA at our institution from April 1997 to October 2005. Nineteen AD recipients received reduced intensity conditioning with cyclophosphamide, low-dose total body irradiation, and antithymocyte globulin (ATG) or Campath. The 4-year overall survival for MSD recipients was 93% versus 89% for AD recipients treated with reduced intensity conditioning regimens at a median follow-up of 52 months (range, 6-99 months). No patient receiving Campath, compared with 3 of 9 patients receiving ATG, developed extensive, chronic GVHD. We conclude that, for children with SAA, AD transplantation is as effective as MSD transplantation. Further, compared with ATG, preparatory regimens containing Campath may be associated with a lower incidence of extensive, chronic GHVD.

Topics: Adolescent; Alemtuzumab; Anemia, Aplastic; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Antilymphocyte Serum; Bone Marrow Transplantation; Child; Child, Preschool; Cyclosporine; Female; Graft Survival; Graft vs Host Disease; Histocompatibility; Humans; Immunosuppressive Agents; Infant; Infections; Kaplan-Meier Estimate; Male; Methotrexate; Peripheral Blood Stem Cell Transplantation; Postoperative Complications; Retrospective Studies; Siblings; Survival Analysis; T-Lymphocyte Subsets; Tacrolimus; Tissue Donors; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Whole-Body Irradiation

Alemtuzumab induction and tacrolimus-based immunosuppression has been effective in pancreas transplantation. Despite the encouraging results of this minimalistic approach to immunosuppression, infection still remains a significant cause of morbidity. The Cylex ImmuKnow [corrected] assay was used in this study to compare pancreas recipient clinical states (stable, rejection, infection) with T cell responses.. Blood samples were taken from pancreas recipients pretransplant and at approximately three-month intervals posttransplant for analysis of T cell responses. When possible, T cell responses were also quantified during changes in clinical status (infection or rejection).. A range between 100-300 ng/ml adenosine triphosphate (ATP) was found in stable patients (mean 194+/-123, n = 51) with good graft function and no infection or rejection. A low T cell response was highly correlated with infectious states. The fourteen patients with infections/posttransplant lymphoproliferative disease had a mean ATP of 48 ng/ml. Risk hazard analysis showed that patients with ATP levels <100 ng/ml were four to seven times more susceptible to infection compared to stable patients. Four patients with rejection showed a T cell response of 550 ng/ml ATP, which was statistically significant compared to stable patients, although the sampling numbers (9) were too small to be conclusive.. The Cylex ImmuKnow [corrected] assay is a valuable tool to more precisely modulate immunosuppression in pancreas transplant patients. In particular, the assay is extremely useful in detecting overly immunosuppressed patients vulnerable to infections.

Topics: Adenosine Triphosphate; Alemtuzumab; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antibodies, Neoplasm; Biological Assay; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Monitoring, Immunologic; Pancreas Transplantation; T-Lymphocytes; Tacrolimus

The safety and efficacy of tacrolimus (Tac)-based immunosuppressive treatments were studied in 115 pediatric renal transplant recipients (mean follow-up period, approximately 20 months). The acute rejection rate was 22.7% 6 months after transplantation and the steroid-resistant acute rejection rate was 6.4%. The 5-year patient and graft survival rates were 98.6% and 95.9%, respectively. Major adverse effects included infection, ie, cytomegalovirus (CMV) antigenemia (41.7%), renal dysfunction (29.6%), and impaired glucose tolerance (20.9%). The incidences of these adverse events were significantly decreased among patients who had undergone transplantation after March 2000 (n = 43), namely, 30.2%, 18.6%, and 11.6%, respectively.

Topics: Adult; Cadaver; Female; Follow-Up Studies; Glucose Intolerance; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Japan; Kidney Transplantation; Living Donors; Male; Nervous System Diseases; Postoperative Complications; Retrospective Studies; Survival Analysis; Tacrolimus; Time Factors; Tissue Donors

To evaluate the impact of mycophenolate mofetil (MMF) on long-term outcomes of tacrolimus and corticosteroids, we analyzed data reported to the Scientific Registry of Transplant Recipients for 11,670 adult patients (3463 with hepatitis C [HCV]) who underwent primary, single-organ, liver transplantation between 1995 and 2001. Patients who were discharged from the hospital on tacrolimus-based immunosuppression with (n = 4466; n = 1323 HCV) or without MMF (n = 7204; n = 2140 HCV) were included in the analysis. Recipients treated at discharge with MMF, tacrolimus, and corticosteroids had significantly increased patient survival (81.0% vs. 77.0% at 4 years, P < 0.0001) and graft survival (76.4% vs. 72.9%, P < 0.0001), and lower rates of acute rejection (29.0% vs. 33.4%, P < 0.001) as compared to recipients treated at discharge with tacrolimus and corticosteroids alone. A trend toward lower rates of death from infection was observed (6.1% at 4 years for MMF vs. 7.1% at 4 years for tacrolimus and corticosteroids, P = 0.0508), but this result did not reach statistical significance. In multiple regression analyses, MMF triple therapy at discharge was associated with a reduced risk of death (hazard ratio [HR] = 0.77, P < 0.001), graft loss (HR = 0.81, P < 0.001), acute rejection (HR = 0.89, P = 0.002), and death from infectious complications (HR = 0.80, P = 0.007). Outcomes were similar for the cohort with HCV.In conclusion, the addition of MMF at discharge to tacrolimus-based immunosuppression is associated with improved long-term outcomes after liver transplantation in patients with and without HCV.

Topics: Adrenal Cortex Hormones; Adult; Aged; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Hepatitis C; Humans; Immunosuppressive Agents; Infections; Liver Diseases; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Care; Postoperative Complications; Recurrence; Registries; Survival Analysis; Tacrolimus; Treatment Outcome

Dysregulated fibroblast proliferation is thought to play an important role in the progression of bronchiolitis obliterans (BO) after lung transplantation. Augmented immunosuppression is often used to treat BO. We investigated the effect of methylprednisolone (mPRED), cyclosporine A (CsA), tacrolimus (FK506), azathioprine (AZA), mycophenolate mofetil (MMF), and everolimus (rapamycin derivative [RAD]) on the proliferative capacity of fibroblasts cultured from transbronchial biopsies of lung transplant recipients.. Primary cultures of human lung fibroblasts were obtained from 14 transbronchial biopsies of lung transplant recipients. Subconfluent cells were serum starved for 24 hr followed by growth stimulation in the presence or absence of the respective drug in six concentrations ranging as follows: 0.01 to 100 mg/L for mPRED; 0.01 to 50 mg/L for CsA and AZA; 0.001 to 5 mg/L for FK506 and MMF; and 0.00001 to 1 mg/L for RAD. Proliferation was quantified by [3H]thymidine incorporation and direct cell count. A toxic drug effect was excluded by trypan blue.. Drug concentrations (mg/L) causing a 50% inhibition of fibroblast proliferation were mPRED 4; CsA 20; FK506 0.3; AZA 7; MMF 0.3; and RAD 0.0006. Drug concentrations (mg/L) causing inhibition of fetal bovine serum-induced proliferation were mPRED 60; CsA 45; FK506 3; AZA 35; MMF 1; and RAD 0.003.. RAD and MMF were the most potent antifibroproliferative drugs and were effective at concentrations achieved clinically, supporting their use for the treatment of patients with early BO. Our method holds promise as an in vitro model to assess the likely in vivo responses of human lung fibroblasts to specific immunosuppressive drugs.

Topics: Adult; Aged; Azathioprine; Bronchi; Bronchiolitis Obliterans; Cell Division; Cells, Cultured; Cyclosporine; Everolimus; Female; Fibroblasts; Humans; Immunosuppressive Agents; Infections; Lung Diseases; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Postoperative Complications; Sirolimus; Tacrolimus

In a pig model of intestinal transplantation, we previously showed that hepatic conditioning through portal donor-specific blood transfusion (pDSBT), high-dose tacrolimus (TAC), and steroids prevented rejection and increased survival Our current study tests a protocol of pDSBT, short-term mycophenolate mofetil (MMF), and low-dose TAC to eliminate the use of steroids, reduce TAC dosage, and increase the level of chimerism in the peripheral blood.. Four groups of outbred, mixed lymphocyte culture (MLC)-reactive pigs underwent bowel transplants and pDSBT. Immunosuppression (group 1, high-dose TAC and steroids; group 2, low-dose TAC and MMF; group 3, low-dose TAC, MMF, and aminoguanidine; group 4, low-dose TAC, MMF, and arginine) was discontinued after 28 days. RNA was extracted from intestinal graft and native liver biopsies for cytokine measurements. Chimerism levels were determined using a Q-PCR analysis.. Pig survival and death rates due to rejection did not significantly differ between the four groups. Chimerism levels determined by Q-PCR analysis were not different until day 28. After discontinuation of immunosuppression, we noted a trend (P = 0.15) toward higher mean chimerism levels on day 60 for groups 2, 3, and 4 (9%) vs. group 1 (0.5%). Tissue cytokine and serum nitrate levels did not significantly differ between the four groups. Attempts to modify nitric oxide synthase activity offered no added benefit.. The combination of pDSBT, MMF, and low-dose TAC (vs. high-dose TAC and steroids) allowed sustained levels of mixed chimerism to develop after discontinuation of immunosuppression.

Topics: Animals; Blood Transfusion; Cytokines; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Graft Rejection; Graft vs Host Disease; Immunosuppressive Agents; Infections; Intestines; Male; Mycophenolic Acid; Nitric Oxide; Portal System; Steroids; Survival Analysis; Swine; Tacrolimus; Tissue Donors; Transplantation Chimera

We reviewed long-term survival among hosts in 3 consecutive series of a rhesus monkey-baboon orthotopic cardiac xenotransplantation model with reference to host immune response, including the effectiveness in preventing rejection and limiting toxicity concerning infection, to evaluate specific immunosuppressive regimens for long-term outcomes.. Six juvenile baboons surviving more than 300 days after transplantation were reviewed. Regimen A consisted of splenectomy, FK506, methotrexate, and antilymphocyte globulin. Regimen B consisted of pretransplantation and chronic maintenance with cyclosporine A (INN: ciclosporin), methotrexate, and antithymocyte globulin. Regimen C was the same as regimen B plus pretransplantation total lymphoid irradiation and intraoperative donor bone marrow cell infusion. Rejections were detected by means of echocardiography.. Long-term survivors in 3 groups were followed for a range of 332 to 515 days (mean, 436 days). Rejection frequency in regimens A, B, and C was 0.35, 0.58, and 0.18 per month, and rescue therapy days were 23 (4.8%), 123 (9.5%), and 20 (2.4%), respectively (P <.0001). Infection frequency was 0.58, 0.56, and 0.19 per month, and therapy days were 192 (38.2%), 164 (12.6%), and 7 (0.9%), respectively (P <.0001). Concerning the host immune response, interleukin 2-activated T cells of all groups during rejection-free periods showed lower numbers compared with those of control animals (P <.0005), and regimen C was the lowest among 3 groups (P <.01). The production of xenoantibody was sufficiently attenuated in all groups.. Regimen C leads to long-term survival with fewer rejection and infection episodes by means of suppression of the interleukin 2 pathway and xenoantibody production.

Topics: Actuarial Analysis; Animals; Antilymphocyte Serum; Bone Marrow Transplantation; Cyclosporine; Graft Rejection; Heart Transplantation; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Macaca mulatta; Methotrexate; Papio; Splenectomy; Tacrolimus; Time Factors; Transplantation, Heterologous

Limited data are available on the use of tacrolimus and mycophenolate mofetil in conjunction with anti-IL-2 receptor antibody, in groups of kidney transplant recipients considered to be at higher risk. This study compared the incidence of acute rejection between African-American (AA), Hispanic (H), and non-African-American, non-Hispanics (non-AA, non-H) first renal transplant recipients. We studied 233 sequential first renal transplants. Of the 233, 37 recipients (16%) were AA, 85 (36.5%) were H and 111 (47.5%) were non-AA, non-H. All received daclizumab induction therapy (1 mg/kg) on the day of surgery, and every other week for a total of 5 doses, as well as mycophenolate mofetil, tacrolimus, and steroids. At 1 year, patient and graft survival were 97% and 95% in AA, 98% and 98% in H, and 96% and 95% in non-AA, non-H, respectively (not statistically different). Biopsy-proven acute rejection episodes were 8.1% in AA, 4.7% in H, and 4.5% in non-AA, non-H (also not statistically different). This immunosuppressive protocol appears to be safe and effective in helping to minimize biopsy-proven acute rejection and optimize renal allograft survival in African-American and Hispanic renal transplant recipients in the first year post transplantation.

Topics: Adult; Aged; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Black or African American; Daclizumab; Graft Rejection; Hispanic or Latino; Humans; Immunoglobulin G; Immunosuppressive Agents; Infections; Kidney Function Tests; Kidney Transplantation; Middle Aged; Mycophenolic Acid; Survival Analysis; Tacrolimus

Tacrolimus (FK) is being increasingly used as an alternative to cyclosporine (CyA) in heart transplantation (HTx). It is believed to engender slightly more powerful protection against acute rejection. However, the increased immunosuppression could result in an excess of infectious complications.. Our study compared the incidence of major infections (MInf), defined as life-threatening infectious episodes requiring admission and intravenous (IV) antimicrobial therapy, among a series of HTx recipients treated with either FK (n=30) or CyA (n=84).. A total of 21 patients received FK in an elective protocol and 9 patients initially treated with CyA were converted to FK. Tacrolimus was combined with azathioprine and prednisone in 21 cases, and with mycophenolate mofetil and steroids in 8 recipients. After a follow-up between 6 and 37 months, 11 patients (37%) in the FK group developed 13 episodes of MInf, most (85%) occurring during the first posttransplant year. Conversely, CyA patients (n=84), a group with similar characteristics and follow-up, showed a MInf incidence of 12% (P<.05). Among the FK group, the most common site of MInf was pulmonary (69%). A variety of opportunistic agents caused MInf in 54% of cases, whereas the remaining ones were attributed to nosocomial bacteria. There were three deaths (27% of all MInf), all in azathioprine-treated patients with initial FK therapy.. Tacrolimus therapy seems to be associated with an increased incidence of severe infections in HTx recipients. We recommend aggressive diagnostic and therapeutic approaches for patients on FK who develop signs or symptoms of infection in the first year after HTx.

Topics: Aged; Azathioprine; Cyclosporine; Drug Therapy, Combination; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Infections; Male; Middle Aged; Postoperative Complications; Prednisone; Retrospective Studies; Tacrolimus

Success of pediatric liver transplantation has improved significantly. Most posttransplant deaths occur early and are related to surgical complications or recipient status at the time of transplantation. The causes of mortality beyond the first year have not been well described.. Three hundred twenty-six pediatric liver transplants were performed between November 1989 and April 1998 using tacrolimus-based immunosuppression. Patients were followed until March 2002. Mean follow-up was 9.2+/-2.4 years.. At 1 year, 279 patients (85.5%) were alive. In the subsequent 12.5 years, 10 of the remaining children died (3.58%) at a mean interval of 3.68+/-1.69 years after transplant. The mean age at transplant was 5.62+/-6.3 years. Six patients had infections as a major contributor to mortality, including two patients with posttransplant lymphoproliferative disorder (PTLD) and one patient that died after retransplantation for hepatitis. Two patients had recurrent malignancy. Other deaths were attributable to chronic rejection, liver failure after being lost to follow-up, and complications of cystic fibrosis.. Pediatric liver transplantation using tacrolimus-based immunosuppression has demonstrated excellent success, with 1- and 10-year survival rates of 85.5% and 82.9%, respectively. Late mortality after pediatric liver transplantation overall remains low, with a rate of 0.32% per year. The most common cause of death was infection (60%), including PTLD-related disease (20%). However, in the recent cohort of patients who underwent transplantation after September 1995, there were no fatal cases of Epstein-Barr virus or PTLD or late mortality thus far, suggesting a benefit from improved infectious disease surveillance using currently available modalities. Mortality from chronic rejection and noncompliance under tacrolimus has been exceedingly rare.

Topics: Cause of Death; Child; Child, Preschool; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Infant; Infections; Liver Failure; Liver Neoplasms; Liver Transplantation; Lymphoproliferative Disorders; Male; Tacrolimus

Topics: Antibodies; Antilymphocyte Serum; Azathioprine; Calcineurin Inhibitors; Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infections; Liver Transplantation; Postoperative Complications; Prednisone; Retrospective Studies; Tacrolimus; Time Factors

Although some previous studies have indicated the possibility of immunosuppression withdrawal in clinical liver transplantation, the mechanism of graft acceptance is not clear. The aim of this study is to elucidate the alloreactivity against the donor and intragraft cytokine profiles in living donor liver transplant (LDLT) recipients with graft acceptance. In October 1999, we had 23 patients who survived without immunosuppression after LDLT with a median drug-free period of 25 months (range: 3-69 months). They consisted of six patients who were electively weaned by an elective weaning protocol and 17 either forcibly or accidentally weaned patients due to various causes but mainly due to infection. We evaluated the alloreactivity against the donor in these patients by a mixed lymphocyte reaction and intragraft cytokine profiles by real-time reverse transcriptase-polymerase chain reaction. The development of donor-specific hyporeactivity was observed in the patients with graft acceptance. The cytokine pattern in the supernatant of the culture medium revealed a down regulation of T helper (Th) 1 cytokine INF gamma against the donor while no significant difference was seen in Th2 cytokine IL-10. Regarding the intragraft cytokine profiles, we could find no amplification of Thl cytokines (IL-2, INF y) and IL-4 while some of the patients revealed a gene expression of IL-10 with no significant difference from that of the normal, untransplanted liver specimen. In addition, no difference was observed in any other cytokines (IL-1beta, IL-8, IL-15, TNFalpha) compared with those of the normal controls. We propose that the down regulation of Th1 cytokine is one possible mechanism of graft acceptance in LDLT recipients.

Topics: Administration, Oral; Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cytokines; Drug Therapy, Combination; Female; Gene Expression Profiling; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Infant; Infant, Newborn; Infections; Injections, Intravenous; Interferon-gamma; Interleukins; Liver; Liver Transplantation; Lymphocyte Culture Test, Mixed; Male; Postoperative Complications; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger; Tacrolimus; Th1 Cells; Tissue Donors; Tumor Necrosis Factor-alpha

Corticosteroids have been a cornerstone of immunosuppression for four decades despite their adverse side effects. Past attempts at steroid withdrawal in pediatric renal transplantation have had little success. This study tests the hypothesis that a complete steroid-free immunosuppressive protocol avoids steroid dependency for suppression of the immune response with its accompanying risk of acute rejection on steroid withdrawal.. An open labeled prospective study of complete steroid avoidance immunosuppressive protocol was undertaken in 10 unsensitized pediatric recipients (ages 5-21 years; mean 14.4 years) of first renal allografts. Steroids were substituted with extended daclizumab use, in combination with tacrolimus and mycophenolate mofetil. Protocol biopsies were performed in the steroid-free group at 0, 1, 3, 6, and 12 months posttransplantation. Clinical outcomes were compared to a steroid-based group of 37 matched historical controls.. Graft and patient survival was 100% in both groups. Clinical acute rejection was absent in the steroid-free group at a mean follow-up time of 9 months (range 3-13.7 months). Protocol biopsies in the steroid-free group (includes 10 patients at 3 months, 7 at 6 months, and 4 at 12 months) revealed only two instances of mild (Banff 1A) subclinical rejection (reversed by only a nominal increase in immunosuppression) and no chronic rejection. At 6 months the steroid-free group had no hypertension requiring treatment (P=0.003), no hypercholesterolemia (P=0.007), and essentially no body disfigurement (P=0.0001). Serum creatinines, Schwartz GFR, and mean delta height Z scores trended better in the steroid-free group. In the steroid-free group, one patient had cytomegalovirus disease at 1 month and three had easily treated herpes simplex stomatitis, but with no significant increase in bacterial infections or rehospitalizations over the steroid-based group. The steroid-free group was more anemic early posttransplantation (P=0.004), suggesting an early role of steroids in erythrogenesis; erythropoietin use normalized hematocrits by 6 months.. Complete steroid-free immunosuppression is efficacious and safe in this selected group of children with no early clinical acute rejection episodes. This protocol avoids the morbid side effects of steroids without increasing infection, and may play a future critical role in avoiding noncompliance, although optimizing renal function and growth.

Topics: Adolescent; Adult; Anemia; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Biopsy; Child; Cohort Studies; Daclizumab; Drug Therapy, Combination; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Hyperlipidemias; Hypertension; Immunoglobulin G; Immunosuppression Therapy; Immunosuppressive Agents; Incidence; Infections; Kidney; Kidney Transplantation; Male; Mycophenolic Acid; Postoperative Complications; Prospective Studies; Steroids; Survival Analysis; Tacrolimus

Several studies have shown that calcineurin may play a critical role in the signalling of cardiac hypertrophy in various experimental models.. To elucidate whether calcineurin is involved in cardiac hypertrophy due to energy metabolic disorder by using the juvenile visceral steatosis (JVS) mouse, which is a murine model of systemic carnitine deficiency.. Cardiac hypertrophy in JVS mice (C3H strain) progresses gradually after birth and is present until eight weeks of age. In this study, calcineurin activity in JVS mice increased significantly at four weeks of age (the developing stage of cardiac hypertrophy) compared with age-matched control mice. Treatment with calcineurin inhibitor FK506 (0.5 or 1.0 mg/kg/day) from the age of four to eight weeks attenuated cardiac hypertrophy without beneficially affecting cardiac function. Gene expression, accompanied by cardiac hypertrophy, was also suppressed by the FK506 treatment.. The activation of calcineurin is involved in the development of cardiac hypertrophy in the JVS mouse, and calcineurin inhibition may be useful for reducing cardiac hypertrophy.

Topics: Animals; Blood Pressure; Cachexia; Calcineurin; Calcineurin Inhibitors; Cardiomegaly; Diabetes Mellitus; Disease Models, Animal; Dose-Response Relationship, Drug; Gene Expression; Hypertension; Infections; Metabolism, Inborn Errors; Mice; Mice, Inbred C3H; Myocardium; Reference Values; Renal Insufficiency; Tacrolimus

The introduction of potent new immunosuppressive agents may allow simultaneous kidney-pancreas transplantation to be performed without antilymphocyte induction.. We analyzed 30 simultaneous kidney-pancreas transplantations receiving tacrolimus, mycophenolate mofetil, and steroids without without antilymphocyte induction. Eighteen patients underwent pancreas transplantation with portal-enteric (P-E) drainage and the remaining 12 had systemic bladder (S-B) drainage. Target 12 hr trough tacrolimus levels for the first 3 months after simultaneous kidney-pancreas transplantation were 15-20 ng/ml. The oral mycophenolate mofetil dose was 2-3 g/day begun immediately posttransplant in two to four divided doses. Steroids were tapered according to protocol.. All patients experienced immediate function of both kidney and pancreas grafts. One-year actuarial patient, kidney, and pancreas graft survival rates are 93, 93, and 90%, respectively. Nine patients (30%) had a total of 13 rejection episodes (12 biopsy proven) including 4 within 2 weeks, 6 between 2 weeks and 3 months, and 3 beyond 3 months after simultaneous kidney-pancreas transplantation. Three rejection episodes were treated with steroids alone and 10 were treated with antilymphocyte therapy (5 OKT3 and 5 ATGAM). A total of seven patients (23%) received antilymphocyte therapy. Three patients (10%) had more than one rejection episode. Two pancreas grafts (7%) and one kidney graft (3%) were lost from rejection. Four patients (13%) developed cytomegalovirus infection, but none had tissue-invasive cytomegalovirus. At present, 22 surviving patients (81%) remain on triple immunosuppression with tacrolimus, mycophenolate mofetil, and prednisone with excellent dual graft function.. Tacrolimus, mycophenolate mofetil, and prednisone immunosuppression without without antilymphocyte induction is safe and effective after simultaneous kidney-pancreas transplantation.

Topics: Adult; Antilymphocyte Serum; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Infections; Kidney Transplantation; Length of Stay; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Postoperative Care; Postoperative Complications; Prednisone; Survival Analysis; Tacrolimus

Currently, limited data exist on the role of tacrolimus (FK506) in pediatric allogeneic marrow transplantation. Forty-one patients who received tacrolimus as prophylaxis were reviewed, with a median age of 9 years (range 0.2-16 years). Twenty-one patients underwent related donor transplants and 20 underwent unrelated donor transplants. All patients received tacrolimus beginning the day prior to transplant at a dose of 0.03 mg/kg/day by continuous i.v. infusion. When clinically possible, patients were switched to oral therapy in two divided doses, at four times the intravenous dose. Tacrolimus levels were monitored twice a week, and dosages adjusted to maintain serum levels 5-15 ng/ml. Common adverse effects included hypomagnesemia (98%), hypertension (49%), nephrotoxicity (34%), and tremors (32%). Less common side-effects (<10% cases) included seizures and hyperglycemia. The median time to ANC recovery (ANC >500 x 106/l) was 15 days. For the related donor group, the incidence of grade II-IV acute GVHD was 33%, and grade III-IV GVHD 19%. For the unrelated donor group, the incidence of grade II-IV acute GVHD was 55%, and grade III-IV GVHD 30%. Overall, tacrolimus therapy was well tolerated as prophylaxis for acute GVHD in pediatric patients undergoing allogeneic transplantation.

Topics: Actuarial Analysis; Acute Disease; Adolescent; Child; Child, Preschool; Female; Graft Survival; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Infant; Infections; Liver Failure; Magnesium Deficiency; Male; Methotrexate; Survival Rate; Tacrolimus; Time Factors; Transplantation, Homologous; Vascular Diseases

Although the introduction of FK506 and MMF has markedly improved patient and graft outcome after pancreas transplantation, this procedure is still associated with a high surgical complication rate. The aim of the following study was to retrospectively analyze a series of 40 consecutive pancreas transplants with enteric drainage with regard to intraabdominal infection (IAI). Between March 1997 and December 1998 a total of 40 whole pancreas transplants were performed. Prophylactic immunosuppression consisted of an intraoperative single shot ATG (Thymoglobulin), FK506, MMF, and prednisone. The mean observation period was 14.6 (5-26) months. Overall incidence of IAI was 27.5% (n = 11) leading to pancreatectomy in 5 patients (12.5%). In the remaining 6 patients the graft could be rescued by necrosectomy and radical drainage of the abscess (5 patients) or percutaneous drainage (1 patient). Pancreatectomy or local infection did not alter kidney graft function in the 11 patients with simultaneous pancreas kidney transplantation. In 10 patients no evidence for leakage at the site of enteric anastomosis was present, one duodenal leak occurred due to ischemia. IAI in the early postoperative period was the predominat risk factor for graft loss. An early and invasive diagnostic approach is recommended to maximize the chance of graft rescue.

Topics: Adult; Antilymphocyte Serum; Female; Graft Survival; Humans; Immunosuppressive Agents; Infections; Intestines; Male; Middle Aged; Mycophenolic Acid; Pancreas Transplantation; Pancreatectomy; Postoperative Complications; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

The immunosuppression required to prevent rejection of intestinal transplants causes a high rate of infection and lymphoma. It is crucial that immunomodulatory strategies be developed to facilitate intestinal engraftment.. We prospectively examined the effect of unpurified donor-specific bone marrow transfusions (DSBMTs) on rejection, infection, graft-versus-host disease (GVHD), and survival after intestinal transplantations in 44 Yorkshire Landrace pigs. Four groups that differed according to presence or abscence of treatment with FK506 and DSBMT were analyzed.. In nonimmunosuppressed pigs, DSBMTs had no effect on survival (8 days versus 9 days in controls; p = 0.9). In FK506 pigs, DSBMTs tended to reduce survival (21 days versus 37 days in FK506 controls; p = 0.1); no difference was seen between two bone marrow dosages 5 x 10(7) or 5 x 10(8) bone marrow cells/kg. No difference in the incidence of death caused by rejection was seen between DSBMTs and controls, but there was a marked tendency toward more deaths caused by rejection in DSBMTs + FK506 versus FK506-only pigs (p = 0.09). Daily stomal assessment showed a higher rate of moderate and severe interstitial rejection in DSBMT + FK506 versus FK506-only pigs; DSBMT was also associated with increased vascular rejection. Finally, groupwise comparison showed an order of susceptibility to lethal GVHD and infection as follows: DSBMT + FK506 > FK506 > DSBMT > controls.. Rather than promoting engraftment, DSBMT can sensitize recipients and cause rejection after intestinal transplantation. It aggravates the risks of generalized GVHD and infection and tends to reduce graft and recipient survival. Before being applied clinically, DSBMT needs to be refined to increase its tolerogenic potential without causing GVHD.

Topics: Animals; Bone Marrow Transplantation; Graft Rejection; Graft vs Host Disease; Immunosuppressive Agents; Infections; Intestines; Postoperative Complications; Survival Analysis; Swine; Tacrolimus; Time Factors; Tissue Donors

Clinically, FK506 is superior to CsA after solitary small bowel transplantation (SBTx). Development of diarrhea after SBTx has been the rationale for adding the colon to small bowel grafts. However, the additional lymphoid and bacterial content transferred with total small plus large bowel transplants (TBTx) might aggravate the alloimmune response-rejection and graft-versus-host disease (GVHD)-and increase the risk of infection. We studied the incidence of rejection, GVHD, and infection after TBTx and the impact of CsA versus FK506. We performed orthotopic TBTx with portal drainage after total enterectomy in outbred Yorkshire Landrace pigs, divided into 3 groups: control pigs (n=6) received no immunosuppression; CsA pigs (n= 14) received CsA (5 mg/kg), antilymphocyte globulin (10 mg/kg for 10 days), prednisone (2 mg/kg), and AZA (2.5 mgtkg); and FK506 pigs (n=9) received FK506 (0.2 mg/kg) and prednisone (2 mg/kg). Trough CsA whole blood levels were >400 ng/ml for the first 7 days and >200 ng/ml thereafter. FK506 levels were > 15 ng/ml. We excluded from further analysis 5 early deaths (<3 days) due to anesthesiologic (n=2) or technical reasons (n=3). Median survival of control pigs was 9.5 days (range, 4-13). Cyclosporine did not extend survival: median, 9 days (range, 5-31) (P=0.6). FK506 prolonged survival: median, 37 days (range, 21-49) (P<0.001 vs. control and CsA pigs). Of FK506 pigs, 60% gained weight (+75 g/day), whereas 100% of controls and 75% of CsA pigs lost weight (-550 g/day and -300 g/day, respectively). All control pigs died of rejection within 2 weeks versus none of the FK506 pigs. However, 36% of CsA pigs died of rejection. Groupwise comparison showed less rejection in FK506 versus control pigs (P<0.001) and in FK506 versus CsA pigs (P<0.03), but no difference between CsA and control pigs. None of the control pigs died of GVHD versus 18% of CsA pigs (by day 31) and 37% of FK506 pigs (by day 49). Groupwise comparison showed increased GVHD in FK506 versus control pigs (P<0.001) and a tendency toward increased GVHD in FK506 versus CsA pigs (P=0.08). None of the control pigs died of infection alone versus 22% of CsA pigs (by day 31) and 67% of FK506 pigs (by day 49). Groupwise comparison showed increased infection in FK506 versus control pigs (P<0.001). We detected significant endotoxemia early and late postoperatively. But we saw no specific correlation between endotoxemia, rejection, GVHD, or infection. Based on this study, we have drawn sev

Topics: Animals; Body Weight; Cyclosporine; Endotoxins; Graft Rejection; Graft vs Host Disease; Immunosuppressive Agents; Infections; Intestine, Large; Intestine, Small; Prospective Studies; Swine; Tacrolimus; Toxemia

In immunocompromised HIV-infected and transplanted patients, there is a risk of developing Epstein-Barr virus (EBV)-associated lymphoproliferative disorders (LPD) and lymphomas. EBV has previously been detected by the polymerase chain reaction (PCR) in cerebrospinal fluid from all AIDS patients with EBV-associated cerebral lymphomas. We therefore thought it would be of interest to determine whether transplant patients with extracerebral EBV-associated LPD have detectable EBV genomes in serum. Nested PCR (nPCR) showed that 58% (18/31) of liver transplant (LTX) patients had EBV DNA in 17% (21/125) of serum samples obtained within the first 3 months after LTX. In 39% (7/18) of the patients, the first EBV nPCR-positive sample was found within 2 weeks post-LTX. Basic immunosuppression with cyclosporin A or FK506 did not seem to influence the frequency of detectable EBV genomes in serum. In contrast, positive EBV nPCR correlated to secondary OKT3 treatment for severe acute rejection (P = 0.009). EBV-associated malignant lymphoma developed in three patients 2-6 months post-LTX. In all of them, EBV DNA was amplifiable within 12-14 days after LTX. The EBV antibody titers were not directly related to detectable EBV DNA in serum. We conclude that monitoring of LTX patients receiving increased immunosuppression by nPCR for EBV DNA in serum may help in the early identification of those at risk of developing EBV-associated LPD.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Antigens, Viral; Child; Child, Preschool; Cyclosporine; DNA, Viral; Female; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Incidence; Infant; Infections; Liver Transplantation; Lymphoma, B-Cell; Male; Middle Aged; Muromonab-CD3; Polymerase Chain Reaction; Postoperative Complications; Postoperative Period; Survival Rate; Tacrolimus; Tumor Virus Infections; Viral Proteins; Viremia; Virus Activation

We reviewed 37 living related liver transplantations (LRLT) performed by our department during the last 27 months on children with end-stage liver disease. The patients were 15 boys and 22 girls aged 7 months to 15 years with biliary atresia (27), cryptogenic cirrhosis (3), Budd-Chiari syndrome (2), progressive intrahepatic cholestasis (2), protoporphyria (1), Wilson's disease (1), and fulminant hepatitis (1). The donors were 14 fathers and 23 mothers. Grafts were made from the left lateral segment (19), left lateral segment with partial S4 (11), left lobe (6), and right lobe (1). After graft harvesting all donors resumed normal liver function and normal life. The recipient underwent total hepatectomy with preservation of the inferior vena cava. FK506 and low-dose steroids were used for immunosuppression. The survival rate was 90% (27/30) in elective cases and 57% (4/7) in emergency cases. Six recipients had functioning grafts but died of extrahepatic complications. Hepatic vein stenosis occurred in 3 cases at 3 months after LRLT and was successfully treated by balloon dilatation. Portal vein stenosis occurred in 1 case at 8 months after LRLT and was also safely dilated. We incurred no hepatic artery thrombosis after introducing microsurgery techniques. Among 12 viral, 5 bacterial, and 3 fungal postoperative infections, 1 Candida pneumonia and 1 EBV-associated lymphoma were lethal. Three patients with ABO-blood group compatible grafts and one with an incompatible graft developed acute rejection, which was controlled in evey case by steroid bolus and/or increasing the dose of FK506. There were no definite episodes of rejection in ABO-identical cases. Children with moderate growth retardation (> or = -1.5 SD of normal growth) caught up in growth soon after LRLT, but those with severe retardation (<-1.5 SD) were slow to attain age-normal height. Appropriate timing, meticulous surgical procedures, and comprehensive management of complications are crucial for successful outcome with LRLT. LRLT is a promising option for alleviating the shortage of livers for pediatric transplantation and may be regarded as an independent modality to supplement cadaver donation.

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Emergencies; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Growth Disorders; Hepatic Veins; Humans; Immunosuppression Therapy; Infant; Infections; Liver Failure; Liver Transplantation; Male; Microsurgery; Portal Vein; Steroids; Survival Analysis; Survival Rate; Tacrolimus; Treatment Outcome; Venous Insufficiency

This prospective study characterizes the incidence, etiology, timing, risk factors, and outcome of the infectious complications after 88 consecutive liver transplantations in 79 patients receiving tacrolimus (FK506) as primary immunosuppression with a median follow-up of 880 days. Infections occurred in 59% (47/79) of the patients, and 39% had major infections. Of the major infections, 55% were bacterial, 22% were viral, and 22% were fungal. Bacteremia accounted for 30% of major bacterial infections. Sixty percent of bacteremias occurring within the first 3 months were catheter related, while 75% of those occurring more than 3 months after transplant were of a biliary source. Patients with recurrent hepatitis C virus hepatitis and patients requiring dialysis after transplant had a significantly higher rate of infections as compared with other patients. Overall mortality was 18%, and 29% of all deaths were associated with infection. Only invasive aspergillosis was associated with infectious mortality. Our data suggest that the potent immunosuppressive agent FK506 is not associated with a higher incidence of infectious complications as compared with previous studies using CsA.

Topics: Adult; Aged; Bacterial Infections; Female; Graft Survival; Humans; Immunosuppression Therapy; Incidence; Infections; Liver Transplantation; Male; Middle Aged; Mycoses; Postoperative Complications; Prospective Studies; Risk Factors; Survival Rate; Tacrolimus; Treatment Outcome; Virus Diseases

The decade from 1982 through 1992 witnessed tremendous growth in pediatric cardiac transplantation. At Children's Hospital of Pittsburgh 66 cardiac transplants were performed during this period (age range 7 hours to 18 years). The cause of cardiomyopathy was congenital (n = 30), cardiomyopathy (n = 29), myocarditis (n = 2), doxorubicin toxicity (n = 2), ischemic (n = 1), valvular (n = 1), and cardiac angiosarcoma (n = 1). Nine children (14%) required mechanical circulatory support before transplantation: extracorporeal membrane oxygenation (n = 8) and Novacor left ventricular assist system (n = 1) (Baxter Healthcare Corp., Novacor Div., Oakland, Calif.). The mean follow-up time was 2 years (range 4 months to 8 years). The overall survival in the group was 67%. In children with congenital heart disease (> 6 months of age) the perioperative (30 day) mortality was 66% before mid-1988 (n = 10) and 0% since mid-1988 (n = 11). The late mortality (> 30 days) in children with cardiomyopathy transplanted prior to mid-1988 was 66% (n = 14) and 7% since mid-1988 (n = 15). Since mid-1988 1- and 3-year survival was 82% in children with congenital heart disease and 90% in children with cardiomyopathy. Twenty-six children have had FK 506 as their primary immunosuppressive therapy since November 1989. Survival in this group was 82% at 1 and 3 years. The actuarial freedom from grade 3A rejection in the FK group was 60% at 3 and 6 months after transplantation versus 20% and 12%, respectively, in the 15 children operated on before the advent of FK 506, who were treated with cyclosporine-based triple-drug therapy (p < 0.001, Mantel-Cox and Breslow). Twenty of 24 children (83%) in the FK 506 group are receiving no steroids. The prevalence of posttransplantation hypertension was 4% in the FK 506 group versus 70% in the cyclosporine group (p < 0.001, Fisher). Renal toxicity in children treated with FK 506 has been mild. Additionally, eight children have been switched to FK 506 because of refractory rejection and drug toxicity. FK 506 has not produced hirsutism, gingival hyperplasia, or abnormal facial bone growth. The absence of these debilitating side effects, together with the observed immune advantage and steroid-sparing effects of FK 506, hold tremendous promise for the young patient facing cardiac transplantation and a future wedded to immunosuppression.

Topics: Adolescent; Cardiomyopathies; Child; Child, Preschool; Cyclosporine; Extracorporeal Membrane Oxygenation; Female; Graft Rejection; Heart Defects, Congenital; Heart Transplantation; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Infections; Kidney; Lymphoproliferative Disorders; Male; Postoperative Complications; Tacrolimus

The experimental immunosuppressive drug FK 506 was given to 36 renal transplant recipients, many of whom were highly sensitized. Ten were undergoing kidney retransplantation, 10 also underwent liver transplantation at an earlier time (6 patients) or concomitantly (4 patients), and 2 patients received a third organ (heart or pancreas) in addition to a liver and kidney. With follow-ups of 4 to 13 months, all but 2 of the 36 patients are alive, 29 (81%) are dialysis free, and most have good renal function. Twenty of the 29 dialysis-free patients are receiving no or low-dose (2.5 to 5.0 mg/d) prednisone therapy. Only one kidney was lost to cellular rejection. However, patients who had antidonor cytotoxic antibodies in current or historical serum samples had a high rate (3 of 9) of irreversible humoral rejection. A low incidence of posttransplant hypertension was noteworthy. Hirsutism and gingival hyperplasia were not observed. Serum cholesterol levels in patients who took FK 506 were unexpectedly low, and the effect on the level of uric acid was minimal. The side effects of FK 506 therapy include nephrotoxicity, neurotoxicity, and potential induction of a diabetic state. These are similar to the side effects of cyclosporine use, but probably less severe. The seeming safety, efficacy, and relative freedom from side effects of FK 506 encourage further trials in kidney transplantation.

Topics: Adult; Anti-Bacterial Agents; Child; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Infections; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Tissue Donors

The new immunosuppressive drug FK 506 was used from the outset with low doses of prednisone to treat 120 recipients of primary liver grafts and 20 more patients undergoing liver retransplantation. The patient survival rate after 2 to 8 months in the primary liver transplantation series is 93.3%, with original graft survival of 87.5%. Of the 20 patients in the hepatic retransplant series, 17 (85%) are living. Almost all of the surviving patients have good liver function. In addition 11 hearts, 2 double lungs, and a heart-lung have been transplanted under FK 506, with survival of all 14 patients. With all of the organ systems so far tested, including the kidney (which has been reported elsewhere), rejection usually has been controlled without additional drugs and with lower average steroid doses than in the past. Nephrotoxicity has been observed, but not to an alarming degree, and there has been a notable absence of hypertension. There is a suggestion that serum cholesterol may be lowered by FK 506, but this is unproved. Although the adverse reactions of FK 506 and the immunosuppressive mechanisms resemble those of cyclosporine, our preliminary observations suggest that FK 506 may have a more advantageous therapeutic index.

Topics: Adolescent; Adult; Anti-Bacterial Agents; Cause of Death; Child; Child, Preschool; Female; Graft Rejection; Graft Survival; Heart Transplantation; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Incidence; Infant; Infections; Kidney Transplantation; Liver Transplantation; Lymphoma; Male; Middle Aged; Reoperation; Tacrolimus; Transplantation