tacrolimus and Cystic-Fibrosis

Solid organ transplant (SOT) recipients with cystic fibrosis (CF) may benefit from the pulmonary and extrapulmonary benefits associated with CF transmembrane conductance regulator modulators. Nevertheless, evolution of modulator safety and efficacy data prompts consideration.. The search terms "transplant" AND "ivacaftor"(IVA) OR "lumacaftor"(LUM) OR "tezacaftor" (TEZ) OR "elexacaftor" (ELX) were utilized to conduct a scoping review of English articles from the period of January 1, 2012 to December 31, 2022. Search results from PubMed and Embase databases were reviewed by title and abstract for relevance. Included studies reported efficacy and safety outcomes of modulators in SOT recipients.. One hundred thirty-six patients from one cohort study (90 lung transplant recipients) and eight case reports and series (29 lung transplant recipients, 16 liver transplant recipients and one lung/liver transplant patient) were included. Post-modulator initiation, 33 patients did not necessitate tacrolimus dose adjustments, 10 required dose uptitration, and 43 required dose reductions. Moreover, LUM/IVA use with azole antifungals may lead to subtherapeutic levels but opposing effects sustained tacrolimus levels. Liver transplant recipients were more likely to experience elevations in transaminases requiring pharmacologic or medical interventions. Majority of patients experienced improvements in pulmonary function, fasting blood glucose, hemoglobin, body mass index, and rhinosinusitis symptoms. However, intolerance or lack of benefit prompted discontinuation of ELX/TEZ/IVA in over 40% of lung-transplant recipients in one study.. Modulator therapy has been reported to produce pulmonary and extra-pulmonary benefits in the CF population with SOT. Considerations for modulator therapy initiation ought to include modulator pharmacokinetics, concomitant medications, and transplant type due to the complex nature of SOT recipients.

Topics: Aminophenols; Benzodioxoles; Cohort Studies; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Humans; Mutation; Organ Transplantation; Tacrolimus

Although significant gains have been made in improving lung function and survival in cystic fibrosis (CF), ultimately respiratory failure is the leading cause of mortality in these patients. For CF patients with end stage lung disease, lung transplantation is an option for treatment. The field of lung transplantation has progressed markedly in the last 20 years. Nonetheless it remains a technically complex and challenging procedure, and patients are at risk for numerous short term and long term complications. Potential transplant recipients must be physically and psychologically prepared for the arduous process involved in lung transplantation. This article will review the history of lung transplantation, indications for transplantation, surgical techniques, and complications of transplantation.

Topics: Bronchiolitis Obliterans; Cystic Fibrosis; Graft Rejection; Heart-Lung Transplantation; Humans; Lung Transplantation; Respiratory Insufficiency; Tacrolimus; Tissue Donors

Lung transplantation has emerged as an option to prolong and increase the quality of life in patients with end-stage pulmonary lung disease. In lung transplant recipients, because of the high potential for acute and chronic allograft rejection, optimal selection, dosage and delivery of immunosuppressive medications is critical. Cystic fibrosis (CF), a multi-organ system disease that often includes pulmonary and gastrointestinal manifestations, represents the leading indication for bilateral lung transplantation. The gastrointestinal manifestations of CF, however, confound post-transplant management by causing significant variation in the rate and extent of absorption of orally administered immunosuppressive medications. Tacrolimus, a new calcineurin inhibitor, is increasingly employed as the primary immunosuppressive agent in lung transplant recipients. Unfortunately, tacrolimus itself exhibits variable bioavailability, particularly in CF transplant recipients. A novel approach to the absorption dilemma is administration of tacrolimus via the sublingual (SL) route. Little published information exists concerning the use of SL immunosuppression in transplant recipients. However, emerging evidence suggests that SL tacrolimus provides is an effective means of drug delivery particularly for CF lung transplant recipients. Preliminary results from a pilot study, demonstrate that SL delivery of tacrolimus achieves therapeutic serum levels, in lung transplant recipients with CF, over the first few postoperative months. In addition, the early postoperative use of SL tacrolimus has been associated with acceptable rates of transplant rejection and normal renal function in a cohort of 22 lung transplant recipients that included CF and non-CF transplant recipients. Potential pharmacokinetic advantages of the SL route of delivery include good permeability, rapid absorption, acceptable bioavailability and easy accessibility. From an economic standpoint, considerable cost savings could be achieved by using the SL rather than the intravenous route of drug delivery for tacrolimus. Comparative, prospective randomized trials are necessary to evaluate the long-term safety and efficacy of SL tacrolimus in lung transplant patients. Until such data are available, the use of SL tacrolimus should be considered in situations where alternative routes of delivery are unavailable or as part of ongoing research studies. Ultimately, SL tacrolimus may prove efficacious for short-term use

Topics: Administration, Oral; Administration, Sublingual; Cost Savings; Cystic Fibrosis; Drug Costs; Humans; Immunosuppressive Agents; Lung Transplantation; Tacrolimus

  We report a case series of four children who developed fixed dilated pupils associated with high tacrolimus levels (>30 nanograms/millilitre [ng/mL]) in the immediate post-operative period following isolated liver or liver and small bowel transplantation.

Topics: Child; Cystic Fibrosis; Electroencephalography; Female; Fixation, Ocular; Humans; Immunosuppressive Agents; Infant; Liver Failure, Acute; Liver Transplantation; Male; Pupil; Short Bowel Syndrome; Tacrolimus

To: (i) test different pharmacokinetic models to fit full tacrolimus concentration-time profiles; (ii) estimate the tacrolimus pharmacokinetic characteristics in stable lung transplant patients with or without cystic fibrosis (CF); (iii) compare the pharmacokinetic parameters between these two patient groups; and (iv) design maximum a posteriori Bayesian estimators (MAP-BE) for pharmacokinetic forecasting in these patients using a limited sampling strategy.. Tacrolimus blood concentration-time profiles obtained on three occasions within a 5-day period in 22 adult lung transplant recipients (11 with CF and 11 without CF) were retrospectively studied. Three different one-compartment models with first-order elimination were tested to fit the data: one with first-order absorption, one convoluted with a gamma distribution to describe the absorption phase, and one convoluted with a double gamma distribution able to describe secondary concentration peaks. Finally, Bayesian estimation using the best model and a limited sampling strategy was tested in the two groups of patients for its ability to provide accurate estimates of the main tacrolimus pharmacokinetic parameters and exposure indices.. The one-compartment model with first-order elimination convoluted with a double gamma distribution gave the best results in both CF and non-CF lung transplant recipients. The patients with CF required higher doses of tacrolimus than those without CF to achieve similar drug exposure, and population modelling had to be performed in CF and non-CF patients separately. Accurate Bayesian estimates of area under the blood concentration-time curve from 0 to 12 hours (AUC12), AUC from 0 to 4 hours, peak blood concentration (Cmax) and time to reach Cmax were obtained using three blood samples collected at 0, 1 and 3 hours in non-CF patients (correlation coefficient between observed and estimated AUC12, R2 = 0.96), and at 0, 1.5 and 4 hours in CF patients (R2 = 0.91).. A particular pharmacokinetic model was designed to fit the complex and highly variable tacrolimus blood concentration-time profiles. Moreover, MAP-BE allowing tacrolimus therapeutic drug monitoring based on AUC12 were developed.

Topics: Adult; Area Under Curve; Bayes Theorem; Cystic Fibrosis; Humans; Immunosuppressive Agents; Lung Transplantation; Models, Biological; Tacrolimus

Elexacaftor/tezacaftor/ivacaftor (ELX/TEZ/IVA) is a highly effective therapy for patients with cystic fibrosis (CF) with potential benefits in lung transplant recipients (LTRs) for extrapulmonary CF manifestations; however, tolerability and efficacy in this population are largely unknown. We report our experience with ELX/TEZ/IVA in LTRs for extrapulmonary complications of CF including tolerability, drug-drug interactions, and therapeutic benefit. All LTRs at a single center initiated on ELX/TEZ/IVA were reviewed. Adverse events and patient-reported outcomes attributed to ELX/TEZ/IVA were documented. Pulmonary function, tacrolimus requirements in mg/kg/dl, body mass index (BMI), and reason for initiation were assessed at the initiation of ELX/TEZ/IVA, and at 12 months post-initiation or at the time of discontinuation for those in whom therapy was discontinued. Thirteen LTRs were initiated on ELX/TEZ/IVA at a mean of 115 ± 92 months post-transplant. All were initiated on ELX/TEZ/IVA for sinus or sinus and gastrointestinal CF manifestations. Five (38.4%) patients discontinued therapy due to declining pulmonary function (2/5, 40%), mood disturbances (2/5, 40%), or lack of benefit (1/5, 20%). Of the eight patients who remain on ELX/TEZ/IVA, four reported adverse effects and three LTRs temporarily held therapy. Six (46.2%) LTRs reported improvement in sinus symptoms, while four (30.7%) reported improved gastrointestinal symptoms. Weight declined in the cohort overall. Tacrolimus dose requirements decreased following initiation of ELX/TEZ/IVA therapy, with a 50% decline in dose requirements observed. In our experience, ELX/TEZ/IVA in LTRs is poorly tolerated with modest perceived extrapulmonary benefit and a significant effect on tacrolimus dose requirements. More data are needed to determine the benefits of ELX/TEZ/IVA therapy in LTRs.

Topics: Aminophenols; Benzodioxoles; Cystic Fibrosis; Cystic Fibrosis Transmembrane Conductance Regulator; Drug Combinations; Humans; Indoles; Lung Transplantation; Mutation; Pyrazoles; Pyridines; Quinolines; Tacrolimus; Transplant Recipients

The CFTR modulator combination elexacaftor/tezacaftor/ivacaftor (ETI) is a genetic mutation-targeted treatment in cystic fibrosis that results in profound improvements in clinical outcomes. Each of the compounds are substrates of CYP3A4/5, the cytochrome P450 enzyme family for which tacrolimus is also a substrate. The use of these compounds in an individual with a solid organ transplant has not been previously studied and there is potential for a drug interaction. In this report, we describe a pediatric liver transplant recipient with clinical decline related to cystic fibrosis who improved substantially with ETI, without significant impact on the systemic exposure of either ETI or tacrolimus.

Topics: Adolescent; Aminophenols; Benzodioxoles; Chloride Channel Agonists; Cystic Fibrosis; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Indoles; Liver Transplantation; Pyrazoles; Pyridines; Pyrrolidines; Quinolones; Tacrolimus

Tacrolimus (TAC) is subject to many drug interactions as a result of its metabolism primarily via CYP450 isoenzyme 3A4. Numerous case reports of TAC and CYP3A4 inducers and inhibitors have been described including antimicrobials, calcium channel antagonists, and antiepileptic drugs. We present the case of a 13-year-old patient with cystic fibrosis and a history of liver transplantation, where subtherapeutic TAC concentrations were suspected to be a result of concomitant TAC and nafcillin (NAF) therapy. The observed drug interaction occurred on two separate hospital admissions, during both of which the patient exhibited therapeutic TAC concentrations prior to exposure to NAF, a CYP3A4 inducer. Upon discontinuation of NAF, TAC concentrations recovered in both instances. This case represents a drug-drug interaction between TAC and NAF that has not previously been reported to our knowledge. Despite the lack of existing reports of interaction between these two agents, this case highlights the importance of therapeutic drug monitoring and assessing for any potential drug-drug or drug-food interactions in patients receiving TAC therapy.

Topics: Adolescent; Anti-Bacterial Agents; Cystic Fibrosis; Cytochrome P-450 CYP3A; Dose-Response Relationship, Drug; Drug Interactions; Drug Monitoring; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Nafcillin; Respiratory Tract Infections; Tacrolimus; Withholding Treatment

We present management strategies utilised for the first case of an urgent live-donor ABO incompatible B blood group renal transplant, in a patient with a prior A blood group lung transplant for cystic fibrosis. Three years on, renal function is excellent and stable, whilst lung function has improved.

Topics: ABO Blood-Group System; Acute Disease; Adult; Cystic Fibrosis; Disease-Free Survival; Female; Graft Rejection; HLA Antigens; Humans; Isoantigens; Kidney Failure, Chronic; Kidney Transplantation; Living Donors; Lung Transplantation; Middle Aged; Mothers; Mycophenolic Acid; Plasmapheresis; Prednisolone; Sepsis; Tacrolimus; Withholding Treatment

The aim of this pharmacokinetic (PK) study was to evaluate tacrolimus (TAC) exposure in stable cystic fibrosis (CF) lung transplant (LT) recipients, converted from TAC twice daily to TAC once daily in an open-label, prospective, single-centre study.. Eligible patients were post-transplant CF patients (18-65 years) with stable lung function, on stable doses of TAC twice daily and who were candidates to switch to TAC once daily. Twelve consecutive patients were included in the study. Patients had their first PK analysis on day 1, still under the stable TAC twice-daily regimen, and were converted to TAC once daily from day 2 onwards. The doses were adjusted according to clinical judgement to achieve target levels, and a second 24-h PK period profile was obtained once the patient was on a stable dosage on the therapeutic range.. The mean total (SD) daily dose of TAC twice daily at baseline upon enrolment was 0.17 (0.10) mg/kg/day. The mean (SD) daily dose of TAC once daily after adjustments was 0.22 (0.12) mg/kg/day. In order to achieve target C min levels with a similar AUC0-24, 82% of subjects who were converted to TAC once daily required an increase of dose, in a range of 0-66.7%, with a mean dose increase of 28%.. Our study results indicate that the switch for conversion from TAC twice daily to TAC once daily in patients with CF may need dose adjustment in order to reach levels within the therapeutic target.

Topics: Administration, Oral; Adult; Area Under Curve; Cystic Fibrosis; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Tacrolimus; Young Adult

Advanced kidney disease is usually considered an absolute contraindication for lung transplantation due to the difficult management of these patients in the post-operative period. Combined lung-kidney transplantation, however, could offer an opportunity for selected patients with renal and pulmonary dysfunction. This study summarizes the long-term success of a double transplantation in a 38-year-old male patient with cystic fibrosis who presented respiratory and kidney failure. After a complicated post-operative period, the patient currently lives completely independently 46 months after the operation and he enjoys excellent pulmonary and renal function.

Topics: Acute Disease; Adult; Antibodies, Monoclonal; Basiliximab; Coinfection; Cystic Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Lung Transplantation; Male; Mycophenolic Acid; Pneumonia; Prednisone; Recombinant Fusion Proteins; Recovery of Function; Renal Dialysis; Respiratory Insufficiency; Tacrolimus

Topics: Adult; Amlodipine; Arthralgia; Calcineurin Inhibitors; Cystic Fibrosis; Humans; Immunosuppressive Agents; Lung Transplantation; Tacrolimus

A 25-year-old woman with a history of bilateral lung transplant secondary to cystic fibrosis presented with non-specific abdominal complaints and was found to have acute kidney injury, thrombocytopaenia and laboratory findings consistent with a microangiopathic haemolytic anaemia. Her thrombotic microangiopathy (TMA) was attributed to tacrolimus, which was discontinued and replaced with cyclosporine with resolution of her TMA and no subsequent complications. This is the fifth reported case of TMA associated with tacrolimus use in a lung transplant patient, and the third to be successfully managed with cyclosporine substitution. Clinicians must be aware of this uncommon, but likely under-reported complication of tacrolimus therapy in lung transplant recipients. Cyclosporine replacement may be used as a successful therapy to treat tacrolimus-associated TMA without increasing the risk of acute rejection that may be associated with other treatment strategies.

Topics: Adult; Cystic Fibrosis; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Tacrolimus; Thrombotic Microangiopathies

Topics: Adult; Bilirubin; Cystic Fibrosis; Hepatitis C; Hepatocytes; Humans; Immunosuppressive Agents; Liver; Liver Diseases; Lung Transplantation; Male; Respiratory Insufficiency; Tacrolimus

Cystic fibrosis (CF) is an inherited condition that causes progressive respiratory failure and is the third most common indication for adult bilateral lung transplantation. Post-transplant hyperlipidemia commonly affects lung transplant recipients, but the impact of lung transplantation on serum lipids in the adult CF population is not well studied. The aim of this study was to examine the impact of lung transplantation on the prevalence of hyperlipidemia in CF adults.. We retrospectively analyzed prospectively collected data in 108 CF adults undergoing bilateral sequential lung transplantation from 1996 to 2007 at our institution.. The prevalence of hypercholesterolemia (>5.2 mmol/liter) and hypertriglyceridemia (>2.2 mmol/liter) increased significantly after lung transplant (14.8% vs 32.4%, p = 0.002; 8.3% vs 41.7%, p < 0.0001, respectively). Cyclosporine A (CsA) use was associated with significantly higher post-transplant total and LDL cholesterol compared with tacrolimus use. Post-transplant calculated Framingham risk score was <10% in all but 1 subject.. Hyperlipidemia was common in our cohort of post-lung transplant CF adults, with a higher prevalence in those receiving CsA. Despite these findings, calculated cardiovascular risk remained low and none of these subjects developed clinically evident cardiovascular disease.

Topics: Adult; Cohort Studies; Cyclosporine; Cystic Fibrosis; Female; Graft Rejection; Humans; Hypercholesterolemia; Hypertriglyceridemia; Immunosuppressive Agents; Lipids; Lung Transplantation; Male; Prevalence; Prospective Studies; Retrospective Studies; Tacrolimus

Topics: Adolescent; Case-Control Studies; Child; Cystic Fibrosis; Female; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Transplantation; Lung Transplantation; Male; Nasal Mucosa; Nitric Oxide; Organ Transplantation; Tacrolimus

Invasive pulmonary aspergillosis (IPA) is a serious cause of death among immune-compromised patients such as organ-transplant recipients. Recently, voriconazole has been approved for first-line therapy in IPA. Theoretically, optimal voriconazole blood level (superior to 1 mg/L according to recent studies) should be reached within 24 h. In practice, a significantly longer time seems to be needed in lung-transplant recipients. Therefore, caspofungin is now used in combination with voriconazole to provide cover against Aspergillus spp. infection during this gap. The first aim of this study was to investigate Aspergillus spp. infection treated with this combination and the atter's tolerability. The median time for attainment of apparently active blood levels in lung transplant recipients were compared between those with cystic fibrosis and those without.. Lung-transplant recipients who received a combination of voriconazole and caspofungin between 2002 and 2008 as primary therapy were identified retrospectively. The median number of days to reach active voriconazole blood levels was compared between cystic fibrosis and other patients by Student's t-test. Statistical significance was defined by P-value <0.05.. Four patients were treated for Aspergillus colonization before transplantation and their culture were negative at 90 days. Eleven patients were treated for proven or probable invasive aspergillosis and 14 of them had a complete response. Hallucinations (n = 2) and significant hepatic toxicity (n = 2) were reported. Among the 15 studied transplant recipients, a median of 12.3 days was observed for active voriconazole blood levels to be reached. With cystic fibrosis patients, time tended to be longer than with other recipients (14.9 days vs. 8.3 days). Tacrolimus blood levels (between 5 and 15 ng/mL) may have been increased by voriconazole.. This retrospective study describes practical experience in the management of this rare and severe disease in a referral centre for cystic fibrosis lung transplantation. Voriconazole and caspofungin combination was acceptably safe and was associated with good clinical outcomes in almost all patients. We showed that in 15 lung-transplant recipients a median of 12.3 days was required for voriconazole to reach high enough blood levels. Caspofungin in combination with voriconazole provides cover against Aspergillus infection during the period when voriconazole may be at subtherapeutic levels with good tolerability.

Topics: Adolescent; Adult; Antifungal Agents; Aspergillus; Caspofungin; Cystic Fibrosis; Drug Interactions; Drug Therapy, Combination; Echinocandins; Female; Humans; Immunocompromised Host; Immunosuppressive Agents; Invasive Pulmonary Aspergillosis; Lipopeptides; Lung Transplantation; Male; Middle Aged; Pyrimidines; Retrospective Studies; Tacrolimus; Treatment Outcome; Triazoles; Voriconazole; Young Adult

Aspergillosis is a high-risk complication in cystic fibrosis (CF) lung transplant patients. Azole antifungal drugs inhibit CYP3A4, resulting in significant metabolic drug-drug interactions. Voriconazole (VRZ) was marketed without therapeutic drug monitoring (TDM) recommendations, consistent with favorable pharmacokinetics, but regular determinations of plasma VRZ concentration were introduced in our center to manage interactions with calcineurin inhibitors and to document the achievement of therapeutic levels.. VRZ TDM data analysis for trough concentration (C0) and peak concentration (C2) was carried out, using validated liquid chromatography assay with ultraviolet detection, for 35 CF lung transplant patients (mean age 25 years, mean weight 47 kg, balanced sex ratio) since 2003. Therapeutic range (C0: 1.5 +/- 0.5 - C2 : 4.0 +/- 1.0 mg/L) was expressed relative to pivotal pharmacokinetic trial data.. The duration of VRZ treatment ranged from 9 days to 22 months. The recommended standard dose of VRZ (200 mg twice a day, following the loading dose) resulted in significant plasma concentrations (>0.5 mg/L) in 20% of CF lung transplant patients. Therapeutic concentrations were obtained using higher doses (average 570 +/- 160 mg/day, +43%, P<0.01). Despite adaptation, C0 remained <0.5 mg/L (11%), even when the drug was administered intravenously, highlighting the variability of VRZ pharmacokinetics, possibly enhanced by CYP2C19 polymorphism. The risk of inefficacy during periods of underdosage was overcome by treatment with antifungal drug combinations (caspofungin, n=10). The therapeutic index was limited by neurologic effects (14%) and hepatic abnormalities (30%). VRZ concentrations correlated significantly (P<0.01) with aspartate aminotransferase levels but not with bilirubin levels. VRZ acted as a metabolic inhibitor of tacrolimus (C0 to dose ratio 5.8 +/- 2.6, n=31/VRZ versus 1.7 +/- 0.9 alone, P<0.001). Large changes in azole concentration affected the magnitude of the drug-drug interactions and adjustment requirements.. TDM is required because VRZ levels are often undetectable in treated CF lung transplant patients, supporting the use of antifungal drug combinations until achievement of VRZ C0 at a steady state between 1 and 2 mg/L. Plasma VRZ concentrations should be determined for the quantitative, individualized management of drug-drug interactions in lung transplant patients, in particular immunosuppressant such as tacrolimus, considering VRZ to be both a target and an inhibitor of CYP3A4.

Topics: Adolescent; Adult; Antifungal Agents; Aspergillosis; Aspergillus; Cystic Fibrosis; Drug Administration Schedule; Drug Interactions; Drug Monitoring; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Mycoses; Pyrimidines; Scedosporium; Tacrolimus; Triazoles; Voriconazole; Young Adult

Oral posaconazole (PSZ), an azole antifungal drug, was recently introduced for the treatment of invasive fungal infections. The prescription of PSZ together with the immunosuppressant tacrolimus (TRL) was evaluated in 14 lung transplant patients with cystic fibrosis. PSZ inhibited CYP3A4 TRL metabolism, resulting in a decrease of TRL dose by a factor of 3, with tapering to a mean of 2 mg/d. Previous studies with itraconazole and voriconazole showed that TRL dose could be decreased by factors of 5 and 4, respectively. Joint therapeutic drug monitoring of TRL and PSZ was carried out to investigate the high risk of interindividual variability associated with this coprescription in such patients.

Topics: Adult; Antifungal Agents; Aspergillosis; Candidiasis; Cystic Fibrosis; Cytochrome P-450 CYP3A; Cytochrome P-450 CYP3A Inhibitors; Drug Interactions; Drug Monitoring; Drug-Related Side Effects and Adverse Reactions; Enzyme Inhibitors; Female; Graft Rejection; Humans; Immunosuppressive Agents; Itraconazole; Lung Transplantation; Male; Microbial Sensitivity Tests; Mycoses; Prescriptions; Pyrimidines; Tacrolimus; Triazoles; Voriconazole

We have analyzed the evolution of renal status beyond the perioperative period in patients with cystic fibrosis (CF) undergoing lung transplantation and presented histological analysis of 15 patients biopsied for an episode of accelerated renal function loss (RFL). Episodes of accelerated RFL after the perioperative period occurred in 32.5% of patients and significantly raised the risk of end-stage renal disease (ESRD) (p < 0.001). The histologic lesions associated with these episodes differed according to the time of onset. Early onset (10 cases) was associated with tubulointerstitial lesions in the form of oxalate nephropathy (50%) and/or a pigmented tubulopathy (80%). This latter was correlated with treatment with antiviral agents (p = 0.002) and aminoside and glycopeptide antibiotics (p = 0.03) administered in the month preceding biopsy. Lesions in late episodes of accelerated RFL (5 cases) were principally vascular: arteriosclerosis and arteriolosclerosis (p = 0.007, p = 0.00002), correlated with diabetic glomerulosclerosis or focal segmental glomerulosclerosis in the absence of prominent diabetic changes. Specific calcineurin-inhibitor nephrotoxicity was present in 93.3% of biopsies associated with thrombotic microangiopathy in 46.7% of cases. The identification of specific etiologies of progressive kidney disease in patients with CF after lung transplantation should permit more effective post-transplant care of these patients.

Topics: Biopsy; Cyclosporine; Cystic Fibrosis; Diabetic Nephropathies; Glomerular Filtration Rate; Glomerulosclerosis, Focal Segmental; Humans; Immunosuppressive Agents; Kidney; Kidney Glomerulus; Kidney Tubules; Lung Transplantation; Retrospective Studies; Tacrolimus

In cystic fibrosis (CF), absorption of tacrolimus through the gastrointestinal tract may be impaired due to fat malabsorption. The aim of this pilot study was to compare tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure in stable lung transplant recipients with and without CF, and to determine the best single-time predictors of exposure. The study included 11 lung transplant recipients with CF and 11 without CF who received tacrolimus twice daily. Blood samples were obtained predose and at 0.5, 1, 1.5, 2, 2.5, 3, 4, 5, 6, 8 and 12 h postdose on 3 separate days within 1 week. Tacrolimus pharmacokinetics and inter- and intrasubject variability of exposure were similar in the two groups, though exposure-per-milligram-dose was approximately 50% lower in CF patients. Tacrolimus trough concentration did not accurately predict the area under the concentration curve (AUC(0-12)), but the concentration measured 3 h postdose (C(3)) was tightly correlated with the AUC(0-12) in both CF (r(2)= 0.86) and non-CF (r(2)= 0.92) patients. In summary, patients with CF have a higher tacrolimus oral clearance, but nonsignificant differences in short-term inter- and intrasubject variability of exposure compared to patients without CF. C(3) is tightly correlated with AUC(0-12) in lung transplant recipients with and without CF.

Topics: Adult; Area Under Curve; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Pilot Projects; Tacrolimus

Topics: Adult; Cystic Fibrosis; Electroretinography; Humans; Immunosuppressive Agents; Male; Optic Nerve Diseases; Tacrolimus; Visual Acuity

Pharmacologic interactions and absorption disturbances after transplantation may induce serologic fluctuation of immunosuppression and adversely affect outcome. We present data showing that trough levels of mycophenolic acid decreased by 50% during combined mycophenolate mofetil (MMF) and cyclosporine therapy compared with levels during combined MMF and tacrolimus therapy. In addition, cystic fibrosis patients required 30% higher doses of MMF to achieve the therapeutic levels of recipients without cystic fibrosis.

Topics: Adult; Calcineurin Inhibitors; Cyclosporine; Cystic Fibrosis; Dose-Response Relationship, Drug; Drug Interactions; Drug Therapy, Combination; Humans; Immunosuppressive Agents; Lung Transplantation; Mycophenolic Acid; Tacrolimus

A 24 year old woman presented with a sudden excruciating headache mimicking an acute vascular event. She had undergone a lung transplantation because of cystic fibrosis and was receiving maintenance treatment with tacrolimus and prednisone. Ancillary investigation excluded vascular causes. Magnetic resonance imaging demonstrated hyperintense lesions in the infratentorial and parieto-occipital regions consistent with posterior leucencephalopathy syndrome. Both her clinical condition improved and the lesions disappeared completely after withdrawal of tacrolimus, suggesting that her condition could be explained by a tacrolimus encephalopathy.

Topics: Acute Disease; Adult; Brain; Brain Diseases; Cyclosporine; Cystic Fibrosis; Diagnosis, Differential; Drug Therapy, Combination; Female; Headache; Humans; Image Enhancement; Immunosuppressive Agents; Lung Transplantation; Magnetic Resonance Imaging; Neurologic Examination; Postoperative Complications; Prednisone; Recurrence; Tacrolimus

In cystic fibrosis (CF) patients, lung transplantation is the only way to improve both quality and length of life. Data in the literature show that, in 80% of the cases, mortality after lung transplantation in CF patients is due to infections.. We microbiologically monitored 34 patients subjected to bilateral lung transplantation in during 1996 to 1999 to ascertain whether a change in the bacterial species isolated from the lower respiratory tract took place that might have influenced the clinical conditions of the patients.. Our results show that the percentage of nonfermenting Gram-negative bacteria isolated from the lower respiratory tract remains high even in the posttransplantation phase. Nevertheless, the general clinical conditions of most of the patients were good and the three patients who died did not do as a consequence of an infection.. Lung transplantation constitutes a valid therapeutic choice for CF patients because the microorganisms that we isolated from the lungs of the patients in our study behave mostly as contaminants rather than as colonizers. However, the transplanted patients remain at risk and thus require constant microbiological surveillance.

Topics: Bronchiolitis Obliterans; Bronchoalveolar Lavage Fluid; Cyclosporine; Cystic Fibrosis; Follow-Up Studies; Gram-Negative Bacteria; Humans; Immunosuppressive Agents; Lung Transplantation; Oxygen Consumption; Sputum; Survival Rate; Tacrolimus

Topics: Biological Availability; Bronchiolitis Obliterans; Cyclosporine; Cystic Fibrosis; Follow-Up Studies; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Retrospective Studies; Tacrolimus; Time Factors

Tacrolimus has a negative effect on the pancreatic beta islet cell, and both glucose intolerance and diabetes mellitus are well-recognized complications of tacrolimus-based immunosuppression among adult solid organ transplant recipients.. To determine the association between tacrolimus and new-onset diabetes mellitus in childhood, we reviewed data on 78 pediatric heart and heart-lung/lung recipients receiving tacrolimus-based immunosuppression. Trough tacrolimus levels, fasting and random blood glucose levels, and corticosteroid requirements were reviewed. Diabetes was defined as glucose intolerance requiring long-term insulin treatment more than 30 days after transplantation.. No patient had diabetes before introduction of tacrolimus. In heart-lung/lung recipients, 12 of 28 (43%) had development of diabetes at a median follow-up of 7 months (range 1 to 39). In this group diabetes developed in three of eight (38%) patients with cystic fibrosis and nine of 20 (45%) without (p = NS). In contrast, only two of 50 (4%) heart transplant recipients had development of diabetes. Of the 14 patients with diabetes, 10 had development of diabetes during augmentation of immunosuppression with pulsed corticosteroids. Tacrolimus trough levels were significantly lower in heart compared with heart-lung/lung transplant recipients (9.4 +/- 3.3 versus 15.3 +/- 0.9 ng/ml) (p < 0.01), and at latest follow-up significantly fewer heart transplant recipients were treated with maintenance corticosteroids (28% versus 75%; p < 0.01). In the heart-lung/lung group, no significant difference in tacrolimus levels was found between patients with and without diabetes, nor was there a significant difference in the average corticosteroid dose or number of pulses of corticosteroids per patient.. New-onset diabetes mellitus is rare in pediatric heart transplant recipients receiving tacrolimus-based immunosuppression, but it occurs with a high incidence after pediatric heart-lung/lung transplantation and usually develops during pulsed corticosteroid therapy. However, it is currently not possible to predict which heart-lung/ lung transplant recipients will have development of this serious complication.

Topics: Adolescent; Adrenal Cortex Hormones; Adult; Child; Child, Preschool; Cystic Fibrosis; Diabetes Mellitus, Type 1; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Follow-Up Studies; Glucose Tolerance Test; Heart Transplantation; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Infant; Islets of Langerhans; Lung Transplantation; Male; Postoperative Complications; Risk Factors; Tacrolimus