tacrolimus and Chronic-Disease

The spectrum of allergic eye diseases includes a variety of conditions, each characterized by complex immunopathologies.Antiallergic drugs, such as antihistamines and mast cell stabilizers, are often insufficient without concomitant topical corticosteroid treatment. The chronic course of the more severe allergic eye diseases, such as vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC), limits the treatment with topical corticosteroids to short courses. In addition, topical corticosteroid treatment puts patients at high risk of developing severe ocular complications, particularly during childhood when VKC most frequently occurs.The immunopathology of chronic diseases, such as VKC and AKC, involves predominantly T lymphocytes, and as such, immunomodulators that inhibit T-cell activation seem to be the appropriate treatment for these chronic diseases. In the past years, there is an increased incidence of managing chronic allergic eye diseases with the immunomodulator tacrolimus. The current review presents an update of the recent clinical experience with topical tacrolimus for the management of chronic allergic eye diseases.. Topical tacrolimus significantly improves the symptoms and signs of the various forms of chronic allergic eye disease. Recent studies also demonstrate the efficacy of low concentrations of topical tacrolimus for VKC.Early medical treatment with topical tacrolimus can also prevent the development of serious ocular complications of VKC, such as shield ulcers or limbal stem cell deficiency.. Topical tacrolimus has significantly changed the management approaches in severe and chronic allergic eye diseases and has minimized the need for topical corticosteroids.

Topics: Administration, Topical; Adrenal Cortex Hormones; Chronic Disease; Conjunctivitis, Allergic; Humans; Immunologic Factors; T-Lymphocytes; Tacrolimus

Ocular graft-versus-host disease (GvHD) following allogeneic blood stem cell transplantation leads to immunologically induced alterations in many ocular tissues, particularly at the ocular surface. Within the framework of the main topic, this article focuses primarily on corneal complications in chronic ocular GvHD.. This article aims to promote understanding of the influencing factors, diagnostics, and therapeutic options pertaining to corneal complications in ocular GvHD. Furthermore, the possibilities for prevention are discussed.. This analysis is based on a literature review as well as on data from the Ophthalmology Clinic at the University Hospital Essen.. Corneal complications often occur secondarily in ocular GvHD, as a consequence of severe inflammatory alterations of the conjunctiva or eyelid. Spontaneous corneal perforations associated with only mild symptoms are less common during the course of disease. From the ophthalmologist's perspective, it is important that the inflammatory activity of all the different ocular tissues is considered. Treatment may follow a stepwise scheme that includes substitution, immunosuppression, and surgical rehabilitation.. Systematic diagnosis of ocular GvHD helps to prevent corneal complications or support early therapeutic intervention. An interdisciplinary approach to diagnosis and treatment planning is recommended, in order to optimize local and systemic immunosuppressive therapy.

Topics: Adrenal Cortex Hormones; Chronic Disease; Combined Modality Therapy; Corneal Diseases; Corneal Ulcer; Cyclosporine; Diagnosis, Differential; Eye Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Interdisciplinary Communication; Intersectoral Collaboration; Keratoplasty, Penetrating; Limbus Corneae; Ophthalmic Solutions; Tacrolimus

​Introduction: As tolerance is not yet achievable, the kidney-transplanted-patients have to take on a daily-basis immunosuppressive drugs in order to avoid acute rejection-AR-. The cornerstone of immunosuppression relies on tacrolimus-therapy which is potentially nephrotoxic. Areas Covered: We identified from the studies published in the recent years those who were reporting on AR in de novo kidney-transplant recipients under tacrolimus-based therapy, as well as those who reported on the attempt to minimize tacrolimus-therapy.. There are many formulations of tacrolimus: immediate-release (Prograf®), slow-release (Advagraf®), or extended-release (Envarsus®). All demonstrate a very good efficacy in preventing AR episodes. Studies in which tacrolimus was minimized or even weaned-off have shown that it was unsafe, i.e. in resulting in AR episode and/or de novo donor-specific alloantibodies. Recent data show that Tacrobell®, a generic of tacrolimus, was as efficient as Prograf® in the short- and long-term. Expert-opinion: Tacrolimus-based immunosuppression is very effective in preventing rejection in kidney-transplant recipients. It might be associated with nephrotoxicity, that can be reduced by avoiding tacrolimus trough levels too high in the long-term. Conversely, tacrolimus ultraminimization should not be attempted.

Topics: Acute Disease; Adult; Animals; Chronic Disease; Delayed-Action Preparations; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Tacrolimus; Transplant Recipients

Allogeneic hematopoietic stem cell transplantation in Japan is very different from that in Western countries in terms of the homogeneous genetic background, the preference for bone marrow to peripheral blood stem cells, use of a single unit in cord blood transplantation, and frequent use of non-myeloablative preconditioning due to a large number of elderly patients. Therefore, conclusions obtained from well-designed prospective and/or comparative studies of treatment of graft-versus-host disease (GVHD) performed in the United States or Europe may not fit Japanese transplant patients. This article reviews the studies of prophylactic and therapeutic treatment of acute and chronic GVHD that have been conducted in Japan. A randomized study demonstrated a lower incidence of acute GVHD in tacrolimus-based prophylaxis than in cyclosporine A-based prophylaxis. Retrospective and non-randomized prospective studies suggest that cyclosporine A-based and tacrolimus-based GVHD prophylaxis regimens are well researched and nearly optimized for Japanese patients, including infusion methods and target blood concentration. However, most other studies were performed in a single institute including a small number of patients, resulting in biased conclusions. There is no conclusive report on steroid-refractory acute and chronic GVHD. This review provides a baseline for starting prospective studies to create new evidence for GVHD treatment from Japan.

Topics: Acute Disease; Bone Marrow Transplantation; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Japan; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous

Topics: Antibodies, Anti-Idiotypic; Antibodies, Monoclonal, Humanized; Autoimmune Diseases; Chronic Disease; Cyclosporine; Disease Management; Female; Histamine Antagonists; Humans; Immunosuppressive Agents; Male; Omalizumab; Prevalence; Tacrolimus; Urticaria

Chronic, progressive, and irreversible loss of a transplanted kidney function, previously named chronic allograft nephropathy, is the leading cause of chronic allograft failure among kidney transplant recipients. Chronic allograft dysfunction (CAD) is a multifactorial process associated with progressive interstitial fibrosis and tubular atrophy. Current Data confirms that an additive series of time-dependent immunological factors such as acute and chronic antibody- and/or cell-mediated rejection and nonimmunological factors are involved in development of interstitial fibrosis and tubular atrophy as the fundamental parts of CAD. The use of calcineurin inhibitors has produced a major impact on achieving successful organ transplantation; however, although this assumption has been doubted recently, calcineurin inhibitors are deemed to be associated with nephrotoxicity and subsequent interstitial fibrosis, tubular atrophy, and kidney dysfunction. The early fibrotic changes are due to implantation stress, T-cell-mediated rejection, and infection; however, usually they do not lead to progressive fibrosis and allograft dysfunction per se. In the setting of CAD, many factors occurring lately after 1 year, such as chronic antibody-mediated rejection, recurrent or de novo glomerulonephritis, and nonadherent adequately address the existence of ongoing injuries and progression to fibrosis. Identification of patients who are at risk, close clinical monitoring, and optimization and individualization of their maintenance immunosuppressive regimen are among the means that could help us to improve the long-term outcome of kidney transplantation.

Topics: Calcineurin Inhibitors; Chronic Disease; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Mycophenolic Acid; Postoperative Complications; Primary Graft Dysfunction; Tacrolimus; Transplantation, Homologous

The purpose of the review is to review the pathophysiology, available data, and our current recommendations for calcineurin inhibitor (cyclosporine and tacrolimus) treatment in antihistamine refractory chronic idiopathic urticaria (CIU) patients.. Low-dose cyclosporine (<5  mg/kg per day) may have unique immunological modulating properties beyond mast cell and basophil stabilization in CIU. Starting CIU treatment with very low cyclosporine dosages (1 mg/kg per day) and titrating based on response and side-effects may decrease adverse events while preserving efficacy. In cyclosporine responsive patients failing cyclosporine taper, case series data support the safety and efficacy of long-term (5-10 years), very low dose (1-2 mg/kg per day) cyclosporine treatment with appropriate clinical monitoring.. For CIU patients refractory to antihistamines, low-dose cyclosporine therapy (<3 mg/kg per day) with appropriate laboratory monitoring provides an alternative with an acceptable side-effect profile. Long-term (>12 months) moderate-dose (2.5-5 mg/kg per day) cyclosporine treatment may cause longitudinal increases in serum creatinine. However, decreasing or stopping cyclosporine dosing reverses measured nephrotoxicity in the vast majority of patients, and some patients with careful monitoring can tolerate very low-dose cyclosporine (<2 mg/kg per day) for longer periods. Tacrolimus is an alternative to cyclosporine with a slightly different adverse effect profile. Minimal data are available on its use in chronic urticaria.

Topics: Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Enzyme Inhibitors; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus; Time Factors; Urticaria

To report the utility of tacrolimus 0.03% dermatologic ointment (Protopic) in a case of refractory atopic keratoconjunctivitis with giant papillae. A review of the medical literature is presented.. A 32-year-old man with a long-standing history of severe atopic disease was referred to our department because of bilateral intense eye pain, itching, photophobia, and epiphora. Biomicroscopy examination showed conjunctival hyperemia, superficial punctata keratitis, and tarsal giant papillae. This patient had undergone previous treatment with systemic and topical steroids, antihistamines, topical antihistamine/mast cell stabilizer drops, cyclosporine A, and even surgical resection-cryopexy of giant papillae-without success.. The patient was started on tacrolimus 0.03% ointment treatment of the conjunctival fornix twice daily. After 2 months, the patient experienced resolution of his clinical symptoms with a significant decrease in papillae size. No side effects were reported. Treatment was continued for 1 month and gradually reduced with increasingly wide intervals between applications. Eight months after treatment, there were no signs of reactivation, and the patient remains asymptomatic.. Application of tacrolimus 0.03% dermatologic ointment into the lower fornix seems to constitute an interesting alternative treatment for atopic keratoconjunctivitis that is refractory to traditional treatment.

Topics: Administration, Topical; Adult; Chronic Disease; Conjunctiva; Conjunctivitis, Allergic; Humans; Immunosuppressive Agents; Male; Ointments; Tacrolimus; Treatment Outcome

Barriers to successful outcomes following pediatric transplantation have shifted from ischemic reperfusion injury and rejection to more long-term complications. Of particular concern is the high prevalence of CKD owing to preexisting damage and nephrotoxicity, as well as other CV complications such as hypertension and cardiomyopathy. All of these contribute to graft loss and shortened life expectancy, thereby limiting the success story of solid-organ transplantation. Managing CKD and related CV morbidity should be integral to the care of pediatric transplant patients, and timely detection of any irregularities would increase the chances of restoring lost kidney function. GFR is still the widely accepted indicator of renal function, and nuclear medicine techniques are the gold standard measurement methods. These methods are limited by costs, radiation exposure and substrate injection, and current practice still uses the Schwartz estimate, despite its well-documented limitations. Newer endogenous markers of GFR, such as cystatin C clearance, give a more accurate measure of true GFR but have not been embraced in the management of pediatric transplant recipients. Furthermore, indirect markers (e.g., microalbuminuria and hypertension) could also aid early detection of renal damage. The effects of mainstay immunosuppressants on kidney and heart function are varied, with available data indicating favorable outcomes with tacrolimus compared with ciclosporin. There is a need for appropriately designed and powered randomized controlled trials to validate innovative concepts for tailored immunosuppression in the pediatric population. To date, very few studies have generated long-term data in pediatric renal transplant patients - results of 1-4-yr study favored tacrolimus over ciclosporin, but other immunosuppressive agents also need to be evaluated.

Topics: Cardiovascular Diseases; Chronic Disease; Glomerular Filtration Rate; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Organ Transplantation; Pediatrics; Risk Factors; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Topics: Acute Disease; Angiotensin Receptor Antagonists; Angiotensin-Converting Enzyme Inhibitors; Animals; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Humans; Kidney Diseases; Kidney Glomerulus; Kidney Transplantation; Kidney Tubules; Renin-Angiotensin System; Tacrolimus; Transplantation, Homologous

Chronic otitis externa (COE) remains a frustrating problem for both patient and physician. The end stage of disease, medial fibrosing otitis externa, is very challenging to repair. New and old therapies and promising approaches to the treatment of this often recalcitrant problem are presented in this review.. Tacrolimus, a nonsteroidal immunosuppressant, and fluocinolone acetonide oil 0.01%, a medium-high potency steroid preparation, may offer additional therapeutic options in the struggle against this inflammatory ear canal/skin condition of often unknown cause. Relative potencies of many steroid preparations will be presented along with several treatment strategies for controlling COE. Underlying autoimmune problems such as Sjögren's disease, sarcoidosis, and amyloidosis must be searched and, if present, addressed and treated for resolution of symptoms. Cutting edge therapies, including use of bacteriophages and inflammatory proteases, will also be reviewed.. No single therapy will be successful for every patient with COE. The search for an underlying cause, the removal of all possible irritants to the ear canal skin (e.g. Q-tips, water), debridement, and both topical and occasionally, systemic therapy will control (not cure …) the disease process in the vast majority of patients.

Topics: Anti-Inflammatory Agents; Bacterial Infections; Bacteriophages; Chronic Disease; Debridement; Fluocinolone Acetonide; Humans; Immunosuppressive Agents; Mycoses; Otitis Externa; Peptide Hydrolases; Tacrolimus

In the critically ill, multiple drug therapies for acute and chronic conditions are often used at the same time and adverse drug events occur frequently. Many pharmacological and disease-related factors, e.g. altered renal and hepatic function, catecholamine-related circulatory changes, altered drug volume of distribution, enteral versus parenteral feeding and morbid obesity, along with concomitant multiple drug regimens may account for the wide inter-individual variability in drug exposure and response in critically ill patients and for the high risk for drug-drug interactions to occur. The practicing intensivist must remain aware of the major mechanisms for drug-drug interactions, among which the drug-metabolizing enzyme inhibitory or induction potential of associated chemical entities are paramount. Metabolism-based drug-drug interactions are largely due to changes in levels of drug-metabolizing enzymes caused by one drug, leading to changes in the systemic exposure clearance of another. Among the numerous drug-metabolizing enzymes identified to date, the activity of cytochrome P450s (CYP450) is a critical determinant of drug clearance and appears to be involved in the mechanism of numerous clinically relevant drug-drug interactions observed in critically ill patients.. This manuscript will cover a practical overview of clinically relevant CYP450-mediated drug-drug interactions. Medications frequently used in the intensive care unit such as benzodiazepines, immunosuppressive agents, opioid analgesics, certain anticonvulsants, the azoles and macrolides have the potential to interact with CYP450-mediated metabolism and may lead to toxicity or therapeutic failure.

Topics: Acute Disease; Analgesics, Opioid; Anti-Bacterial Agents; Anticonvulsants; Benzodiazepines; Catecholamines; Chronic Disease; Critical Care; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Drug Interactions; Drug Monitoring; Humans; Immunosuppressive Agents; Intensive Care Units; Midazolam; Tacrolimus

The use of the calcineurin inhibitors cyclosporine and tacrolimus led to major advances in the field of transplantation, with excellent short-term outcome. However, the chronic nephrotoxicity of these drugs is the Achilles' heel of current immunosuppressive regimens. In this review, the authors summarize the clinical features and histologic appearance of both acute and chronic calcineurin inhibitor nephrotoxicity in renal and nonrenal transplantation, together with the pitfalls in its diagnosis. The authors also review the available literature on the physiologic and molecular mechanisms underlying acute and chronic calcineurin inhibitor nephrotoxicity, and demonstrate that its development is related to both reversible alterations and irreversible damage to all compartments of the kidneys, including glomeruli, arterioles, and tubulo-interstitium. The main question--whether nephrotoxicity is secondary to the actions of cyclosporine and tacrolimus on the calcineurin-NFAT pathway--remains largely unanswered. The authors critically review the current evidence relating systemic blood levels of cyclosporine and tacrolimus to calcineurin inhibitor nephrotoxicity, and summarize the data suggesting that local exposure to cyclosporine or tacrolimus could be more important than systemic exposure. Finally, other local susceptibility factors for calcineurin inhibitor nephrotoxicity are reviewed, including variability in P-glycoprotein and CYP3A4/5 expression or activity, older kidney age, salt depletion, the use of nonsteroidal anti-inflammatory drugs, and genetic polymorphisms in genes like TGF-beta and ACE. Better insight into the mechanisms underlying calcineurin inhibitor nephrotoxicity might pave the way toward more targeted therapy or prevention of calcineurin inhibitor nephrotoxicity.

Topics: Acute Disease; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Diagnosis, Differential; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Risk Assessment; Risk Factors; Tacrolimus

Despite improving immunosuppressive protocols in renal transplantation, chronic allograft nephropathy (CAN) remains a major impediment to long-term graft survival. The optimal immunosuppressive regimen for a patient with CAN is unknown. The aim of this study is to evaluate the various immunosuppressive management strategies of biopsy-proven CAN and of chronic allograft dysfunction (CAD) (no biopsy). A systematic review of randomized trials (n = 12 trials with 635 patients) was conducted. Studies included patients who were >6 mo post-transplant. All patients were on a calcineurin inhibitor (CNI), most often cyclosporine, and were randomized to convert to mycophenolate mofetil (MMF), tacrolimus, or sirolimus (Rapa) or to add azathioprine, MMF or Rapa to their current regimen. Follow-up time was 6 to 36 mo. The outcome measures evaluated were renal function in 11 of 12 studies and repeat renal biopsy results in one study. The methodological quality scores of the trials were generally low, using the Jadad scale (median value 2/5). Results varied between studies but suggested that CNI withdrawal is safe and that conversion to MMF or Rapa may be beneficial. The incidence of adverse effects ranged from 0% to 68% between the studies, and medication withdrawal occurred in 0% to 24% of patients. The review did not result in a consensus regarding the management of CAN and CAD. Further studies are required to determine the best therapeutic option for patients with CAD and CAN.

Topics: Azathioprine; Biopsy; Calcineurin Inhibitors; Chronic Disease; Drug Therapy, Combination; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Mycophenolic Acid; Sirolimus; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Heart transplantation remains the best therapeutic option for the treatment of end-stage heart failure. However, good survival rates can be obtained only if patients are closely monitored, particularly for their immunosuppressive regimens. Currently, a triple-drug regimen usually based on calcineurin-inhibitors (cyclosporin A or tacrolimus), anti-proliferative agents and steroids is used in most recipients. New agents such as the mTOR inhibitors, a more recently developed class of immunosuppressive drugs, can also be used in some patients. The aim of this article is to review currently used immunosuppressive regimens after heart transplantation, and to propose some individualized options depending on specific patient characteristics and recent pharmacological developments in the field.

Topics: Chronic Disease; Clinical Trials as Topic; Cyclosporine; Drug Therapy, Combination; Glucocorticoids; Graft Rejection; Graft Survival; Heart Failure; Heart Transplantation; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Meta-Analysis as Topic; Monitoring, Immunologic; Mycophenolic Acid; Protein Kinases; Randomized Controlled Trials as Topic; Sirolimus; Survival Analysis; T-Lymphocytes; Tacrolimus; TOR Serine-Threonine Kinases; Treatment Outcome

Urticaria is a rash, that typically involves skin and mucosa, and is characterized by lesions known as hives or wheals. In some cases there is an involvement of deep dermis and subcutaneous tissue that causes a skin/mucosa manifestation called angioedema. Urticaria and angioedema are very often associated: urticaria-angioedema syndrome. The acute episodic form is the most prevalent in the pediatric population, and it is often a recurrent phenomenon (recurrent urticaria). Acute episodic urticaria it is usually triggered by viruses, allergic reactions to foods and drugs, contact with chemicals and irritants, or physical stimuli. In many instances it is not possible to identify a specific cause (idiopathic urticaria). Chronic urticaria is a condition that can be very disambling when severe. In children is caused by physical factors in 5-10% of cases. Other trigger factors are infections, foods, additives, aeroallergens and drugs. The causative factor for chronic urticaria is identified in about 20% of cases. About one-third of children with chronic urticaria have circulating functional autoantibodies against the high affinity IgE receptor or against IgE. (chronic urticaria with autoantibodies or "autoimmune" urticaria). It is not known why such antibodies are produced, or if the presence of these antibodies alter the course of the disease or influence the response to treatment. Urticaria and angioedema can be symptoms of systemic diseases (collagenopathies, endocrinopathies, tumors, hemolytic diseases, celiachia) or can be congenital (cold induced familiar urticaria, hereditary angioedema). The diagnosis is based on patient personal history and it is very important to spend time documenting this in detail. Different urticaria clinical features must guide the diagnostic work-up and there is no need to use the same blood tests for all cases of urticaria. The urticaria treatment includes identification of the triggering agent and its removal, reduction of aspecific factors that may contribute to the urticaria or can increase the itch, and use of anti-H1 antihistamines (and/or steroids for short periods if antihistamines are not effective). In some instances an anti-H2 antihistamine can be added to the anti-H1 antihistamines, even if the benefits of such practice are not clear. The antileucotriens can be beneficial in a small subgroup of patients with chronic urticaria. In case of chronic urticaria resistant to all the aforementioned treatments, cyclosporine and

Topics: Autoantibodies; Child; Chronic Disease; Cyclosporine; Epinephrine; Histamine H1 Antagonists; Histamine H2 Antagonists; Humans; Receptors, IgE; Tacrolimus; Urticaria

Topics: Acute Disease; Adult; Chronic Disease; Drug Eruptions; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Peripheral Blood Stem Cell Transplantation; Risk; Steroids; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Infliximab-daclizumab was used to treat acute and chronic liver and gut graft-versus-host disease (GVHD) in two children after standard immunosuppressive therapy failed. Infliximab (10 mg/kg weekly, 4 doses) and daclizumab (1 mg/kg, days 1, 4, 8, 15, and 22) were given over 1 month. In case 1, grade 2 chronic GVHD of the liver developed 1 year after transplantation and failed to improve with tacrolimus, mycophenolate mofetil, and prednisone. In case 2, corticosteroid-unresponsive grade 3 acute liver and gut GVHD developed on day +37. In both patients, GVHD responded to the infliximab-daclizumab regimen without toxicity and immunosuppressive therapy was discontinued.

Topics: Acute Disease; Adrenal Cortex Hormones; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Antineoplastic Combined Chemotherapy Protocols; Child; Chronic Disease; Combined Modality Therapy; Daclizumab; Drug Resistance; Drug Therapy, Combination; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Interleukin-2 Receptor alpha Subunit; Intestinal Mucosa; Leukemia, Myelomonocytic, Chronic; Liver; Mycophenolic Acid; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Prednisone; Recurrence; Remission Induction; Reoperation; Tacrolimus; Transplantation, Homologous; Tumor Necrosis Factor-alpha

Graft-versus-host disease (GvHD) is the major cause of transplant-related mortality and morbidity. As it is closely related to the major therapeutic principle, graft-versus-leukaemia (GvL) effect, risk assessment has to balance both risks depending on the pre-transplant status. This is clearly demonstrated when comparing the two major strategies for prevention of GvHD. While the majority of approaches aiming at T-cell depletion show efficacy in reducing acute and chronic GvHD and transplant-related mortality, T-cell depletion also affects graft-versus-leukaemia effects and thus results in a higher relapse rate. Thus, standard prophylaxis relying on calcineurin inhibitors frequently results in at least equivalent or even superior long-term disease-free survival, and the risk of relapse has to be considered when selecting regimens for prevention of GvHD. In addition to this general dilemma, drug-specific side-effects and risks have to be considered when selecting regimens for GvHD prevention and treatment.

Topics: Acute Disease; Adrenal Cortex Hormones; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft vs Host Disease; Graft vs Leukemia Effect; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Methotrexate; Methylprednisolone; Mycophenolic Acid; Risk Assessment; T-Lymphocytes; Tacrolimus

Topics: Acute Disease; Chronic Disease; Clinical Trials as Topic; Cyclosporine; Disease Progression; Dose-Response Relationship, Drug; Drug Synergism; Drug Therapy, Combination; Graft Rejection; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Postoperative Complications; Sirolimus; Tacrolimus

One of the leading causes of late graft loss is chronic allograft nephropathy, characterized in part by deteriorating renal function. Registry data have demonstrated that renal function within the first year post-transplant is an important predictor of long-term transplant outcome, with serum creatinine concentrations < or =1.5 mg/dl at 6 or 12 months being associated with the highest rate of 5 year graft survival. These findings are supported by a retrospective, pooled analysis of two multicentre trials in the USA, as well as by our own data showing that serum creatinine concentrations may be predictive of long-term survival as early as 1 month post-transplant. Analysis of 216 renal transplantations carried out at our centre (1996-2000) using immunosuppressive therapy based on tacrolimus, corticosteroids and azathioprine (n = 51) or mycophenolate mofetil (MMF; n = 70) vs ciclosporin microemulsion, azathioprine and corticosteroids (n = 95) showed that the best 3 year graft survival was achieved with tacrolimus/MMF therapy. While serum creatinine concentrations at this time point were similar for the tacrolimus and ciclosporin treatment groups (1.69 and 1.65 mg/dl, respectively), the proportion of patients with functioning grafts was significantly higher in the tacrolimus group (84 vs 67%, P = 0.007). Similar findings of improved renal function or graft outcomes with tacrolimus- vs ciclosporin-based therapy have been reported in other single-centre and multicentre trials and a USRDS registry survey. Accumulating data suggest that renal function compares well between tacrolimus-based and calcineurin inhibitor (CNI)-sparing regimens. Consequently, the vast majority of renal transplant recipients maintain good long-term renal function with tacrolimus cornerstone immunosuppression without adopting CNI minimization or withdrawal strategies.

Topics: Calcineurin Inhibitors; Chronic Disease; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

Despite current standard preventive strategies that include optimizing donor selection and the combination of methorexate and a calcineurine inhibitor, acute and chronic GVHD remains a major barrier to successful hematopoietic cell transplantation for a sizeable proportion of patients. When acute and chronic GVHD become manifest a standard primary therapy approach has been the addition of glucocorticoid therapy to a background of calcineurine inhibition. When this approach fails patients with GVHD require secondary therapy. Ideally, second-line agents should promote transplantation tolerance so that the morbidity associated with prolonged use of glucocorticoids and other immunosuppressive agents can be minimized. Promising new agents or strategies which warrant further controlled clinical trials include: mycophenolate mofetil, sirolimus, humanized or chimeric monoclonal antibodies such as visilizumab, daclizumab and infliximab, and extracorporeal photopheresis. Co-operative studies are necessary to hasten the process of evaluating novel treatment strategies for acute and chronic GVHD.

Topics: Acute Disease; Anti-Bacterial Agents; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Child; Chronic Disease; Cyclosporine; Daclizumab; Glucocorticoids; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Mycophenolic Acid; Photopheresis; Prednisone; Prodrugs; Sirolimus; Tacrolimus

Oral lichen planus (OLP) is a chronic mucosal condition commonly encountered in clinical dental practice. Lichen planus is believed to represent an abnormal immune response in which epithelial cells are recognized as foreign, secondary to changes in the antigenicity of the cell surface. It has various oral manifestations, the reticular form being the most common. The erosive and atrophic forms of OLP are less common, yet are most likely to cause symptoms. Topical corticosteroids constitute the mainstay of treatment for symptomatic lesions of OLP. Recalcitrant lesions can be treated with systemic steroids or other systemic medications. However, there is only weak evidence that these treatments are superior to placebo. Given reports of a slightly greater risk of squamous cell carcinoma developing in areas of erosive OLP, it is important for clinicians to maintain a high index of suspicion for all intraoral lichenoid lesions. Periodic follow-up of all patients with OLP is recommended.

Topics: Carboxymethylcellulose Sodium; Carcinoma, Squamous Cell; Chronic Disease; Diagnosis, Differential; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Mouth Neoplasms; Precancerous Conditions; Steroids; Tacrolimus

Graft-versus-host disease (GVHD) remains a major complication of allogeneic hematopoietic stem cell transplantation. Polymyositis can occur in association with chronic GVHD and mimics the idiopathic form of the disease. We report two cases of chronic GVHD-associated polymyositis and review the published literature. The two patients presented 13 and 19 months after allogeneic transplantation with characteristic features of muscular hypotrophy, proximal muscle weakness, pain, elevated creatine phosphokinase (CPK), aldolase and SGPT. Interestingly, both patients had HLA DR52 genes, which is frequently reported in association with idiopathic polymyositis. Electromyogram (EMG) and muscle biopsy confirmed the diagnosis. Treatment with cyclosporine or tacrolimus resulted in complete and sustained remission of polymyositis in both cases. A review of the literature shows cyclosporine and steroids are well-described treatment options for patients with myositis in post transplant, as well as idiopathic cases. The duration of immunosuppressive treatment has varied in different reports, and there is a risk of recurrence when immunosuppression is tapered.

Topics: Adult; Chronic Disease; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Leukemia, Myeloid; Male; Middle Aged; Polymyositis; Tacrolimus; Transplantation, Homologous

Acute and chronic graft versus host disease (GVHD) remain the major barriers to successful hematopoietic cell transplantation. The induction of GVHD may be divided into three phases: recipient conditioning;donor T-cell activation; andeffector cells mediating GVHD. This review examines GVHD prevention and treatment using this conceptual model as framework. The various pharmacological agents discussed impact on different phases of the GVHD cascade. For example, keratinocyte growth factor and interleukin (IL)-11 are cytokines that may be useful in disrupting phase I of the GVHD cascade by blocking gastrointestinal tract damage, and lowering serum levels of lipopolysaccharide and tumour necrosis factor (TNF)-alpha. Cyclosporin, tacrolimus (FK-506) and sirolimus (rapamycin) are some of the main agents that disrupt phase II (donor T-cell activation). Mycophenolate mofetil and tresperimus probably act on this phase as well. Other novel drugs that affect phase II are tolerance-induction agents such as CTLA-4 and anti-CD40-ligand monoclonal antibodies, and preliminary results using CTLA-4 monoclonal antibody in GVHD prevention are encouraging. Examples of agents that disrupt phase III are the IL-2 receptor antagonist daclizumab and the anti-TNFalpha monoclonal antibody infliximab. These anti-cytokine antibodies have shown promising results in early studies. The most effective approach to GVHD prevention will probably be a combination regimen where the three phases of the GVHD cascade are disrupted. Once GVHD has occurred, all three phases of the cascade are activated. Developments of combination therapy for treatment of both acute and chronic GVHD are likely to yield better results than monotherapy. The numerous new treatment modalities presented should improve the outlook for patients with acute and chronic GVHD.

Topics: Acute Disease; Animals; Antibodies, Monoclonal; Antibodies, Monoclonal, Humanized; Carbamates; Chronic Disease; Combined Modality Therapy; Cyclosporine; Daclizumab; Fibroblast Growth Factor 7; Fibroblast Growth Factors; Graft vs Host Disease; Humans; Immunoglobulin G; Immunosuppressive Agents; Infliximab; Interleukin-11; Mycophenolic Acid; Receptors, Interleukin-2; Sirolimus; T-Lymphocytes; Tacrolimus

Topics: Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Kidney Transplantation; Mycophenolic Acid; Renal Insufficiency; Sirolimus; Tacrolimus

Chronic graft-versus-host disease (cGvHD) continues to be the major problem in long-term survivors of allogeneic haematopoietic stem cell transplants and is the principal cause of morbidity and non-relapse mortality. Over the past twenty years, diagnosis, prophylaxis and treatment of cGvHD have slowly evolved. An effective therapy for cGvHD is designed to prevent complications through targeting the disease mechanisms. None of the present therapies for cGvHD are successful in the majority of patients. Conventional drugs in different combinations can control the disease in approximately 50% of patients. Attempts to improve survival have led to evaluation of several alternative approaches in the treatment of refractory cGvHD with varying degrees of success. Clinical trials are needed to establish the role of these new approaches in the treatment of cGvHD as first line or salvage therapy without causing significant side effects. This review summarises the currently available knowledge on conventional and new treatment approaches for cGvHD.

Topics: Chronic Disease; Graft vs Host Disease; Humans; Lymphoid Tissue; Mycophenolic Acid; Photochemotherapy; Tacrolimus; Thalidomide

Chronic inflammatory skin disorders, such as atopic eczema, can cause considerable impairment of life quality. Their treatment is mainly driven by systemic or topical glucocorticosteroids which have the risk of many side effects. Recently, immunosuppressive macrolides which act via the inhibition of cytokine expression in T-lymphocytes have been shown to exert good therapeutic potency in inflammatory skin disorders. Cyclosporin, widely used in transplantation medicine, is also effective in psoriasis and atopic eczema but is not suitable for topical treatment. Tacrolimus (FK506) has been found to be 10-100 times more potent than cyclosporin and to penetrate skin much better due to a lower molecular weight. Initial clinical investigations have shown efficacy of topical tacrolimus in patients with atopic eczema. Large multi-centre studies have proven that long-term therapy with 0.03% and 0.1% tacrolimus ointment reveals effectiveness and safety both in adults and in children with severe atopic eczema. A burning sensation at the site of application is the most frequently observed local side effect. Relevant systemic adverse events were not detected. In Japan and the US, the drug is already licensed for the treatment of atopic eczema. The European admission for the pharmaceutical market is expected in the year 2002. Tacrolimus represents a milestone in topical therapy of inflammatory skin disorders which has so far been dominated by corticosteroid formulations and gives hope for the development of further topical immunosuppressive agents of its class in the future.

Topics: Administration, Oral; Administration, Topical; Adult; Child; Chronic Disease; Clinical Trials as Topic; Contraindications; Dermatitis; Drug Interactions; Drug Tolerance; Eczema; Humans; Immunosuppressive Agents; Molecular Structure; Tacrolimus

The calcineurin inhibitors cyclosporin A (CsA) and tacrolimus (FK506) are associated with dose- and efficacy-limiting adverse events, including nephrotoxicity, which may diminish their overall benefits for long-term graft survival. Nephrotoxicity is difficult to distinguish from chronic allograft rejection and is a particular problem in the setting of renal transplantation. Minimizing immunosuppressant-induced nephrotoxicity could improve long-term renal allograft survival. However, to obtain significant long-term improvement in renal allograft outcomes, it may be necessary to adopt new immunosuppressive regimens that rely less on calcineurin inhibitors. Recipients of other transplanted organs, as well as patients with autoimmune diseases who require immunosuppressant therapy, could also benefit from this change in immunosuppressive drug strategy because their healthy, native kidneys are particularly susceptible to the nephrotoxic effects of CsA and FK506. CsA- and FK506-sparing regimens, which use reduced doses of CsA and FK506 in combination with other nonnephrotoxic immunosuppressants, may be the best current option for reducing nephrotoxicity. The chemical immunosuppressant mycophenolate mofetil (MMF) has been used as part of CsA- and FK506-sparing regimens that provide improved renal function while maintaining adequate immunosuppression. Such regimens should reduce patient morbidity and mortality. Also, because immunosuppressant-induced nephrotoxicity has been associated with significant financial costs, CsA- and FK506-sparing regimens should result in substantial savings in health care costs.

Topics: Acute Disease; Chronic Disease; Costs and Cost Analysis; Cyclosporine; Diagnosis, Differential; Forecasting; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Monitoring, Physiologic; Risk Factors; Tacrolimus; Time Factors

Despite conventional and new therapies for the treatment of chronic GVHD (cGVHD), this syndrome continues to account for significant morbidity and mortality after allogeneic hematopoietic stem cell transplantation. With the expanded use of allogeneic peripheral blood stem cell transplantation, matched unrelated as well as mismatched related donors there is an increased incidence of cGVHD that poses a new clinical challenge. Over the past 10 years some new agents have been used, particularly, as a salvage therapy for the treatment of cGVHD. Many of the new agents discussed in this paper may have a role in the future as a therapy for cGVHD. Randomized clinical trials must be performed earlier in the course of cGVHD to establish the efficacy of these new drugs.

Topics: Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Photochemotherapy; Tacrolimus; Thalidomide; Transplantation, Homologous; Whole-Body Irradiation

The increasing number of allogeneic stem cell transplants, particularly those involving donors other than HLA-identical siblings, has made the management of acute and chronic graft-versus-host disease (GVHD) a continuing problem for transplant experts. There have been improvements in the prevention of acute GVHD with cyclosporine- and FK506-based combination therapies, as well as lymphocyte depletion. However, fewer than 50% of patients have durable improvement after initial treatment. FK506 and mycophenolate mofetil (MMF) are promising salvage therapies in steroid-resistant GVHD, as are the anti-cytokine antibodies and the purine nucleoside analog, pentostatin. The incidence of chronic GVHD has unfortunately not decreased, despite advances in treatment of acute GVHD. Treatment of chronic GVHD involves treatment of the underlying immunologic process and supportive therapies. Initial therapy has tended to be cyclosporine and prednisone. Refractory patients have hope with combination MMF and FK506, etretinate, plaquenil, and nonpharmacologic approaches, such as PUVA. Supportive care is an integral part of chronic GVHD management with emphasis on infection control and symptom control. Death in chronic GVHD is still largely attributable to infection. The progress in therapies for GVHD has been encouraging, but the future of GVHD management lies in a better understanding of its pathogenesis.

Topics: Acute Disease; Chronic Disease; Drug Therapy, Combination; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous

Topics: Chronic Disease; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Pilot Projects; Prognosis; Pyelonephritis; Randomized Controlled Trials as Topic; Tacrolimus; Treatment Outcome

The above snapshot of the relevant literature on chronic Cyclosporine and Tacrolimus nephropathy indicate fertile areas for further study. The reader is referred to recent reviews for a more in-depth analysis of this problem (2).

Topics: Acute Disease; Animals; Chronic Disease; Cyclosporine; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Prognosis; Sirolimus; Tacrolimus

It has been known for some time that a variety of liver diseases affect kidney function, but renal dysfunction associated with orthotopic liver transplantation has received scant attention. Although the mechanisms mediating these abnormalities are incompletely defined, advances in the understanding of renal pathophysiology after liver transplantation have made it possible to develop new treatment strategies. Aggressive and early intervention to diagnose and treat renal complications associated with liver transplantation should be the goal for transplant centres.

Topics: Chronic Disease; Cyclosporine; Hepatitis C; Hepatorenal Syndrome; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Failure; Liver Transplantation; Prostaglandins; Renal Dialysis; Renal Insufficiency; Tacrolimus

Although the main immunosuppressive drugs used commonly after transplantation and in the treatment of autoimmune disease are cyclosporine and FK506, both have similar nephrotoxic properties that may limit their clinical use. The complexity of both the functional and structural characteristics of cyclosporine and FK506 nephrotoxicity strongly suggests a multifactorial process involving complex physiologic and intracellular signaling processes that have obvious implications for the design and development of new immunosuppressive drugs. This review summarizes recent concepts regarding the mechanisms responsible for the renal dysfunction related to these drugs and outlines methods of possible therapeutic intervention.

Topics: Acute Disease; Animals; Chronic Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Tacrolimus

A combination of three post-transplant drugs, cyclophosphamide (PTCy), a calcineurin inhibitor, and mycophenolate mofetil, has long been used for prophylaxis of graft-versus-host-disease (GVHD) after HLA-haploidentical allogeneic hematopoietic cell transplantation (allo-HCT). Recently, this combination has been used following HLA-matched allo-HCT as well, but the optimal combination of drugs for GVHD prophylaxis in an HLA-matched setting remains unclear. This prospective phase II study evaluated the safety and efficacy of PTCy plus tacrolimus (TAC) for GVHD prophylaxis after allo-HCT from HLA-matched related donors (MRD) or HLA-matched unrelated donors (MUD). The cumulative incidences of grades II-IV and III-IV acute GVHD at 100 days post-transplantation were 18% and 5.9%, respectively, in the MRD group, and 18% and 9.1%, respectively, in the MUD group. The cumulative incidences of moderate to severe chronic GVHD at 1 year were 12% and 9.1% in the MRD and MUD groups, respectively. The 1-year overall survival rates in the MRD and MUD groups were 88% and 64%, respectively, and the 1-year GVHD-free, relapse free survival rates were 59% and 50%, respectively. These results suggest that GVHD prophylaxis with a less intensive double drug combination (PT/Cy and TAC) might be feasible after HLA-matched allo-HCT.Clinical Trial Notation This trial was a prospective single-center trial registered at the University Hospital Medical Information Network Clinical Trials Registry (UMIN-CTR; identification number: UMIN000023890) and the Japan Registry of Clinical Trials (jRCTs051180143).

Topics: Adult; Aged; Calcineurin Inhibitors; Chronic Disease; Cyclophosphamide; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; HLA Antigens; Humans; Immunosuppressive Agents; Male; Middle Aged; Patient Acuity; Postoperative Care; Survival Rate; Tacrolimus; Transplantation, Homologous

Calcineurin inhibitors (CNI) are standard components of graft-versus-host disease (GVHD) prophylaxis after hematopoietic cell transplantation (HCT). Prior data suggested that CNI-free approaches using donor T-cell depletion, either by ex vivo CD34 selection or in vivo post-transplant cyclophosphamide (PTCy) as a single agent, are associated with lower rates of chronic GVHD (cGVHD).. This multicenter phase III trial randomly assigned patients with acute leukemia or myelodysplasia and an HLA-matched donor to receive CD34-selected peripheral blood stem cell, PTCy after a bone marrow (BM) graft, or tacrolimus and methotrexate after BM graft (control). The primary end point was cGVHD (moderate or severe) or relapse-free survival (CRFS).. Among 346 patients enrolled, 327 received HCT, 300 per protocol. Intent-to-treat rates of 2-year CRFS were 50.6% for CD34 selection (hazard ratio [HR] compared with control, 0.80; 95% CI, 0.56 to 1.15;. CNI-free interventions as performed herein did not result in superior CRFS compared with tacrolimus and methotrexate with BM. Lower rates of moderate and severe cGVHD did not translate into improved survival.

Topics: Adolescent; Adult; Aged; Calcineurin Inhibitors; Chronic Disease; Cyclophosphamide; Disease-Free Survival; Drug Therapy, Combination; Female; Germany; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Methotrexate; Middle Aged; Myeloablative Agonists; Recurrence; Tacrolimus; Time Factors; Transplantation Conditioning; United States; Young Adult

An open-label phase 2 study of topical dexamethasone versus tacrolimus solutions in new-onset oral chronic graft-versus-host disease (cGVHD) revealed the superior efficacy of dexamethasone. The objective of this study was to report long-term patterns of topical therapy utilization and clinical outcomes in this cohort after completing the 30-day trial. A retrospective record review was performed from the date of study completion to January 2017. Topical therapies, systemic immunosuppressive therapies, objective measurements (National Institutes of Health severity score, oral mucosal scores), patient- reported outcomes (dryness, sensitivity, pain), and adverse events were recorded for oral cGVHD-related outpatient visits. Follow-up (FU) periods were defined as FU1 (0-1 month), FU2 (1-3 months), FU3 (3-6 months), FU4 (6-12 months), FU5 (12-18 months), and FU6 (18-24 months). Forty patients (52.5% males, median age, 56 years) completed the clinical trial and were included in the analysis. Topical therapies used were dexamethasone, tacrolimus, clobetasol, or a combination of these agents. At FU1, all 40 patients were receiving topical therapy, which decreased to 54.5% (12 out of 22) at FU6. Clinician-reported oral mucosal scores (0-12) and patient-reported sensitivity scores (0-10) decreased over time from FU1 (median mucosal score, 3; sensitivity, 3) to FU6 (mucosal score, 1; sensitivity, 2). Intralesional steroid therapy was provided to 6 patients for management of refractory oral ulcerations, all within the first year of follow-up. Patients with de novo symptomatic oral cGVHD may require long-term care with topical immunomodulatory therapy for up to 2 years, if not longer. Topical steroid and tacrolimus therapies are safe and effective in managing symptomatic oral cGVHD. Second-line topical therapy for refractory oral cGVHD requires further investigation.

Topics: Chronic Disease; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Mouth Diseases; Retrospective Studies; Tacrolimus

Chronic graft-versus-host disease (cGVHD) is major cause of morbidity and mortality following allogeneic hematopoietic cell transplantation (HCT). Ixazomib is an oral, second-generation, proteasome inhibitor that has been shown in preclinical models to prevent GVHD. We conducted a phase I/II trial in 57 patients to evaluate the safety and efficacy of ixazomib administration for cGVHD prophylaxis in patients undergoing allogeneic HCT. Oral ixazomib was administered on a weekly basis for a total of 4 doses, beginning days +60 through +90, to recipients of matched related donor (MRD, n = 25) or matched unrelated donor (MUD, n = 26) allogeneic HCT in phase II portion of the study, once the recommended phase II dose of 4 mg was identified in phase I (n = 6). All patients received peripheral blood graft and standard GVHD prophylaxis of tacrolimus and methotrexate. Ixazomib administration was safe and well tolerated, with thrombocytopenia, leukopenia, gastrointestinal complaints, and fatigue the most common adverse events (>10%). In phase II (n = 51), the cumulative incidence of cGVHD at 1 year was 36% (95% confidence interval [CI], 19% to 54%) in the MRD cohort and 39% (95% CI, 21% to 56%) in the MUD cohort. One-year cumulative incidence of nonrelapse mortality (NRM) and relapse was 0% and 20% (95% CI, 8% to 36%) in the MRD cohort, respectively. In the MUD cohort, the respective NRM and relapse rates were 4% (0% to 16%) and 34% (17% to 52%). The outcomes on the study were compared post hoc with contemporaneous matched Center for International Blood and Marrow Transplant Research (CIBMTR) controls. This post hoc analysis showed no significant improvement in cGVHD rates in both the MRD (hazard ratio [HR] = 0.85, P = .64) or MUD cohorts (HR = 0.68, P = .26) on the study compared with CIBMTR controls. B cell activating factor plasma levels were significantly higher after ixazomib dosing in those who remained cGVHD free compared with those developed cGVHD. This study shows that the novel strategy of short-course oral ixazomib following allogeneic HCT is safe but did not demonstrate significant improvement in cGVHD incidence in recipients of MRD and MUD transplantation compared with matched CIBMTR controls. This study is registered at www.clinicaltrials.gov as NCT02250300.

Topics: Boron Compounds; Chronic Disease; Glycine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Tacrolimus; Transplantation Conditioning

Chronic rejection (CR) is an uncommon but important cause of graft dysfunction, leading to graft loss and often requires retransplantation. This study evaluates the incidence and outcome of the patients with CR at a large living donor liver transplant (LDLT) center.. Data of patients with CR were retrospectively analyzed in 1232 adult (age >18 years) LDLT on tacrolimus (mainly)-based immunosuppression. Sirolimus/everolimus (mammalian target of rapamycin [mTOR] inhibitors) was added to baseline immunosuppression as rescue therapy in patients with CR. Data are shown as median (interquartile range [IQR]).. Twenty-three patients (22 males), aged 42 (IQR 45-56) years, had biopsy-proven chronic rejection at 21 (8-44) months after liver transplantation. The incidence of chronic rejection was 1.9% in this cohort. The patients with CR (n = 23) had a significantly higher incidence of cytomegalovirus (CMV) viremia, acute cellular rejection, and history of anastomotic biliary strictures as compared to patients without CR. Five patients were noncompliant with immunosuppression before the diagnosis of CR. Twelve patients (52%) responded to addition of mTOR inhibitors, whereas 11 did not respond and had poor outcome.. The incidence of chronic rejection is low in LDLT. Treatment with mTOR inhibitors can reverse graft dysfunction in approximately half of the patients.

Topics: Adult; Chronic Disease; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; India; Liver Transplantation; Living Donors; Male; Middle Aged; Postoperative Complications; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus

We enrolled 30 patients on a prospective phase II trial utilizing a total body irradiation (TBI)-based myeloablative preparative regimen (fludarabine 30 mg/m2/day × 3 days and TBI 150 cGy twice per day on day -4 to -1 [total dose 1200 cGy]) followed by infusion of unmanipulated peripheral blood stem cells from a haploidentical family donor (haplo). Postgrafting immunosuppression consisted of cyclophosphamide 50 mg/kg/day on days 3 and 4, mycophenolate mofetil through day 35, and tacrolimus through day 180. Median patient age was 46.5 years (range, 24 to 60). Transplantation diagnosis included acute myelogenous leukemia (n = 16), acute lymphoblastic leukemia (n = 6), chronic myelogenous leukemia (n = 5), myelodysplastic syndrome (n = 1), and non-Hodgkin's lymphoma (n = 2). Using the Dana Farber/Center for International Blood and Marrow Transplant Research/Disease Risk Index (DRI), patients were classified as low (n = 4), intermediate (n = 12), high (n = 11), and very high (n = 3) risk. All patients engrafted with a median time to neutrophil and platelet recovery of 16 and 25 days, respectively. All evaluable patients achieved sustained complete donor T cell and myeloid chimerism by day +30. Acute graft-versus-host disease (GVHD) grades II to IV and III and IV was seen in 43% and 23%, respectively. The cumulative incidence of chronic GVHD was 56% (severe in 10%). After a median follow-up of 24 months, the estimated 2-year overall survival (OS), disease-free survival (DFS), nonrelapse mortality, and relapse rate were 78%, 73%, 3%, and 24%, respectively. Two-year DFS and relapse rate in patients with low/intermediate risk disease was 100% and 0%, respectively, compared with 39% and 53% for patients with high/very high risk disease. When compared with a contemporaneously treated cohort of patients at our institution receiving myeloablative HLA-matched unrelated donor (MUD) transplantation (acute myelogenous leukemia [n = 17], acute lymphoblastic leukemia [n = 15], chronic myelogenous leukemia [n = 7], myelodysplastic syndrome [n = 7], non-Hodgkin lymphoma [n = 1], chronic lymphoblastic leukemia [n = 1]), outcomes were statistically similar, with 2-yr OS and DFS being 78% and 73%, respectively after haplo transplantation versus 71% and 64%, respectively, after MUD transplantation. In patients with DRI low/intermediate risk disease, 2-yr DFS was superior after haplo compared with MUD transplantations (100% versus 74%, P = .032), whereas there was no difference i

Topics: Acute Disease; Adult; Chronic Disease; Cyclophosphamide; Female; Graft vs Host Disease; Haplotypes; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; Humans; Immunosuppressive Agents; Male; Middle Aged; Mycophenolic Acid; Myeloablative Agonists; Prospective Studies; Recurrence; Risk; Survival Analysis; Tacrolimus; Transplantation Conditioning; Transplantation, Isogeneic; Unrelated Donors; Whole-Body Irradiation

Effective pharmacological strategies employed in allogeneic hematopoietic cell transplantation should prevent serious chronic graft-versus-host disease and facilitate donor-recipient immune tolerance. Based on demonstrated pro-tolerogenic activity, sirolimus (rapamycin) is an agent with promise to achieve these goals. In a long-term follow-up analysis of a randomized phase II trial comparing sirolimus/tacrolimus versus methotrexate/tacrolimus for graft-versus-host disease prevention in matched sibling or unrelated donor transplant, we examined the impact of prolonged sirolimus administration (≥ 1 year post-transplant). Median follow-up time for surviving patients at time of this analysis was 41 months (range 27-60) for sirolimus/tacrolimus and 49 months (range 29-63) for methotrexate/tacrolimus. Sirolimus/tacrolimus patients had significantly lower National Institutes of Health Consensus moderate-severe chronic graft-versus-host disease (34% vs. 65%; P=0.004) and late acute graft-versus-host disease (20% vs. 43%; P=0.04). While sirolimus/tacrolimus patients had lower prednisone exposure and earlier discontinuation of tacrolimus (median time to tacrolimus discontinuation 368 days vs. 821 days; P=0.002), there was no significant difference in complete immune suppression discontinuation (60-month estimate: 43% vs. 31%; P=0.78). Prolonged sirolimus administration represents a viable approach to mitigate risk for moderate-severe chronic and late acute graft-versus-host disease. Further study of determinants of successful immune suppression discontinuation is needed.

Topics: Acute Disease; Antimetabolites, Antineoplastic; Chronic Disease; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Methotrexate; Severity of Illness Index; Siblings; Sirolimus; Survival Analysis; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Treatment Outcome; Unrelated Donors

Long-term use of corticosteroids is associated with considerable morbidity, including cardiovascular and metabolic adverse effects.. This study evaluated the long-term efficacy and safety of two steroid-free regimens compared with a triple immunosuppressive therapy in renal transplant recipients. This was a 3-year follow-up to a 6-month, open-label, randomized, multicenter study.. Data from 3 years were available for 421 (93.3%) of 451 patients in the original intent-to-treat population (143 tacrolimus/basiliximab [Tac/Bas], 139 tacrolimus/mycophenolate mofetil [Tac/MMF], and 139 tacrolimus/MMF/steroids [triple therapy]). In the time interval from 6 months to 3 years after transplantation, the incidence of biopsy-proven acute rejection was low and similar (Tac/Bas, 2.1%; Tac/MMF, 2.2%; triple therapy, 2.2%); Most rejection episodes occurred during the first 6 months of the study. Graft survival was high (Kaplan-Meier estimates: 92.7%, 92.5%, and 92.5%), as was patient survival (93.1%, 96.4%, and 97.0%). There were 10 graft losses (n=2, 4, and 4) and 12 patient deaths (n=5, 2, and 5). Renal function was well preserved throughout the study and similar between groups. There was a trend toward improved cardiovascular risk factors in the Tac/Bas group, including reduced total and low-density lipoprotein cholesterol and lower new-onset insulin use. There were no between-group differences in the incidence or type of adverse events.. Higher rates of acute rejection early in treatment were seen with the steroid-free regimens, but this did not translate into poorer long-term outcomes, such as graft and patient survival and renal function. A trend for a more favorable cardiovascular risk profile was observed for steroid-free immunosuppression with Tac/Bas.

Topics: Acute Disease; Adrenal Cortex Hormones; Adult; Antibodies, Monoclonal; Basiliximab; Biopsy; Chi-Square Distribution; Chronic Disease; Drug Therapy, Combination; Europe; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Recombinant Fusion Proteins; Risk Assessment; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

The objective of this study was to assess the treatment of chronic superficial keratitis (CSK) in dogs with the use of tacrolimus and DMSO. The study was conducted on 16 dogs - 7 males and 9 females, aged 3 to 11 years, diagnosed with CSK. The disease was treated with ophthalmic drops containing 0.02% tacrolimus and 50% DMSO, administered to the ocular surface three times a day. Prior to the treatment and after 5 weeks of therapy, the corneal neovascularisation, pigmentation, and also the redness and depigmentation of the third eyelid margin were assessed. The percentage of the corneal surface afflicted with inflammatory processes was calculated on the basis of photographs taken with the use of IsoCalc.com's Get Area software for Corel DRAW 12. It was found that the application of tacrolimus and DMSO caused a reduction of inflammatory process and neovascularisation in the cornea. The mean corneal surface afflicted with inflammatory processes was statistically significantly reduced from 69.9% to 43.9% (p < or = 0.01)--in case of the right corneas, and from 58.9% to 38.6% in case of the left corneas. Of 32 corneas diagnosed with the pigmentation, the reduction of the pigmentation was observed in 14, while in 16 the pigmentation increased. The treatment of CSK with the use of tacrolimus and DMSO causes the reduction in terms of inflammatory processes and neovascularisation, but in many cases does not inhibit the progress of the pigmentation.

Topics: Animals; Chronic Disease; Dimethyl Sulfoxide; Dog Diseases; Dogs; Female; Free Radical Scavengers; Immunosuppressive Agents; Keratitis; Male; Tacrolimus

The optimal graft-versus-host disease (GVHD) prophylaxis after umbilical cord blood transplantation has not been established. Our previous observation using single calcineurin inhibitors revealed a high incidence and severity of early immune-mediated complications, especially for older patients or those with poor performance status.. We conducted a single institute pilot study assessing the safety and effectiveness of mycophenolate mofetil (MMF) and tacrolimus (FK) combination as a GVHD prophylaxis for 29 patients (FK+MMF), and the results were compared with matched-pairs extracted from our historical database who received FK alone as GVHD prophylaxis (control).. FK+MMF group showed superior engraftment rate compared with control group (cumulative incidence until day 60 posttransplant; 90%±0% vs. 69%±1%, P=0.02). A cumulative incidence of severe type preengraftment immune reactions was significantly decreased in FK+MMF group (16%±1%) compared with that of control group (52%±2%, P=0.03), and, remarkably, there was no nonrelapse mortality (NRM) observed up to day 30 posttransplant in FK+MMF group, whereas 21%±1% of NRM was observed in the control group. However, the incidences of acute and chronic GVHD, estimated overall and progression-free survivals were comparable between two groups.. MMF and FK in combination was well tolerated and decreased early NRM possibly by better control of preengraftment immune reactions. Subsequent NRM or disease progression needs to be overcome to further improve survival.

Topics: Acute Disease; Age Factors; Aged; Chronic Disease; Cord Blood Stem Cell Transplantation; Databases, Factual; Disease Progression; Disease-Free Survival; Female; Graft vs Host Disease; Hematologic Diseases; Humans; Immunosuppressive Agents; Incidence; Male; Matched-Pair Analysis; Middle Aged; Mycophenolic Acid; Pilot Projects; Tacrolimus

Chronic hand dermatitis is common and difficult to treat.. Our aim was to assess the efficacy of pimecrolimus cream 1% in mild-to-moderate chronic hand dermatitis.. Adult patients (n = 652) were randomized to pimecrolimus 1% or vehicle cream twice daily with overnight occlusion for 6 weeks, followed by a 6-week open-label pimecrolimus treatment. Primary efficacy was 5-point Investigators' Global Assessment of prospectively selected 'target hand' as treatment success (Investigators' Global Assessment 0 or 1) and treatment failure. Pruritus relief was also assessed.. Following double-blind phase treatment, target hand treatment success was achieved in 29.8 and 23.2% of the patients in the pimecrolimus and vehicle groups, respectively (p = 0.057). The proportion of patients experiencing pruritus relief was significantly higher in the pimecrolimus group compared to the vehicle group at all time points throughout the double-blind phase.. The groups were comparable with respect to treating disease signs. Pruritus relief, however, was significantly greater in the pimecrolimus group.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Dermatologic Agents; Double-Blind Method; Emollients; Female; Hand Dermatoses; Humans; Male; Middle Aged; Pruritus; Severity of Illness Index; Tacrolimus; Treatment Outcome; Young Adult

In an effort to mitigate progression of IF/TA associated with chronic renal allograft injury, we hypothesize that adjuvant immunosuppression with sirolimus (SRL) will delay progression compared with MMF. Subjects 5-17 yr old, >1-yr post-transplant with mild or moderate IF/TA (Banff criteria) and tacrolimus dose minimization were randomized to continue MMF or convert to SRL and followed for two yr. For the entire cohort (n = 20), there was significant progression of %GGS, ci, ct, cv, and ah scores over the follow-up period (p < 0.05). There was no difference in rates of progression of Banff scores, %GGS, or % IF over two yr between the two groups, though power was low. Both groups exhibited similar rates of eGFR decline (MMF: -12.3 vs. SRL: -11.8 mL/min/1.73 m²/yr), which was correlated with ct score (p < 0.05). The SRL group had more episodes of acute allograft dysfunction and oral ulcers. Proteinuria at 24 months was significantly increased in the SRL group (6/9 subjects) but was not correlated with eGFR or %GGS. We conclude that neither MMF nor SRL, combined with low-dose tacrolimus, was effective at mitigating progressive histological changes or functional decline associated with chronic renal allograft injury.

Topics: Adolescent; Child; Child, Preschool; Chronic Disease; Cohort Studies; Disease Progression; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mycophenolic Acid; Prospective Studies; Renal Insufficiency; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Recent studies have established the pivotal role of irritants and allergens in development of chronic paronychia and the significant improvement with corticosteroid therapy.. The objective of this randomized, unblinded, comparative study was to compare the efficacy of tacrolimus ointment 0.1% vs. betamethasone 17-valerate 0.1% in the treatment of chronic paronychia.. Forty-five patients with chronic paronychia were randomized 1:1:1 to apply twice daily either betamethasone 17-valerate 0.1% or tacrolimus 0.1% ointment or emollient. Protective measures were counselled to all patients. Treatment duration was 3 weeks and patients were followed for an additional 6 weeks.. Eight patients in the betamethasone group were considered as cured, two as improved and four as nonresponders at the end of the treatment period. Thirteen patients in the tacrolimus group were considered as cured and one as improved at the end of the treatment period. Nine patients in the emollient group were considered as stable and six failed to respond. Both betamethasone and tacrolimus groups presented statistically significantly greater cure or improvement rates when compared with the emollient group (P<0.001).. Tacrolimus ointment appears to be a more efficacious agent than betamethasone 17-valerate or placebo for the treatment of chronic paronychia.

Topics: Betamethasone Valerate; Candidiasis; Chronic Disease; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Paronychia; Tacrolimus; Treatment Outcome

This study compared topical pimecrolimus with betamethasone in the treatment of pruritus and chronic skin lesions due to sulfur mustard exposure. Seventy male chemical-injured war veterans participated in this investigator-blinded clinical trial. They were randomized to receive pimecrolimus cream 1% (n = 35) or betamethasone cream 0.1% (n = 35) two times a day for 6 weeks. Dermatological examination and assessment of pruritus severity by a pruritic score questionnaire and visual analogue scale were done before and after the treatment course. A significant decrease (P < 0.05) in pruritus, burning sensation, and skin dryness was shown in both groups after the treatment. However, the severity of hyper- and hypopigmentation, vesicle, erythema, fissure, lichenification and excoriation did not decrease significantly in either group (P > 0.05). Mean (+/- standard deviation) pruritic scores at baseline for the pimecrolimus and betamethasone groups were 30.4 (+/- 8.0) and 33.6 (+/- 7.2), respectively (P = 0.103). These scores decreased to 18.8 (+/- 4.8) in the pimecrolimus and 20.8 (+/- 4.0) in the betamethasone groups after treatment; both showed a statistically significant decrease (P < 0.001). Change of pruritus score from baseline to after the treatment course was not statistically different between the two groups (P = 0.502). No serious side-effects were reported during the course of the treatment. Topical pimecrolimus 1% was as effective as betamethasone cream 0.1% in controlling pruritus, burning sensation and skin dryness of sulfur mustard-exposed patients.

Topics: Administration, Cutaneous; Adult; Aged; Anti-Inflammatory Agents; Betamethasone; Chemical Warfare Agents; Chronic Disease; Drug Administration Schedule; Humans; Male; Middle Aged; Mustard Gas; Ointments; Pruritus; Severity of Illness Index; Single-Blind Method; Tacrolimus; Treatment Outcome

Antibody response to the inactivated influenza vaccine is not well described in kidney transplant recipients administered newer, but commonly used, immunosuppression medications. We hypothesized that kidney transplant recipient participants administered tacrolimus-based regimens would have decreased antibody response compared with healthy controls.. Prospective cohort study of 53 kidney transplant recipients and 106 healthy control participants during the 2006-2007 influenza season. All participants received standard inactivated influenza vaccine.. Kidney transplant recipients administered tacrolimus-based regimens at a single academic medical center and healthy controls.. Presence of kidney transplant.. Proportion of participants achieving seroresponse (4-fold increase in antibody titer) and seroprotection (antibody titer > or = 1:32) 1 month after vaccination.. Antibody titers before and 1 month after vaccination by means of hemagglutinin inhibition assays for influenza types A/H1N1, A/H3N2, and B.. A smaller proportion of the transplantation group compared with the healthy control group developed the primary outcomes of seroresponse or seroprotection for all 3 influenza types at 1 month after vaccination. The response to influenza type A/H3N2 was statistically different; the transplantation group had 69% decreased odds of developing seroresponse (95% confidence interval, 0.16 to 0.62; P = 0.001) and 78% decreased odds of developing seroprotection (95% confidence interval, 0.09 to 0.53; P = 0.001) compared with healthy controls. When participants less than 6 months from the time of transplantation were considered, this group had a significantly decreased response to the vaccine compared with healthy controls.. Decreased sample size, potential for confounders, outcome measure used is the standard but does not give information about vaccine efficacy.. Kidney transplant recipients, especially within 6 months of transplantation, had diminished antibody response to the 2006-2007 inactivated influenza vaccine.

Topics: Adult; Antibodies, Viral; Chronic Disease; Cohort Studies; Female; Humans; Immunity; Immunosuppressive Agents; Influenza Vaccines; Influenza, Human; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Orthomyxoviridae; Prospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Chronic renal dysfunction is a frequent and severe complication in solid-organ transplant recipients. Calcineurin inhibitors (CNIs) are the main pathogenic factors of renal dysfunction. Switching from CNIs to nonnephrotoxic drugs, such as mammalian target of rapamycin inhibitors (everolimus and sirolimus), can improve renal function in these patients, but available data about the efficacy and safety of everolimus in liver transplant recipients are scarce. Twenty-one liver transplant recipients (19 males, mean age = 60.6 +/- 7.8 years) with chronic renal dysfunction (creatinine >or= 1.5 mg/dL) were prospectively included. The basal creatinine values were 1.79 +/- 0.39 mg/dL (range = 1.50-2.90 mg/dL). The basal creatinine clearance, evaluated with the Cockroft-Gault formula, was 54.64 +/- 12.47 mL/minute. Everolimus was initiated at a dosage of 0.75 mg twice daily, with target levels of 3 to 8 ng/mL. The withdrawal of CNIs was initiated after the target levels of everolimus were reached. Periodic controls of the weight, arterial pressure, liver function tests, serum creatinine, everolimus levels, proteinuria, creatinine clearance, and glomerular filtration rate at days 30, 90, 180, and 360 were made. After a median follow-up of 19.8 months, the respective creatinine values at 30, 90, 180, and 360 days were 1.68 +/- 0.40 (P = 0.012 with respect to basal values), 1.67 +/- 0.34 (P = 0.107), 1.70 +/- 0.41 (P = 0.521), and 1.57 +/- 0.30 mg/dL (P = 0.047). The respective creatinine clearance values at 30, 90, 180, and 360 days were 58.64 +/- 16.50 (P = 0.013 with respect to basal values), 59.49 +/- 13.27 (P = 0.028), 59.82 +/- 16.83 (P = 0.124), and 64.46 +/- 16.79 mL/minute (P = 0.025). CNIs were withdrawn in 20 recipients (95.2%). Rejection was not detected in any case. In conclusion, the application in liver transplant recipients with chronic renal dysfunction of an immunosuppressive protocol with everolimus and the withdrawal of CNIs was associated with an initial improvement of renal function tests without an increase in the risk of rejection.

Topics: Adult; Aged; Biomarkers; Calcineurin Inhibitors; Chronic Disease; Creatinine; Cyclosporine; Drug Administration Schedule; Everolimus; Feasibility Studies; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

The objective of this study was to evaluate the efficacy and safety of converting from a calcineurin inhibitor (CNI) to sirolimus among renal transplant recipients with chronic allograft nephropathy (CAN).. In 16 patients with CAN, substituted sirolimus for CsA or FK506 and observed the incidence of acute rejection and changes in serum creatinine, triglycerides, cholesterol, blood uric acid, and peripheral blood leukocyte/platelet counts within 12 months. All recipients underwent an allograft biopsy before conversion. The targeted sirolimus level was 4-8 ug/L.. After conversion to sirolimus, the creatinine level of 7 cases decreased and the efficacy rate was (43.8%). No acute rejection occurred during the follow-up. The cases with hypercholesteremia increased from 3 to 7 after conversion; hypertriglyceridemia increased from 3 to 5; leukopenia occurred in 2; subnormal platelet counts increased from 2 to 3; and hyperuricemia increased from 6 to 7. Meanwhile, the average level of peripheral blood leukocytes obviously decreased in the first month, the average peripheral blood cholesterol increased over 12 months, but the average content of peripheral blood platelets, triglyceride and blood uric acid failed to display as statistic difference. Eight patients showed C4d deposition in peritubular capillary in graft tissue before conversion, 7 cases of whom showed no improvement in renal function. In 6 cases there was no C4d deposition in peritubular capillary in graft tissue. Only 2 of 6 cases showed no improvement in renal function. There were 6 patients whose creatinine level was <2.48 mg/dL before conversion, and renal function in 5 of them improved in a year after conversion. In contrast, among 10 patients whose blood creatinine level was >2.48 mg/dL, only 2 cases improved.. It is safe for patients with CAN to use substitute sirolimus for CNI; the incidence of acute rejection did not increase. In this study, 43.8% of patients showed improved renal function. The main adverse reactions after conversion to sirolimus were hypercholesteremia and decreased peripheral blood leukocytes. The serum creatinine level and the deposition of C4d in peritubular capillary were important factors influencing therapeutic efficacy.

Topics: Adult; Calcineurin Inhibitors; Chronic Disease; Creatinine; Drug Therapy, Combination; Female; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Platelet Count; Prednisolone; Safety; Sirolimus; Tacrolimus; Transplantation, Homologous

Chronic kidney disease after organ transplantation is a serious complication that negatively impacts on long-term patient survival. We describe long-term renal function after intestinal transplantation by serial measurements of glomerular filtration rates (GFR) with Chromium EDTA clearance.. Ten patients with at least 6 months survival form the basis of this report. Glomerular filtration rate measurements were performed at baseline, 3 months posttransplantation, and yearly thereafter. Median follow-up time for the cohort was 1.5 years (0.5-7.8 years). Tacrolimus (Prograf) was discontinued in four patients because of impaired renal function. These four patients were switched to sirolimus (Rapamune) at 11, 18, 24, and 40 months posttransplantation.. Median baseline GFR was 67 (22-114) mL/min/1.73 m. In the adult patients, GFR 3 months posttransplantation had decreased to 50% of the baseline. At 1 year, median GFR in the adult patients was reduced by 72% (n=5). Two patients developed renal failure within the first year and required hemodialysis. One of the pediatric patients fully recovered her renal function, the second pediatric patient lost 20% of her baseline GFR at 6 months posttransplantation. Glomerular filtration rate calculated with the modified diet in renal disease formula consistently overestimated GFR by approximately 30% compared with measured GFR.. Chronic kidney disease and renal failure are common after intestinal transplantation. These two factors significantly contribute to poor long-term survival rates. Measurements of GFR may help to identify those individuals at risk for developing chronic kidney disease to implement renal sparing strategies.

Topics: Adult; Aged; Anti-Infective Agents; Child, Preschool; Chromium Radioisotopes; Chronic Disease; Digestive System Surgical Procedures; Disease Progression; Edetic Acid; Female; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Intestines; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Reoperation; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

Recurrent exacerbation of chronic external otitis represents a special challenge for the attending physician. The goal of our study was to evaluate the effectiveness of novel topical immunomodulators acting through an anti-inflammatory, nonsteroidal mechanism.. In a prospective study, in 33 patients an ear wick containing tacrolimus ointment (Protopic 0.1%) was inserted every 2-3 days. Altogether, the wick was changed three times. Therapeutic outcomes were assessed by reexaminations, video-otoscopy, and a standardized findings sheet.. Twenty-eight patients showed significant improvement of clinical symptoms, with 13 of them showing complete healing (follow-up 10-22 months). Relapses (15 cases) were associated with significantly extended symptom-free intervals and reduced numbers of further recurrent episodes.. Because of the safe and successful anti-inflammatory effects, topical immunomodulators represent a new alternative in chronic inflammatory stages of otherwise therapy-resistant external otitis.

Topics: Administration, Topical; Adolescent; Adult; Aged; Aged, 80 and over; Child; Child, Preschool; Chronic Disease; Drug Resistance; Female; Humans; Immunologic Factors; Immunosuppressive Agents; Male; Middle Aged; Otitis Externa; Tacrolimus; Treatment Outcome

Chronic allograft nephropathy (CAN) is a multifactorial process with immunologic and nonimmunologic factors. Because tacrolimus (Tac) has been ascribed a beneficial effect on some of these factors when compared to cyclosporine A (CyA), a randomized controlled trial was conducted to investigate whether conversion from CyA to Tac can ameliorate the progression of renal dysfunction in kidney transplant recipients (KTR) with CAN.. Of the 46 patients with biopsy-proven CAN enrolled, 24 were converted from CyA to Tac, whereas 22 patients were maintained on CyA. Serum creatinine (SCrea), lipid profiles and an antihypertensive score (AHS) were determined after 3, 6 and 12 months. AHS is based on the total number and dosages of antihypertensive medications used. SCrea and AHS were additionally evaluated at 36 months.. SCrea was decreased in the Tac group (Tac(baseline): 297 +/- 67 micromol/L; Tac(6): 261+/- 70 micromol/L, P < 0.001; Tac(12): 254 +/- 55 micromol/L, P < 0.001; Tac(36): 255 +/- 78 micromol/L, P = 0.235), whereas a significant increase of SCrea was detected in the CyA group (CyA(baseline): 279 +/- 77 micromol/L, CyA(12): 333 +/- 98 micromol/L, P < 0.001; CyA(36): 317 +/- 89 micromol/L, P < 0.001). Compared to CyA therapy, SCrea in the Tac group declined after 12 and 36 months (P = 0.011 and 0.048, respectively) as well as AHS (Tac(12): 59 +/- 13, CyA(12): 83 +/- 14, P < 0.001; Tac(36): 60 +/- 12, CyA(36): 84 +/- 14, P < 0.001). LDL cholesterol was lower in the Tac group after 12 months (Tac(12): 2.5 +/- 0.5 mmol/L, CyA(12): 3.5 +/- 0.6 mmol/L, P < 0.001).. Conversion from CyA to Tac in KTR with CAN improves allograft function, lowers blood pressure, and reduces LDL cholesterol. This superior profile may translate into improved long-term graft survival.

Topics: Adult; Chronic Disease; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Transplantation, Homologous

Only very recently studies were conducted in order to evaluate the impact of regulatory T (Treg) cells in the pathophysiology of atopic dermatitis (AD). Nine adult patients with moderate-to-severe AD in riacutization period of a chronic disease were given tacrolimus ointment, while seven hydrocortisone butyrate ointment, that served as controls. We performed lesional-skin biopsies before and after treatment, that were stained immunohistochemically with monoclonal antibodies to CD4, CD25, forkhead/winged helix transcription factor (FoxP3), interleukin (IL)-10 and transforming growth factor (TGF)-beta. CD4+ cells were significantly reduced in post-treatment series. Tacrolimus treatment achieved a significant reduction of CD25+ cells. FoxP3+ cells were present in untreated AD lesions. Both treatments did not significantly modify the number of FoxP3+ cells. The number of IL-10+ cells increased in post-treatment series. Tacrolimus enhanced the production of TGF-beta, while hydrocortisone did not. Restoration of TGF-beta-producing Treg cells may represent another important pharmacodynamic effect of tacrolimus on AD.

Topics: Adult; Biopsy; Chronic Disease; Dermatitis, Atopic; Female; Forkhead Transcription Factors; Humans; Hydrocortisone; Immunohistochemistry; Interleukin-10; Male; Middle Aged; Ointments; T-Lymphocytes, Regulatory; Tacrolimus; Transforming Growth Factor beta

Tolerability and safety of 0.1% tacrolimus ointment in treating nickel-induced allergic contact dermatitis (ACD) were evaluated.. Patients allergic to nickel applied nickel patches to each upper inner aspect of the arm for 4 to 8 hours daily. Tacrolimus was applied to patch site on one arm and vehicle to patch site on the other, twice daily. Physician's Global Assessment, signs and symptoms of ACD, pruritus scores, and adverse events were evaluated.. After 8 weeks, dermatitis in 45% of patients was clear or almost clear (Physician's Global Assessment) with tacrolimus; and 1% with vehicle (P < .001). Significant results were achieved as early as day 8. Tacrolimus was superior in ACD signs and symptoms improvement and pruritus reduction (P < .001). Adverse events were similar between treatments.. This model, involving one agent, may not be generalizable for other agents.. Tacrolimus ointment 0.1% is well tolerated and significantly more effective than vehicle in treating chronically exposed, nickel-induced ACD.

Topics: Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Dermatitis, Allergic Contact; Double-Blind Method; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Nickel; Ointments; Prospective Studies; Tacrolimus

Humoral alloresponses may contribute to chronic allograft nephropathy (CAN) in a subset of kidney transplant recipients. For chronic humoral rejection, the efficacy of rescue therapy with tacrolimus and mycophenolate mofetil has been suggested.. Eleven recipients with C4d-positive CAN (index biopsy performed after a median of 3 years posttransplantation), who had been on cyclosporine A-based immunosuppression, were converted to tacrolimus, and if not part of basal therapy, to mycophenolate mofetil. We evaluated the effect of this tacrolimus/mycophenolate mofetil rescue therapy on clinical outcomes and on alloantibody formation detected with flow cytometric testing of panel-reactive antibody.. Tacrolimus/mycophenolate mofetil rescue therapy (plus anti-rejection treatment in six recipients with additional signs of acute cellular rejection) failed to prevent progressive deterioration of graft function. Four patients returned to dialysis after 4 to 18 months. Serial post-transplant serology detected HLA class I and/or II reactivity in seven recipients. Tacrolimus/mycophenolate mofetil therapy did not affect the time course of alloantibody levels. One patient with C4d-positive transplant glomerulopathy, who did not respond to tacrolimus/mycophenolate mofetil rescue therapy, developed nephrotic-range proteinuria associated with a rapid decline of allograft function. Despite considerable reduction in alloantibody levels and nearly complete clearance of C4d deposits, immunoadsorption failed to prevent graft failure in this patient.. Our data argue against the efficacy of tacrolimus/mycophenolate mofetil rescue therapy in established C4d-positive chronic allograft dysfunction. Prospective trials are needed to evaluate whether early initiation of this or other antihumoral strategies are capable of effectively preventing alloantibody-mediated chronic graft injury.

Topics: Adult; Aged; CD4 Antigens; Chronic Disease; Drug Combinations; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Recovery of Function; Severity of Illness Index; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Tacrolimus and ciclosporin might have different effects on intra-renal fibrosis and allograft function in chronic allograft nephropathy (CAN). It is difficult to predict the response to calcineurin inhibitor minimization in patients with CAN.. This prospective randomized study compared ciclosporin A (CsA)-to-tacrolimus conversion (group A, target tacrolimus trough level 6-8 ng/ml) vs CsA minimization (group B, target CsA trough level 80-100 ng/ml) with regard to efficacy and safety in patients with CAN and deteriorating allograft function. The primary efficacy endpoint was improvement in the slope of inverse serum creatinine (1/SCr) vs time plot.. There were 34 evaluable patients (n=16 in group A; n=18 in group B), with similar baseline characteristics. Both groups reached target drug levels after a 3-month run-in period. Over the ensuing 12 months, nine (56.3%) subjects in group A and 10 (55.6%) in group B reached the primary end point (P=0.968). Both groups showed considerable improvement in the slope of 1/SCr vs time plot. There was no significant difference in the slope between groups before and after intervention. Graft survival was 87% in group A and 100% in group B (P=0.121). Acute rejection was encountered in two group A subjects. There was no significant change or difference in blood glucose, lipids, and blood pressure between groups.. Our results suggest that in patients with CAN and deteriorating allograft function, CsA-to-tacrolimus conversion or CsA minimization achieved comparable efficacies in retarding the decline of graft function. Such contention may be biased by the low patient number. Further studies with a larger cohort are needed for validation.

Topics: Adolescent; Adult; Aged; Chronic Disease; Creatinine; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus

Chronic vulvar pruritus has been a most distressing physical and sociologic disorder for many patients, as well as for their physicians. Potent topical steroids are the conventional therapy for this distressing condition. Side effects or steroid resistance can be encountered. A second-line therapy is required.. A single-centre, non-controlled, open-label study was designed to assess the efficacy of topical pimecrolimus in the treatment of chronic vulvar pruritus.. Fifteen married adult women with symptoms of vulvar pruritus > or =4 months were included in the study. The patients did not have any relief with topical steroids. There were no objective physical findings. Topical pimecrolimus 1% cream (Elidel cream, Novartis) was applied twice daily to the vulvar region. Patients were followed up 4 weeks later. After the trial was stopped, the patients remained in regular review for 3 months.. Thirteen patients tolerated pimecrolimus. They showed a clinical response within 2-4 weeks. Ten patients showed a complete response, three showed a partial response. After the trial had stopped, the patients with complete response were followed-up by telephone for another 3 months, and were found to be in remission.. We found that topical pimecrolimus provides relief for chronic vulvar pruritus. Pimecrolimus can be chosen as the second-line therapy in patients with vulvar pruritus.

Topics: Administration, Cutaneous; Adult; Chronic Disease; Dermatologic Agents; Female; Humans; Middle Aged; Prospective Studies; Pruritus Vulvae; Tacrolimus; Treatment Outcome

We report the result of a pilot study of low-dose tacrolimus for the treatment of patients with severe chronic idiopathic urticaria (CIU). Nineteen patients with severe CIU were treated with tacrolimus for 12 weeks. Two patients dropped out after 1 week of treatment because of side effects. Following 3 months of treatment, 12 of 17 patients (70.5%) had a clinical response to tacrolimus. In 9 patients, the urticaria had been improved significantly (urticarial score 0-1), enabling them to discontinue antihistamines and, in the case of two patients, corticosteroids. The remaining 3 patients had moderate improvement (urticarial score 2). Three months after the discontinuation of tacrolimus, 3 of 10 responders had a complete resolution of their urticaria (urticarial score 0), 3 had mild deterioration (urticarial score 1-2) controllable by antihistamines alone, and 4 patients had a full relapse (urticarial score 3). Our preliminary results suggest tacrolimus as a treatment option for patients with severe CIU.

Topics: Adult; Chronic Disease; Female; Humans; Immunosuppressive Agents; Male; Prospective Studies; Tacrolimus; Urticaria

Chronic graft-versus-host disease (cGVHD) remains a major cause of morbidity and mortality in haematopoietic transplant recipients. Sirolimus is a macrocyclic triene antibiotic with immunosuppressive, antifungal and antitumour properties, that has activity in the prevention and treatment of acute GVHD. We conducted a phase II trial of sirolimus combined with tacrolimus and methylprednisolone in patients with steroid-resistant cGVHD. Thirty-five patients who developed GVHD after day 100 post-transplant were studied. Six patients had a complete response and 16 a partial response with an overall response rate of 63%. Major adverse events related to the combination of tacrolimus and sirolimus were hyperlipidaemia, renal dysfunction and cytopenias. Four patients had thrombotic microangiopathy (TMA) and 27 (77%) had infectious complications. The median survival for the whole group was 15 months. A significantly better outcome was observed in patients with a platelet count > or = 100 x 10(9)/l, as well as in those with true chronic manifestations of GVHD compared to those with acute GVHD beyond day 100. Controlled trials comparing this approach with alternative strategies to determine which can best achieve the goal of GVHD-free survival are warranted.

Topics: Adult; Aged; Chronic Disease; Drug Therapy, Combination; Female; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hyperlipidemias; Immunosuppressive Agents; Male; Methylprednisolone; Middle Aged; Proportional Hazards Models; Sirolimus; Tacrolimus

A multicenter, randomized, vehicle-controlled, 3-week study was conducted in patients with chronic hand dermatitis (HD) of various etiologies and locations to identify subgroups particularly responsive to twice-daily application of pimecrolimus cream 1% with overnight occlusion. A total of 294 patients were randomized to the study. By the final visit on day 22, there was a trend toward greater clearance in patients who received pimecrolimus than in those treated with vehicle cream. An analysis of treatment success by various stratification factors was performed, and it was found that palmar involvement had notable impact on response (P = .033). Patients in the pimecrolimus group continued to improve throughout the study; however, in the vehicle group, improvement plateaued after 15 days. Pimecrolimus was well tolerated, with a low rate of application-site reactions such as burning. Pimecrolimus cream 1%, when used twice daily with overnight occlusion, may be of benefit in the management of chronic HD.

Topics: Administration, Topical; Adolescent; Adult; Aged; Aged, 80 and over; Chronic Disease; Dermatitis, Atopic; Double-Blind Method; Emollients; Female; Follow-Up Studies; Hand Dermatoses; Humans; Male; Middle Aged; Probability; Reference Values; Risk Assessment; Tacrolimus; Treatment Outcome

Tacrolimus (Tac) has immunosuppressant properties similar to those of cyclosporine A (CsA), but it is more potent. At present, however, its immunosuppressive activity in renal transplant recipients with ongoing chronic rejection has not been clarified.. We studied changes in kidney function, mixed lymphocyte culture, cell-mediated lympholysis, cytotoxic antibodies, lymphocyte population, and cytokine response before and after the conversion from CsA to Tac in 14 pediatric renal transplant recipients with chronic rejection. CsA (5.9+/-0.2 mg/kg/d) was replaced by Tac (0.1+/-0.004 mg/kg/d).. Serum creatinine decreased (2.3+/-0.2-1.9+/-0.2 mg/dL, P <0.005), creatinine clearance increased (36.8+/-2.5-46.1+/-4.4 mL/min/1.73 m, P <0.005), and urinary protein excretion decreased (0.4+/-0.01-0.2+/-0.04 g/24 hr, P <0.03) after 6 months, and these values were maintained after 2 years with Tac treatment. During Tac therapy, anti-donor and anti-control mixed lymphocyte culture decreased 38% and 31% (P <0.05), respectively. Cell-mediated lympholysis did not change. CD3 decreased from 87%+/-2% to 80%+/-2% (P <0.005), and CD8 decreased from 34%+/-3% to 27%+/-2% (P <0.005). The switch to Tac decreased the interferon-gamma production in vitro (P <0.05) and increased tumor necrosis factor-alpha levels (P <0.05). The release of interleukin-10 was strikingly augmented with CsA or Tac therapy (P <0.01), but transforming growth factor-beta secretion was similar.. Our data indicate that conversion from CsA to Tac therapy leads to an improvement in renal function without altering key elements of the immunosuppression in children with ongoing chronic rejection.

Topics: Adolescent; Antibody Formation; Child; Child, Preschool; Chronic Disease; Cyclosporine; Cytokines; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Retreatment; Tacrolimus

This study was conducted to assess the effect of immunosuppression conversion on progression of chronic allograft nephropathy (CAN).. Forty-two cyclosporin-treated renal transplant recipients were studied. Patients were included if they had a negatively sloping reciprocal of creatinine vs time (ROCT) plot for >6 months and biopsy-proven CAN. Patients were excluded if they had previously been treated with tacrolimus/mycophenolate mofetil (MMF) or their serum creatinine was >400 micromol/l. Subjects were randomly treated with either: (A) MMF/reduced dose cyclosporin [MMF for azathioprine 0.5-1.0 g bd; cyclosporin trough level (C(0)): 75-100 ng/ml]; (B) tacrolimus for cyclosporin (C(0): 5-10 ng/ml); or (C) continuation of standard therapy. Glomerular filtration rate (GFR) was measured at baseline and after 6 months.. Two patients started dialysis within 6 months (one each from groups A and B). One patient in group A was intolerant of MMF, six others reported gastrointestinal symptoms and three developed anaemia. Cyclosporin dose was reduced by 24% [interquartile range (IQR): 14-27%] in group A [end-of-study C(0): 99 ng/ml (IQR: 90-113 ng/ml)]. In group B, the end-of-study tacrolimus C(0) was 7 ng/ml (5-9 ng/ml). The end-of-study cyclosporin C(0) in group C was 163 ng/ml (145-215 ng/ml). Comparison of ROCT slopes before and after intervention revealed a treatment advantage for group A (P<0.05). The GFR analysis was supportive (P = 0.05). When patients with GFR <20 ml/min/1.73 m(2) at enrollment were excluded from the analysis, the treatment advantage for group A reached statistical significance (n = 27, P<0.05).. MMF/reduced dose cyclosporin is superior to tacrolimus-for-cyclosporin and standard dose cyclosporin in patients with CAN, at least in the short term. The cyclosporin dose reduction component is likely to be of particular importance. Other findings suggest that early intervention is beneficial.

Topics: Chronic Disease; Cyclosporine; Disease Progression; Drug Therapy, Combination; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Tacrolimus; Transplantation, Homologous

We report long-term outcomes for allogeneic peripheral blood stem cell (PBSC) recipients, evaluating cumulative incidence (CI) of acute and chronic graft-versus-host disease (GVHD), after use of tacrolimus with or without minidose methotrexate for GVHD prophylaxis. From April 1996 to April 1998, 97 adults underwent allogeneic PBSC transplantation. The first 49 received tacrolimus monotherapy as GVHD prophylaxis and the subsequent 48 received combination therapy. The median follow-up for survivors was 67 months. Compared to combination therapy, tacrolimus monotherapy resulted in enhanced neutrophil engraftment, shortened hospitalization, comparable rates of GVHD, and equivalent 100-day survival. The CI of grades II-IV acute GVHD was 35% with tacrolimus and 23% with the combination (P=0.19). The CI of III-IV GVHD was 22% for tacrolimus and 19% for the combination. CI of chronic GVHD was similar between the two groups (P=0.5). Patients with good-risk disease had superior overall survival (OS) when compared to those with poor-risk features (P<0.001). Within the good-risk disease category, patients receiving methotrexate had a trend towards improved OS (P=0.07). Multivariate analysis indicated good-risk disease status and methotrexate were independently associated with improved OS, progression-free survival (PFS), and relapse. In addition, patients developing chronic GVHD had a significantly reduced risk of relapse and improved PFS.

Topics: Acute Disease; Adult; Chronic Disease; Cohort Studies; Drug Therapy, Combination; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Hospitalization; Humans; Immunosuppressive Agents; Incidence; Male; Methotrexate; Middle Aged; Multivariate Analysis; Risk Factors; Secondary Prevention; Survival Rate; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Atopic dermatitis (AD) is a common, chronic, relapsing, severely pruritic, eczematous skin disease. Topical steroids are the mainstay of treatment. However, the adverse effects of steroids on hormonal function are the major obstacle for their use as long-term topical therapy. Intermittent dosing with potent topical steroids and/or combination therapy with steroid and tacrolimus have been frequently used in the daily management of AD to overcome the problems accompanying the long term use of steroids. We compared the clinical effects of topical steroid/tacrolimus and steroid/emollient combination treatments in 17 patients with AD. An intermittent topical betamethasone butyrate propionate/tacrolimus sequential therapy improved lichenification and chronic papules of patients with AD more efficiently than an intermittent topical betamethasone butyrate propionate/emollient sequential therapy after four weeks of treatment. Only one out of 17 patients complained of a mild, but temporary, burning sensation after tacrolimus application. The intermittent topical steroid/tacrolimus sequential therapy may be a useful adjunctive treatment for AD.

Topics: Acute Disease; Administration, Topical; Adolescent; Adult; Betamethasone; Chi-Square Distribution; Chronic Disease; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Emollients; Female; Follow-Up Studies; Humans; Male; Middle Aged; Probability; Risk Assessment; Tacrolimus; Treatment Outcome

Graft-versus-host disease (GVHD) may be resistant to accepted treatments. Therefore, the aim of the present preliminary study was to evaluate the efficacy of topical treatment with tacrolimus, an immunosuppressive agent, for cutaneous GVHD. Ten patients with chronic steroid-dependent cutaneous GVHD were treated with 0.03-0.1% tacrolimus ointment, twice to three times a day. The dermal manifestations of GVHD were monitored, and a score was given to the cutaneous response by both the physician and patient. Seven patients demonstrated a response to the tacrolimus ointment. Three out of the ten patients were scored as showing a "good" or "complete" response in the objective examiner's view or subjective patient's view. Another four patients showed "moderate" or "mild" response; only three patients showed "no response". Topical tacrolimus is suggested as an alternative treatment for cutaneous chronic steroid-dependent GVHD. This conclusion concurs with a previous study on this medication.

Topics: Administration, Topical; Adult; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Pilot Projects; Retreatment; Skin Diseases; Steroids; Tacrolimus; Treatment Failure; Treatment Outcome

Corticosteroid therapy contributes significant toxicity to liver transplantation. The safety and efficacy of early steroid withdrawal were determined in patients treated with either tacrolimus or microemulsion cyclosporin A (micro-CsA). The primary outcome was the proportion of patients who were steroid-free 1 year posttransplantation. From the seven Canadian adult liver transplant centers, 143 patients were randomly allocated oral treatment with either tacrolimus (n = 71) or micro-CsA (n = 72), together with corticosteroids and azathioprine. Eligibility criteria for steroid withdrawal included freedom from acute rejection for a minimum of 3 months, and prednisone

Topics: Acute Disease; Adolescent; Adrenal Cortex Hormones; Adult; Aged; Aged, 80 and over; Canada; Child; Chronic Disease; Cyclosporine; Emulsions; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus

Pimecrolimus cream 1% (Elidel, SDZ ASM 981) is a novel, non-steroid inflammatory cytokine inhibitor, effective in the treatment of atopic dermatitis. Here, we evaluate the treatment of chronic hand dermatitis with pimecrolimus cream 1%.. To determine pimecrolimus blood concentrations, and evaluate the safety, tolerability and efficacy following application of pimecrolimus cream 1% to subjects with chronic hand dermatitis.. In this open-label, multiple-topical-dose, non-controlled, pharmacokinetic study, pimecrolimus cream 1% was applied twice daily to dorsal and palmar areas (affected and unaffected) of both hands. Evening applications (except day 8) were immediately followed by overnight occlusion (> or =6 h). Full pharmacokinetic profile (days 1, 8 and 22), trough concentrations (days 3 and 15), physical examinations, laboratory measurements and adverse events were recorded. Efficacy was assessed via Investigators' Global Assessment (IGA), total key signs and symptoms and the subject's overall self-assessment.. Twelve patients completed the study. The majority of pimecrolimus blood concentrations (73.6%) remained below the limit of quantitation (0.1 ng/ml). The maximum concentration observed was 0.91 ng/ml and the maximum area under the concentration-time curve from 0-12 h post dose was 7.6 ng.h/ml. Treatment was well tolerated locally and systemically. No serious adverse events occurred; 4/13 subjects showed a total of 6 adverse events at the application site: burning (n=4), and pruritus (n=2). No clinically relevant or drug-related changes were observed. Clear efficacy of the treatment was shown by all 3 assessment methods. Disease state at day 22 had improved in 11 (85%) subjects compared with baseline (IGA).. Twice daily topical treatment of moderate to severe chronic hand dermatitis with pimecrolimus cream 1% results in low pimecrolimus blood levels, is well tolerated, safe, and effective.

Topics: Administration, Topical; Adult; Biological Availability; Chronic Disease; Dermatitis, Atopic; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Follow-Up Studies; Hand Dermatoses; Humans; Immunosuppressive Agents; Male; Maximum Tolerated Dose; Middle Aged; Ointments; Tacrolimus; Treatment Outcome

Previous studies have demonstrated that shifting immunosuppressive therapy from cyclosporine (CyA) to tacrolimus (FK) may arrest the decline in forced expiratory volume in 1 second (FEV(1)) during chronic rejection after lung transplantation. Exhaled nitric oxide (eNO) has been shown to be elevated during chronic rejection. We report the concomitant stabilization of FEV(1) and decrease in eNO after changing from CyA to FK therapy in patients with chronic rejection after lung transplantation.. We used a prospective design. The study included 10 lung transplant patients (5 men and 5 women), mean age 44 +/- 14 years at time of transplantation, with a progressive decline in FEV(1) that was attributed to chronic rejection. Four patients underwent heart-lung transplantation and 3 had a sequential single and 3 a single-lung transplantation. The switch from CyA to FK occurred at 36 +/- 23 months after transplantation (Time 0). The eNO was measured using a chemiluminescence analyzer, according to standardized European Respiratory Society (ERS) criteria.. At Time 0, there were 6 patients in bronchiolitis obliterans syndrome (BOS) Stage 0-p, with a mean decline in FEV(1) of 15 +/- 3%; 2 in BOS Stage 1; and 2 in BOS Stage 2. Compared with the best post-operative FEV(1), there was a progressive and significant decline until Time 0, from 2.56 +/- 0.9 liters to 2.03 +/- 0.94 liters (p = 0.0047). Thereafter, FEV(1) stabilized: 2.03 +/- 0.94 liters at Time 0 and 2.05 +/- 0.94 liters 6 months later (p = non-significant). Concomitantly, there was a gradual increase in eNO during the 6 months before Time 0, from 11.4 +/- 2.5 ppb at the time of best FEV(1) to 20.5 +/- 14.8 ppb at Time 0. After switching, there was a non-significant decline in eNO, from 20.5 +/- 14.8 ppb to 14.9 +/- 5.4 ppb. There was no significant difference in eNO levels between the patients in BOS Stage 0-p and patients in higher BOS stages at either timepoint in the study.. This study illustrates that a switch from CyA to FK can stabilize pulmonary function in lung transplant patients with chronic rejection. This stabilization of FEV(1) is accompanied by a decrease in eNO, indicating that this treatment shift can reduce inflammation of airways during the course of chronic rejection. Consequently, measuring eNO may be extremely valuable in guiding the treatment of chronic rejection after lung transplantation.

Topics: Adult; Breath Tests; Bronchiolitis Obliterans; Chronic Disease; Cyclosporine; Female; Forced Expiratory Volume; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Nitric Oxide; Prospective Studies; Tacrolimus

This study was designed to assess the efficacy and safety of two immunosuppressant regimens in kidney transplantation based on the administration of tacrolimus-one of them with tacrolimus, azathioprine, and corticosteroids (n=239) and the other with tacrolimus, and corticosteroids (n=236). After completing the initial 3-month study, the patients remaining in the study (197 and 195, respectively) were assessed for 3 years. The incidence of acute rejection (AR) episodes treated during this period was 28.8% with dual-drug therapy and 29.7% with triple-drug therapy. Late AR: episodes between 4 and 36 months were scarce (3.3% in dual and 4.2% in triple therapy). Chronic rejection incidence was 7.7% and 8.9%, respectively. The patients who experienced AR episodes during the first 3 months developed chronic rejection more frequently than those who did not suffer AR. Patient survival at 3 years was 95% vs 95.6%, and graft survival was 86.6% vs 86.5% (NS). Doses and blood levels of tacrolimus were similar in the two groups. Adverse effects were similar among both treatment groups. Median SCr was 123.8 micromol/L vs 114.9 micromol/L in patients who did experience AR: 145.9 micromol/L vs 132.6 micromol/L in those with early AR; and 194.5 micromol/L vs 152 micromol/L in those who presented with late AR. Need for de novo posttransplant insulin was 4.2% in the dual-drug group and 3.8% in the triple-drug cohort. These results demonstrate that, after 3 years of follow up, there were similar efficacy data among the dual- and triple-drug regimens. Thus, addition of azathioprine does not contribute any advantage in the middle term.

Topics: Acute Disease; Adrenal Cortex Hormones; Azathioprine; Chronic Disease; Creatinine; Drug Therapy, Combination; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Italy; Kidney Transplantation; Recurrence; Spain; Survival Analysis; Tacrolimus; Time Factors

In pediatric kidney transplant recipients, tacrolimus has been proposed either for primary immunosuppression or as a rescue agent for refractory acute rejection, chronic rejection, and cyclosporine toxicity. This paper describes our experience with tacrolimus conversion from cyclosporine-based therapy in six selected cases: four due to refractory acute rejections unresponsive to conventional therapy, one to chronic graft rejection, and one to cyclosporine-related hypertrichosis. A "simple-switch" conversion was used without any overlap, starting with a dose of 0.2 mg/kg per day. The time to conversion varied from 10 to 730 days after the transplant. In the patients with acute rejection, the median time to reversal after tacrolimus conversion was 12 days. The symptoms of the patient with cyclosporine toxicity completely resolved without any loss of allograft function. The patient with chronic rejection maintained stable renal function for more than 1 year after conversion. A new onset of post-transplant diabetes mellitus and dose-related nephrotoxicity were recorded as adverse events. In conclusion, our experience suggests that tacrolimus can play an important role in the salvage treatment of pediatric kidney transplantations with deteriorating graft function due to acute rejection refractory to standard therapy. Tacrolimus conversion also provides excellent results in the presence of cyclosporine toxicity.

Topics: Adolescent; Child; Chronic Disease; Cyclosporine; Diabetes Complications; Drug Resistance; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Tacrolimus

Chronic erosive oral lichen planus (EOLP) is a severe form of lichen of the buccal mucosa that is often resistant to systemic or topical therapies.. To evaluate the efficacy and safety of topical tacrolimus, 0.1 mg per 100 mL of water, in treating EOLP.. Open-label, prospective, noncomparative study, with 6 months of treatment and 6 months of follow-up.. Dermatology department at a university hospital in Nice, France.. Ten patients with histologically proved EOLP that was refractory to treatment. Two patients were withdrawn because of noncompliance; findings in 8 were available for evaluation.. Mouthwashes with tacrolimus, 0.1 mg per 100 mL of distilled water, 4 times daily for 6 months.. Efficacy was assessed using a calculated score that combined the intensity of spontaneous and meal-triggered pain and the surface area of erosions. Safety assessment included the monitoring of adverse effects, clinical laboratory values, and blood concentrations of tacrolimus.. Among the 8 patients evaluated, 1 had no improvement and 7 were improved. The mean score decreased from 7.00 at baseline to 5.43 (a 22.43% decrease) at 1 month, 4.14 (a 40.86% decrease) at 2 months, 3.00 (a 57.14% decrease) at 3 months, 2.43 (a 65.29% decrease) at 4 months, 2.57 (a 63.29% decrease) at 5 months, and 3.43 (a 51.00% decrease) at 6 months. A decrease of symptoms was reported by the 7 responding patients as soon as the first month of treatment. No severe adverse effects were observed. All patients had whole-blood concentrations of tacrolimus below the detection limit of the assay (1.5 ng/mL) at all intervals. At 9 months, 6 patients had had a relapse within a mean of 38.6 days. At 12 months, all patients had had a relapse and required treatment with topical corticosteroids or systemic hydroxychloroquine sulfate.. Results of our study suggest a rapid and important palliating effect of low concentration of topical tacrolimus in distilled water in patients with EOLP.

Topics: Administration, Topical; Adult; Aged; Chronic Disease; Drug Administration Schedule; Female; Follow-Up Studies; Humans; Lichen Planus, Oral; Male; Middle Aged; Prospective Studies; Severity of Illness Index; Tacrolimus; Treatment Outcome

Chronic actinic dermatitis (CAD) is difficult to treat. Topical corticosteroids induce adverse effects after long-term use, especially on light-exposed skin.. Our purpose was to study the effects of tacrolimus ointment in the treatment of elderly patients with CAD.. In an open trial, 6 male patients between 51 and 80 years old with CAD applied 0.1% tacrolimus ointment twice a day to the face and neck. According to improvements, the frequency of application was reduced. Sunscreen agents were also applied outdoors.. Tacrolimus ointment effectively treated cutaneous changes in all patients. Symptoms were moderately improved in 2 weeks, and greatly in 4 weeks. A brief and localized irritating sensation occurred in all patients, but no other adverse events developed throughout the study course from 0.5 to 2.5 years.. Topical tacrolimus ointment for facial lesions of CAD appears to be effective and well tolerated and may provide long-term benefits.

Topics: Administration, Topical; Aged; Aged, 80 and over; Chronic Disease; Facial Dermatoses; Female; Follow-Up Studies; Humans; Japan; Male; Middle Aged; Ointments; Photosensitivity Disorders; Tacrolimus; Treatment Outcome

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

Chronic renal failure is a major cause of morbidity and mortality after orthotopic liver transplantation. We did a randomised controlled trial of mycophenolate mofetil monotherapy in liver transplant patients who developed renal failure associated with calcineurin-inhibitor (ciclosporin or tacrolimus) immunosuppressive therapy. Although renal failure improved when the calcineurin-inhibitor dose was reduced and ultimately stopped, the trial was stopped when three of five patients on monotherapy developed organ rejection requiring a second transplantation.

Topics: Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Liver Transplantation; Mycophenolic Acid; Renal Insufficiency; Tacrolimus

Tacrolimus (formerly FK 506) is an immunosuppressive drug that works by inhibiting calcineurin, a calcium-dependent protein phosphatase required for immune function. Tacrolimus has been shown to be effective topically in atopic dermatitis and systemically in psoriasis and graft-vs-host disease (GVHD). However, its efficacy in treating cutaneous GVHD when applied topically has not been reported.. To assess the therapeutic efficacy of 0.1% tacrolimus ointment on chronic cutaneous GVHD in patients with symptoms refractory to systemic corticosteroid therapy.. Tacrolimus ointment effectively treated pruritus and/or erythema in 13 (72%) of 18 patients with chronic GVHD. Responding patients had a rapid effect within several hours to days. Effectiveness was measured by means of patient report, results of physical examination, side-by-side comparisons of tacrolimus vs a vehicle control, and temporal flares of the cutaneous symptoms of the disease in the context of stopping tacrolimus ointment therapy. Because of the progression of GVHD and in 2 cases, loss of drug efficacy, all patients eventually went on to receive more aggressive treatment, including increases in steroid dosage, psoralen-UV-A therapy, and extracorporeal photopheresis.. This case series suggests that tacrolimus ointment has efficacy in treating the erythema and pruritus of steroid-refractory, chronic cutaneous GVHD in most patients. The rapid response of tacrolimus ointment may provide a useful therapeutic bridge to systemic therapies that have slower onset, such as psoralen-UV-A therapy or extracorporeal photopheresis.

Topics: Adult; Bone Marrow Transplantation; Chronic Disease; Erythema; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Pruritus; Skin Diseases; Tacrolimus; Treatment Outcome

Chronic graft-versus-host disease (GVHD) is the principal cause of transplantation-related morbidity and nonrelapse mortality late after allogeneic hematopoietic stem cell transplantation. The safety and potential efficacy of tacrolimus for the salvage treatment of chronic GVHD was evaluated in a single-arm, open-label phase 2 study. A total of 39 evaluable patients with chronic GVHD who failed previous immunosuppressive therapy with cyclosporine and prednisone were treated with tacrolimus starting at a median of 20 months (range, 3-68 months) after transplantation. At 3 years after the start of treatment, 5 patients (13%) had discontinued tacrolimus and were in complete remission, and 3 were considered clinically stable but not able to discontinue tacrolimus. A total of 31 patients (79%) experienced treatment failure; 22 (56%) who failed therapy had a change in immunosuppressive regimen because of progression (n = 18) or toxicity (n = 4). Nine patients (23%) died during continued treatment with tacrolimus. Two patients were lost to follow-up, at 11 and 19 months. The median duration of treatment with tacrolimus was 9 months (range, 1-29 months). Infections (144 episodes) were the most frequent adverse event. Nephrotoxicity occurred in 16 patients (41%); tacrolimus was discontinued in only 2 patients because of progressive deterioration in renal function. The Kaplan-Meier estimate of survival was 64% (95% confidence interval, 49%-79%) at 3 years posttransplantation. Seven patients had discontinued all immunosuppression at last contact, leading to an estimated 29% probability of stopping all immunosuppression by 3 years posttransplantation. Four patients died after relapse of malignancy. The response rate is consistent with previous reports of salvage treatment for chronic GVHD, indicating that a small group of patients failing cyclosporine may respond or stabilize with tacrolimus.

Topics: Adolescent; Adult; Child; Child, Preschool; Chronic Disease; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Salvage Therapy; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Cyclosporine for the treatment of psoriasis constitutes a new approach. Alternative systemic cyclosporine derivatives have been studied to find an immunosuppressive drug with fewer adverse effects. Tacrolimus is one of these new immunosuppressive drugs. Systematically, it has been proven effective in treating psoriasis. A topical formulation of tacrolimus is attractive because it has fewer adverse effects and is useful for a large group of patients. We report for the first time on the efficacy of nonocclusive topical tacrolimus in the treatment of psoriasis.. After a washout phase of 2 weeks, patients were randomized to receive 0.005% calcipotriol ointment twice daily, placebo ointment once daily, or 0.3% tacrolimus ointment once daily. One psoriatic plaque was treated with a surface area of 40 to 200 cm2. Efficacy was estimated using the local psoriasis severity index. The reduction in the local psoriasis severity index score after 6 weeks was 62.5% in the calcipotriol group, 33.3% in the tacrolimus group, and 42.9% in the placebo group.. There was no statistically significant difference between the efficacy of tacrolimus and placebo ointment (P = .77). Calcipotriol ointment, applied twice daily, had a better effect than tacrolimus ointment and placebo ointment once daily.

Topics: Administration, Cutaneous; Chronic Disease; Humans; Immunosuppressive Agents; Pilot Projects; Psoriasis; Tacrolimus

Mycophenolate mofetil (MMF) has been used successfully as an immunosuppressive agent after kidney and heart transplantation, but experience with MMF after liver transplantation is still limited. Between August 1995 and January 1996, we treated 20 patients with MMF after orthotopic liver transplantation in an open, prospective study. Five out of eight patients with acute rejection and one patient with early chronic rejection showed a complete response after MMF was added to the immunosuppression. Three patients with chronic rejection did not improve, one died, and two have stable graft function at present. In eight patients who suffered from toxicity, a reduction in the dosage of tacrolimus was attempted with simultaneous MMF therapy. One patient died due to multiple organ failure. Liver function improved completely in one other patient, and partially in three patients after adding MMF. In the remaining three patients, a reduced dosage of tacrolimus or cyclosporin, together with MMF, reduced toxicity, not significantly. In conclusion, MMF appears to be a safe and potentially useful adjuvant immunosuppressive agent for rescue and maintenance therapy.

Topics: Acute Disease; Adult; Chronic Disease; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Mycophenolic Acid; Prodrugs; Tacrolimus

Topics: Actuarial Analysis; Acute Disease; Adolescent; Adult; Aged; Chronic Disease; Cyclosporine; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Survival Rate; Tacrolimus; Time Factors; Treatment Failure

Topics: Acute Disease; Chronic Disease; Cyclosporine; Drug Resistance; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Liver Transplantation; Muromonab-CD3; Steroids; Tacrolimus

A phase II study of the efficacy and safety of FK506, a new potent immunosuppressant, has been conducted in 49 patients with GVHD after allogeneic BMT. Eighteen patients with acute GVHD and 31 with chronic GVHD entered the study. FK506 was administered at an initial dose of 0.05 mg/kg i.v. or 0.15 mg/kg orally twice a day to those whose GVHD had become uncontrollable with cyclosporin and/or other immunosuppressants. The response to FK506 was evaluated in 13 patients with acute and 26 with chronic GVHD. A marked response was observed in 5 and a good response in 2 of 13 patients with acute GVHD. For those with chronic GVHD, the response was marked in 2 patients, good in 10 and poor in 8. The most common adverse effects were renal toxicity (53.1%), followed by nausea and vomiting (30.6%) and a feeding of warmth (18.4%). There was a correlation between renal toxicity and whole blood levels of FK506. The dose should be adjusted to keep a trough level between 15 and 25 ng/ml. FK506 is promising in the treatment of both acute and chronic GVHD, even if it is intractable with other immunosuppressants, and may be most effective if administered early in the course of GVHD.

Topics: Acute Disease; Adolescent; Adult; Azathioprine; Bone Marrow Transplantation; Child; Chronic Disease; Cyclosporine; Female; Flushing; Graft vs Host Disease; Humans; Immunosuppressive Agents; Kidney Diseases; Male; Methotrexate; Middle Aged; Nausea; Prednisolone; Tacrolimus; Treatment Outcome

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

Topics: Acute Disease; Adolescent; Adult; Aged; Chronic Disease; Europe; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Incidence; Liver Transplantation; Middle Aged; Survival Rate; Tacrolimus

Topics: Acute Disease; Azathioprine; Chronic Disease; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Male; Tacrolimus; Time Factors; Treatment Outcome

This report describes the clinical characteristics and demographics of patients enrolled into this rescue trial for patients experiencing refractory rejection after liver transplantation. Actuarial graft and patient survival at 12 months postconversion was 50% and 72%, respectively. Actual treatment success at 3 months postconversion was 70%. Karnofsky scores and liver function tests were significantly improved for patients continuing on therapy indicating clinical benefit in these patients. The safety profile of FK 506 is acceptable for such a high-risk group of patients. These preliminary clinical results support the conclusion that FK 506 can effectively control and reverse refractory rejection in a majority of liver transplantation patients.

Topics: Acute Disease; Acute Kidney Injury; Adrenal Cortex Hormones; Bilirubin; Chronic Disease; Communicable Diseases; Cyclosporine; Female; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Liver Function Tests; Liver Transplantation; Male; Muromonab-CD3; Renal Dialysis; Survival Analysis; Tacrolimus; Time Factors

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

Use of tacrolimus in mild to moderate myasthenia gravis (MG) is generally limited to glucocorticoid-refractory cases; the advantage of mono-tacrolimus over mono-glucocorticoids is unknown.. We included mild to moderate MG patients treated with mono-tacrolimus (mono-TAC) or mono-glucocorticoids (mono-GC). The correlation between the immunotherapy options and the treatment efficacy and side effects were examined in 1:1 propensity-score matching. The main outcome was time to minimal manifestations status or better (MMS or better). Secondary outcomes include time to relapse, the mean changes in Myasthenia Gravis-specific Activities of Daily Living (MG-ADL) scores and the rate of adverse events.. Baseline characteristics showed no difference between matched groups (49 matched pairs). There were no differences in median time to MMS or better between the mono-TAC group and mono-GC group (5.1 vs. 2.8 months: unadjusted hazard ratio [HR], 0.73; 95% CI, 0.46-1.16; p = 0.180), as well as in median time to relapse (data unavailable for the mono-TAC group since 44 of 49 [89.8%] participants remained in MMS or better; 39.7 months in mono-GC group: unadjusted HR, 0.67; 95% CI, 0.23-1.97; p = 0.464). Changes in MG-ADL scores between the two groups were similar (mean differences, 0.3; 95% CI, -0.4 to 1.0; p = 0.462). The rate of adverse events was lower in the mono-TAC group compared to the mono-GC group (24.5% vs. 55.1%, p = 0.002).. Mono-tacrolimus performs superior tolerability with non-inferior efficacy compared to mono-glucocorticoids in mild to moderate myasthenia gravis patients who refuse or have a contraindication to glucocorticoids.

Topics: Activities of Daily Living; Chronic Disease; Glucocorticoids; Humans; Myasthenia Gravis; Neoplasm Recurrence, Local; Tacrolimus

Other than single-center case studies, little is known about generalized pustular psoriasis (GPP) flares.. To assess GPP flares and their treatment, as well as differences between patients with and patients without flares documented in US electronic health records (EHRs).. This retrospective cohort study included adult patients with GPP (International Statistical Classification of Diseases and Related Health Problems, Tenth Revision code L40.1) identified in Optum deidentified EHR data between July 1, 2015, and June 30, 2020. The index GPP diagnosis was the first occurrence in the EHR, with no coded history of GPP for at least 6 months prior. Flare episodes were identified using an algorithm based on diagnosis coding, care setting, type of clinician, GPP disease terms, and flare terms and attributes in the EHR.. Flare episodes were characterized by the frequency of occurrence per patient, the care setting in which they were identified, the type of specialist managing the episode, associated symptoms, and the type of treatment before, during, and after the episode. Patients were divided into groups based on whether or not they had a flare episode documented in their EHR. Comparisons were made between the groups based on demographic characteristics, comorbidity burden, health care use, and treatments.. Of 1535 patients with GPP (1018 women [66.3%]; mean [SD] age, 53.4 [14.7] years), 271 had 513 flares documented. Compared with patients without flares, patients with flares had a 34% higher mean (SD) Charlson Comorbidity Index score (2.80 [3.11] vs 2.09 [2.52]), were almost 3 times more likely to have inpatient visits (119 of 271 [44%] vs 194 of 1264 [15%]), were more than twice as likely to have emergency department (ED) visits (126 of 271 [47%] vs 299 of 1264 [24%]), and had higher use of almost all treatment classes. Flares were identified in outpatient (271 of 513 [53%]), inpatient (186 of 513 [36%]), and ED (48 of 513 [9%]) settings. The most common treatments during flares were topical corticosteroids (35% of episodes [178 of 513]), opioids (21% [106 of 513]), other oral treatments, (eg, methotrexate, cyclosporine, tacrolimus; 13% [67 of 513]), and oral corticosteroids (11% [54 of 513]). Almost one-fourth of flare episodes (24% [122 of 513]) had no dermatologic treatment 30 days before, during, or 30 days after a flare episode.. This cohort study suggests that there is significant unmet need for the treatment of GPP and its flares, as evidenced by patients seeking treatment in inpatient and ED settings, as well as the lack of advanced treatments.

Topics: Acute Disease; Adult; Chronic Disease; Cohort Studies; Cyclosporine; Electronic Health Records; Female; Humans; Methotrexate; Middle Aged; Psoriasis; Retrospective Studies; Skin Diseases, Vesiculobullous; Tacrolimus

Belatacept improves long-term graft survival, but control of some primary viral infections may be impaired. We evaluated the impact of belatacept and tacrolimus on cytomegalovirus (CMV) viral control, remission and relapse in CMV high-risk and moderate-risk recipients.. Using a multistate Markov model, we evaluated viral load state transitions of 173 kidney transplant recipients with at least one episode of viremia within 1 year after transplant: state 1, undetectable/low viral load; state 2, moderate viremia; and state 3, severe viremia.. Among high-risk recipients, belatacept-treated recipients exhibited a significantly higher probability of entering moderate viremia (.36; 95% CI = .31, .41) than tacrolimus-treated recipients (.20; 95% CI = .13, .29). The expected number of days in viremic states differed. High-risk belatacept-treated recipients persisted in moderate viremia for significantly longer (128 days, 95% CI = 110, 146) than did tacrolimus-treated recipients (70.0 days, 95% CI = 45.2, 100) and showed a trend of shorter duration in low/undetectable viral load state (172 days, 95% CI = 148, 195) than did tacrolimus-treated recipients (239 days, 95% CI = 195, 277). Moderate-risk recipients showed better viral load control and with no differences by immunosuppression.. High-risk belatacept-treated recipients showed defects in sustaining viral control relative to tacrolimus-treated recipients. Avoidance of initial use belatacept in high-risk recipients or development of modified management protocols should be considered.

Topics: Abatacept; Antiviral Agents; Chronic Disease; Cytomegalovirus; Cytomegalovirus Infections; Humans; Kidney Transplantation; Recurrence; Tacrolimus; Transplant Recipients; Viral Load; Viremia

Allergic conjunctivitis (AC) is the most common ocular condition in allergic children. In tropical countries, the study about the clinical features and outcome of treatment is very limited.. To review clinical characteristics and outcomes of treatment in children with ocular allergy.. Children with history of AC were classified to seasonal allergic conjunctivitis (SAC), perennial allergic conjunctivitis (PAC), vernal keratoconjunctivitis (VKC) and atopic keratoconjunctivitis (AKC). The clinical history and outcome of treatment were recorded.. One hundred and sixty-four children were recruited. PAC was the most common type (61.6%), followed by SAC (21.3%), VKC (12.2%), and AKC (4.9%). Male preponderance was found in all groups. Mean age of onset was 6.8 ± 2.8 years. Allergic rhinitis was the most common co-morbidity (97.6%). The common sensitized allergen is house-dust mites (86.1%). Standard treatments in all groups were natural tear and topical olopatadine. Add-on medications were usually needed in severe types of AC (VKC, AKC). History of topical corticosteroid use was 68.8% and 12.5% in VKC and AKC, respectively. All of them can discontinue topical corticosteroid when topical tacrolimus was applied. The overall remission was found 35% in VKC group and 63% in AKC group. The median duration of treatment was 20.5 months in VKC group and 11 months in AKC group.. most Thai children with AC sensitized to house-dust mites. In severe forms of AC, most patients needed addon medication. The use of topical calcineurin inhibitor as an add-on therapy can decrease the use of topical corticosteroid.

Topics: Allergens; Child; Child, Preschool; Chronic Disease; Conjunctivitis, Allergic; Dust; Humans; Male; Southeast Asian People; Tacrolimus

Tacrolimus is a common immunosuppressant used in solid organ transplant recipients. Although most patients develop diarrheal symptoms, data regarding patterns of injury in patients taking tacrolimus are limited. We performed this study to characterize tacrolimus-related features of colonic injury. We retrospectively identified colonic samples from 20 patients receiving tacrolimus monotherapy. Records were reviewed for symptoms, endoscopic findings, other medications, and infections. None of the patients had gastrointestinal infections or used other drugs known to cause colonic injury; none had received mycophenolate within 6 months of presentation. Cases were evaluated for the nature and distribution of inflammation and crypt abnormalities, including distortion, destruction, and apoptosis. Eighteen (90%) patients were solid organ transplant recipients. Seventeen (85%) had gastrointestinal symptoms, particularly diarrhea (75%). More than 50% had endoscopic colitis and 15% had ulcers and/or erosions. Most (90%) cases showed regenerative epithelial changes; apoptotic crypt cells were present in 55% and numerous in 10% of cases. Neutrophilic cryptitis was present in 60% of cases; 35% showed crypt destruction. Plasma cell-rich lamina propria inflammation and crypt distortion were observed in 40% and 25% of cases, respectively. There was no correlation between therapy duration and features of chronic injury. We conclude that tacrolimus can cause symptomatic colitis. Histologic abnormalities are often mild, featuring regenerative crypts and scattered apoptotic debris. However, 40% of symptomatic patients have chronic colitis, most likely reflecting drug-induced immune dysregulation. Pathologists should be aware of these associations because colitis often resolves with decreasing drug dosage rather than treatment directed toward inflammatory bowel disease.

Topics: Adolescent; Adult; Aged; Biopsy; Calcineurin Inhibitors; Child; Child, Preschool; Chronic Disease; Colitis; Colon; Colonoscopy; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Prognosis; Retrospective Studies; Tacrolimus; Young Adult

To unearth the clinical efficacy of tacrolimus ointment + 3% boric acid lotion joint Chinese angelica decoction in chronic perianal eczema.. Patients with chronic perianal eczema admitted to hospital from June 2018 and June 2019 were retrospectively analyzed. Patients in the control group (. No significant differences were found in the baseline information between the observation group and control group before therapy. After therapy, pruritus ani score (. With respect to tacrolimus ointment + 3% boric acid lotion, patients with chronic perianal eczema displayed better clinical efficacy after jointly being treated by Chinese angelica decoction.

Topics: Adult; Angelica; Animals; Anus Diseases; Boric Acids; Case-Control Studies; Chronic Disease; Computational Biology; Drug Therapy, Combination; Drugs, Chinese Herbal; Eczema; Female; Humans; Immunosuppressive Agents; Male; Middle Aged; Ointments; Phytotherapy; Pruritus Ani; Retrospective Studies; Skin Cream; Tacrolimus; Treatment Outcome

The aim of this study was to evaluate patients with complete response of oral chronic graft-versus-host disease to immunosuppressive treatment.. A total of 29 patients submitted to allogeneic hematopoietic stem cell transplantation, with oral chronic graft-versus-host disease, were enrolled in this retrospective study, from September 2012 to February 2018. Patients were treated with combined topical dexamethasone solution and topical tacrolimus ointment, combined topical dexamethasone and topical tacrolimus, systemic immunosuppressive medication, and topical dexamethasone only.. The mean time of complete response of lichenoid lesions, erythema, and ulcers using dexamethasone and systemic immunosuppressive medication was of 105, 42 and 42 days, respectively (p=0.013).When we associated dexamethasone, tacrolimus and systemic immunosuppressive medication, the mean time of complete response of lichenoid lesions, erythema and ulcers was of 91,84 and 77 days (p=0.011). When dexamethasone was used alone, the mean time of complete response of lichenoid lesions, erythema and ulcers was 182, 140, 21 days, respectively (p=0.042).. Our study shows that lichenoid lesions require more time to heal. Notably, lichenoid lesions tend to respond better to dexamethasone combined with tacrolimus and systemic immunosuppressive medication, whereas erythema and ulcers respond better to dexamethasone combined with systemic immunosuppressive medication and dexamethasone only, respectively.

Topics: Chronic Disease; Graft vs Host Disease; Humans; Immunosuppressive Agents; Mouth Diseases; Retrospective Studies; Tacrolimus

Here, we present our initial experience with a prospective protocol of belatacept conversion in patients with chronic active antibody-mediated rejection (caAMR) and a high degree of chronicity at the time of diagnosis.. We converted 19 patients (mean age, 45 ± 12 y) with biopsy-proven caAMR from tacrolimus to belatacept at a median of 44 months post-kidney transplant.. At a median of 29 months (interquartile range, 16-46 mo) postconversion, death-censored graft and patient survivals were 89% and 95%, respectively. When compared to a 1:2 propensity-matched control cohort from the INSERM U970 registry maintained on calcineurin inhibitor, the belatacept group had progressive improvement (P = 0.02) in estimated glomerular filtration rate from a mean of 33.9 ± 10 at baseline to 37.8 ± 13 at 6 months and 38.5 ± 12 mL/min/1.73 m2 at 12 months postconversion, as compared to a steady decline noted in the controls (36.2 [baseline] → 33.1 [6 mo] → 32.7 mL/min/1.73 m2 [12 mo] of follow-up). A paired histologic comparison of preconversion and postconversion (performed at median 9.5 mo postconversion) biopsies showed no worsening in microvascular inflammation or chronicity. The paired tissue gene expression analysis showed improved mean total rejection score (0.68 ± 0.26-0.56 ± 0.33; P = 0.02) and a trend toward improved antibody-mediated rejection score (0.64 ± 0.34-0.56 ± 0.39; P = 0.06).. Here, we report that in patients diagnosed with caAMR who were not subjected to intensive salvage immunosuppressive therapies, isolated belatacept conversion alone was associated with stabilization in renal function. These results are bolstered by molecular evidence of improved inflammation.

Topics: Abatacept; Biopsy; Chronic Disease; Drug Substitution; Female; Gene Expression; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Tacrolimus

Autoimmune hepatitis (AIH) is a chronic liver disease able to progress to acute liver failure, cirrhosis, and liver cancer. A significant proportion of patients fail to first-line therapy or develop severe toxicity.. To assess safety and effectiveness of tacrolimus as a second-line therapy in AIH patients.. Multicentric retrospective study of AIH patients treated with tacrolimus for at least 3 months as a second-line therapy. Effectiveness was defined as complete normalization of transaminases and IgG.. A total of 23 AIH patients were included in the final analysis. In 13% of patients tacrolimus was initiated because of toxicity to previous first-line treatments and the rest were switched because of previous non-efficacy. Tacrolimus was effective in 18 patients (78%; 95%CI: 55.20-91.92%). The median time receiving tacrolimus was 16 months (IQR 20). There was a sustained response with a significant improvement in all liver enzymes and IgG on last follow-up. Only one patient discontinued tacrolimus at the third month because of severe neuropathy, and ototoxicity. Responders were significantly older at diagnosis of AIH (41 ± 13 vs. 27 ± 10 years old; p = 0.0496).. Tacrolimus is effective and well tolerated as a second-line therapy in patients with AIH.

Topics: Adult; Chronic Disease; Female; Hepatitis, Autoimmune; Humans; Immunoglobulin G; Immunosuppressive Agents; Liver; Male; Middle Aged; Retrospective Studies; Tacrolimus

Topics: Administration, Topical; Chronic Disease; Combined Modality Therapy; Humans; Hydroxychloroquine; Immunosuppressive Agents; Stomatitis; Tacrolimus

Ocular graft-versus-host disease (GVHD) is one of the most severe complications of hematopoietic stem cell transplantation. It manifests as an impairment of the ocular surface, such as severe dry eye disease, and deteriorates the recipient's visual function and quality of life. We encountered an "overlap syndrome" of ocular GVHD, which is characterized by the presence of both acute and chronic GVHD symptoms. In this report, we present the treatment progress of the overlap syndrome in a case with ocular GVHD.. A 57-year-old man with acute myeloblastic leukemia underwent hematopoietic stem cell transplantation. Six weeks after the treatment, the recipient complained of eye pain and discharge. He was diagnosed with the overlap syndrome due to low tear volume, severe corneal epithelitis, hyperemia, and a pseudomembrane on the conjunctiva. Immune cells infiltration, fibrinoid degeneration, fibroblastic and spindle-shaped cells, and fibrosis were observed in the pathology of the pseudomembrane. The recipient was treated with topical immunosuppression and pseudomembrane removal. One week after the initial treatment, ocular GVHD improved. Twelve weeks after the treatment, the topical steroid was discontinued due to the elevation of intraocular pressure.. The assessment of conjunctival pseudomembrane in ocular GVHD is important to determine the stage of the case and to assess systemic GVHD. Furthermore, prompt removal of the pseudomembrane after diagnosis is an appropriate management to reduce the symptoms of ocular GVHD. The combination of topical steroids and immunosuppressive agents is suggested to be an effective treatment in management of overlap syndrome.

Topics: Acute Disease; Betamethasone; Chronic Disease; Conjunctival Diseases; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Intestinal Diseases; Leukemia, Myeloid, Acute; Male; Middle Aged; Ophthalmologic Surgical Procedures; Skin Diseases; Tacrolimus

While tacrolimus and sirolimus (T/S)-based graft-versus-host disease (GvHD) prophylaxis has been effective in preventing acute GvHD post hematopoietic cell transplantation (HCT), its efficacy and long-term outcome in matched (MUD) and mismatched unrelated donor (mMUD) setting is not well defined.. Herein, we evaluated a consecutive case-series of 482 patients who underwent unrelated donor HCT (2005-2013) with T/S-based GvHD prophylaxis.. With a median follow-up of 6.2 years (range = 2.4-11.3), the 5-year overall survival (OS) and relapse/progression-free survival were 47.5% (95% confidence interval [CI]: 43.0-52.0) and 43.6% (95% CI: 39.1-48.1), respectively; and the 5-year cumulative incidence of nonrelapse mortality (NRM) and relapse were 24.9%, and 31.5%, respectively. In this cohort, mMUD was associated with worse OS (39.0% versus 50.7% at 5 y; P = 0.034), primarily due to greater risk of NRM (33.5% versus 21.7%; P = 0.038). While rates of relapse, acute (II-IV or III-IV) or chronic GvHD (limited or extensive) were not different, death caused by chronic GvHD (20.8% versus 12.8%; P = 0.022) and infection (33.0% versus 18.1%; P < 0.01) were significantly greater in mMUD. In multivariable analysis, high-risk disease (hazard ratio [HR] = 2.21, 95% CI: 1.16-4.23; P < 0.01) and mMUD (HR = 1.55, 95% CI: 1.15-2.08; P = 0.004) were independent predictive factors for OS.. T/S-based GvHD prophylaxis is an effective and acceptable GvHD prophylactic regimen. However, survival after mMUD remained poor, possibly related to the severity of chronic GvHD.

Topics: Chronic Disease; Disease-Free Survival; Female; Follow-Up Studies; Forecasting; Graft vs Host Disease; Hematologic Neoplasms; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; HLA Antigens; Humans; Immunosuppressive Agents; Incidence; Male; Middle Aged; Prognosis; Retrospective Studies; Sirolimus; Survival Rate; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; United States; Unrelated Donors

T-cell activation releases inositol 1,4,5-trisphosphate (IP3), inducing cytoplasmic calcium (Ca2+) influx. In turn, inositol 1,4,5-trisphosphate 3-kinase B (Itpkb) phosphorylates IP3 to negatively regulate and thereby tightly control Ca2+ fluxes that are essential for mature T-cell activation and differentiation and protection from cell death. Itpkb pathway inhibition increases intracellular Ca2+, induces apoptosis of activated T cells, and can control T-cell-mediated autoimmunity. In this study, we employed genetic and pharmacological approaches to inhibit Itpkb signaling as a means of controlling graft-versus-host disease (GVHD). Murine-induced, Itpkb-deleted (Itpkb-/-) T cells attenuated acute GVHD in 2 models without eliminating A20-luciferase B-cell lymphoma graft-versus-leukemia (GVL). A highly potent, selective inhibitor, GNF362, ameliorated acute GVHD without impairing GVL against 2 acute myeloid leukemia lines (MLL-AF9-eGFP and C1498-luciferase). Compared with FK506, GNF362 more selectively deleted donor alloreactive vs nominal antigen-responsive T cells. Consistent with these data and as compared with FK506, GNF362 had favorable acute GVHD and GVL properties against MLL-AF9-eGFP cells. In chronic GVHD preclinical models that have a pathophysiology distinct from acute GVHD, Itpkb-/- donor T cells reduced active chronic GVHD in a multiorgan system model of bronchiolitis obliterans (BO), driven by germinal center reactions and resulting in target organ fibrosis. GNF362 treatment reduced active chronic GVHD in both BO and scleroderma models. Thus, intact Itpkb signaling is essential to drive acute GVHD pathogenesis and sustain active chronic GVHD, pointing toward a novel clinical application to prevent acute or treat chronic GVHD.

Topics: Animals; Chronic Disease; Disease Models, Animal; Graft vs Host Disease; Graft vs Leukemia Effect; Immunosuppressive Agents; Leukemia, Experimental; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Mice, Knockout; Phosphotransferases (Alcohol Group Acceptor); Tacrolimus

Chronic allograft dysfunction (CAD), defined as the replacement of functional renal tissue by extracellular matrix proteins, remains the first cause of graft loss. The aim of our study was to explore the potential role of the cannabinoid receptor 1 (CB1) during CAD. We retrospectively quantified CB1 expression and correlated it with renal fibrosis in 26 kidney-transplanted patients who underwent serial routine kidney biopsies. Whereas CB1 expression was low in normal kidney grafts, it was highly expressed during CAD, especially in tubular cells. CB1 expression significantly increased early on after transplantation, from day 0 (D0) to month 3 post-transplant (M3) (22.5% ± 15.4% vs 33.4% ± 13.8%, P < .01), and it remained stable thereafter. CB1 expression correlated with renal fibrosis at M3 (P = .04). In an in vitro model of tacrolimus-mediated fibrogenesis by tubular cells, we found that tacrolimus treatment significantly induced mRNA and protein expression of CB1 concomitantly to col3a1 and col4a3 up regulation. Administration of rimonabant, a CB1 antagonist, blunted collagen synthesis by tubular cells (P < .05). Overall, our study strongly suggests an involvement of the cannabinoid system in the progression of fibrosis during CAD and indicates the therapeutic potential of CB1 antagonists in this pathology.

Topics: Animals; Cells, Cultured; Chronic Disease; Female; Fibrosis; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Mice; Mice, Inbred C57BL; Middle Aged; Primary Graft Dysfunction; Receptor, Cannabinoid, CB1; Retrospective Studies; Tacrolimus

Recent reports have indicated that the risk of anti-D alloimmunization following D-incompatible platelet (PLT) transfusion is low in hematology and oncology patients. We investigated the rate of anti-D alloimmunization in RhD-negative (D. We reviewed the blood bank database from January 2003 to October 2016. D. Six of the 56 eligible patients (10.7%) had anti-D antibodies. All had received whole blood-derived PCs. Four of 20 patients (20%) untransplanted or transfused before LT and only two of 36 patients (5.6%) transfused during or after LT produced anti-D antibodies. These two patients were on maintenance immunosuppression based on low-dose steroids and tacrolimus. The factors identified as significantly associated with anti-D immune response were the presence of red blood cell immune alloantibodies before D. D

Topics: Aged; Blood Banks; Chronic Disease; Female; Humans; Immunosuppression Therapy; Liver Diseases; Male; Middle Aged; Platelet Transfusion; Rho(D) Immune Globulin; Risk Factors; Steroids; Tacrolimus

Topics: Administration, Ophthalmic; Adolescent; Adult; Chronic Disease; Conjunctivitis, Allergic; Dermatitis, Atopic; Female; Humans; Immunosuppressive Agents; Male; Ophthalmic Solutions; Prospective Studies; Tacrolimus; Treatment Outcome; Young Adult

Janus kinase (JAK) inhibitors are thought to be promising candidates to aid renal transplantation. However, the effectiveness of JAK inhibitors against features of chronic rejection, including interstitial fibrosis/tubular atrophy (IF/TA) and glomerulosclerosis, has not been elucidated. Here, we investigated the effect of AS2553627, a novel JAK inhibitor, on the development of chronic rejection in rat renal transplantation.. Lewis (LEW) to Brown Norway (BN) rat renal transplantation was performed. Tacrolimus (TAC) at 0.1mg/kg was administered intramuscularly once a day for 10 consecutive days starting on the day of transplantation (days 0 to 9) to prevent initial acute rejection. After discontinuation of TAC treatment from days 10 to 28, AS2553627 (1 and 10mg/kg) was orally administered with TAC. At 13weeks after renal transplantation, grafts were harvested for histopathological and mRNA analysis. Creatinine and donor-specific antibodies were measured from plasma samples. Urinary protein and kidney injury markers were also evaluated.. AS2553627 in combination with TAC exhibited low plasma creatinine and a marked decrease in urinary protein and kidney injury markers, such as tissue inhibitor of metalloproteinase-1 and kidney injury molecule-1. At 13weeks, histopathological analysis revealed that AS2553627 treatment inhibited glomerulosclerosis and IF/TA. In addition, upregulation of cell surface markers, fibrosis/epithelial-mesenchymal transition and inflammation-related genes were reduced by the combination of AS2553672 and TAC, particularly CD8 and IL-6 mRNAs, indicating that AS2553627 prevented cell infiltration and inflammation in renal allografts.. These results indicate the therapeutic potential of JAK inhibitors in chronic rejection progression, and suggest that AS2553627 is a promising agent to improve long-term graft survival after renal transplantation.

Topics: Allografts; Animals; Chronic Disease; Disease Models, Animal; Drug Therapy, Combination; Glomerulosclerosis, Focal Segmental; Graft Rejection; Humans; Interleukin-6; Janus Kinases; Kidney Transplantation; Piperidines; Pyrroles; Rats; Rats, Inbred Lew; Tacrolimus

The Japan Marrow Donor Program (JMDP) has facilitated unrelated peripheral blood stem cell transplantation (URPBSCT) since 2010. We conducted a prospective multicenter observational study to evaluate the feasibility of such transplantation. Between 2011 and 2014, 51 patients underwent URPBSCT from 8/8 allele-matched donors for hematological malignancies. The median age of the patients was 50 years; 21 had high-risk disease. Myeloablative conditioning regimens were used in 31 patients, and tacrolimus based graft-versus-host disease (GVHD) prophylaxis was used for all patients. The cumulative rate of engraftment was 96%. With a median follow-up period of 610 days for survivors, 100-day and 1-year overall survival rates were 86 and 59%, respectively. The cumulative incidence of non-relapse mortality and relapse at 1 year were 14 and 35%, respectively. The incidence of grade II to IV acute GVHD at 100 days and extensive type of chronic GVHD at 1 year were 25 and 32%, respectively. The probability of overall survival was comparable with that of bone marrow transplantation from HLA matched-unrelated donors in Japan, although the incidence of chronic GVHD was higher. Further follow-up with more patients is clearly warranted to establish the optimal use of URPBSCT together with the approaches of minimizing chronic GVHD.

Topics: Adolescent; Adult; Aged; Chronic Disease; Feasibility Studies; Follow-Up Studies; Graft vs Host Disease; Hematologic Neoplasms; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Peripheral Blood Stem Cell Transplantation; Prospective Studies; Tacrolimus; Time Factors; Transplantation Conditioning; Unrelated Donors; Young Adult

Topics: Adult; Ascites; Chronic Disease; Cyclophosphamide; Female; Humans; Lupus Erythematosus, Systemic; Mycophenolic Acid; Peritonitis; Prednisolone; Severity of Illness Index; Tacrolimus; Tomography, X-Ray Computed; Treatment Outcome

Extracorporeal photopheresis (ECP) is a second-line therapy for steroid-refractory chronic graft-versus-host disease (cGVHD).. We describe the long-term efficacy and tolerability of ECP according to the cutaneous phenotype of cGVHD and report on the reduced need for immunosuppressant drugs in this setting.. Fourteen patients (8 females) with cutaneous and/or mucosal cGVHD, treated with ECP between October 2010 and May 2016 within a single center, were included. Final analyses included patients who had received ECP for at least 12 months. We prospectively evaluated the efficacy of ECP using lesion-specific clinical scores and by recording changed doses of systemic immunosuppressants.. Of the 14 patients, sclerotic skin lesions were present in 10 (71%). The mRODNAN score decreased in all patients from month 9 onwards, with 40 and 77% reductions at 12 and 36 months, respectively. Six patients (43%) presented with cutaneous lichenoid lesions: this score was reduced in all patients by month 3, reaching a 93% reduction by month 12. Five patients (36%) experienced oral mucosal lichenoid lesions: these scores were decreased by 55% at month 12 and by 100% by month 33. The use of systemic immunosuppressants was reduced in all patients; 4 patients could stop all immunosuppressant drugs after 2 years. ECP was stopped in 3 patients after a complete response. No major ECP-associated adverse effects were observed.. ECP was an effective long-term therapy for oral and cutaneous cGVHD: consequently, dose levels of therapeutic immunosuppression could be reduced.

Topics: Adult; Chronic Disease; Cyclosporine; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Lichenoid Eruptions; Male; Middle Aged; Mouth Diseases; Mouth Mucosa; Mycophenolic Acid; Photopheresis; Prednisone; Sclerosis; Skin; Tacrolimus

There are only a few cases of pericarditis complications following allogeneic bone marrow transplantation described in the literature and there are no data available on the risk and frequency of this condition. The aim of this study was to assess the frequency of exudative pericarditis complicating chronic graft-vs-host disease in allogeneic hematopoietic cell transplant recipients.. Retrospective analysis involved a group of 105 patients of the Outpatient Transplantation Service of the Department of Hematology, Medical University of Warsaw, who received transplants in the years 2010-2016 and were evaluated for the years 2014-2016. In this group, 50 patients suffered from chronic graft-vs-host disease (cGVHD), including 24 with moderate or severe disease. Cardiology parameters evaluated included electrocardiography, echocardiography, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systematic clinical follow-up.. Pericarditis was diagnosed in 6 patients (aged 20-56 years) within 4 to 23 months after allogenic hematopoietic stem cell transplantation. All patients suffered from severe cGVHD with involvement of at least 2 organs but none had earlier history of heart disease. All patients had elevated NT-proBNP and demonstrated signs of heart insufficiency grade II or III according to the New York Heart Association. There were no major changes in electrocardiogram. Only 1 patient improved following glucocorticosteroids as monotherapy, while others required complex approaches including tacrolimus plus sirolimus, rituximab, and extracorporeal photopheresis.. Late pericarditis may occur in up to 5% of allogenic hematopoietic stem cell transplantation survivors, primarily affecting patients with moderate and severe grade cGVHD. It requires escalation of immunosuppressive treatment but usually has favorable outcome. Early diagnosis may be achieved by systematic NT-proBNP testing and periodic echocardiograph evaluation.

Topics: Adult; Bone Marrow Transplantation; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Pericarditis; Photopheresis; Retrospective Studies; Risk Factors; Rituximab; Sirolimus; Tacrolimus; Young Adult

CD4

Topics: Adult; Aged; Animals; Apoptosis; Calcineurin Inhibitors; Case-Control Studies; Chronic Disease; End Stage Liver Disease; Female; Flow Cytometry; Forkhead Transcription Factors; Gene Expression Regulation; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Interleukin-2; Interleukin-7; Kidney Transplantation; Leukocyte Common Antigens; Liver Transplantation; Male; Mice; Mice, Inbred BALB C; Mice, Inbred C57BL; Middle Aged; Phenotype; Signal Transduction; T-Lymphocytes; T-Lymphocytes, Regulatory; Tacrolimus; Transplantation Tolerance

To report a case of refractory ulcerated necrobiosis lipoidica (NL) with significant response to treatment with topical tacrolimus.. A 55-year-old woman without diabetes and with a previous history of NL presented to the Helen L. and Martin S. Kimmel Hyperbaric and Advanced Wound Healing Center of NYU Langone Medical Center, New York, with bilateral lower-leg ulcerations resistant to wound healing techniques at other institutions.. Repeat biopsy performed at the author's institution confirmed the diagnosis of NL. Initial therapy was based on reports of other successful treatment methods, which included collagen wound grafts and collagen-based dressings coupled with compression. These methods initially showed promising results; however, the wounds reulcerated, and any gains in wound healing were lost. Alternative options were initiated, including topical clobetasol and narrowband ultraviolet B; however, no significant improvement was observed. The patient's lower-extremity wounds began to deteriorate. The patient also refused systemic therapy. Treatment was changed to topical 0.1% tacrolimus ointment and was applied daily for 10 months with multilayer compression wraps.. Both lower-extremity ulcerations began to show significant improvement, with the ulcers progressing toward closure except for 1 very small area on the left lower extremity.. Topical tacrolimus seems to be an effective treatment option for patients with refractory chronic ulcerated NL who do not want systemic oral therapy. The authors found that successful wound closure may require a multimodal approach, which promotes wound healing, but also concurrently addresses the underlying disease process.

Topics: Administration, Topical; Biopsy, Needle; Chronic Disease; Compression Bandages; Female; Follow-Up Studies; Humans; Immunohistochemistry; Leg Ulcer; Long-Term Care; Middle Aged; Necrobiosis Lipoidica; Severity of Illness Index; Tacrolimus; Treatment Outcome; Wound Healing

The pathology and diagnosis of acute and chronic rejection in intestinal transplantation (ITX) are far from being completely understood. We established models of acute and chronic intestinal graft rejection and analyzed peripheral and intragraft immune responses.. We performed ITX from Dark Agouti into Lewis rats applying single-dose tacrolimus (TAC) at varying concentrations. Graft histology and immunohistology were assessed on postoperative day (POD)7, 14, and 45. Intragraft and peripheral gene expressions of inflammatory and anti-inflammatory markers and lipopolysaccharide binding protein (LBP) plasma as well as alloantibodies were measured simultaneously.. A 1-mg TAC resulted in acute rejection and recipient death; 3 mg and 5 mg prolonged survival and led to severe or moderate chronic rejection, respectively, with 50% of the 5-mg TAC recipients surviving the observation period. Consequently, we observed severe infiltration on POD7 in untreated and 1-mg TAC recipients compared with minor histological alterations in 3 and 5 mg TAC groups. Only 5-mg TAC treatment prevented accumulation of CD4+ T cells and ED1+ macrophages over the entire observation period. Peripheral and intragraft expressions of T cell activation inhibitor-mitochondrial were stable in long-term surviving 5-mg TAC recipients but declined before acute or chronic rejection in 1 and 3 mg TAC recipients. In contrast, LBP levels increased during acute and chronic rejections.. We studied acute and chronic rejections in a preclinical model of ITX, which recapitulates clinical findings and highlights the importance of monitoring peripheral T cell activation inhibitor-mitochondrial expression, LBP levels, and antidonor antibodies for revealing rejection.

Topics: Acute Disease; Acute-Phase Proteins; Animals; Biomarkers; Carrier Proteins; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Graft Rejection; Graft Survival; Immunosuppressive Agents; Intestines; Isoantibodies; Lymphocyte Activation; Membrane Glycoproteins; Random Allocation; Rats; Rats, Inbred Lew; Severity of Illness Index; Tacrolimus

HLA-matched related or unrelated donors are not universally available. Consequently, patients can be offered hematopoietic stem cell transplantation (HSCT) from alternative donors, including mismatched unrelated donors (MMURD), known to cause a higher incidence of acute GVHD (aGVHD) and chronic GVHD. In vivo T-cell-depletion strategies, such as antithymocyte globulin (ATG) therapy, significantly decrease the risk of GVHD. We performed a multicenter, retrospective study comparing tacrolimus (TAC) and sirolimus (SIR) with or without ATG in 104 patients (TAC-SIR=45, TAC-SIR-ATG=59) who underwent MMURD HSCT. Use of ATG was associated with a lower incidence, albeit not statistically significant, of grades 2-4 aGVHD (46% vs 64%, P=0.09), no difference in grades 3-4 aGVHD (10% vs 15%, P=0.43), a trend for a lower incidence of moderate/severe chronic GVHD (16% vs 37%, P=0.09) and more frequent Epstein-Barr virus reactivation (54% vs 18%, P=0.0002). There were no statistically significant differences in 3-year overall survival (OS) (TAC-SIR-ATG=40% (95% confidence interval (CI)=24-56%) vs TAC-SIR=54% (95% CI=37-70%), P=0.43) or 3-year cumulative incidence of relapse/progression (TAC-SIR-ATG=40% (95% CI=28-58%) vs TAC-SIR=22% (95% CI=13-39%), P=0.92). An intermediate Center for International Blood & Marrow Transplant Research disease risk resulted in a significantly lower non-relapse mortality and better OS at 3 years. Our study suggests that addition of ATG to TAC-SIR in MMURD HSCT does not affect OS when compared with TAC-SIR alone.

Topics: Acute Disease; Adolescent; Adult; Aged; Allografts; Chronic Disease; Disease-Free Survival; Female; Graft vs Host Disease; HLA Antigens; Humans; Lymphocyte Depletion; Male; Middle Aged; Retrospective Studies; Sirolimus; Stem Cell Transplantation; Survival Rate; T-Lymphocytes; Tacrolimus; Unrelated Donors

Topics: Adult; Allografts; Anemia, Aplastic; Bone Marrow Transplantation; Chronic Disease; Graft vs Host Disease; Humans; Immunosuppressive Agents; Influenza Vaccines; Infusions, Intravenous; Lymphohistiocytosis, Hemophagocytic; Male; Methylprednisolone; Prednisolone; Tacrolimus; Treatment Outcome

Chronic actinic dermatitis (CAD) is a recurrent photosensitive dermatitis that occurs predominantly on sun-exposed areas with unknown etiology. In severe cases, it may present with erythroderma, which is clinicopathologically analogous to cutaneous T-cell lymphoma. Typically, inflammatory infiltrates in the skin lesions are mainly CD8. Twenty patients with CAD ranging in age from 45 to 86 years (median, 64), including 17 males and three females (M/F ratio, 5.7), were examined. All patients were phototested for UV light. In addition, seven of the 20 patients with extensive eruption were also tested for visible light. All biopsy specimens were obtained from the CAD eruptions (n = 25 lesions). Histopathologic and immunohistochemical studies were performed. Furthermore, flow cytometric analysis was performed to determine the CD4/8 ratio using peripheral blood mononuclear cells of 13 of the 20 patients.. In 11 of the 20 patients (55%), the eruption was localized to sun-exposed areas. Skin-infiltrating T cells were CD8-dominant in the CAD eruption. Three patients (15%) showed erythroderma with a reduced CD4/8 ratio (median, 0.7) of peripheral mononuclear cells. As for treatment, eight of the 20 patients (40%) required oral cyclosporine in addition to topical therapies. Subsequently, the reduced CD4/8 ratio was normalized after treatment in two of the three patients with erythroderma.. We considered that there appeared to be a relationship between the reduced CD4/8 ratio of circulating T cells (hematologic burden) and the affected area (skin burden).

Topics: Administration, Cutaneous; Adrenal Cortex Hormones; Aged; Aged, 80 and over; CD4 Lymphocyte Count; CD8-Positive T-Lymphocytes; Chronic Disease; Cyclosporine; Dermatitis, Exfoliative; Female; Humans; Immunohistochemistry; Immunosuppressive Agents; Male; Middle Aged; Photosensitivity Disorders; Severity of Illness Index; Sunscreening Agents; Tacrolimus; Ultraviolet Rays

Topics: Administration, Oral; Aged; Anti-Inflammatory Agents; Azathioprine; Chronic Disease; Humans; Immunosuppressive Agents; Male; Middle Aged; Occlusive Dressings; Ointments; Photosensitivity Disorders; Prednisolone; Retreatment; Tacrolimus

Lichen sclerosus (LS) is a chronic, inflammatory condition of the skin, affecting primarily the anogenital region potentially leading to changes in vaginal architecture and vulvar squamous cell carcinoma. Current recommended treatment for LS is high-potency corticosteroids. Calcineurin inhibitors may also have a role.. The objective of this study is to introduce a treatment regimen involving clobetasol to induce remission, then tacrolimus to maintain remission in pediatric females with LS.. As a retrospective case series, we report 14 pediatric females between 2 and 10 years of age with LS treated with clobetasol 0.05% topical ointment and systematically bridged to tacrolimus 0.1% topical ointment. For each patient, gender, age at disease onset, and clinical symptoms and features were noted. Time in weeks to 75% clearance and to complete clearance were recorded.. Thirteen patients showed complete clearance. One patient showed significant clearance of the disease. The time to complete clearance averaged 43.1 weeks, with a range of 4-156 weeks.. The use clobetasol to induce remission and tacrolimus to maintain remission can be used to treat LS in pediatric females. This regimen may minimize side effects associated with long-term, high-potency corticosteroid use and reduce the risk of changes to genital architecture secondary to LS.

Topics: Calcineurin Inhibitors; Child; Child, Preschool; Chronic Disease; Clobetasol; Dermatologic Agents; Female; Glucocorticoids; Humans; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Retrospective Studies; Tacrolimus

Chronic rejection remains a major cause of graft failure with indication for re-transplantation. The incidence of chronic rejection remains high in the pediatric population. Although several risk factors have been implicated in adults, the prognostic factors for the evolution and reversibility of chronic rejection in pediatric liver transplantation are not known. Hence, the current study aimed to determine the factors involved in the progression or reversibility of pediatric chronic rejection by evaluating a series of chronic rejection cases following liver transplantation.. Chronic rejection cases were identified by performing liver biopsies on patients based on clinical suspicion. Treatment included maintaining high levels of tacrolimus and the introduction of mofetil mycophenolate. The children were divided into 2 groups: those with favorable outcomes and those with adverse outcomes. Multivariate analysis was performed to identify potential risk factors in these groups.. Among 537 children subjected to liver transplantation, chronic rejection occurred in 29 patients (5.4%). In 10 patients (10/29, 34.5%), remission of chronic rejection was achieved with immunosuppression (favorable outcomes group). In the remaining 19 patients (19/29, 65.5%), rejection could not be controlled (adverse outcomes group) and resulted in re-transplantation (7 patients, 24.1%) or death (12 patients, 41.4%). Statistical analysis showed that the presence of ductopenia was associated with worse outcomes (risk ratio=2.08, p=0.01).. The presence of ductopenia is associated with poor prognosis in pediatric patients with chronic graft rejection.

Topics: Adolescent; Biopsy; Child; Child, Preschool; Chronic Disease; Cyclosporine; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Infant; Kidney Diseases; Liver Transplantation; Male; Multivariate Analysis; Mycophenolic Acid; Prognosis; Remission Induction; Survival Rate; Tacrolimus

The Fischer-to-Lewis (LEW) rat model of kidney transplantation is a widely accepted and well-characterized model of chronic rejection. In contrast to transplantation in a clinical setting, however, the absence of treatment with immunosuppressants and only minor mismatch of major histocompatibility complexes (MHCs) are critical discrepancies. Here, we established a rat model of chronic rejection using fully MHC-mismatched strains in which kidney disease progresses even under immunosuppressive therapy.. LEW (RT1(l)) rats were used as donors and Brown Norway (BN, RT1(n)) rats as recipients. Intramuscular administration of 0.1mg/kg of tacrolimus was initiated on the day of transplantation. Post-transplantation, this dose was maintained until Day 9, suspended until Day 28 and then resumed from Day 29. Renal function, histopathology, and levels of donor-specific antibody (DSA) and several biomarkers of renal injury were assessed.. On Day 91 post-transplantation, recipients received tacrolimus treatment with short-term suspension exhibited reduced renal function and changes in histology. Those were characteristics of chronic rejection including glomerulosclerosis, interstitial fibrosis, and tubular atrophy in human transplantation recipients. Urinary protein excretion increased in a linear fashion, and elevated levels of several biomarkers of renal injury and DSA were observed even under administration of an immunosuppressant.. We established an allograft rejection model with impaired renal function and typical histopathological changes of chronic rejection in fully MHC-mismatched rats by controlling administration of an immunosuppressant. These findings suggest that this model more accurately reflects transplantation in a clinical setting than existing models and enables the evaluation of therapeutic agents.

Topics: Animals; Atrophy; Biomarkers; Chronic Disease; Disease Models, Animal; Feasibility Studies; Fibrosis; Graft Rejection; Histocompatibility Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Transplantation; Rats; Rats, Inbred BN; Rats, Inbred Lew; Sclerosis; Tacrolimus; Transplantation, Homologous

Annular lichenoid dermatitis of youth, first described in 2003, is a rare and occasionally chronic skin disease. We report a case of annular lichenoid dermatitis of youth relapsing over the course of 5 years successfully treated and maintained with topical pimecrolimus cream.

Topics: Child; Chronic Disease; Dermatologic Agents; Humans; Lichenoid Eruptions; Male; Tacrolimus

To investigate the efficacy and safety of long-term maintenance treatment with tacrolimus ointment in chronic ocular graft-vs-host disease (GVHD) with ocular surface inflammation.. A retrospective interventional consecutive case series.. Long-term maintenance treatment (≥6 months) with topical 0.02% tacrolimus ointment was applied to patients with chronic ocular GVHD with ocular surface inflammation (at least grade 2 inflammatory score). We evaluated the inflammatory score, steroid score and steroid use period of total duration, and numbers of inflammatory aggravations before and after tacrolimus treatment. The clinical outcomes were assessed by symptom score, ocular surface staining, Schirmer I test, tear break-up time (TBUT), and classification of chronic GVHD conjunctivitis at the initial and final examinations.. Thirteen patients (24 eyes) were treated with tacrolimus ointment for up to 20 months (average 12.2 months). The ocular surface inflammatory score decreased from 2.8 to 0.6 (P = .001) within 2-8 weeks after starting tacrolimus ointment treatment. The numbers of inflammatory aggravation and the need for steroid treatment also decreased after initiating tacrolimus treatment. At the final follow-up, all patients reported improvement in clinical outcomes, compared to initial findings. Except for blurred vision or mild burning sensation, there were no reported side effects.. Considering the chronic course of GVHD, long-term maintenance treatment with tacrolimus ointment could be useful and safe to locally treat ocular surface inflammation in chronic ocular GVHD.

Topics: Adolescent; Adult; Child, Preschool; Chronic Disease; Conjunctivitis; Female; Follow-Up Studies; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Keratitis; Leukemia; Male; Middle Aged; Ointments; Retrospective Studies; Tacrolimus; Treatment Outcome; Visual Acuity; Young Adult

Calcineurin inhibitors reduce the acute rejection rate and greatly improve renal allograft survival. However, they are associated with some adverse events, including nephrotoxicity, a risk factor for allograft failure. Chronic calcineurin inhibitor-induced nephrotoxicity causes irreversible damage to renal components, such as arteriolar hyaline thickening. The aim of this study is to investigate the risk factors for tacrolimus-induced chronic nephrotoxicity using zero-time biopsy specimens.. Between January 2001 and December 2010, 483 patients who underwent living-related kidney transplantation and had also been placed on a tacrolimus-based regimen were enrolled in this study. There were 1859 specimens evaluated comprising 483 zero-time biopsy specimens and 1376 protocol and for-cause biopsy specimens. De novo arteriolar hyaline thickening due to tacrolimus-induced chronic nephrotoxicity was scored according to the Banff classification aah score. In this study, tacrolimus-induced nephrotoxicity was defined as a positive aah score.. Of the 483 patients, 108 patients (22.4%) had biopsy-proven tacrolimus-induced chronic nephrotoxicity. Multivariate analysis showed that interlobular arteriosclerosis proven by zero-time biopsy (OR: 2.23, 95%CI: 1.38-3.58, P < 0.01) and acute rejection episodes (OR: 1.58, 95%CI: 1.00-2.47, P = 0.04) were independent risk factors for tacrolimus-induced chronic nephrotoxicity. However, tacrolimus-induced chronic nephrotoxicity did not affect long-term graft survival.. This is the first report showing that arteriosclerosis in zero-time biopsy specimens is a risk factor for histological tacrolimus-induced chronic nephrotoxicity.

Topics: Acute Disease; Adult; Allografts; Arterioles; Arteriosclerosis; Biopsy; Calcineurin Inhibitors; Chi-Square Distribution; Chronic Disease; Female; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney; Kidney Diseases; Kidney Transplantation; Living Donors; Male; Middle Aged; Multivariate Analysis; Odds Ratio; Predictive Value of Tests; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

The role of donor-specific HLA antibodies (DSA) after pediatric liver transplantation (LTx) is not clearly established. We completed a cross-sectional study to characterize DSA in long-term survivors of pediatric LTx and assess the impact of C1q-binding DSA on allograft outcomes.. Serum samples were collected at routine clinic visits from 50 pediatric LTx recipients classified into 3 clinical phenotypes: nontolerant (n = 18) with de novo autoimmune hepatitis (DAIH) and/or late acute cellular rejection (ACR); stable (n = 25) on maintenance tacrolimus; operationally tolerant (n = 7). Samples were blinded, and antibody detection was performed using Luminex single antigen class I and II beads. Patients with positive DSA were tested for C1q-binding DSA.. DSA were detected in 54% (n = 27) of the patients, with the majority directed at HLA class II antigens (DR, 41%; DQ, 53%). Patients with DSA were younger at the time of LTx (P = 0.016) and time of study (P = 0.024). Mean aspartate aminotransferase, alanine aminotransferase, total bilirubin, and gamma glutamyl transferase were higher in DSA-positive patients, though did not reach statistical significance. Nontolerant patients were significantly more likely to have DQ DSA (61%) compared to stable (20%) and tolerant (29%) patients (P = 0.021). The nontolerant phenotype was associated with DSA and C1q-binding DSA, with odds ratios of 13 (P = 0.015) and 8.6 (P = 0.006), respectively. The presence of DQ DSA was associated with DAIH and late ACR, with odds ratios of 12.5 (P = 0.004) and 10.8 (P = 0.006), respectively.. Allograft dysfunction is not always evident in patients with DSA, but DQ DSA are strongly associated with DAIH, late ACR, and chronic rejection.

Topics: Acute Disease; Adolescent; Age Factors; Biomarkers; Chi-Square Distribution; Child; Child, Preschool; Chronic Disease; Complement C1q; Cross-Sectional Studies; Female; Graft Rejection; Graft Survival; Hepatitis, Autoimmune; Histocompatibility; Histocompatibility Testing; HLA Antigens; HLA-DQ Antigens; Humans; Immunosuppressive Agents; Infant; Infant, Newborn; Isoantibodies; Liver Transplantation; Logistic Models; Male; Multivariate Analysis; Odds Ratio; Phenotype; Risk Factors; Tacrolimus; Time Factors; Transplantation Tolerance; Treatment Outcome; Young Adult

Erratic tacrolimus blood levels are associated with liver and kidney graft failure. We hypothesized that erratic tacrolimus exposure would similarly compromise lung transplant outcomes. This study assessed the effect of tacrolimus mean and standard deviation (SD) levels on the risk of chronic lung allograft dysfunction (CLAD) and death after lung transplantation.. We retrospectively reviewed 110 lung transplant recipients who received tacrolimus-based immunosuppression. Cox proportional hazard modeling was used to investigate the effect of tacrolimus mean and SD levels on survival and CLAD. At census, 48 patients (44%) had developed CLAD and 37 (34%) had died.. Tacrolimus SD was highest for the first 6 post-transplant months (median, 4.01; interquartile range [IQR], 3.04-4.98 months) before stabilizing at 2.84 μg/liter (IQR, 2.16-4.13 μg/liter) between 6 and 12 months. The SD then remained the same (median, 2.85; IQR, 2.00-3.77 μg/liter) between 12 and 24 months. A high mean tacrolimus level 6 to 12 months post-transplant independently reduced the risk of CLAD (hazard ratio [HR], 0.74; 95% confidence interval [CI], 0.63-0.86; p < 0.001) but not death (HR, 0.96; 95% CI, 0.83-1.12; p = 0.65). In contrast, a high tacrolimus SD between 6 and 12 months independently increased the risk of CLAD (HR, 1.46; 95% CI, 1.23-1.73; p < 0.001) and death (HR, 1.27; 95% CI, 1.08-1.51; p = 0.005).. Erratic tacrolimus levels are a risk factor for poor lung transplant outcomes. Identifying and modifying factors that contribute to this variability may significantly improve outcomes.

Topics: Adult; Allografts; Chronic Disease; Dose-Response Relationship, Drug; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; New Zealand; Prognosis; Proportional Hazards Models; Queensland; Retrospective Studies; Risk Factors; Survival Rate; Tacrolimus

We retrospectively evaluated single-institute outcomes of allogeneic hematopoietic stem cell transplantation (allo-HSCT) with a reduced-intensity conditioning regimen consisting of fludarabine (125 mg/m²) and melphalan (140 mg/m²) for multiple myeloma. Twenty-three patients (median age: 46 years) were evaluated. Stem cell sources were bone marrow or peripheral blood stem cells from siblings (n = 4) and bone marrow from unrelated donors (n = 19). For graft-versus-host disease prophylaxis, cyclosporine A or tacrolimus with short-term methotrexate was given. Disease status at time of transplant was complete response in four patients, very good partial or partial response in 13, and stable or progressive disease in six. The median follow-up period of 7 survivors at analysis was 73.2 months (range 46.0-158.9 months). During the follow-up, disease recurrence or progression was observed in 21 patients, and was primary causes of death in 88% of the patients. The 5-year overall survival and progression-free survival rates were 38.6% (95% CI 19.3-57.7%) and 5.4% (95% CI 0.4-21.6%), respectively. Although allo-HSCT with this conditioning could be safely performed, further refinement of this approach aiming at more effective eradication of myeloma cells is clearly warranted.

Topics: Acute Disease; Adult; Allografts; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Multiple Myeloma; Retrospective Studies; Tacrolimus; Transplantation Conditioning; Treatment Outcome

Bronchiectasis is characterized by abnormal, permanent and irreversible dilatation of the bronchi, usually responsible for daily symptoms and frequent respiratory complications. Many causes have been identified, but only limited data are available concerning the association between bronchiectasis and renal transplantation.. We conducted a retrospective multicenter study of cases of bronchiectasis diagnosed after renal transplantation in 14 renal transplantation departments (French SPIESSER group). Demographic, clinical, laboratory and CT scan data were collected.. Forty-six patients were included (mean age 58.2 years, 52.2 % men). Autosomal dominant polycystic kidney disease (32.6 %) was the main underlying renal disease. Chronic cough and sputum (50.0 %) were the major symptoms leading to chest CT scan. Mean duration of symptoms before diagnosis was 1.5 years [0-12.1 years]. Microorganisms were identified in 22 patients, predominantly Haemophilus influenzae. Hypogammaglobulinemia was observed in 46.9 % patients. Bronchiectasis was usually extensive (84.8 %). The total bronchiectasis score was 7.4 ± 5.5 with a significant gradient from apex to bases. Many patients remained symptomatic (43.5 %) and/or presented recurrent respiratory tract infections (37.0 %) during follow-up. Six deaths (13 %) occurred during follow-up, but none were attributable to bronchiectasis.. These results highlight that the diagnosis of bronchiectasis should be considered in patients with de novo respiratory symptoms after renal transplantation. Further studies are needed to more clearly understand the mechanisms underlying bronchiectasis in this setting.

Topics: Adult; Agammaglobulinemia; Aged; Aged, 80 and over; Azathioprine; Bronchiectasis; Chronic Disease; Cough; Cyclosporine; Everolimus; Female; Forced Expiratory Volume; Graft Rejection; Haemophilus Infections; Haemophilus influenzae; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Polycystic Kidney, Autosomal Dominant; Respiratory Tract Infections; Retrospective Studies; Risk Factors; Rituximab; Sirolimus; Tacrolimus; Tomography, X-Ray Computed; Vital Capacity; Young Adult

A 57-year old male patient was admitted to our hospital because of severe vomiting and abdominal pain with massive ascites. He had been diagnosed as mixed connective tissue disease in 1997 and lupus nephritis ISN III (A/C) + V in 2003. Treatment was started with intravenous steroid pulse therapy combined with an immunosuppressant resulting in improvement of his proteinuria and serological activity. In 2008, the disease activity flared and he was admitted to our hospital with nephrotic syndrome. Hemodialysis was unavoidable, despite treatment with intravenous steroid pulse therapy and plasma exchange. We continued to treat him with oral prednisolone and tacrolimus. However, for personal reasons, he terminated tacrolimus treatment and massive ascites remained because of insufficient hemodialysis. Since the end of 2011, he suffered repeated abdominal pain with ileus and encapsulating peritoneal sclerosis (EPS) was detected. In February 2013, he underwent synechotomy for EPS. Here, we present a rare case of EPS in a hemodialysis patient.

Topics: Ascites; Chronic Disease; Digestive System Surgical Procedures; Humans; Ileus; Immunosuppressive Agents; Lupus Erythematosus, Systemic; Lupus Nephritis; Male; Middle Aged; Mixed Connective Tissue Disease; Peritoneal Fibrosis; Prednisolone; Renal Dialysis; Tacrolimus; Tomography, X-Ray Computed

Chronic allograft injury is the most frequent cause of long-term kidney allograft loss. Cyclosporine (CsA) nephrotoxicity is an important factor contributing to graft loss. Increased fibrosis has been reported in renal transplants under CsA as compared with tacrolimus (Tac). Platelet-derived growth factor (PDGF) is a well-characterized fibrogenic growth factor in renal disease.. Here we investigated the effect of Tac on kidney grafts and PDGF expression both early after transplantation as well as during long-term follow-up of rat renal allografts, and compared it to CsA. Tac and CsA were also studied on PDGF secretion in macrophages in vitro.. Kidney allografts were immunosuppressed with Tac or CsA. Grafts were analyzed by histology and immunohistochemistry. ELISA was used to measure PDGF-levels in Tac and CsA-treated macrophage cultures.. Tac ameliorated markedly both acute and chronic changes, whereas moderate to intense histological changes were seen in CsA-treated allografts. Tac also significantly inhibited PDGF expression compared to CsA. At clinically adjusted concentration CsA induced PDGF in macrophages whereas Tac did not.. Tac may be less fibrogenic than CsA by decreasing PDGF expression in kidney grafts as well as in macrophages. Data presented here suggests that decreased PDGF induction by Tac may be beneficial for later outcome of the kidney graft.

Topics: Animals; Cells, Cultured; Chronic Disease; Cyclosporine; Fibrosis; Gene Expression Regulation; Graft Rejection; Immunosuppression Therapy; Kidney; Kidney Transplantation; Macrophages; Male; Platelet-Derived Growth Factor; Rats; Rats, Inbred WF; Tacrolimus; Transplantation, Homologous

Atopic dermatitis (AD) is a commonly encountered inflammatory skin disease. Although acute lesions of acute AD are characterized by intense inflammation, the hallmarks of chronic AD lesions include lichenified fibrosis and thickening of the upper dermis. The increased expression of transforming growth factor beta 1 (TGF-β1), a well-known fibrogenic cytokine, is observed in chronic AD lesions. Tacrolimus (FK506) ointment has been reported to be effective for treating AD as well as some TGF-β1-induced fibrotic diseases.. To evaluate the effect of tacrolimus on TGF-β1-stimulated cultured normal human dermal fibroblasts and explore the potential signalling pathways involved.. Fibroblasts cultured from healthy adult human foreskins were treated with TGF-β1 with or without tacrolimus. The impact on cell viability and proliferation were assessed by [3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide] (MTT) assay and BrdU incorporation assay respectively. Reverse transcription-polymerase chain reaction (RT-PCR), quantitative real-time PCR, enzyme-linked immunosorbent assay (ELISA) and western blotting were performed to evaluate the relevant expressions of mRNA or proteins in fibroblasts.. Our results revealed that the increased expressions of transforming growth factor-β receptor I (TGF-βRI) and TGF-βRII in TGF-β1-treated fibroblasts were suppressed by tacrolimus treatment. In addition, tacrolimus significantly inhibited fibroblast proliferation enhanced by TGF-β1. TGF-β1 increased type I collagen production, and this enhancing effect was suppressed by tacrolimus. The down-regulation of MMP-1 and up-regulation of TIMP-1 induced by TGF-β1 were reversed by tacrolimus. The increase in phosphorylated p38 mitogen-activated protein kinase (p38MAPK) expression stimulated by TGF-β1 was down-regulated by tacrolimus. Moreover, the fibroblasts treated with p38MAPK inhibitor significantly reduced type I collagen expression induced by TGF-β1.. The present results demonstrated that tacrolimus significantly inhibited physiological functions of fibroblasts enhanced by TGF-β1 in vitro. Clinically, we propose that topical tacrolimus may not only reduce AD recurrence but also ameliorate dermal fibrosis often seen in chronic AD lesions.

Topics: Cell Proliferation; Cell Survival; Cells, Cultured; Chronic Disease; Collagen Type I; Dermatitis, Atopic; Down-Regulation; Fibroblasts; Humans; Immunosuppressive Agents; MAP Kinase Signaling System; Matrix Metalloproteinase 1; p38 Mitogen-Activated Protein Kinases; Protein Serine-Threonine Kinases; Receptor, Transforming Growth Factor-beta Type I; Receptor, Transforming Growth Factor-beta Type II; Receptors, Transforming Growth Factor beta; RNA, Messenger; Tacrolimus; Tissue Inhibitor of Metalloproteinase-1; Transforming Growth Factor beta1; Up-Regulation

Topics: Acute Disease; Bone Marrow Transplantation; Boronic Acids; Bortezomib; Chronic Disease; Clinical Trials as Topic; Cyclohexanes; Cyclophosphamide; Cyclosporine; Evidence-Based Medicine; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Hydroxamic Acids; Immunosuppressive Agents; Maraviroc; Methotrexate; Pentostatin; Peripheral Blood Stem Cell Transplantation; Pyrazines; Quality of Life; Tacrolimus; Triazoles; Vorinostat

The topical calcineurin antagonist tacrolimus plays an important role in the treatment of different forms of eczema because of its favorable risk profile. In addition, different off-label indications have been clinically tested where tacrolimus ointment has achieved clinical improvement. This article discusses off-label treatment of vitiligo, seborrheic dermatitis, steroid rosacea, perioral dermatitis, rosacea and lichen sclerosus.

Topics: Administration, Topical; Chronic Disease; Dermatologic Agents; Drug-Related Side Effects and Adverse Reactions; Evidence-Based Medicine; Humans; Immunosuppressive Agents; Off-Label Use; Skin Diseases; Tacrolimus; Treatment Outcome

Lichen sclerosus is a chronic inflammatory dermatosis presenting with significant sclerosis, atrophy and pruritus. The treatment for this condition remains unsatisfactory, with potent corticosteroids being the most effective therapy. In this study, we investigated the efficacy and safety of tacrolimus ointment in patients with genital and extragenital lichen sclerosus. Sixteen patients with active lichen sclerosus (10 with anogenital and six with extragenital localization) were treated with topical tacrolimus ointment twice daily. The therapeutic effects were evaluated according to 3 grades: complete response (>75% improvement), partial response (25-75% improvement), or no response (<25% improvement). Applications were continued until complete disappearance or stabilization of the cutaneous lesions. In addition, we conducted telephone surveys to determine the long-term treatment outcome and relapse rate. Objective response to therapy occurred in nine of 10 patients (90%) with anogenital and one of six patients (16.7%) with extragenital lesions. Out of 10 patients with anogenital lichen sclerosus, five showed more than 75% improvement. Complete, partial and no response were achieved in five (50%), four (40%) and one (10%) patient, respectively. During the follow-up period of a mean of 29.3 months, six of nine patients had a relapse of symptoms. However, most patients with extragenital involvement did not respond to tacrolimus, except one patient showing partial response. No significant adverse effects were observed. Topical tacrolimus ointment was a safe and effective treatment for genital lichen sclerosus and should be used for long-term duration to prevent relapse. However, it was not useful for patients with extragenital lichen sclerosus.

Topics: Adolescent; Adult; Aged; Child; Chronic Disease; Female; Genital Diseases, Female; Genital Diseases, Male; Humans; Immunosuppressive Agents; Lichen Sclerosus et Atrophicus; Male; Middle Aged; Ointments; Tacrolimus; Treatment Outcome; Young Adult

Although currently not authorized in many countries, medical-grade silicone (MGS) injections have been used for 50 years. Sometimes chronic and severe adverse effects refractory to usual therapy other than corticosteroids appear.. To evaluate the effectiveness of tacrolimus in the treatment of refractory cases of late-onset adverse effects related to MGS injections.. Case-series study of seven patients with late-onset adverse effects related to MGS injections. Cases had been treated with a mean of six drugs with poor response before low-tacrolimus dose was introduced. Patients who had received MGS injections with immediate adverse effects or drug responsiveness were excluded. Patients underwent clinical management and follow-up.. Average latency period to onset of symptoms was 65 months (range: 6-144 months). Large, tender, inflammatory nodules; plaques; angioedema; and severe panniculitis were commonly seen. An average of 18 months after tacrolimus administration, five patients were experiencing mild, sparse bouts of inflammatory processes, including nodules, plaques, angioedema, and panniculitis. that were rapidly reversible, and two were in remission. No side effects related to tacrolimus had appeared.. Tacrolimus is an effective and well-tolerated drug in cases of severe and refractory late-onset inflammatory reactions, including large panniculitis, that complicate silicone gel injections.

Topics: Adult; Biocompatible Materials; Chronic Disease; Female; Humans; Immunosuppressive Agents; Inflammation; Injections; Male; Middle Aged; Silicones; Tacrolimus

We hypothesized that Nox2, the classical phagocytic NADPH oxidase, plays an important role in calcineurin inhibitor (CNI)-induced renal fibrosis. We tested this hypothesis in vitro, in animal and in human studies. Cyclosporine A (CsA) and tacrolimus (TAC) were associated with greater levels of Nox2 mRNA and epithelial to mesenchymal transition (EMT) in NRK52E cells. CsA increased Nox2, α-SMA and phosphorylated-p38MAPK, Smad3 and NFκB proteins. Nox2 upregulation and EMT were inhibited in TGF-β1 knockout cells suggesting that TGF-β1 is required for Nox2 activation. Fisher344 rats treated with high dose CsA showed increased Nox2 in the tubulointerstitium and greater Nox2, α-SMA, phosphorylated Smad3 and nitrotyrosine by immunoblot analyses. Inhibition of Nox2 by coadministration of apocynin or diphenyleneiodonium was associated with reduced fibrogenesis. We validated these findings by treating wild type and Nox2 null (B6.129S-Cybb(Tm1Din)/J) mice with high dose CsA. Western blot analyses confirmed the absence of Nox2 and significantly lower levels of α-SMA and 4-hydroxynonenal (HNE) in CsA-treated knockout mice. These findings were clinically relevant since Nox2 and α-SMA were increased in the tubulointerstitium of kidneys from 15 liver transplant recipients with biopsy-confirmed chronic CsA or TAC nephrotoxicity. In conclusion, specific Nox2 inhibition strategies may improve chronic CNI nephrotoxicity in solid organ transplantation.

Topics: Animals; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Epithelial-Mesenchymal Transition; Humans; Immunosuppressive Agents; Kidney; Liver Transplantation; Male; Membrane Glycoproteins; NADPH Oxidase 2; NADPH Oxidases; Rats; Rats, Inbred F344; Real-Time Polymerase Chain Reaction; RNA, Messenger; Tacrolimus; Transforming Growth Factor beta1

Acute graft-versus-host disease (aGVHD) is a major cause of morbidity and mortality in patients undergoing unrelated hematopoietic stem cell transplantation. We prospectively evaluated the efficacy of intermediate-dose rabbit anti-thymocyte globulin (Thymoglobulin® a total of 4.5 mg/kg given over days -3, -2, and -1) in combination with tacrolimus and sirolimus for the prevention of aGVHD. We enrolled 47 recipients who underwent unrelated hematopoietic stem cell transplantation. Patients received daily granulocyte colony-stimulating factor starting on day +6 until neutrophil engraftment (median duration, 11 days; range, 9-15 days). Twenty-two patients received HLA 8/8 and 25 received 7/8 matched grafts, respectively. The median follow-up duration was 23.6 months (range, 18.8-27.9 months). The cumulative incidence of grade II to IV aGVHD was 23.4% (95% confidence interval, 12.4-36.3). At 2-year follow-up, the cumulative incidence of nonrelapse mortality was 31.9%, cumulative incidence of relapse was 24.6%, and cumulative incidence of chronic GVHD was 33%. Progression-free survival at 1 year was 54%, with a median of 17.7 months. Overall survival at 1 year was 65%, with no median reached. These results suggest that the combination of Thymoglobulin, tacrolimus, and sirolimus in patients undergoing unrelated hematopoietic stem cell transplantation is well tolerated and associated with a low incidence and severity of aGVHD and chronic graft-versus-host disease.

Topics: Acute Disease; Adult; Aged; Antilymphocyte Serum; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility Testing; HLA Antigens; Humans; Male; Middle Aged; Myeloablative Agonists; Prospective Studies; Recurrence; Severity of Illness Index; Sirolimus; Survival Rate; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Unrelated Donors

Tacrolimus (FK506) is associated with renal fibrosis in long-term use. Mycophenolatemofetil (MMF) can also inhibit or attenuate the progression of renal fibrosis. This study aimed to determine the different effects of FK506 and MMF on fibrosis-associated genes in the kidney in rats that underwent chronic allograft nephropathy (CAN).. Fisher (F344) kidneys were orthotopically transplanted into Lewis rat recipients. All recipients were given Cyclosporin A (CsA) 10 mg/kg-1.d-1 × 10 day and were then randomly divided into three oral treatment groups (n = 9 in each group): (1) the vehicle group was given vehicle orally; (2) the FK506 group was given 0.15 mg/kg-1.d-1 FK506; and (3) the MMF group was given 20 mg/kg-1.d-1 MMF. At 4, 8, and 12 weeks post-transplantation, serum creatinine (SCr), collagen deposition, Connective tissue growth factor (CTGF), alpha smooth muscle actin (α-SMA) and E-cadherin expressions were determined and hematoxylin-eosin (HE) and Periodic acid-Schiff (PAS) stains were performed.. Renal function progressively deteriorated and showed typical CAN morphology in the vehicle and FK506 groups, while SCr and inflammatory infiltration (Banff score) showed a significant decrease in the MMF group after 8 weeks post-transplantation compared with those in the other groups (p < 0.05). Furthermore, expression levels of CTGF and α-SMA in the MMF group were significantly reduced, and the down-regulated expression of E-cadherin was abated (p < 0.05).. MMF showed favorable effects on renal interstitial fibrosis, thus efficiently retarding the progression of CAN.

Topics: Animals; Chronic Disease; Drug Interactions; Fibrosis; Immunosuppressive Agents; Kidney Diseases; Kidney Transplantation; Mycophenolic Acid; Rats; Rats, Inbred F344; Rats, Inbred Lew; Tacrolimus; Treatment Outcome

To investigate the effect of zinc finger protein A20 on chronic liver allograft dysfunction in rats.. Allogeneic liver transplantation from DA rats to Lewis rats was performed. Chronic liver allograft dysfunction was induced in the rats by administering low-dose tacrolimus at postoperative day (POD) 5. Hepatic overexpression of A20 was achieved by recombinant adenovirus (rAd.)-mediated gene transfer administered intravenously every 10 d starting from POD 10. The recipient rats were injected with physiological saline, rAdEasy-A20 (1 × 10(9) pfu/30 g weight) or rAdEasy (1 × 10(9) pfu/30 g weight) every 10 d through the tail vein for 3 mo starting from POD 10. Liver tissue samples were harvested on POD 30 and POD 60.. Liver-transplanted rats treated with only tacrolimus showed chronic allograft dysfunction with severe hepatic fibrosis. A20 overexpression ameliorated the effects on liver function, attenuated liver allograft fibrosis and prolonged the survival of the recipient rats. Treatment with A20 suppressed hepatic protein production of tumor growth factor (TGF)-β1, interleukin-1β, caspase-8, CD40, CD40L, intercellular adhesion molecule-1, vascular cell adhesion molecule-1 and E-selectin. A20 treatment suppressed liver cell apoptosis and inhibited nuclear factor-κB activation of Kupffer cells (KCs), liver sinusoidal endothelial cells (LSECs) and hepatic stellate cells (HSCs), and it subsequently decreased cytokine mRNA expression in KCs and LSECs and reduced the production of TGF-β1 in HSCs.. A20 might prevent chronic liver allograft dysfunction by re-establishing functional homeostasis of KCs, LSECs and HSCs.

Topics: Adenoviridae; Animals; Apoptosis; Biomarkers; Cells, Cultured; Chronic Disease; Cysteine Endopeptidases; Cytokines; Disease Models, Animal; Endothelial Cells; Gene Expression Regulation; Gene Transfer Techniques; Genetic Therapy; Genetic Vectors; Hepatic Stellate Cells; Immunosuppressive Agents; Inflammation Mediators; Intracellular Signaling Peptides and Proteins; Kupffer Cells; Liver; Liver Cirrhosis; Liver Diseases; Liver Transplantation; Male; NF-kappa B; Rats; Rats, Inbred Lew; Tacrolimus; Time Factors; Transforming Growth Factor beta1; Tumor Necrosis Factor alpha-Induced Protein 3

The relationship between anticalcineurin (CNI) drugs and the development new-onset diabetes mellitus after kidney transplantation (NODAT) is well established. Among these agents cyclosporine shows lesser diabetogenicity than tacrolimus. It has been described that conversion from tacrolimus to cyclosporine improves glycemic control; however, there are no studies showing whether this reduced risk is maintained upon long-term follow-up.. To evaluate whether CNI drugs conversion from tacrolimus to cyclosporine helps to maintain better glycemic control.. We retrospectively evaluated the evolution of glucose metabolism at 5 years after conversion from tacrolimus to cyclosporine in eight patients (six men) with NODAT. Mean age was 42.8 ± 15 years, and time after transplantation to conversion 128 ± 40 months. We analyzed fasting serum glucose, lipid metabolism, renal function, and cyclosporine levels at 0, 6, 12, 24, 36, 48, and 60 months after conversion.. At 6 months after conversion, improved glucose metabolism was observed (268 ± 161 versus 121 ± 31 mg/dL; P < .01) although it was minimal in one case with persistent high blood glycemic levels. Only two patients maintained a normal glucose at the end of follow-up. Five subjects showed increased glycemia at 12 to 24 months after conversion requiring antidiabetic therapy: three patients, insulin and two oral antidiabetic agents. Two patients lost their allografts due to chronic rejection at 32 and 50 months respectively. Among the other six patients, renal function remained stable (1.9 ± 0.6 versus 2.11 ± 0.97 mg/dL; P = NS). There was no significant differences among the other variables. Cyclosporine levels remained stable during the follow-up.. Conversion of renal transplant patients with NODAT from tacrolimus to cyclosporine improves glucose metabolism in the short term but glycemia increases thereafter.

Topics: Adult; Biomarkers; Blood Glucose; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Diabetes Mellitus; Drug Substitution; Female; Graft Rejection; Graft Survival; Humans; Hypoglycemic Agents; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lipids; Male; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adult; Anti-Inflammatory Agents; Atrophy; Brain; Chronic Disease; Cyclophosphamide; Encephalitis; Epilepsy; Facial Hemiatrophy; Female; Humans; Immunosuppressive Agents; Male; Tacrolimus; Young Adult

Chronic kidney disease is directly associated with cardiovascular complications. Heart remodelling, including fibrosis, hypertrophy, and decreased vascularization, is frequently present in renal diseases. Our objective was to investigate the impact of calcineurin inhibitors (CNI) on cardiac remodelling and function in a rat model of renal disease.. Male Sprague Dawley rats were divided into six groups: sham-operated rats, 5/6 nephrectomized rats (Nx) treated with vehicle, CNI (cyclosporine A 5.0 or 7.5, or tacrolimus 0.5 mg/kg/day) or hydralazine (20 mg/kg twice a day) for 14 days, starting on the day of surgery. Creatinine clearance was significantly lower and blood pressure significantly higher in Nx rats when compared with controls. Morphological and echocardiographic analyses revealed increased left ventricular hypertrophy and decreased number of capillaries in Nx rats. Treatment with CNI affected neither the renal function nor the blood pressure, but prevented the development of cardiac hypertrophy and improved vascularization. In addition, regional blood volume improved as confirmed by contrast agent-based echocardiography. Hydralazine treatment did not avoid heart remodelling in this model. Gene expression analysis verified a decrease in hypertrophic genes in the heart of CNI-treated rats, while pro-angiogenic and stem cell-related genes were upregulated. Moreover, mobilization of stem/progenitor cells was increased through manipulation of the CD26/SDF-1 system.. We conclude from our studies that CNI-treatment significantly prevented cardiac remodelling and improved heart function in Nx rats without affecting renal function and blood pressure. This sheds new light on possible therapeutic strategies for renal patients at high cardiovascular risk.

Topics: Animals; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Heart Diseases; Hypertrophy, Left Ventricular; Immunosuppressive Agents; Kidney Diseases; Male; Nephrectomy; Random Allocation; Rats; Rats, Sprague-Dawley; Tacrolimus; Ventricular Remodeling

Chronic kidney disease (CKD) is common in liver transplant recipients receiving calcineurin inhibitors.. The goals of this case-control study were to identify risk factors associated with CKD and its effect on mortality in 294 liver transplant recipients receiving calcineurin inhibition with tacrolimus.. Hepatitis C virus (HCV) was the most common indication (42%) for transplantation. CKD 4 and 5 (estimated glomerular filtration rate (eGFR) of <=29 ml/min/1.73 m2) developed in 10.8% of recipients during a mean follow-up of 52 months. The incidence density of CKD was 2.56 per 100 patient-years. End-stage renal disease developed in 2.7%. By univariate analysis, CKD patients were older (mean±sd, 57±10 vs. 51±11, p<0.05) with hypertension (56 vs. 32%, p<0.05), had lower preoperative hematocrit (31±6 vs. 34±5, p<0.05), alanine aminotransferase (median (95% confidence limit) 46 (34–80) vs. 68 (56–77), <0.05) and eGFR (56±28 vs. 91±35 ml/ min/1.73 m2, p<0.05), had higher preoperative prothrombin time (16.1 (14.6–17.2) vs. 14.8 (14.5–15.1) seconds, p<0.05), and required more perioperative renal replacement therapy (RRT) (41% vs. 6.5%, p<0.05) compared to controls. Perioperative need for RRT (hazard ratio (95% CI) 2.72 (1.05–7.03)) and lower preoperative eGFR: 60–89 (4.08 (1.23–13.5)), 30–59 (4.26 (1.18–15.36)), and<=29 (5.91 ((1.28–27.19)) vs. eGFR>=90 ml/min/1.73 m2 were independently associated with development of CKD adjusting for important covariates. The development of CKD (2.36 (1.22–4.59)) was independently associated with late mortality with an attributable risk of 12.8%.. Data demonstrate that CKD is an important clinical event associated with increased risk for death after primary liver transplantation.

Topics: Adult; Aged; Calcineurin Inhibitors; Case-Control Studies; Chi-Square Distribution; Chronic Disease; Drug Therapy, Combination; Florida; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Failure, Chronic; Liver Transplantation; Male; Middle Aged; Proportional Hazards Models; Renal Replacement Therapy; Retrospective Studies; Risk Assessment; Risk Factors; Tacrolimus; Time Factors

This study investigated the increase in interstitial fibrosis (IF) from 0 hr to 1 month and 1 year posttransplantation in biopsy sections and assessed the risk of developing IF in 118 living kidney recipients.. A quantitative analysis of IF was performed using computer-assisted imaging. The percent IF (%IF) in the cortical region at 0 hr was defined as the baseline, and the increases in %IF at 1 month and 1 year were calculated. Demographics, higher (regimen 1) and lower (regimen 2) target trough concentrations of tacrolimus, and the cytochrome P450 (CYP) 3A5 polymorphism were tested as risk factors.. The mean %IF at 0 hr, 1 month, and 1 year was 10.3%+/-4.2%, 15.0%+/-5.8%, and 19.0%+/-7.7%, respectively. %IF increased 1.7- and 2.2-fold from 0 hr to 1 month and 1 year posttransplantation, respectively. At 1 year, the increase was higher in patients with the CYP3A5*3/*3 genotype (nonexpressers), those treated with regimen 1, and those with a lower estimated glomerular filtration rate and higher body mass index. In a multivariate analysis, CYP3A5 nonexpression correlated with the development of IF (odds ratio 2.63, P=0.018). Tacrolimus blood levels in the early stage posttransplantation were higher in nonexpressers than CYP3A5 expressers in both regimens 1 and 2, despite therapeutic drug monitoring.. The higher concentrations of tacrolimus, especially in the nonexpressers treated with regimen 1, might influence the development of IF. This study suggested that a new regimen with lower and narrow target trough levels of tacrolimus or a dosing strategy based on the CYP3A5 genotype is needed to reduce the risk of developing IF.

Topics: Adult; Aged; Body Mass Index; Chronic Disease; Cohort Studies; Cytochrome P-450 CYP3A; Female; Fibrosis; Glomerular Filtration Rate; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Postoperative Complications; Tacrolimus; Treatment Outcome; Young Adult

Topics: Administration, Cutaneous; Adolescent; Chronic Disease; Dry Eye Syndromes; Graft vs Host Disease; Humans; Inflammation; Male; Ointments; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Tacrolimus; Treatment Outcome

Atopic dermatitis (AD) is a common chronic relapsing pruritic skin disease of dogs for which treatment has varied over time and geographical location. Recent high quality randomized controlled trials and systematic reviews have established which drugs are likely to offer consistent benefit. The International Task Force for Canine AD currently recommends a multi-faceted approach to treat dogs with AD. Acute flares should be treated with a combination of nonirritating baths and topical glucocorticoids, once an attempt has been made to identify and remove the suspected causes of the flare. Oral glucocorticoids and antimicrobial therapy must be added when needed. In dogs with chronic AD, a combination of interventions should be considered. Again, factors that trigger flares of AD must be identified and, if possible, avoided. Currently recognized flare factors include food, flea and environmental allergens, Staphylococcus bacteria and Malassezia yeast. Skin and coat hygiene and care must be improved by bathing with nonirritating shampoos and dietary supplementation with essential fatty acids. The severity of pruritus and skin lesions can be reduced with a combination of anti-inflammatory drugs. Currently, medications with good evidence of high efficacy include topical and oral glucocorticoids, and calcineurin inhibitors such as oral ciclosporin and topical tacrolimus. The dose and frequency of administration of these drugs should be tailored to each patient considering each drug's efficacy, adverse effects and cost. Allergen-specific immunotherapy should be offered, whenever feasible, in an attempt to prevent recurrence of clinical signs upon further exposure to environmental allergens to which the patient is hypersensitive.

Topics: Acute Disease; Administration, Oral; Administration, Topical; Animals; Anti-Infective Agents; Anti-Inflammatory Agents; Baths; Chronic Disease; Cyclosporine; Dermatitis, Atopic; Dermatologic Agents; Dog Diseases; Dogs; Drug Therapy, Combination; Glucocorticoids; Tacrolimus

Topics: Chronic Disease; Drug Resistance, Bacterial; Ethics, Research; Humans; Immunosuppressive Agents; Otitis Externa; Pruritus; Tacrolimus

Topics: Administration, Topical; beta-Thalassemia; Bone Marrow Transplantation; Chemotherapy, Adjuvant; Child; Chronic Disease; Combined Modality Therapy; Dermatitis, Seborrheic; Dermatologic Agents; Follow-Up Studies; Graft vs Host Disease; Humans; Male; Radiotherapy, Adjuvant; Severity of Illness Index; Tacrolimus; Treatment Outcome

A 64-year-old woman underwent allogeneic peripheral blood-derived stem cell transplantation for acute lymphocytic leukemia. She complained of dyspnea and was admitted to hospital 116 days after transplantation. Because of positive serum testing for the Aspergillus antigen and antibody, and ground-glass opacity in the right upper lobe on high-resolution computed tomography (HRCT), we made a diagnosis of pulmonary aspergillosis and administered an antifungal agent. Although tests for the Aspergillus antibody became negative and the ground-glass opacities disappeared, her dyspnea persisted. Progressive bronchiectasis was seen on HRCT, predominantly in the lower lobes. A pulmonary function test showed mixed impairment. We made a diagnosis of bronchiolitis obliterans after chronic graft versus host disease (GVHD). Prednisolone and an increased dose of tacrolimus (FK506) were administered, but type II respiratory failure progressed and she died 2 months after admission. On HRCT, each lobe was graded for bronchiectasis using a scale: 0 = normal, 1 = less than 2 x the diameter of an adjacent pulmonary artery, 2 = 2 - 3 x the diameter of an adjacent pulmonary artery, and 3 = more than 3 x the diameter of an adjacent pulmonary artery. A total score was calculated by summing the scores of all the lobes (maximum 15). In this case, the total score increased rapidly from 0 to 13 in 2 months.

Topics: Bronchiectasis; Bronchiolitis Obliterans; Chronic Disease; Disease Progression; Fatal Outcome; Female; Graft vs Host Disease; Humans; Middle Aged; Peripheral Blood Stem Cell Transplantation; Precursor Cell Lymphoblastic Leukemia-Lymphoma; Respiratory Insufficiency; Severity of Illness Index; Tacrolimus; Tomography, X-Ray Computed; Transplantation, Homologous

This retrospective study was conducted to assess the efficacy and safety of immunosuppression conversion on progression of chronic allograft nephropathy (CAN).. One-hundred and seventy-four cyclosporin (CsA)-treated renal transplant recipients were studied. Patients were included if they had a biopsy-proven CAN (mild to moderate) with serum creatinine < or =3.5 mg/dL. Patient treatment was switched to either: (A) MMF/reduced dose CsA (MMF for azathioprine (Aza); n = 132); or (B) Aza/Tac for CsA (n = 42). Patient records were checked for graft function and survival, and for co-morbidities after conversion.. Mean follow-up before conversion was 52.2 +/- 31.1 and 47.9 +/- 27.4 months for groups A and B, respectively. There was significant deterioration of graft function in group B after five years (P < 0.5). Ten-year actuarial graft survival was 38% in group A and 19% in group B (P = 0.04). Nine patients (five patients and four patients in groups A and B, respectively) started dialysis within 12 months. Tacrolimus-treated patients had a lower insignificant incidence of hyperlipidemia (P = 0.05), but a significantly higher incidence of diabetes mellitus (P = 0.04).There was no significant change or difference in blood pressure between groups.. Our results suggest that in patients with CAN and deteriorating allograft function, CsA minimization and addition of MMF achieved favorable efficacies in retarding the decline of graft function. Further prospective studies with larger cohorts are needed for validation.

Topics: Adult; Azathioprine; Chronic Disease; Cyclosporine; Disease Progression; Drug Therapy, Combination; Female; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kaplan-Meier Estimate; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

Renal disease is commonly encountered by primary care physicians during their day-to-day visits with patients. Common renal disorders include hypertension, proteinuria, kidney stones, and chronic kidney disease. Despite their prevalence, many physicians may be unfamiliar with the diagnosis and initial treatment of these common renal disorders. Early recognition and intervention are important in slowing the progression of chronic kidney disease and preventing its complications. The evidence-based pearls in this article will help primary care physicians avoid common pitfalls in the recognition and treatment of such disorders and guide their decision to refer their patients to a specialist.

Topics: Aluminum; Anemia; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Antacids; Blood Pressure; Blood Urea Nitrogen; Cardiovascular Diseases; Cathartics; Chronic Disease; Contraindications; Creatinine; Cyclosporine; Disease Progression; Drug Interactions; Drug-Related Side Effects and Adverse Reactions; Erythropoietin; Evidence-Based Medicine; Glomerular Filtration Rate; Humans; Hypertension; Immunosuppressive Agents; Kidney Diseases; Magnesium; Nephrolithiasis; Nephrology; Phosphates; Primary Health Care; Proteinuria; Recombinant Proteins; Referral and Consultation; Tacrolimus; Urinalysis

We evaluated the efficacy of a post-grafting immunosuppressive regimen consisting of tacrolimus, methotrexate, and mycophenolate mofetil (MMF) in 21 adults (median age, 55 years) with poor-risk hematologic malignancy who underwent unrelated bone marrow transplantation after fludarabine-based reduced-intensity conditioning (RIC). In combination with intravenous tacrolimus and minidose methotrexate (5 mg/m2 on days 1, 3, and 6), MMF was orally administered at 30 mg/kg daily in three divided doses between days 7 and 27. All patients achieved neutrophil recovery with donor-type chimerism at a median of 19 days (range, 13-35). Cumulative incidences of grades II-IV and III-IV acute graft-versus-host disease (GVHD) were 33% (95% CI, 15-53%) and 5% (95% CI, 0.3-20%), respectively. Five of 20 evaluable patients developed extensive chronic GVHD. Toxicities associated with the use of MMF were acceptable, although one patient experienced intractable GVHD immediately after the cessation of MMF. With a median follow-up of 24 months, overall survival at 3 years was 38% (95% CI, 14-63%). No late graft failure was observed. In conclusion, post-transplant MMF combined with tacrolimus and methotrexate was well tolerated and conferred stable donor cell engraftment, low risk of severe acute GVHD, and encouraging overall survival in unrelated donor marrow transplantation after RIC regimens.

Topics: Acute Disease; Adult; Aged; Bone Marrow Transplantation; Chronic Disease; Dose-Response Relationship, Drug; Graft vs Host Disease; Humans; Leukemia; Methotrexate; Middle Aged; Mycophenolic Acid; Survival Rate; Tacrolimus; Transplantation Conditioning

In this study, we investigated the effects of low-dose antithymocyte globulin (ATG, thymoglobulin) in the prevention of acute graft-versus-host disease (aGVHD) in mismatched, unrelated hematopoietic stem cell transplantations (uHSCTs) in patients with the single disease entity of acute myelogenous leukemia (AML). Patients (n = 103) with a variable risk for AML who received uHSCTs from available Asian and Caucasian donors were enrolled. First, we compared HLA-matched (group 1, n = 54) and HLA-mismatched (group 2, n = 49) transplantation patients. Then, we divided the patients in group 2, who had received transplants from allele(s)/antigen-mismatched donors, into 2 subgroups: patients who used ATG (group 3, n = 24) and those who did not (group 4, n = 25). To prevent the development of aGVHD, the patients in group 3 received ATG at a dose of 1.25 mg/kg body weight per day for 2 consecutive days, together with our standard regimen of methotrexate (MTX) and tacrolimus. The median CD34(+) cell infusion was 4.2 x 10(6)/kg (range: 1.2-34.4). The median patient age was 41 years (range: 16-57), and the median follow-up duration of patients who were event-free survivors was 23 months (range: 2-72). The overall incidences of aGVHD and chronic GVHD (cGVHD) were 38% and 56%, respectively. Of 48 evaluable patients in group 2, 10 (21%) developed moderate to severe aGVHD (grades II-IV). In contrast, 2 (8%) of the 24 patients in group 3 and 7 (29%) of the 24 evaluated patients in group 4 required therapy for aGVHD (grades II-IV; P = .038). The incidence of cGVHD was not different between groups 3 and 4. The estimated probabilities of overall survival (OS) and event-free survival (EFS) at 2 years for group 2 were 55% and 44%, respectively. In comparison, the estimated probabilities of OS and EFS at 2 years for groups 3 and 4 were 68% versus 38% (P = .043) and 58% versus 38% (P = .103), respectively. The overall cumulative incidence of nonrelapse mortality (NRM) was 29% in group 2. The cumulative incidence of NRM differed markedly between group 3 (16%; 95% confidence interval [CI], 4%-28%) and group 4 (44%, 95% CI, 34%-54%) (P = .013). We found no difference in cytomegalovirus (CMV) reactivation between groups 3 and 4. These results suggest that in mismatched uHSCT, a low dose of ATG (total 2.5 mg/kg) may prevent moderate to severe aGVHD, with comparable rates of relapse and CMV reactivation and a greatly decreased rate of NRM.

Topics: Acute Disease; Adolescent; Adult; Antilymphocyte Serum; Chronic Disease; Disease-Free Survival; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Histocompatibility; HLA Antigens; Humans; Incidence; Leukemia, Myeloid; Living Donors; Male; Methotrexate; Middle Aged; Prospective Studies; Survival Analysis; T-Lymphocytes; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous; Young Adult

Chronic graft versus host disease (GVHD) is a common late complication of hematopoietic stem cell transplantation. Polymyositis is a rare manifestation of chronic GVHD after donor lymphocyte infusion (DLI). Patients with both polymyositis and myocarditis have not been reported to date. Here, we report an 18-year-old female patient who developed polymyositis and myocarditis after a DLI. The patient developed the symptoms of fever, generalized myalgia, dysarthria, and asymptomatic sinus tachycardia at DLI day +102, and 17 days after the discontinuation of immunosuppressants. The laboratory testing showed elevated muscle enzymes, and the electromyographic examination revealed myopathic abnormalities compatible with the diagnosis of myositis. The muscle biopsy showed CD8+ T cell infiltration of the muscle fibers. The electrocardiogram (ECG) showed sinus tachycardia with an incomplete right bundle branch block, anteroseptal ST elevation and lateral ST depression. Echocardiography showed mild hypokinesia of the left interventricular septal wall without evidence of infection or leukemic relapse. The patient was immediately treated with 60 mg/day of prednisone and tacrolimus after the diagnosis of polymyositis and myocarditis, apparently associated with chronic GVHD. The cardiac and muscle enzymes decreased and the ECG normalized after immunosuppressant treatment. The follow-up ECG 2 weeks after initiation of therapy was normal.

Topics: Acute Disease; Adolescent; Anti-Inflammatory Agents; Blood Donors; Chronic Disease; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia; Lymphocyte Transfusion; Myocarditis; Polymyositis; Prednisone; Tacrolimus

Increased risk of cardiovascular and cerebrovascular disease in liver transplant recipients results in particular from the side effects of calcineurin inhibitor-based immunosuppressive therapy. Several studies have demonstrated a more favourable outcome for patients receiving tacrolimus (TAC) as compared with ciclosporin (CS).. To investigate the effects of conversion from CS to TAC on cardiovascular risk factors and renal function in liver transplant recipients.. In a prospective study, all except two patients had chronic kidney disease stages 2-4 (n = 80), according to estimated glomerular filtration rate using the abbreviated Modification of Diet in Renal Disease equation.. Conversion was accompanied with a mean decrease of total cholesterol from 194.6 +/- 54.0 mg/dL to 175.8 +/- 44.2 mg/dL (P < 0.001), low density lipoprotein cholesterol from 106.7 +/- 39.2 mg/dL to 90.9 +/- 28.6 mg/dL (P < 0.001) and mean arterial blood pressure values from 102.2 +/- 13.2 mm Hg to 95.9 +/- 11.7 mm Hg (P < 0.001). Renal function remained stable. No cases of de novo diabetes mellitus were identified. The Framingham risk score was significantly reduced from 5.2 +/- 4.4 at baseline to 4.4 +/- 5.3 after 12 months (P = 0.006).. Conversion from CS to TAC has been shown to improve the cardiovascular risk profile and may retard further decline of renal function after liver transplantation.

Topics: Adult; Aged; Cardiovascular Diseases; Chronic Disease; Cyclosporine; Disease Progression; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Kidney Diseases; Kidney Function Tests; Liver Diseases; Liver Transplantation; Male; Middle Aged; Prospective Studies; Risk Factors; Tacrolimus; Treatment Outcome

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

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

Topics: Adult; Blood Vessels; Chronic Disease; Eosinophils; Eyelid Diseases; Eyelids; Fibrosis; Humans; Immunosuppressive Agents; Male; Neutrophils; Plasma Cells; Tacrolimus; Vasculitis, Leukocytoclastic, Cutaneous

Switching from cyclosporine to tacrolimus without steroid pulse was suggested as a therapeutic option in chronic allograft nephropathy (CAN). Thirty-one renal transplant recipients with CAN were prospectively converted from cyclosporine to tacrolimus (group A), in parallel 31 matched cyclosporin A (CsA) patients (group B) without CAN were followed up for 30 months. In six matching patients of groups A and B inulin and para-aminohippurate (PAH)-clearances and mycophenolate were measured over a span of 3 months. Transplant biopsies of group A were scored according to BANFF. While group A presented with transplant dysfunction compared with group B before switching (2.7 +/- 0.16 mg/dl vs. 1.7 +/- 0.09 mg/dl; P < 0.001), transplant function was equal 30 months later: it ameliorated in group A (2.0 +/- 0.18 mg/dl vs. 2.7 +/- 0.16 mg/dl; P < 0.001) and decreased in group B (1.9 +/- 0.13 mg/dl vs. 1.7 +/- 0.09 mg/dl, P < 0.05). Especially, patients with biopsy scores I and II according to BANFF benefited from tacrolimus. Within 3 months, mycophenolate acid (MPA) levels increased under tacrolimus (P < 0.05) whereas inulin and PAH-clearances remained unchanged. At switching, antihypertensive treatment was more intense in group B, but this difference evened out. Adverse side effects were more frequent under tacrolimus. Patients with mild to moderate CAN significantly benefited from switching to tacrolimus. Increased MPA-levels under tacrolimus might have contributed to this effect.

Topics: Adult; Biopsy; Blood Pressure; Chronic Disease; Cyclosporine; Female; Glomerular Filtration Rate; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Transplantation, Homologous

To investigate the risk factors of insulin resistance (IR) and the role of IR and metabolic syndrome in the pathogenesis of chronic allograft nephropathy (CAN).. One hundred and twenty-seven kidney transplant recipients with normal renal function and no proteinuria at the 6th month after transplantation, and without the experience of acute rejection, calcinurine intoxication and severe infection, were involved in the study. Their primary disease of ESRF was chronic glomerulonephritis but not diabetes mellitus and hypertension. Half year and one year after transplantation, blood and urine biochemical determinations and physical examination were performed in the recipients, and HOMA calculated. 200 ordinary community residents were randomized selected as controls.. The incidence of MS in the recipients was significantly higher than controls. The incidences of obesity and overweight between recipients and controls were no significant difference. While the insulin resistance level and urine albumin level, and the incidence of MS and microalbuminuria (MAU) were significantly higher in recipients with obesity or overweight than that in recipients without obesity or overweight. The insulin resistance level in tacrolimus-treated recipients was markedly higher than CsA-treated recipients, and there was a positive correlation between the blood concentration of tacrolimus and insulin resistance level. MAU positive recipients had higher insulin resistance levels than the recipients without MAU. The recipients with metabolic syndrome had higher insulin resistance levels compared to recipients without metabolic syndrome, and higher insulin resistance levels existed in recipients with hypertriglyceridemia or hypercholesterolemia, hypertension.. It is shown in the study that obesity or overweight, tacrolimus (especially when its blood concentration was high) were risk factors resulting in insulin resistance in kidney transplant recipients. It is suggested in the study that insulin resistance often accompanied with hypertriglyceridemia, hypercholesterolemia and hypertension in kidney transplant recipients might be involved in the pathogenesis of the pathogenesis of CAN.

Topics: Adult; Chronic Disease; Cyclosporine; Female; Glomerulonephritis; Humans; Incidence; Insulin Resistance; Kidney Transplantation; Male; Metabolic Syndrome; Middle Aged; Overweight; Risk Factors; Tacrolimus

Topics: Adrenal Cortex Hormones; Biopsy, Needle; Chronic Disease; Disease Progression; Drug Therapy, Combination; Female; Humans; Immunohistochemistry; Lichen Planus; Needs Assessment; Prognosis; Quality of Life; Risk Assessment; Severity of Illness Index; Tacrolimus; Vulvovaginitis

Topics: Adult; Chronic Disease; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Male; Middle Aged; Mouth Diseases; Tacrolimus

Female NC/Jic mice were sensitized and challenged repeatedly at 48 h intervals for 10 and 30 days by painting 1% 2,4,6-trinitrochlorobenzene (TNCB) on both ears. Mice challenged with TNCB for 30 days developed an inflammatory dermatitis with high immunoglobulin E (IgE) titer. Histological analysis with acidic Toluidine Blue staining revealed that dermal mast cells markedly differentiated and intensely degranulated, consistent with a dramatic increase in scratching behavior. A significant increase in total scratching events could be observed in mice treated with TNCB for a short period of 10 days. Extending the term of TNCB application to 30 days, the IgE titer and number of mast cells elevated significantly, and thus various drugs were evaluated pharmacologically by using the mice treated with TNCB for 30 days. Terfenadine and cyproheptadine attenuated the chronic scratching behavior. Tacrolimus and dexamethasone were less effective and cromolyn showed no effect. In addition, terfenadine and tacrolimus suppressed the degranulation of mast cells. The present chronic scratching model could be suitable to evaluate drugs effective for suppression of mast cell differentiation and degranulation by irritation, and may represent a promising tool to develop new drugs for inflammatory pruritus associated with, for example, atopic dermatitis.

Topics: Animals; Antipruritics; Cell Degranulation; Chronic Disease; Cromolyn Sodium; Cyproheptadine; Dermatitis, Atopic; Dexamethasone; Disease Models, Animal; Dose-Response Relationship, Drug; Drug Evaluation, Preclinical; Female; Immunoglobulin E; Mast Cells; Mice; Picryl Chloride; Pruritus; Tacrolimus; Terfenadine; Time Factors

The aim of this study was to assess the efficacy of FK778 to prevent acute and chronic allograft rejection compared with other immunosuppressive agents.. Heterotopic Brown-Norway (BN)-to-Lewis rat cardiac transplantations and heterotopic BN-to-Lewis tracheal transplantations were performed to study acute heart rejection and the development of chronic obliterative airway disease (OAD), respectively. Recipients were treated with FK778, tacrolimus, MMF, or sirolimus for 10 days (acute rejection study) or 28 days (chronic OAD study) at varying doses.. In untreated recipients, cardiac allograft survival was 6.2 +/- 0.4 days. FK778 (20 mg/kg), tacrolimus (2 or 8 mg/kg), mycophenolate mofetil (MMF; 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly prolonged graft survival to 17.0 +/- 2.8, 18.5 +/- 2.7, 25.0 +/- 2.5, 20.7 +/- 3.8, 14.5 +/- 2.2, and 23.2 +/- 1.5 days, respectively (P < .05). Tracheal grafts in untreated recipients showed intense infiltration and complete luminal obliteration by day 28. FK778 (20 mg/kg), tacrolimus (1 or 4 mg/kg), MMF (10 or 40 mg/kg), or sirolimus (0.5 or 2 mg/kg) significantly inhibited tracheal luminal obliteration (19.5% +/- 16.4%, 44.2% +/- 33.6%, 12.3% +/- 3.3%, 61.7% +/- 18.6%, 18.3% +/- 11.3%, 55.0% +/- 30.9%, and 8.5% +/- 3.5% (P < .05). All 4 high-dose groups showed similar efficacy.. When used in therapeutic doses, tacrolimus and sirolimus were more effective than FK778 to prolong cardiac allograft survival. However, with its antiproliferative effects on smooth muscle cells, its good tolerability, and its blockade of cytomegalovirus replication, FK778 proved effective to prevent chronic OAD development. Thus, FK778 may acquire an important role in maintenance therapy for the prevention of long-term fibroproliferative complications.

Topics: Acute Disease; Alkynes; Animals; Chronic Disease; Disease Models, Animal; Graft Rejection; Graft Survival; Heart Transplantation; Immunosuppressive Agents; Isoxazoles; Nitriles; Rats; Rats, Inbred BN; Rats, Inbred Lew; Sirolimus; Tacrolimus; Trachea; Transplantation, Homologous

Topics: Acute Disease; Calcineurin Inhibitors; Chronic Disease; Cyclosporine; Drug Interactions; Graft Rejection; Humans; Immunosuppressive Agents; Patient Selection; Tacrolimus; Transplantation Immunology

The present study calculated the risk of developing subclinical progressive chronic/sclerosing allograft nephropathy (CAN) under tacrolimus-based immunosuppression according to genetic polymorphisms of cytokines and growth factors, and clinical events including delayed graft function (DGF), acute rejection (AR) and cytomegalovirus (CMV) infection.. The subjects were 50 recipients with stable graft function more than one year after renal transplantation. The criteria for subclinical progressive CAN were CAN grade 2 or 3 changes on Banff classification and stable serum creatinine (SCr) levels. Ten genetic polymorphisms were assessed.. Eleven patients (22.0%) developed progressive CAN. The mean ages and SCr levels of recipients with and without progressive CAN were 41.2 and 47.1 years, and 1.46 and 1.22 mg/dL, respectively. There were no significant differences in donor age, number of HLA mismatches, DGF or CMV infection. Although the rate of AR episode seemed to be greater in patients with subclinical progressive CAN, the difference did not reach significance (P = 0.093). The frequencies of the interleukin (IL)-2 T-330G TT genotype (P = 0.046) and IL-4 C-590T C allele (P = 0.092) were higher in patients with progressive CAN. In univariate analysis, the presence of IL-2 T-330G TT (OR 4.57, P = 0.044) was associated with CAN development.. The presence of IL-2 T-330G TT genotype may be a risk factor for CAN. Further studies with a large number of subjects and analyses of many cytokine polymorphisms would contribute to the ability to make prognostic determinations or tailor immunomodulatory regimens after renal transplantation.

Topics: Chronic Disease; Creatinine; Female; Follow-Up Studies; Genotype; Humans; Immunosuppressive Agents; Interleukin-2; Interleukin-4; Japan; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Polymorphism, Single Nucleotide; Risk Factors; Tacrolimus

Topics: Blepharitis; Chronic Disease; Conjunctivitis; Conjunctivitis, Allergic; Humans; Immunosuppressive Agents; Keratoconjunctivitis; Tacrolimus; Treatment Outcome

Topics: Adrenal Cortex Hormones; Chronic Disease; Disease Progression; Graft vs Host Disease; Humans; Immunosuppressive Agents; Leukemia, Myeloid, Acute; Male; Middle Aged; Prognosis; Risk Factors; Stem Cell Transplantation; Tacrolimus

Topics: Adult; Chronic Disease; Dry Eye Syndromes; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Tacrolimus; Tears; Treatment Outcome

Progressive renal-function decline caused by chronic allograft nephropathy is the main cause of long-term failure after kidney transplantation. Moreover, chronic cyclosporine (CsA)-induced nephrotoxicity is an important nonimmunologic factor contributing to graft dysfunction and loss, and adverse events may require CsA withdrawal.. Tacrolimus (Tac) replaced CsA-based immunosuppression in 133 transplant patients (114 kidney, 15 kidney-pancreas, 4 pancreas after kidney) with progressive loss of renal function (71% of patients) or CsA intolerance (29% of patients) not responding to CsA dose-lowering. The primary end-points of this prospective study focusing on renal function were the safety and efficacy of Tac immunosuppression.. Tac was generally well tolerated but definitively withdrawn for 23 (17%) patients (21 graft failures, 1 case of diabetes, and 1 case of clinical intolerance). Differential creatinemia (creatinemia-nadir creatinemia after transplantation) decreased significantly from 85.4+/-9.8 to 39.0+/-7.5 mumol/L (P<0.001; mean+/-SEM) after 1 year and 3.6+/-18.1 mumol/L (P<0.01) after 4 years. For patients with CsA intolerance, switch to Tac improved intolerance symptoms in all cases. Blood urea, creatinine clearance, blood total cholesterol, and triglycerides improved significantly, and the percentage of hypertensive patients remained stable with no de novo hypertension. During follow-up, one patient experienced an acute rejection episode (not histologically proven), and four died. Twenty-one (16%) transplants failed, significantly more frequently in patients with advanced renal impairment before Tac (P<0.0001).. Switching from CsA to Tac can be an alternative strategy in kidney-transplant patients suffering from chronic allograft dysfunction or CsA toxicity. The persistently improved renal function over several months of evaluation suggests that in these patients, Tac might be less nephrotoxic than CsA and could prolong transplant function despite CsA failure.

Topics: Adolescent; Adult; Aged; Chronic Disease; Cyclosporine; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Pancreas Transplantation; Prospective Studies; Tacrolimus

Nephrotoxicity of calcineurin inhibitors (CNI) complicates the management of chronic renal allograft dysfunction. Rapamycin is a promising immunosuppressive agent free of nephrotoxicity. The effect of conversion from CNI to rapamycin in recipients with chronic allograft dysfunction is still unclear. We investigated the effect of rapamycin in patients with chronic allograft dysfunction.. We conducted a prospective study on kidney transplant recipients with chronic allograft dysfunction. The patients were under classic CNI, mycophenolate mofetil, and prednisolone triple therapy. They had progressive deterioration of the allograft function. They were converted from CNI to rapamycin directly and observed for 6 months. The CNI serum levels before the conversion were within recommended range. Allograft function, clinical features and adverse effects were evaluated before and after the rapamycin conversion.. A total of 16 patients were enrolled. Six of them (37.5%) failed to have a smooth conversion because of deterioration of allograft function and intractable adverse effects. Ten patients (62.5%) went through the 6-month observation period with improved graft function. The average reduction of serum creatinine was 27.7% (p < 0.001) in successful conversion. There were no significant differences on age, gender, lipid profile, sugar control, and rapamycin levels between successful and failed conversion. Anemia and diastolic blood pressure were significantly improved after successful conversion. The failed patients had a longer transplantation period (6.1 +/- 4.1 vs. 11.2 +/- 3.4 yr, p < 0.05). Two of them (12.5%) developed bacteria pneumonia. Self-limited diarrhea developed in three patients (18.8%).. We suggested that conversion from CNI to rapamycin was beneficial in some kidney transplant recipients with chronic allograft dysfunction.

Topics: Adult; Aged; Blood Glucose; Blood Pressure; Calcineurin Inhibitors; Case-Control Studies; Chronic Disease; Creatinine; Cyclosporine; Female; Follow-Up Studies; Graft Survival; Hemoglobins; Humans; Immunosuppressive Agents; IMP Dehydrogenase; Kidney; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisolone; Prospective Studies; Sirolimus; Tacrolimus

Topics: Chronic Disease; Female; Humans; Immunosuppressive Agents; Middle Aged; Necrobiosis Lipoidica; Ointments; Tacrolimus

Pimecrolimus (SDZ ASM 981), an ascomycin derivative, as one of the new classes of immunomodulating macrolactams, is specifically effective in the treatment of inflammatory skin diseases. The interest in pimecrolimus is highly important for its significant anti-inflammatory activity, cell-selective inhibition of inflammatory cytokines, immunomodulatory capabilities, and low systemic immunosuppressive potential. The mechanism of action of pimecrolimus is the blockage of T cell activation, blocking signal transduction pathways in T cells, and inhibition of the synthesis of inflammatory cytokines, specifically Th1- and Th2-type cytokines. Several studies have evaluated the effectiveness of pimecrolimus as the treatment of choice for inflammatory skin diseases.

Topics: Chronic Disease; Dermatitis, Atopic; Eczema; Immunologic Factors; Immunosuppressive Agents; Inflammation; Psoriasis; Skin Diseases; Tacrolimus

To report 4 cases of patients treated with topical tacrolimus ointment 0.03% for ocular inflammatory conditions refractory to traditional treatment.. Four patients were treated topically with tacrolimus 0.03% ointment twice daily: 2 patients with blepharokeratoconjunctivitis, 1 patient with severe atopic keratoconjunctivitis, and 1 patient with chronic follicular conjunctivitis.. Three patients had a dramatic improvement of their ocular condition as early as 2 weeks after starting tacrolimus ointment. One patient developed a herpes simplex virus dendrite after 1 week of tacrolimus use.. Tacrolimus ointment appears to be an effective alternative for certain ocular inflammatory conditions refractory to traditional treatments. There may be an increased risk of herpes simplex virus keratitis associated with topical use. Our results support previous literature of patients benefiting from topical tacrolimus use.

Topics: Administration, Topical; Adult; Aged; Blepharitis; Chronic Disease; Conjunctivitis; Conjunctivitis, Allergic; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Keratitis, Dendritic; Keratoconjunctivitis; Male; Middle Aged; Ointments; Tacrolimus; Treatment Outcome

Chronic graft versus host disease (cGVHD) is the most common late complication after allogeneic hematopoietic stem cell transplantation (allo-HSCT) and it represents the major cause of mortality in long-term survivors. Over the past decade, although conventional therapy has achieved complete responses in approximately 50% of patients, the prophylaxis and treatment of cGVHD are still not satisfactory. In the late years, utilization of new immunosuppressant such as tacrolimus (FK506), mycophenolate mofetil (MMF) on cGVHD improved the curative effects. This study tried to analyze the results of combination of methylprednisolone (MP), MMF and FK506 or cyclosporine A (CSA) as immunosuppressive therapies for cGVHD and to explore the effective regimen for children.. Forty-five patients received allo-HSCT. Among them 32 received UCBT and 13 received PBSCT. The conditional regimen mainly consisted of busalphan, cyclophosphamide, antihuman thymocyte globulin, fludarabin, melphalan, thiotepa and total lymph node irradiation. Prophylaxis of GVHD consisted of CSA, MP and MMF. Patients with cGVHD received a regimen with combination of MP, MMF and FK506 or CSA.. Seventeen out of 32 patients who received UCBT were engrafted. while 9 out of 13 patients who received PBSCT were engrafted. Nine cases of the 30 engrafted patients developed cGVHD (morbidity 30%). Among the 17 patients who received UCBT, 3 developed cGVHD (18%). Among the 13 patients who received PBSCT, 6 developed cGVHD (46%). Six cGVHD continued from aGVHD (6/9). One patient was given CSA plus MMF, and 8 were given three-drug regimen with MP, MMF and FK506. The overall response rate was 100%. Two patients died of CMV-IP or septicemia (mortality 20%). Seven (78%) patients survived (event free survival, EFS) longer than 3 years. The side effects included hepatotoxicity, nephrotoxicity, hypertension, articular capsulitis and arrhythmia. The main complication and the major causes of death were infection.. The incidence of cGVHD is low in children. The incidence of cGVHD after PBSCT is higher than that after UCBT. aGVHD is a highly dangerous factor. Combined therapy of MP plus MMF and FK506 or CSA is safe and effective for the treatment of cGVHD in children.

Topics: Child; Child, Preschool; Chronic Disease; Drug Therapy, Combination; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Incidence; Male; Methylprednisolone; Mycophenolic Acid; Tacrolimus

Chronic urticaria is a common skin disorder, which causes considerable morbidity. In approximately 40% of cases, patients have an autoimmune disorder in which functional antibodies cause degranulation of mast cells and basophils, and C5a complement augments this in varying amounts from patient to patient. Since the calcineurin inhibitor ciclosporin has been used in chronic autoimmune urticaria, we examined the effect of ciclosporin and other drugs on the release of histamine from basophils when stimulated by sera from patients with chronic autoimmune urticaria.. Leucocytes from healthy donors were isolated and incubated in varying concentrations of ciclosporin, ascomycin, methotrexate, diphenhydramine or hydroxyzine for 30 min prior to stimulation with serum from urticaria patients known to have functional immunoglobulin (Ig)G antibodies directed against the alpha subunit of the IgE receptor. Histamine release was then measured.. Pre-incubating cells with ciclosporin and ascomycin produced dose-dependent inhibition of histamine release when cells were stimulated by sera of urticaria patients, by purified IgG from these sera, but not by C5a. Inhibition was not prevented by C5a receptor blocking antibodies. No inhibition was seen with methotrexate, diphenhydramine or hydroxyzine.. This is the first demonstration of inhibition of histamine release by calcineurin inhibitors employing sera of patients with chronic autoimmune urticaria. These drugs may work by interfering with intracellular signalling in cells following cross-linking of the IgE receptor, but not following stimulation of the C5a receptor.

Topics: Basophils; Calcineurin Inhibitors; Cells, Cultured; Chronic Disease; Complement C5a; Cyclosporine; Diphenhydramine; Dose-Response Relationship, Immunologic; Histamine H1 Antagonists; Histamine Release; Humans; Hydroxyzine; Immunoglobulin G; Immunosuppressive Agents; Leukocytes; Methotrexate; Recurrence; Tacrolimus; Urticaria

Cytotoxic nitric oxide (NO) is produced during ischemia-reperfusion injury and acute and chronic rejection in allografts by expression of inducible (i) NO synthase (NOS). Therefore, continuous inhibition of iNOS may prevent early graft dysfunction and immune injury (rejection) and consequently improve graft survival. FR260330 is a potent and selective inhibitor of iNOS activity that works by preventing iNOS monomers from dimerization. In this study, the authors evaluated the effect of FR260330 in prevention of chronic rejection in a model of rat aortic allografts.. Male Lewis (LEW, RT1l) rats received male ACI (RT1a) aorta allografts or LEW aorta isografts. Fourteen groups (n > or = 6) were involved in this study. FR260330, tacrolimus, or both were administered orally for 14 or 90 days, according to protocol. The degree of intimal proliferation of graft aorta was determined by a computerized image system.. Both low and high doses of FR260330- or tacrolimus-treated grafts showed significantly decreased intima/(intima+media) ratios at day 90 compared with placebo controls. Combination therapy of low-dose FR260330 with low-dose tacrolimus produced a significant decrease of intima/(intima+media) ratios with intact endothelium compared with placebo controls. Anti-alpha-actin immunohistochemical staining demonstrated that one of the mechanisms of intimal proliferation is related to migration of vascular smooth muscle cells.. A selective inhibitor of NOS, FR260330 plays a protective role in chronic aortic allograft rejection in the rat. Combination therapy of low-dose FR260330 with tacrolimus produces significant protection of immune injury and may serve to improve long-term graft survival and function.

Topics: Actins; Animals; Aorta; Body Weight; Chronic Disease; Dose-Response Relationship, Drug; Drug Therapy, Combination; Enzyme Inhibitors; Graft Rejection; Graft Survival; Hyperplasia; Immunosuppressive Agents; Male; Muscle, Smooth, Vascular; Myocytes, Smooth Muscle; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Piperidines; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Tacrolimus; Transplantation, Homologous; Tunica Intima; Tunica Media

High pretransplantation sCD30 levels have been shown to be associated with lower 5-year kidney graft survival in mainly Cyclosporine A (CsA)-treated recipients (Collaborative Transplant Study database). To analyze the effect of different immunosupressive regimens (CsA/Azathioprine [Aza], CsA/Mycophenolate Mofetil [MMF], Tacrolimus [Tacr]/Aza) on sCD30, we assessed serum sCD30 and neopterin together with in vitro cytokine responses in a prospective randomized study of 84 renal transplant recipients before, 4 months, and 1 year after transplantation. Panel-reactive antibody (PRA) formation, HLA matching, ATG induction therapy, and acute rejections had no impact on sCD30 levels, whereas cytomegalovirus (CMV) infections induced an up-regulation of sCD30 4 months posttransplantation (P = .003). Whereas MMF showed no effect on sCD30 compared with Aza therapy, we found a significant impact of Tacr versus CsA treatment (1-year sCD30 > or = 60 U/mL: 14/42 (33%), CsA; 1/38 (3%), Tacr; P < .0005). Chronic rejection 2 years posttransplantation was associated with elevated 1-year sCD30 (P = .001) and neopterin levels (P = .006). Our data indicate that the Th2 activation marker sCD30 provides a risk factor for chronic rejection independent of classical immunological risk factors and may be down-regulated using Tacr treatment.

Topics: Antigens, CD; Chronic Disease; Cyclosporine; Cytokines; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Ki-1 Antigen; Kidney Transplantation; Mycophenolic Acid; Risk Factors; Tacrolimus

A patient with myelodysplastic syndrome developed pericardial effusion 20 month after allogenic peripheral blood stem cell transplantation. Sclerotic and erythematous skin lesions were observed over the face and extremities, and a diagnosis of chronic graft vs. host disease (GVHD) was made based on skin biopsy findings. Pericardial fluid contained numerous CD8+/HLA-DR+ lymphocytes, but no leukaemic cells. Tumour necrosis factor alpha (TNFalpha) and soluble Fas (sFas) levels were highly elevated in both the effusion and serum. The patient was treated with methylprednisolone and tacrolimus. Skin GVHD improved rapidly associated with resolution of pericardial effusion and reductions in cytokine levels. We concluded that pericardial effusion was due to pericarditis and was a manifestation of chronic GVHD in this patient, and that cytotoxic lymphocytes and specific cytokines played significant roles.

Topics: Adult; CD8-Positive T-Lymphocytes; Chronic Disease; fas Receptor; Female; Graft vs Host Disease; HLA-DR Antigens; Humans; Immunosuppressive Agents; Myelodysplastic Syndromes; Pericarditis; Pericardium; Peripheral Blood Stem Cell Transplantation; Tacrolimus; Tumor Necrosis Factor-alpha

Switching from calcineurin inhibitors (CNIs) to sirolimus might improve renal function in chronic renal transplant patients.. In a prospective study, we assessed long-term efficacy and safety parameters in 43 renal transplant recipients who were switched from a CNI (cyclosporin A, 65%; and tacrolimus, 35%) to sirolimus for either chronic allograft dysfunction (n = 38) or recurrent cutaneous cancers (n = 5). A kidney biopsy was done in 79% of patients prior to conversion, and showed either chronic allograft nephropathy (n = 26) or CNI nephrotoxicity (n = 7). Conversion was either abrupt or progressive, with CNI withdrawal over 3 weeks. All patients also received steroids with or without mycophenolate mofetil or azathioprin. Patient data were recorded at baseline (D0), at 1 (D30) and 6 months (D180), and at 1, 1.5 and 2 years post-conversion.. After a mean post-conversion follow-up of 27+/-1.5 months, 58% of the patients were still on sirolimus. The survival of intent to treat patients and grafts was 95.3 and 93%, respectively. Overall, there was significant improvement in renal function, creatinine clearance increasing from 49.4+/-14.9 to 53+/-16.3 ml/min at D30 (P = 0.01), and to 54.7+/-20 ml/min at D180 (P = 0.01). Thereafter, creatinine clearance was not different from baseline, i.e. 54.7+/-21.7, 52.8+/-20 and 51.7+/-20.3 ml/min at years 1, 1.5 and 2, respectively. We divided the patients into two groups: responders (n = 29), those with an increase in creatinine clearance at 6 months post-conversion compared with D0, and non-responders (n = 14), those with a decrease in creatinine clearance at 6 months post-conversion compared with D0. In univariate analysis, factors predictive of response included proteinuria at D0 and the magnitudes of the differences between D30 and D0 for serum creatinine and lactate dehydrogenase. The conversion was associated with (i) significant decreases in serum calcium, phosphorus and uric acid, and in haemoglobin levels; (ii) significant increases in serum alkaline phosphatase, total cholesterol, parathyroid hormone, and the number of patients on statin and recombinant erythropoietin therapies; and (iii) the appearance of de novo proteinuria of >1 g/day in 28% of patients (P < 0.0009), which was >2 g/day in 12% of the entire cohort. Kidney biopsies in 17 patients 2 years after conversion showed the same Banff scores as observed at baseline. We identified three independent predictive factors for a renal response to the switch: absence of proteinuria, presence of antihypertensive therapy at D0 and serum lactate dehydrogenase level at D30.. Conversion from CNIs to sirolimus in renal transplant patients with chronic allograft nephropathy was associated with improved renal function; however, 33% of the patients developed overt proteinuria.

Topics: Biopsy; Calcineurin Inhibitors; Chronic Disease; Creatinine; Cyclosporine; Drug Therapy, Combination; Enzyme Inhibitors; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Transplantation; Male; Middle Aged; Prospective Studies; Sirolimus; Tacrolimus; Time Factors; Transplantation, Homologous; Treatment Outcome

The tuberculostatic compound rifampin (INN, rifampicin) induces the expression of a number of drug metabolism-related genes involved in multidrug resistance (P-glycoprotein and multidrug resistance proteins 1 and 2), cytochromes (cytochrome P450 [CYP] 3A4), uridine diphosphate-glucuronosyltransferases, monoamine oxidases, and glutathione S -transferases. Drugs that depend on these enzymes for their metabolism are prone to drug interactions when coadministered with rifampin. A novel, clinically relevant drug interaction is described between rifampin and mycophenolate mofetil (MMF), a cornerstone immunosuppressive molecule used in solid organ transplantation. Long-term rifampin therapy caused a more than twofold reduction in dose-corrected mycophenolic acid (MPA) exposure (dose-interval area under the concentration curve from 0 to 12 hours [AUC 0-12]) when administered simultaneously in a heart-lung transplant recipient, whereas subsequent withdrawal of rifampin resulted in reversal of these changes after 2 weeks of washout (dose-corrected AUC 0-12 after rifampin withdrawal, 19.7 mg.h.L-1.g -1 versus 6.13 mg.h.L-1.g-1 before rifampin withdrawal [221% change]; dose-uncorrected AUC 0-12 after rifampin withdrawal, 29.6 mg.h/L [daily MMF dose, 3 g] versus 18.4 mg.h/L [daily MMF dose, 6 g] during rifampin administration [60.8% change]). Failure to recognize this drug interaction could potentially lead to MPA underexposure and loss of clinical efficacy. The effect of rifampin on MPA metabolism can, at least in part, be explained by simultaneous induction of renal, hepatic, and gastrointestinal uridine diphosphate-glucuronosyltransferases and organic anion transporters with subsequent functional inhibition of enterohepatic recirculation of MPA.

Topics: Area Under Curve; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Interactions; Drug Therapy, Combination; Enterohepatic Circulation; Glucuronosyltransferase; Heart-Lung Transplantation; Histiocytosis, Langerhans-Cell; Humans; Hypertension, Pulmonary; Male; Metabolic Clearance Rate; Middle Aged; Mycophenolic Acid; Pharmacology, Clinical; Respiratory Insufficiency; Rifampin; Tacrolimus; Time Factors; Uridine Diphosphate; Withholding Treatment

We have previously shown the long-term influence of renal ischemia/reperfusion (I/R) injury and immunosuppression on fibrotic genes and apoptosis in a rat model. For the first time, we have now investigated the effects of I/R and immunosuppression on inflammation and caspase activation.. I/R injury was induced in the right kidney and the left was removed. Cyclosporin (CsA) (10 mg/kg), tacrolimus (0.2 mg/kg), rapamycin (1 mg/kg), or mycophenolate mofetil (MMF) (10 mg/kg) was then administered for 16 weeks. The effects of I/R and immunosuppressants on interstitial inflammation, interleukin (IL)-1beta expression, caspase-1 and caspase-3 activation, tubulointerstitial damage, and fibrosis were evaluated.. ED-1+ (a specific rat monocyte/macrophage marker) cells were mainly localized in the tubulointerstitium and periglomerular areas and increased in I/R group compared to controls (P < 0.01). This was further increased by CsA, but decreased by tacrolimus, rapamycin, or MMF (P < 0.05). The 17 kD active IL-1beta remained unchanged, but 35 kD IL-1beta precursor was decreased by rapamycin in comparison with I/R group (P < 0.05). The 45 kD or 20 kD caspase-1 was increased by I/R or CsA, respectively, and decreased by rapamycin (P < 0.05). The 24 kD caspase-3, which proved to be an active caspase-3 subunit, was increased in I/R and CsA groups and deceased by tacrolimus, rapamycin, or MMF (P < 0.05), but not 32 kD precursor or 17 kD active caspase-3. The activity data of caspase-1 and caspase-3 exhibited the same trend as Western blotting data. The staining of active caspase-3 was scattered in kidneys, mainly in tubular and interstitial areas, which was consistent with that of ED-1+ cells. There was a strong positive correlation between interstitial inflammation and 24 kD caspase-3 expression or caspase-3 activity (r = 0.814 or 0.484), all of which were also closely related with urinary protein (r = 0.537, 0.529, or 0.517), serum creatinine (r = 0.463, 0.573, or 0.539), tubulointerstitial damage (r = 0.794, 0.618, or 0.712) and fibrosis (r = 0.651, 0.567, or 0.469), all P < 0.01.. This study shows that the mechanisms of long-term I/R injury and immunosuppressants treatment include interstitial inflammation and caspase activation, most clearly demonstrated by the 24 kD active caspase-3.

Topics: Animals; Apoptosis; Caspase 1; Caspase 3; Caspases; Chronic Disease; Cyclosporine; Electrophoresis, Polyacrylamide Gel; Extracellular Matrix; Fibrosis; Glomerulonephritis; Immunosuppressive Agents; Interleukin-1; Male; Mycophenolic Acid; Rats; Rats, Wistar; Reperfusion Injury; Sirolimus; Tacrolimus

Hand dermatitis is a common chronic skin condition that has many clinical forms including contact, hyperkeratotic, frictional, nummular, atopic, pompholyx and chronic vesicular hand dermatitis. Topical steroids are the first line agents used. Here, we report the successful response to topical pimecrolimus 1% cream in a patient with steroid resistant chronic vesicular hand dermatitis.

Topics: Administration, Topical; Chronic Disease; Female; Follow-Up Studies; Hand Dermatoses; Humans; Middle Aged; Severity of Illness Index; Skin Diseases, Vesiculobullous; Tacrolimus; Treatment Outcome

A retrospective study involving 13 institutions was performed to assess the efficacy of conversion from cyclosporine (INN: ciclosporin) to tacrolimus.. Data from 244 patients were analyzed. Indications for conversion were recurrent-ongoing rejection (n = 110) and stage 1 to 3 bronchiolitis obliterans syndrome (n = 134).. The incidence of acute rejection decreased significantly within 3 months after versus before the switch from cyclosporine to tacrolimus (P <.01). For patients with recurrent-ongoing rejection, the forced expiratory volume in 1 second decreased by 1.96% of predicted value per month (P =.08 vs zero slope) before and increased by 0.34% of predicted value per month (P =.32 vs zero slope) after conversion (P <.06). For patients with stage 1 to 3 bronchiolitis obliterans syndrome, a significant reduction of rejection episodes was observed (P <.01). In single transplant recipients a decrease of the forced expiratory volume in 1 second averaged 2.25% of predicted value per month (P <.01 vs zero slope) before and 0.29% of predicted value per month after conversion. Corresponding values for bilateral transplant recipients were 3.7% of predicted value per month (P <.01 vs zero slope) and 0.9% of predicted value per month (P = 0.04 vs zero slope), respectively. No significant difference in the incidence of infections within 3 months before and after conversion was observed.. Conversion from cyclosporine to tacrolimus after lung transplantation is associated with reversal of recurrent-ongoing rejection. Conversion for bronchiolitis obliterans syndrome allows short-term stabilization of lung function in most patients.

Topics: Acute Disease; Adult; Australia; Azathioprine; Bronchiolitis Obliterans; Canada; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Europe; Female; Follow-Up Studies; Forced Expiratory Volume; Graft Rejection; Humans; Hypertension, Pulmonary; Immunosuppressive Agents; Incidence; Kidney; Lung Transplantation; Male; Middle Aged; Postoperative Complications; Pulmonary Disease, Chronic Obstructive; Pulmonary Fibrosis; Retrospective Studies; Tacrolimus; Time Factors; Treatment Outcome

Acute and chronic renal dysfunction (ARD, CRD) are common complications after liver transplantation and are associated with poor outcome.. We reviewed the results of 181 liver transplants performed in our institution between January 1, 1998 and December 31, 2000 in which the recipients were alive with good liver function at the end of the follow-up period (mean 2.7 years). Renal dysfunction was defined as a serum creatinine (Cr) greater than or equal to 2 mg/dL in both acute and chronic settings.. The incidence of ARD during the first posttransplant week was 39.2% (n=71), whereas late CRD occurred in 6.0% (n=11) of the patients by the end of the follow-up period. Among the variables we examined for association with CRD, five factors were found to be statistically significant in univariate analysis: pretransplant diabetes (PRTDM) (0.000), Cr greater than or equal to 2 during the first postoperative week (0.003), posttransplant diabetes (POTDM) (0.014), age greater than 50 (0.025), and tacrolimus level greater than 15 ng/mL at postoperative day 15 (0.058). In binary logistic regression analysis, PRTDM (odds ratio [OR]=5.7, 95% confidence interval [CI]) and early postoperative ARD (OR=10.2 95% CI) remained consistently significant. Nine of 11 patients with CRD also had a history of ARD during the first postoperative week. These patients progressed to CRD despite the fact that seven of nine had normalized their renal function by day 90 posttransplant.. We suggest that a combination of events during the first postoperative week after liver transplant serve as a physiologic "stress test" for the kidneys. Patients who fail the test (peak Cr >/=2 mg/dL during the first postoperative week) as well as the patients with diabetes mellitus are at increased risk of CRD. In such cases, conversion to a less nephrotoxic regimen may be beneficial.

Topics: Acute Disease; Adult; Aged; Aging; Chronic Disease; Creatinine; Diabetes Complications; Dose-Response Relationship, Drug; Female; Humans; Immunosuppressive Agents; Incidence; Kidney; Kidney Diseases; Liver Transplantation; Male; Middle Aged; Postoperative Period; Prognosis; Retrospective Studies; Tacrolimus

Bone marrow transplantation (BMT) is a common treatment used for deficiencies of host marrow or in the control of blood malignancies. Post-allogeneic BMT complications include graft-versus-host disease (GVHD). GVHD occurs when immunologically active T lymphocytes are transplanted into an immunosuppressed recipient who is genetically disparate from the donor. In this case report we describe the occurrence of oral lichen planus-like lesions as the first manifestation of chronic GVHD (c-GVHD) and the subsequent management of this disease with topical tacrolimus.. Diagnostic aids included routine histology and direct immunofluorescence studies to rule out immunobullous diseases and to confirm the c-GVHD. Treatment consisted of topical application of 0.1% tacrolimus ointment three times a day.. Routine histology confirmed the clinical diagnosis of oral lichen planus-like c-GVHD. Treatment with tacrolimus ointment completely resolved the oral lesions after 2 months of therapy.. Topical tacrolimus at low concentrations (0.1%) shows promise in the management of oral lichen planus-like c-GVHD. Controlled studies are necessary to assess the efficacy, the duration of therapy required for effective results, and the safety of this treatment over the long-term.

Topics: Administration, Topical; Bone Marrow Transplantation; Chronic Disease; Graft vs Host Disease; Humans; Immunosuppressive Agents; Lichen Planus, Oral; Male; Middle Aged; Tacrolimus

Despite recent advances, graft-versus-host disease (GVHD) remains the main cause of treatment failure for patients undergoing allogeneic hematopoietic stem cell transplantation (HSCT). Tacrolimus (FK506) has been increasingly used in place of cyclosporine (CSP), and several studies have shown that FK506 reduces the incidence of acute GVHD more effectively than does CSP. However, no survival benefits have been demonstrated, and no established consensus exists on the choice of these immunosuppressive agents. To compare a CSP-based and an FK506-based regimen, we performed a large-scale retrospective study by using the data of 1935 patients who underwent HSCT from HLA-identical sibling donors (SIB-HSCT) and 777 patients who underwent HSCT from unrelated donors (UD-HSCT). For patients undergoing UD-HSCT, FK506 significantly reduced the risk of acute GVHD and treatment-related mortality (TRM) without an increase in relapse, thus improving overall survival (OS) (hazard ratio (HR): 2.20, 95% confidence interval (CI): 1.60-3.04, P<0.0001 for grade II-IV acute GVHD; HR: 1.81, 95% CI: 1.32-2.48, P=0.0003 for TRM; HR: 1.62, 95% CI: 1.23-2.14, P=0.0007 for OS). This superiority of FK506 was not observed in SIB-HSCT cases. These findings indicate that the use of FK506 instead of CSP for GVHD prophylaxis is beneficial for patients undergoing UD-HSCT.

Topics: Acute Disease; Adolescent; Adult; Aged; Chronic Disease; Cyclosporine; Female; Follow-Up Studies; Graft vs Host Disease; Histocompatibility Testing; Humans; Immunosuppressive Agents; Japan; Male; Middle Aged; Siblings; Stem Cell Transplantation; Tacrolimus; Time Factors; Tissue Donors; Treatment Outcome

Chronic active Epstein-Barr virus infection (CAEBV) is a heterogeneous EBV-related disorder, ranging from mild/moderate forms to rapidly lethal disorders. The lethal form of CAEBV is characterized by multiple organ failure, hemophagocytic syndrome, and development of lymphomas. Allogeneic stem cell transplantation is considered as the only potentially curative treatment for the lethal form of CAEBV, but it is not always desirable because of the high incidence of regimen-related toxicities. A 17-year-old female with CAEBV, who was refractory to conventional therapies and considered to be unable to receive a myeloablative regimen because of multiple organ dysfunction, underwent allogeneic nonmyeloablative stem cell transplantation (allo-NST) before developing a hematological malignancy. She has been well without any signs of CAEBV for 27 months after allo-NST, and we confirmed that specific cytotoxic T lymphocyte activity against EBV was reconstituted. This outcome suggests that allo-NST can control CAEBV by reconstituting the host immunity against EBV.

Topics: Adolescent; B-Lymphocytes; Cell Line, Transformed; Cell Transformation, Viral; Chronic Disease; Cyclosporine; DNA, Viral; Drug Resistance; Epstein-Barr Virus Infections; Etoposide; Female; Hepatitis, Viral, Human; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Multiple Organ Failure; Peripheral Blood Stem Cell Transplantation; T-Lymphocytes, Cytotoxic; Tacrolimus; Transplantation Conditioning; Transplantation, Homologous

Oral involvement of chronic graft-versus-host disease (GvHD) is a most distressing and disabling complication of hematopoietic cell transplantation, for which systemic immunosuppression as well as topical corticosteroid treatment may offer only limited symptomatic relief. Here we report encouraging preliminary results with the application of tacrolimus (FK-506) as a 0.1% ointment in three patients with severe oral chronic GvHD, heavily pretreated without success, who experienced rapid, consistent, complete or at least marked, subjective and objective improvement with topical tacrolimus.

Topics: Administration, Topical; Adult; Chronic Disease; Female; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia; Leukemia, Lymphocytic, Chronic, B-Cell; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Middle Aged; Mouth Diseases; Tacrolimus; Treatment Outcome

We evaluate whether cyclosporine (CsA) or tacrolimus (FK) could be reduced or eliminated after sirolimus was added in chronic allograft nephropathy (CAN). By reducing doses of CsA or FK, we expected that renal function would improve.. Twenty-one patients with CAN had sirolimus added as an immunosuppressive agent. We evaluated the creatinine (Cr) level 3 months after addition. The doses of CsA and FK were decreased gradually and then eliminated over a course of 4 to 6 weeks. If the Cr level rose rapidly or other prominent signs of rejection occurred; low-dose CsA or FK would be added per protocol. We evaluated the duration of engraftment before sirolimus and the Cr level when it was added.. Renal function improved in 13 of 21 cases. The improvement in Cr ranged from 12.5% maximally to 1.84% minimally. Seven of 13 cases still required low-dose CsA. The average duration of engraftment before sirolimus was 13.66 +/- 10.80 months. The average Cr level before sirolimus was 1.65 +/- 0.56 mg/dL. In the other eight cases, the Cr level kept rising from 5.1% to 20.4%. The average duration of engraftment was 88.38 +/- 42.21 months. The average Cr level before sirolimus was 2.85 +/- 0.54 mg/dL. Hyperuricemia was noted in 31.3% and hyperlipidemia in 68.8%.. Sirolimus is a safe alternative to reduce or eliminate CsA or FK in CAN. In cases with a long duration of engraftment and high Cr level, sirolimus might have some effect as a substitute for CNI and thus prevent further nephrotoxicity.

Topics: Chronic Disease; Creatinine; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Sirolimus; Tacrolimus; Treatment Failure; Treatment Outcome

Therapeutically, chronic actinic dermatitis is a problematic condition. Frequently applied sunscreen usually fails to mitigate the clinical symptoms, and steroids--while efficient--exert many undesired side-effects with prolonged usage. We present a case of chronic actinic dermatitis responding well to topically applied tacrolimus (Protopic) in combination with chemical and physical UV protection.

Topics: Administration, Topical; Agriculture; Chronic Disease; Dermatitis, Photoallergic; Dose-Response Relationship, Drug; Drug Administration Schedule; Facial Dermatoses; Follow-Up Studies; Humans; Male; Middle Aged; Severity of Illness Index; Tacrolimus; Treatment Outcome; Ultraviolet Rays

Chronic tacrolimus (FK506) nephrotoxicity is characterized by renal fibrosis with interstitial inflammation. Since nuclear factor-kappaB (NF-kappaB) plays a key role in chronic inflammatory diseases including renal disease, the present study was conducted to elucidate the role of NF-kappaB in the pathogenesis of chronic FK506-induced nephropathy.. FK506 (1 mg/kg/day, SC) was administered daily to rats maintained on low sodium diet for 42 days. Some rats were treated with a putative NF-kappaB inhibitor, pyrrolidine dithiocarbamate (PDTC; 100, 200 mg/kg/day, by gavage). The renal function, renal histology, renal NF-kappaB-DNA binding activity and gene expression profile were examined.. FK506 caused a decline in glomerular filtration and induced characteristic renal morphologic changes including arteriolopathy, tubular atrophy and interstitial fibrosis. FK506 markedly activated renal cortical NF-kappaB-DNA binding. PDTC administration inhibited NF-kappaB-DNA binding activity in a dose dependent manner. With higher dose, NF-kappaB-DNA binding activity was decreased to a control level. PDTC had little effect on FK506-induced renal dysfunction. Renal cortical monocyte/macrophage infiltration observed in FK506-treated rats was dramatically suppressed by PDTC. FK506 up-regulated renal cortical gene expression of chemoattractant proteins, monocyte chemoattractant protein-1 (MCP-1) and osteopontin. PDTC significantly blocked MCP-1 gene expression but had no effect on osteopontin gene expression. Tubular atrophy and tubulointerstitial fibrosis, but not arteriolopathy, were significantly attenuated by PDTC. FK506 increased renal mRNA expression of fibrogenic molecules and extracellular matrices that also were attenuated by PDTC treatment.. NF-kappaB plays an important role in mediating cortical monocyte/macrophage infiltration and in the pathogenesis of tubular injury and interstitial fibrosis in experimental FK506-induced chronic nephropathy.

Topics: Animals; Chemokine CCL2; Chronic Disease; Electrophoretic Mobility Shift Assay; Immunohistochemistry; Immunosuppressive Agents; Kidney; Kidney Diseases; Macrophages; Male; Monocytes; NF-kappa B; Osteopontin; Pyrrolidines; Rats; Rats, Sprague-Dawley; RNA, Messenger; Sialoglycoproteins; Tacrolimus; Thiocarbamates

The prognosis of HIV-1-infected patients has dramatically improved but progression to liver failure occurs now frequently in subjects coinfected with hepatitis C virus (HCV). This has raised the issue of organ transplantation, but the knowledge about the effect of concomitant antiretroviral and immunosuppressive therapy is limited. The objective of the study was to describe viral and immunological events in antiretroviral-treated orthotopic liver transplant (OLT) recipients with primary (PHI) or chronic HIV-1 infection. Three HIV-1-infected patients with liver cirrhosis due to chronic HCV infection underwent OLT. A fourth patient developed PHI at OLT. Immunosuppressive drugs and combination antiretroviral therapy were given. The effects on HIV-1 load, viral diversity and divergence, and CD4(+) T cell counts, were studied. One patient died after 3 months. Three subjects were alive after 9 months, 14 months, and 3 years, respectively. In the PHI patient, viral load decreased during the second week of illness despite immunosuppression. During the third week the viremia increased until antiretroviral treatment was initiated. In all four patients, the HIV-1 replication was effectively inhibited during follow-up by the treatment, as determined by undetectable plasma viremia, lack of viral sequence changes, and increase in CD4(+) T cells. The pattern of viral dynamics may suggest that the innate immunity causes the earliest decline of viral load in PHI patients. A lack of adaptive immunity may thereafter lead to an increase in viremia in heavily immunosuppressed individuals. However, a specific HIV-1 immunity is not necessary to efficiently inhibit the viral replication when potent antiretroviral therapy is given in liver transplant recipients with primary or chronic HIV-1 infection.

Topics: Acute Disease; Anti-HIV Agents; CD4 Lymphocyte Count; Chronic Disease; DNA, Viral; Drug Therapy, Combination; Female; HIV Antibodies; HIV Infections; HIV-1; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Molecular Sequence Data; Reverse Transcriptase Inhibitors; Sequence Analysis, DNA; Tacrolimus; Treatment Outcome; Viral Load

Although the outcome of liver transplantation has improved significantly during the past two decades, graft loss caused by chronic rejection after liver transplantation still occurs in 2% to 20% of recipients. The overall incidence of chronic rejection is also reported to be low in adult recipients, and risk factors have been identified. Chronic rejection is associated with the inability to maintain baseline immunosuppression. Additionally, the diagnoses of primary biliary cirrhosis, primary sclerosing cholangitis, autoimmune hepatitis, hepatitis B virus, and hepatitis C virus, common indications for liver transplantation in adults, are associated with a higher incidence of chronic rejection. Fortunately, these diagnoses are rarely seen in children. Little is known about chronic rejection in long-term pediatric liver transplant survivors. The purpose of this longitudinal study was to examine the incidence of biopsy-proven chronic rejection in long-term survivors of primary pediatric liver transplantation under tacrolimus-based immunosuppression.. From October 1989 to December 1992, 166 children (boys=95, girls=71; mean age=5.0+/-2.9 years) received a primary liver transplant. These patients were followed until March 2000 with a mean follow-up of 9+/-0.8 (range, 7.4-10.4) years. All liver biopsy specimens and explanted grafts were evaluated for evidence of chronic rejection using the International Banff Criteria.. The mortality rate during the follow-up period was 15% (n=25). Retransplantation was required in 11% (n=18) of recipients. Actuarial patient and graft survival rates at 10 years were 84.9% and 80.1%, respectively. There were 535 liver biopsy samples available for evaluation, including the 18 explanted allografts. Biopsy specimens of three other functioning allografts showed evidence of chronic rejection. Immunosuppression had been discontinued or drastically reduced in these recipients because of life-threatening infections, noncompliance, or both. On restoring baseline immunosuppression, all three children had normalized liver function and the allografts were maintained; the liver transplant patients who are alive currently have normal liver functions.. The findings of this study suggest that chronic rejection does not occur in pediatric liver transplant recipients receiving tacrolimus-based immunosuppression, provided baseline immunosuppression is maintained.

Topics: Biopsy; Child; Child, Preschool; Chronic Disease; Drug Therapy, Combination; Female; Glucocorticoids; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Liver; Liver Transplantation; Longitudinal Studies; Male; Prednisone; Tacrolimus

Topics: Administration, Cutaneous; Adult; Chronic Disease; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Severity of Illness Index; Tacrolimus; Ultraviolet Rays; Vitiligo

Giving the immunosuppressive drug tacrolimus (FK506) to liver transplant patients has helped to considerably reduce oral side effects such as gingival hyperplasia. Patients taking cyclosporin who suffer from gingival hyperplasia are often switched to tacrolimus.. We present here a pediatric liver transplantation case study. The patient has been followed for 5.5 years. She developed oral lesions that resulted in the immunosuppressive therapy being changed from tacrolimus to cyclosporin. In clinical terms, the atypical pathology consisted of hyperpigmented patches on the gingival margin, the internal surfaces of the cheeks, and the intraoral surfaces of the lips. When located on the lips, the hyperpigmented patches were associated with pruriginous and edematous lesions.. Optical and electronic microscopic examinations of a gingival tissue sample revealed the presence of melanin incontinence and lichenoid lesions with degenerated keratinocytes and a mild infiltrate of lymphocytes. This points to a chronic graft-versus-host disease (cGvHD)-like syndrome linked to tacrolimus. This diagnosis was given further credence by improvement in the lesions following the switch to cyclosporin.. To our knowledge, this is the first reported case of tacrolimus-associated chronic GvHD-like syndrome occurring in the oral mucosa.

Topics: Chronic Disease; Diagnosis, Differential; Female; Gingival Diseases; Graft vs Host Disease; Humans; Immunosuppressive Agents; Infant; Lichen Planus, Oral; Liver Transplantation; Melanosis; Prurigo; Tacrolimus

Topics: Administration, Topical; Adult; Chronic Disease; Female; Humans; Immunosuppressive Agents; Pityriasis Lichenoides; Tacrolimus; Treatment Outcome

We evaluated levels of intestinal expression of absorptive-barrier P-glycoprotein (PGP) and cytochrome P-450 IIIA4 (CYP3A4) and immunosuppressant therapy in a patient who underwent living donor liver transplantation (LDLT) and received a second living donor liver transplant after chronic rejection of the first. PGP and CYP3A4 expression were measured using part of a Roux-en-Y limb. After the first LDLT, the concentration-dose ratio of orally administered tacrolimus was 159.8 +/- 125.3 (average +/- SD of 32 different days), similar to the average for 46 recipients of living donor liver transplants in our hospital (161.3 +/- 88.1). However, the recipient required very large oral doses of cyclosporine (703.9 +/- 385.4 mg/d, average +/- SD of 13 different days) after the second LDLT. Although intestinal PGP level was increased markedly at the second LDLT, CYP3A4 level was decreased. In addition, levels of messenger RNA expression of several gene products related to the local inflammation, such as cyclooxygenase 2, interleukin-1beta (IL-1beta), IL-2, IL-6, IL-8, IL-10, and tumor necrosis factor-alpha, were increased. These results suggest that hepatic failure after LDLT, including chronic rejection and/or cholangitis, was accompanied by upregulation of intestinal PGP expression, which could depress the bioavailability of the immunosuppressant.

Topics: Adult; ATP Binding Cassette Transporter, Subfamily B, Member 1; Chronic Disease; Cyclosporine; Cytochrome P-450 CYP3A; Cytochrome P-450 Enzyme System; Enterocytes; Gene Expression; Graft Rejection; Humans; Immunosuppressive Agents; Intestinal Absorption; Liver Transplantation; Living Donors; Male; RNA, Messenger; Tacrolimus

Graft-versus-host disease (GVHD) is still a major problem in allogeneic bone marrow transplantation (BMT). Prophylactic regimens used against GVHD in unrelated BMT, including cyclosporine (CsA)-plus-methotrexate (MTX), CsA-plus-MTX-plus-prednisone, and tacrolimus (FK506)-plus-MTX, are still unsatisfactory (34-70% occurrence of grades II-IV GVHD). To address this problem, we examined the efficacy of FK506-plus-MTX-plus-methylprednisolone (mPSL) in 20 patients who underwent BMT from unrelated donors.. All patients received FK506 beginning the day before transplantation at a dose of 0.03 mg/kg per day by continuous intravenous (IV) infusion. MTX was administered at a dose of 10 mg/m(2) IV on day 1, and 7 mg/m(2) on days 3, 6, and 11. Intravenous administration of mPSL was started at a dose of 2 mg/kg per day on day 1. In the absence of acute GVHD, mPSL was gradually tapered from day 29.. Development of acute GVHD was almost completely suppressed (one patient with grade I, none with grades II-IV). However, the incidence and severity of chronic GVHD did not decrease. Eight of 12 patients with extensive chronic GVHD died of thrombotic microangiopathy or infection. A vigorous fluctuation (>100 U/mL per 10 days) of the soluble interleukin 2 receptor level in the serum after engraftment was highly related to the occurrence of chronic GVHD.. An FK506-plus(+)-MTX-plus(+)-mPSL prophylactic regimen could almost completely suppress acute GVHD but not chronic GVHD in unrelated BMT. In this GVHD prophylactic system, the extent of the change of soluble interleukin 2 receptor level may be a good predictor of development of chronic GVHD.

Topics: Acute Disease; Adolescent; Adult; Antigens, Viral; Bone Marrow Transplantation; Cause of Death; Chronic Disease; Cytomegalovirus Infections; Drug Therapy, Combination; Female; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Methotrexate; Methylprednisolone; Tacrolimus; Transplantation, Homologous

Topics: Administration, Topical; Chronic Disease; Facial Dermatoses; Female; Humans; Immunosuppressive Agents; Lupus Erythematosus, Discoid; Lupus Erythematosus, Systemic; Middle Aged; Scalp Dermatoses; Tacrolimus

Topics: Acute Disease; Chronic Disease; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors; Treatment Outcome

Topics: Acute Disease; Adult; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Incidence; Kidney Transplantation; Middle Aged; Pathology; Tacrolimus

Topics: Child; Child, Preschool; Chronic Disease; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Retrospective Studies; Tacrolimus; Time Factors

Topics: Administration, Topical; Adult; Chronic Disease; Dermatitis, Photoallergic; Facial Dermatoses; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Tacrolimus; Treatment Outcome

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

Poor functional recovery after peripheral nerve injury is attributable, at least in part, to chronic motoneuron axotomy and chronic Schwann cell (SC) denervation. While FK506 has been shown to accelerate the rate of nerve regeneration following a sciatic nerve crush or immediate nerve repair, for clinical application, it is important to determine whether the drug is effective after chronic nerve injuries. Two models were employed in the same adult rats using cross-sutures: chronic axotomy and chronic denervation of SCs. For chronic axotomy, a chronically (2 months) injured proximal tibial (TIB) was sutured to a freshly cut common peroneal (CP) nerve. For chronic denervation, a chronically (2 months) injured distal CP nerve was sutured to a freshly cut TIB nerve. Rats were given subcutaneous injections of FK506 or saline (5 mg/kg/day) for 3 weeks. In the chronic axotomy model, FK506 doubled the number of regenerated motoneurons identified by retrograde labeling (from 205 to 414 TIB motoneurons) and increased the numbers of myelinated axons (from 57 to 93 per 1000 microm2) and their myelin sheath thicknesses (from 0.42 to 0.78 microm) in the distal nerve stump. In contrast, after chronic denervation, FK506 did not improve the reduced capacity of SCs to support axonal regeneration. Taken together, the results suggest that FK506 acts directly on the neuron (as opposed to the denervated distal nerve stump) to accelerate and promote axonal regeneration of neurons whose regenerative capacity is significantly reduced by chronic axotomy.

Topics: Animals; Axons; Axotomy; Cell Count; Chronic Disease; Denervation; Female; Fluorescent Dyes; Immunosuppressive Agents; Injections, Subcutaneous; Motor Neurons; Nerve Regeneration; Peripheral Nervous System Diseases; Peroneal Nerve; Rats; Rats, Sprague-Dawley; Schwann Cells; Tacrolimus; Tibial Nerve; Time Factors

Renal failure is a common complication following non-renal solid organ transplantation. The purpose of our study was to define the rate of decline in renal function and to identify independent risk factors associated with renal failure following lung or heart-lung transplantation.. Between May 1986 and December 1998, 219 patients underwent lung or heart-lung transplantation at the University of Minnesota and survived at least six months (33 heart-lung, 66 bilateral single lung, and 120 unilateral single lung transplants). The mean age at the time of transplant was 45.9 +/- 11.6 years (mean +/- SD; range, 15 to 65 years), and the mean pre-transplant serum creatinine level was 0.88 +/- 0.19 mg/dL. All patients were treated with a calcineurin inhibitor (164 cyclosporine, 55 tacrolimus).. During the follow-up period (median 44 months, range 6.8 to 163 months), 16 patients (7.3%) developed end-stage renal disease. The cumulative incidence of doubling of serum creatinine was 34% at one year, 43% at two years and 53% by five years. Factors associated with the primary end point of the time to doubling of the baseline serum creatinine by proportional hazards regression were cumulative periods with diastolic blood pressure greater than 90 mm Hg [relative risk (RR) 1.30, P = 0.02] and the serum creatinine value at one month post-transplantation (RR 1.28, P = 0.03). Use of tacrolimus during the first six months after transplantation was associated with a significant decrease in the risk for time to doubling of serum creatinine (RR 0.38, P = 0.009) and a lower rate of acute rejection.. These results suggest that potential renoprotective strategies following lung or heart-lung transplantation include avoidance of peri-transplant renal injury, diligent blood pressure control, and preferential use of tacrolimus over cyclosporine.

Topics: Acute Disease; Adolescent; Adult; Blood Pressure; Chronic Disease; Creatinine; Female; Forecasting; Graft Rejection; Heart Transplantation; Humans; Immunosuppressive Agents; Incidence; Kidney; Lung Transplantation; Male; Middle Aged; Postoperative Period; Proportional Hazards Models; Risk Assessment; Tacrolimus

Chronic allograft nephropathy is the major cause of progressive renal failure in renal transplant recipients. It has no definitive treatment.. One hundred eighteen renal transplant recipients with declining kidney function and biopsy-proven chronic allograft nephropathy had their cyclosporine or tacrolimus dose reduced or discontinued with either the addition or continuation of mycophenolate mofetil and low-dose steroids at a mean of 853.3 days post-transplantation. Their renal function was modeled before and after this intervention by two methods: A least-square regression was used to assess the decay of renal function after the intervention and to compare that with the slope pre-intervention, whereas a hinge regression line method was used to assess the correlation of the intervention with the inflection point and the impact of the intervention on the decay of renal function. Mean follow-up was 651.0 days after the intervention. Serum creatinine at the time of intervention was 2.8 +/- 0.9 mg/dL in the reduced dose cyclosporine (N = 67) and reduced dose tacrolimus (N = 33) groups, and was 2.7 +/- 0.7 mg/dL in the group with discontinued calcineurin inhibitor (N = 18).. Using the least-square method, 91.7% of the no calcineurin inhibitor group, 51.6% of the reduced dose cyclosporine group, and 59.3% of the reduced dose tacrolimus group had improved or lack of deterioration in slope after the intervention. Using the hinge regression line method, there was a statistically significant correlation of the inflection point with the intervention (P = 0.001). Moreover, there was a similar relationship with stabilized or improved graft function observed with the hinge regression line method and the least-square method, as 72.2% of the calcineurin inhibitor withdrawal group, 54.4% of reduced-dose cyclosporine group, and 40% of the reduced-dose tacrolimus group had improved the slope of decay of renal function or lack of deterioration after the inflection point. The difference between the calcineurin inhibitor withdrawal group and the reduced-dose cyclosporine/tacrolimus groups on the decay in renal function was significant (P = 0.038) with the least-square method and nearly significant (P = 0.056) using the hinge regression line method.. This intervention was safe, well tolerated, and associated with a minimal risk of acute rejection. We conclude that the reduction and possible withdrawal of calcineurin inhibitors may be necessary to slow the rate of loss of renal function in patients with chronic allograft nephropathy and deteriorating renal function.

Topics: Adrenal Cortex Hormones; Adult; Calcineurin; Chronic Disease; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Humans; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Tacrolimus; Time Factors

Early chronic liver allograft rejection (CR) is characterized by distinctive cytological changes in biliary epithelial cells (BECs) that resemble cellular senescence, in vitro, and precede bile duct loss. If patients suffering from early CR are treated aggressively, the clinical and histopathological manifestations of CR can be completely reversed and bile duct loss can be prevented. We first tested whether the senescence-related p21(WAF1/Cip1) protein is increased in BECs during early CR, and whether treatment reversed the expression. The percentage of p21+ BECs and the number of p21+ BECs per portal tract is significantly increased in early CR (26 +/- 17% and 3.6 +/- 3.1) compared to BECs in normal liver allograft biopsies or those with nonspecific changes (1 +/- 1% and 0.1 +/- 0.3; P: < 0.0001 and P: < 0.02), chronic hepatitis C (2 +/- 3% and 0.7 +/- 1; P: < 0.0001 and P: < 0.04) or obstructive cholangiopathy (7 +/- 7% and 0.7 +/- 0.6; P: < 0.006 and P: = 0.04). Successful treatment of early CR is associated with a decrease in the percentage of p21+ BECs and the number of p21+ BECs per portal tract. In vitro, nuclear p21(WAF1/Cip1) expression is increased in large and multinucleated BECs, and is induced by transforming growth factor (TGF)-beta. TGF-beta1 also increases expression of TGF-beta receptor II, causes phosphorylation of SMAD-2 and nuclear translocation of p21(WAF1/Cip1), which inhibits BEC growth. Because conversion from cyclosporine to tacrolimus is an effective treatment for early CR, we next tested whether these two immunosuppressive drugs directly influenced BEC growth in vitro. The results show that cyclosporine, but not tacrolimus, stimulates BEC TGF-beta1 production, which in turn, causes BEC mito-inhibition and up-regulation of nuclear p21(WAF1/Cip1). In conclusion, expression of the senescence-related p21(WAF1/Cip1) protein is increased in BECs during early CR and decreases with successful recovery. Replicative senescence accounts for the characteristic BEC cytological alterations used for the diagnosis of early CR and lack of a proliferative response to injury. The ability of cyclosporine to inhibit the growth of damaged BECs likely accounts for the relative duct sparing properties of tacrolimus.

Topics: Animals; Antibodies; Bile Ducts; Biomarkers; Cell Division; Cellular Senescence; Chronic Disease; Cyclin-Dependent Kinase Inhibitor p21; Cyclins; Cyclosporine; Epithelial Cells; Graft Rejection; Humans; Immunosuppressive Agents; Intracellular Membranes; Liver Transplantation; Male; Mice; RNA, Messenger; Signal Transduction; Tacrolimus; Time Factors; Transforming Growth Factor beta

We present two cases of severe dry eye in patients with chronic graft-versus-host disease (CGVHD) after hematopoietic stem cell transplantation (SCT) who were successfully treated by the systemic administration of FK506 and corticosteroids.. A 29-year-old man with chronic myelogenous leukemia underwent SCT. Oral and lung CGVHD developed on approximately day 130, and dry eye associated with CGVHD was diagnosed on day 168. The patient began receiving cyclosporin A (150 mg/d) for the treatment of oral and lung CGVHD. Treatment with prednisolone (1 mg/kg/d) began on approximately day 300. Oral and lung GVHD improved slightly, but worsened again although systemic administration of cyclosporin A and prednisolone were continued. Cyclosporin A was discontinued, and systemic administration of FK506 was started on day 376. Forty-four days later, marked improvement in the ocular surface and other organs was observed. However, the dry eye worsened while tapering FK506, with no flare of other affected organs. A 43-year-old woman with myelodysplastic syndrome underwent SCT. She received FK506 for prophylaxis of CGVHD. She had mild dry eye before SCT. Oral and intestinal CGVHD developed, and the dry eye worsened significantly on approximately day 150 while tapering FK506. Treatment with prednisolone (1 mg/kg/d) began, and the dose of FK506 was increased. By day 240, the symptoms of dry eye and the findings of the ocular surface markedly improved, and CGVHD in other organs was completely resolved. However, the improvement in the dry eye was lost when FK506 was tapered for the second time.. Systemic administration of FK506 with corticosteroids is an effective treatment of severe dry eye in patients with CGVHD, but long-term administration may be required to achieve a lasting response. These cases also suggest that further investigation into the use of topical FK506 and prednisolone as a maintenance therapy should be pursued.

Topics: Adult; Chronic Disease; Drug Therapy, Combination; Dry Eye Syndromes; Female; Glucocorticoids; Graft vs Host Disease; Hematopoietic Stem Cell Transplantation; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Myelodysplastic Syndromes; Prednisolone; Tacrolimus

Topics: Animals; Chronic Disease; Cyclosporine; Graft Rejection; Immunosuppressive Agents; Kidney Glomerulus; Kidney Transplantation; Male; Mycophenolic Acid; Rats; Rats, Inbred F344; Rats, Inbred Lew; Renal Circulation; Tacrolimus; Transplantation, Homologous

Topics: Antibodies, Monoclonal; Antilymphocyte Serum; Azathioprine; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Humans; Immunosuppression Therapy; Immunosuppressive Agents; Liver Transplantation; Prednisolone; Receptors, Interleukin-2; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Hypertension is an important risk factor for chronic transplant nephropathy. Therapy is usually based on casual office blood pressure (BP) measurements. However, it is not well known how casual BP predicts 24-hour BP in this population. The main focus of this study is to compare casual office BP with 24-hour ambulatory BP monitoring in renal transplant recipients with signs of chronic transplant nephropathy. Moreover, in this group, the day-night BP profile was assessed. In 36 renal transplant recipients with incipient or progressive proteinuria or an increase in serum creatinine level greater than 20%, 24-hour ambulatory BP was performed. Patients were defined as a nondipper if the mean BP decreased by less than 10% during the nighttime period. The correlation between single office and 24-hour ambulatory BPs was 0.61 for systolic BP and 0.55 for diastolic BP (P < 0.001). The mean difference between 24-hour ambulatory and single office BPs was -4.2 +/- 18.6 mm Hg (range, -44 to 36 mm Hg) for systolic BP and -1.1 +/- 10.7 mm Hg (range, -34 to 27 mm Hg) for diastolic BP; 94.5% of patients were classified as nondippers. There was a significant relation between the nightly decline in mean arterial pressure and calculated creatinine clearance (r = 0.34; P < 0.05). In conclusion, in renal transplant recipients with chronic transplant nephropathy, a large difference between office and ambulatory BPs is present, with both overestimation and underestimation of 24-hour BP by office BP measurements. Moreover, a severely disturbed day-night BP rhythm was observed. In transplant recipients with compromised graft function, office BP may not reflect 24-hour BP adequately, and ambulatory BP measurements should be considered.

Topics: Adult; Aged; Aged, 80 and over; Blood Pressure; Blood Pressure Determination; Blood Pressure Monitoring, Ambulatory; Chronic Disease; Circadian Rhythm; Cyclosporine; Female; Humans; Hypertension; Immunosuppressive Agents; Kidney; Kidney Diseases; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Tacrolimus

We examined the effects of the immunosuppressant tacrolimus (FK506) on the discrimination learning impairment induced by chronic cerebral hypoperfusion in rats. Chronic cerebral hypoperfusion was prepared by permanent ligation of bilateral common carotid arteries for male Wistar rats aged 9 weeks. FK506 (0.05 mg/kg, s.c.) recovered the learning impairment and also prevented the rarefaction of white matter and striatal neuronal cell damage. Our findings suggest that FK506 ameliorates the learning impairment mainly due to preventing neuropathological alterations.

Topics: Animals; Brain; Cerebrovascular Circulation; Chronic Disease; Corpus Callosum; Dementia, Vascular; Frontal Lobe; Hypoxia-Ischemia, Brain; Immunosuppressive Agents; Learning Disabilities; Male; Neostriatum; Nerve Degeneration; Nerve Fibers, Myelinated; Rats; Rats, Wistar; Recovery of Function; Tacrolimus

In renal transplantation, chronic rejection is a major cause of late allograft loss. Recent studies indicate that a subset of chronic rejection is associated with anti-HLA donor specific antibodies (DSA) and complement C4d deposition in peritubular capillaries (PTC). Since rescue therapy with tacrolimus and mycophenolate mofetil has been found to limit antidonor B-cell responses in recipients with acute humoral rejection, we sought to determine whether a similar immunosuppressive regimen might be effective in patients with 'chronic humoral rejection'.. Four renal allograft recipients with 'chronic humoral rejection' were prospectively identified. The diagnosis was based on: (1) progressive rise in serum creatinine over 12 months; (2) typical pathologic features by light microscopy (transplant arteriopathy and glomerulopathy); (3) widespread C4d deposits in PTC by immunofluorescence; (4) detection of 'de novo' DSA at the time of biopsy. Maintenance immunosuppression was CsA, prednisone and azathioprine (n=3) or prednisone and azathioprine (n=1). Rescue therapy with tacrolimus and mycophenolate mofetil was initiated in all patients, 12 hr after cyclosporine and azathioprine discontinuation.. At diagnosis, the mean serum creatinine was 3.9 mg/dl (range: 3.3 to 5.4 mg/dl). DSA was an IgG directed against HLA class II (n=3) or class I (n=2), that is one patient had both anti-HLA class I and class II antibodies. Pretreatment antibody titers varied between 1:8 and 1:128. Rescue therapy was associated with a rapid and sustained decrease in antibody titers. In two patients, DSA became undetectable after 9 months and a repeat biopsy performed after 12 months revealed a decrease in C4d deposition in PTC.. These results suggest that a decrease in DSA production can be induced in renal allograft recipients with 'chronic humoral rejection' by using an immunosuppressive regimen that combines tacrolimus and mycophenolate mofetil. Limitation of antidonor antibody synthesis may be important for the treatment or the prevention of chronic rejection in organ transplantation.

Topics: Adult; Antibodies; Antibody Formation; Antibody Specificity; B-Lymphocytes; Chronic Disease; Drug Therapy, Combination; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Prospective Studies; Tacrolimus; Tissue Donors; Transplantation, Homologous

The aim of this study was to compare the effects of cyclosporine, tacrolimus, mycophenolate mofetil and SDZ RAD on an animal model of transplant arteriosclerosis involving alloantigen dependent and independent mechanisms.

Topics: Animals; Aorta, Abdominal; Arteriosclerosis; Chronic Disease; Cyclosporine; Disease Models, Animal; Everolimus; Graft Rejection; Immunosuppressive Agents; Isoantigens; Male; Mycophenolic Acid; Rats; Rats, Inbred F344; Rats, Inbred Lew; Sirolimus; Tacrolimus

We assessed T cell association with acinar cell apoptosis and a preventive effect of tacrolimus, a T cell suppressant, on the development of chronic pancreatitis in male Wistar Bonn/Kobori rats. At 15 wk, cellular infiltrates composed of F4/80-positive cells (monocytes/macrophages), CD4-positive cells, and CD8-positive cells were extensive in the interlobular connective tissue and parenchyma. In particular, CD8-positive cells invaded pancreatic lobules and formed close associations with acinar cells, some of which demonstrated features of apoptosis. At 20 wk, CD8-positive cells were still abundant in the fibrotic tissue formed with loss of acinar cells. Repeated subcutaneous injection of 0.1 mg x kg(-1) x day(-1) but not 0.025 mg x kg(-1) x day(-1) of tacrolimus for 10 wk completely prevented the occurrence of acinar cell apoptosis, infiltration of CD4- and CD8-positive cells, and development of pancreatitis at the age of 20 wk, but these maneuvers did not recover the decreased plasma corticosterone levels, which may be responsible for the development of disease. We demonstrated that T cells, possibly CD8-positive cells, are involved in inducing apoptosis of acinar cells, raising the possibility that tacrolimus might find clinical application in the treatment of autoimmune chronic pancreatitis.

Topics: Animals; Apoptosis; Autoimmune Diseases; CD4-Positive T-Lymphocytes; CD8-Positive T-Lymphocytes; Chronic Disease; Corticosterone; Immunosuppressive Agents; In Situ Nick-End Labeling; Male; Pancreatitis; Rats; Rats, Wistar; T-Lymphocytes; Tacrolimus

Hypertrophic obstructive cardiomyopathy (HOCM) associated with the use of tacrolimus is a rare complication of liver and intestinal transplantation seen almost exclusively among pediatric patients. Reduction of tacrolimus dosage or conversion to cyclosporin A (CsA) has been used as an effective treatment in reviewed cases. We present three pediatric transplant recipients who developed hypertrophic obstructive cardiomyopathy while under tacrolimus immunosuppression and were treated with conversion to sirolimus (Rapamycin). The patients (ages 6 yr, 12 yr and 11 months) were transplant recipients (liver, n = 2; liver and intestine, n = 1) who developed significant cardiomyopathy 15 and 96 months post-transplant. One patient died of post-transplant lymphoproliferative disorder 21 days after starting sirolimus. One patient had received two liver transplants and had been on CsA for 12 yr before conversion to tacrolimus at 60 months post-transplant for acute and chronic rejection. The surviving patients were receiving mycophenolate mofetil, tacrolimus and steroids at the time of diagnosis. Dose reduction of tacrolimus and treatment with beta blockers failed to alleviate the hemodynamic changes. The patients were converted to sirolimus 1.6, 37 and 148 months post-transplant and maintained a whole-blood trough level of 15-20 ng/mL 21 days after starting sirolimus. Repeat echocardiograms in the surviving patients showed improvement in cardiomyopathy. One patient had one rejection episode (intestinal biopsy, mild acute cellular rejection) after starting sirolimus that responded to a transient increase in steroids. The early demise of the third patient after sirolimus conversion prevented an adequate assessment of cardiomyopathy. Conversion to sirolimus was associated with a reduction in the cardiomyopathy of the two surviving patients while still providing effective immunosuppression. To our knowledge this observation has not been previously reported.

Topics: Acute Disease; Cardiomyopathy, Hypertrophic; Child; Chronic Disease; Graft Rejection; Humans; Immunosuppressive Agents; Infant; Intestine, Small; Liver Transplantation; Sirolimus; Tacrolimus

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

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

Predisposing factors, long-term occurrence, and histopathological changes associated with recovery or progression to allograft failure from chronic rejection (CR) were studied in adult patients treated primarily with tacrolimus.. CR cases were identified using stringent criteria applied to a retrospective review of computerized clinicopathological data and slides.. After 1973 days median follow-up, 35 (3.3%) of 1049 primary liver allograft recipients first developed CR between 16 and 2532 (median 242) days. The most significant risk factors for CR were the number (P<0.001) and histological severity (P<0.005) of acute rejection episodes and donor age >40 years (P<0.03). Other demographic and matching parameters were not associated with CR in this cohort. Ten patients died with, but not of, CR. Eight required retransplantation because of CR at a median of 268 days. Ten resolved either histologically or by normalization of liver injury tests over a median of 548 days. CR persisted for 340 to 2116 days in the remaining seven patients. More extensive bile duct loss (P<0.01), smallarterial loss (P<0.03), foam cell clusters (P<0.01) and higher total bilirubin (P<0.02) and aspartate aminotransferase (P<0.03) were associated with allograft failure from CR.. Early chronic liver allograft rejection is potentially reversible and a combination of histological, clinical, and laboratory data can be used to stage CR. Unique immunological and regenerative properties of liver allografts, which lead to a low incidence and reversibility of early CR, can provide insights into transplantation biology.

Topics: Adolescent; Adult; Aged; Chronic Disease; Disease Progression; Female; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Liver; Liver Transplantation; Longitudinal Studies; Male; Middle Aged; Reoperation; Retrospective Studies; Tacrolimus; Transplantation, Homologous

CD40 ligand (CD40L) gene expression is increased in rejecting allograft biopsies. We, therefore, tested the possibility that CD40L gene expression is heightened in peripheral CD4+ T cells during renal allograft rejection.. CD40L gene expression in peripheral blood CD4+ T cells from two renal transplant groups was measured by quantitative reverse transcription-polymerase chain reaction (RT-PCR). Group 1: 20 patients with excellent renal transplant function; group 2: 25 patients with findings of acute and/or chronic allograft nephropathy (CAN); and group 3 of 12 normal controls. CD4+ cells were isolated by positive selection. The modifying effect of cyclosporine (CsA) and FK506 on CD40L gene expression was further tested in vitro in CD4+ T lymphocytes separated from pokeweed mitogen- (PWM) activated peripheral blood lymphocytes (PBL) preparations.. Mean+/-SD expressions of CD40L gene, in aM, in groups 1-3 were as follows: 0.0052+/-0.0094; 0.022+/-0.023 (P=0.0038 vs. group 2); and 0.014+/-0.005. Levels of CD40L gene expression correlated significantly with acute rejection Banff 97 score (R2=0.44, P=0.0004) and severity of intertubular capillary changes (ITCC) (R2=0.33, P=0.011). After in vitro activation, CD40L gene expression increased by approximately 4-fold and the addition of CsA or FK506 diminished CD40L gene expression to a base level.. Peripheral CD4+ T cell CD40L gene expression increases significantly in acute rejection and CAN and may serve as a non-invasive method to monitor allograft function and determine the biological response to CsA and FK506.

Topics: Acute Disease; Adult; Base Sequence; Case-Control Studies; CD4-Positive T-Lymphocytes; CD40 Antigens; CD40 Ligand; Chronic Disease; Cyclosporine; DNA Primers; Gene Expression; Graft Rejection; Humans; Immunosuppressive Agents; In Vitro Techniques; Kidney Transplantation; Ligands; Membrane Glycoproteins; Middle Aged; Tacrolimus

A newly developed liver/small bowel transplantation model (LSBTx) was used to investigate the tolerogenic effect of a liver allograft toward a simultaneously transplanted small bowel. Small bowel transplantation (SBTx) under high-dose immunosuppression was compared to LSBTx with a lower FK506 dosage. Syngeneic Lewis [(LEW) to LEW] and two fully allogeneic rat strain combinations (Brown Norway-to-LEW and Dark Agouti-to-LEW) were used. Clinical course and histological findings after SBTx demonstrated a chronic rejection of the small bowel allograft within 100 days. However, after LSBTx long-term acceptance (> 150 days) was achieved after a transient rejection crisis, although initial immunosuppression was significantly lower. Furthermore, indicator heart transplantations demonstrated the induction of donor-specific tolerance in both allogeneic strain combinations. In contrast to other LSBTx rat models, these results reflect observations after human LSBTx, in which the rate of acute and chronic rejection is also significantly lower than after human SBTx.

Topics: Acute Disease; Animals; Chronic Disease; Graft Rejection; Graft Survival; Humans; Immune Tolerance; Immunosuppressive Agents; Intestine, Small; Liver Transplantation; Rats; Rats, Inbred BN; Rats, Inbred Lew; Rats, Inbred Strains; Tacrolimus; Transplantation, Homologous; Transplantation, Isogeneic

Topics: Alanine Transaminase; Aspartate Aminotransferases; Child, Preschool; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Family; Female; Graft Rejection; Guanidines; Humans; Immunosuppressive Agents; Liver Transplantation; Living Donors; Lymphocytes; Male; Methylprednisolone; Reoperation; Tacrolimus

Topics: Acute Disease; Adolescent; Adult; Child; Child, Preschool; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Hypertension; Immunosuppressive Agents; Incidence; Infant; Liver Transplantation; Middle Aged; Retrospective Studies; Tacrolimus

Topics: Adolescent; Adult; Chronic Disease; Cyclosporine; Diabetes Mellitus, Type 1; Diabetes Mellitus, Type 2; Female; Follow-Up Studies; Graft Survival; Humans; Immunosuppressive Agents; Male; Middle Aged; Pancreas Transplantation; Pancreatitis; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Erosive mucosal lichen planus is a painful and disabling inflammatory skin disease that is highly resistant to topical treatment. We report on six patients with severe recalcitrant erosive mucosal lichen planus who benefited from topical application of tacrolimus ointment. After 4 weeks of treatment, complete resolution was observed in three cases, and substantial improvement was achieved in the other three patients. In these cases, prolonged treatment resulted either in further improvement or in complete healing. All patients reported rapid relief from pain and burning. No severe side-effects were observed.

Topics: Administration, Topical; Aged; Chronic Disease; Female; Humans; Immunosuppressive Agents; Lichen Planus; Male; Middle Aged; Tacrolimus

Topics: Chronic Disease; Female; Humans; Immunosuppressive Agents; Middle Aged; Prednisolone; Pyoderma Gangrenosum; Tacrolimus

In recent years, tacrolimus (FK506, TAC) has been increasingly utilized in liver transplantation. However, long-term risks and benefits as compared with conventional cyclosporin A (CsA) have not been fully elucidated. This retrospective study examined the potential outcome differences between TAC- and CsA-based immunosuppressive therapy in pediatric liver transplant recipients. From March 1988 to December 1996, 218 children (aged 0.1-17 yr) underwent 238 orthotopic liver transplantations; 58.7% (128/218) were under 2 yr of age at time of transplant. Initially, the maintenance immunosuppressive regimen consisted of CsA and prednisone, with antilymphocytic preparations (MALG, ATGAM, and OKT3) as induction therapy. Subsequently, TAC was used first as rescue therapy for steroid refractory rejection in CsA patients and then as maintenance immunosuppression. Fifty-seven out of the 147 CsA patients were converted to TAC for various reasons while 71 patients were placed on TAC as primary maintenance immunosuppression. 62.6 per cent (92/147) of liver recipients on CsA experienced at least one biopsy-proven acute rejection episode as compared to 50.7% (36/71) for TAC patients (p = 0.09); likewise, 34% (50/147) of CsA patients had more than one episode of rejection vs. 18.3% (13/71) for patients on TAC (p < 0.02). Rejection was the reason for conversion from CsA to TAC in 29 of 57 patients. Conversely, 19.0% (28/147) of CsA patients had to be switched to TAC for reasons not related to rejection (i.e. side-effects). The overall incidence of histologically proven chronic rejection was 7.8% (17/218). 10.9 per cent (16/147) of the children who were on CsA initially developed chronic rejection, which was significantly higher compared with one of 71 TAC recipients (p < 0.02). Of these 16 CsA patients with chronic rejection, 50.0% (8/16) underwent retransplantation for graft failure (mean interval from time of diagnosis of chronic rejection to re-transplant, 4.0 months; range 1-8 months), whereas the TAC patient has remained clinically stable with normal liver function tests after 23 months of follow-up. One year after liver transplantation, 72.8% (107/147) of CsA patients were still on steroids (mean dosage 0.20 mg/kg/d), as compared to 42.3% (30/71) of the TAC patients (mean dosage 0.14 mg/kg/d). The incidence of post-transplant lymphoproliferative disorder (PTLD) in Epstein-Barr virus (EBV)-infected patients was 2.2% (2/90), 7.0% (5/71) and 12.3% (7/57) for CsA, primary

Topics: Acute Disease; Adolescent; Child; Child, Preschool; Chronic Disease; Cyclosporine; Graft Rejection; Herpesviridae Infections; Herpesvirus 4, Human; Humans; Immunosuppressive Agents; Infant; Liver Function Tests; Liver Transplantation; Retrospective Studies; Tacrolimus; Treatment Outcome; Tumor Virus Infections

The aim of the present study was to differentiate acute rejection, chronic rejection, and tacrolimus nephrotoxicity with color and power Doppler imaging of renal transplants. One hundred examinations were obtained from 45 patients. Pulsatility and resistive indices were calculated from color Doppler images. The grade of renal vascularization was quantified using computer-assisted pixel analysis in a rectangular region-of-interest. The percentage of vessel-covered renal parenchyma (POV) was calculated using a histogram that discriminated renal vessels from renal parenchyma via power Doppler images. Furthermore, the distance from the most peripherally located vessels to the renal capsule (PVD) was measured. A reduced POV < or = 55% proved to be the best discriminator when chronic rejection was suspected (sensitivity 79%, specificity 87%). Tacrolimus nephrotoxicity showed not only a moderate elevation of the Doppler signal but also an increased PVD > or = 3.9 mm and a normal POV. We conclude that the evaluation of renal vessels by power Doppler images improves diagnostic accuracy for patients with renal allografts.

Topics: Acute Disease; Adolescent; Adult; Aged; Chronic Disease; Diagnosis, Differential; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Tacrolimus; Transplantation, Homologous; Ultrasonography, Doppler; Ultrasonography, Doppler, Color

The successful use of tacrolimus (Tac)-based immunosuppressive therapy in organ transplantation and our own positive experience in heart transplantation led us to investigate regimens including this agent at our center for lung transplantation.. From 1991 to 1998, 86 patients underwent lung transplants at our center and 78 of them were included in this analysis. The first 34 patients were treated with cyclosporin (CsA), azathioprine (Aza), and rabbit antilymphocyte globulin; the subsequent 30 patients received Tac with Aza, and the most recent 12 patients Tac with mycophenolate mofetil (MMF). In addition, all patients received prednisone.. The number of acute rejection episodes per 100 patient days was 1.5, 0.6, and 0.3 for three treatment groups, respectively. Similarly, the incidence of refractory acute rejection per 100 patient days was lower in both Tac groups (0.20, 0.03, and 0, respectively). Freedom from acute rejection was highest in the Tac-MMF group (P=0.0037 vs. Tac/Aza, P=0.0007 vs. CsA/Aza). Freedom from recurrent acute rejection was significantly higher in both Tac groups (P=0.027 Tac/ Aza vs. CsA/Aza and P=0.025 Tac/MMF vs. CsA/Aza). The incidence of infections per 100 patient days was similar (0.8, 0.5, and 0.8) in all three treatment groups, with a similar distribution of fungal, bacterial, and viral infections. Freedom from infection also showed no difference. The survival rate was significantly higher for the Tac population, with actuarial 1- and 3-year survival rates of 93% and 71%, compared with the CsA group (71% and 51%, respectively, P=0.04). Prevalence of renal dysfunction (creatinine >2.0 mg/ dL) was 18%, 13%, and 0% in the 3 treatment groups, respectively. The development of glucose metabolism disorders was lower in the CsA group than in the Tac-Aza group (15% vs. 27%, P<0.05).. Tac-based immunosuppressive therapy results in a lower rate of acute rejection after pulmonary transplantation, with similar infection rates and a slightly higher incidence of new onset diabetes mellitus compared with CsA-based therapy.

Topics: Acute Disease; Adult; Animals; Antilymphocyte Serum; Azathioprine; Chronic Disease; Creatinine; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Diseases; Lung Transplantation; Male; Middle Aged; Mycophenolic Acid; Prednisone; Rabbits; Retrospective Studies; Tacrolimus

Topics: Acute Disease; Adult; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Retrospective Studies; Tacrolimus

Topics: Adjuvants, Immunologic; Adult; Bone Marrow Transplantation; Chronic Disease; Combined Modality Therapy; Drug Therapy, Combination; Graft vs Host Disease; Humans; Immunosuppressive Agents; Male; Prednisolone; Sulfasalazine; Tacrolimus; Transplantation, Homologous; Treatment Outcome

The effects of the anticytokine interleukin 10 (IL-10) are mediated by specific receptors. In this study we examined the role of the IL-10 receptor (IL-10R) in the pathophysiology of atopic eczema.. For this purpose we analyzed the expression of IL-10R in the skin of patients with acute and chronic atopic eczema in comparison to the expression in healthy individuals using in situ binding experiments with fluorescently labeled IL-10 and semiquantitative reverse transcriptase-PCR specific for IL-10R1. In addition, we studied the influence of the Th2-associated cytokine interleukin-4 (IL-4), the Th1-associated gamma-interferon (IFN-gamma), the immunosuppressive drug FK506, the H1-antagonist loratadine and UVA irradiation on the expression of IL-10R1 in cultured normal human keratinocytes.. We found that IL-10 receptor mRNA and protein are strongly downregulated in acute phase atopic lesions. Furthermore we could show that IL-4, IFN-gamma, FK506, loratadine and UVA enhance the mRNA levels of the IL-10R1 in vitro in normal cultured keratinocytes. We could also demonstrate restored IL-10R1 mRNA levels in lesional atopic skin of a patient after UVA1 therapy.. Our results demonstrate for the first time that IL-10 receptors may have a role in the pathogenesis of atopic eczema and its upregulation by FK506 and UVA could explain the therapeutic efficacy of these agents.

Topics: Acute Disease; Adult; Aged; Cells, Cultured; Chronic Disease; Cytokines; Dermatitis, Atopic; Gene Expression Regulation; Humans; Immunosuppressive Agents; Keratinocytes; Middle Aged; Receptors, Interleukin; Receptors, Interleukin-10; RNA, Messenger; Tacrolimus; Ultraviolet Therapy

Topics: ABO Blood-Group System; Adult; Azathioprine; Blood Group Incompatibility; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Female; Glomerulonephritis, IGA; Graft Rejection; Histocompatibility Testing; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Methylprednisolone; Tacrolimus; Treatment Failure; Treatment Outcome

A 40-year-old man with chronic myelogenous leukemia in chronic phase received an allogeneic marrow graft from his HLA identical brother. He was conditioned with busulfan (16 mg/kg) and cyclophosphamide (120 mg/kg). Graft-versus-host disease (GVHD) prophylaxis was attempted with cyclosporine A (CYA) and methotrexate. On day 30, weight gain, ascites and hepatomegaly developed in addition to an elevation of total bilirubin (TB). He was diagnosed as having veno-occlusive disease (VOD) and treated conservatively. The TB level increased up to 20.1 mg/dl on day 66, then reduced to 2.1 mg/dl on day 129. By that time ascites and hepatomegaly also had completely resolved. However, on day 134. The TB level started to increase again, when the lesions of chronic GVHD were observed in the eye, the mouth, and the skin. CYA was started on day 142, and FK506 was substituted for CYA on day 161. Despite the improvement of oral and skin lesions, TB level continued to rise, and he died of respiratory failure due to ARDS on day 186. Autopsy revealed both acute and old hepatic VOD lesions, suggesting the occurrence of late-onset VOD which probably contributed to the liver dysfunction observed after clinical resolution of the first episode of VOD.

Topics: Adult; Bone Marrow Transplantation; Busulfan; Chronic Disease; Cyclophosphamide; Cyclosporine; Graft vs Host Disease; Hepatic Veno-Occlusive Disease; Humans; Immunosuppressive Agents; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Male; Methotrexate; Recurrence; Respiratory Distress Syndrome; Tacrolimus

Neuroprotective effects of immunosuppressive agents have been shown in cerebral ischemia. To investigate the role of immunosuppressive agents in chronic cerebral ischemia and to design a drug protocol with safe therapeutic windows, we examined the effects of FK506, a potent immunosuppressive agent, on chronic cerebral ischemia. Both common carotid arteries were ligated in 73 male Wistar rats. Fifty-eight of these rats received a chronic injection of FK506 (0.2, 0.5, 1.0 mg/kg) and the remaining 15 received a vehicle solution injection. Microglia/macrophage was investigated with immunohistochemistry for leukocyte common antigen and major histocompatibility complex, and astroglia was examined with glial fibrillary acidic protein as markers. White matter rarefaction and the number of immunopositive glial cells were assessed from 7 to 30 days after the ligation. In the vehicle-treated animals, there was persistent and extensive activation of the microglia/macrophages and astroglia in the white matter, including the optic nerve, optic tract, corpus callosum, internal capsule, anterior commissure and traversing fiber bundles of the caudoputamen. In the FK506-treated rats, the number of activated microglia/macrophages was significantly reduced in a dose-dependent manner (p<0.01) as compared to the vehicle-treated rats. Rarefaction of the white matter was also inhibited by FK506 in a dose-dependent manner (p<0. 01). Thus, a clinically-relevant dosage of FK506 attenuated both glial activation and white matter changes in chronic cerebral ischemia in the rat. These results indicate a potential use for FK506 in cerebrovascular diseases.

Topics: Animals; Blood Glucose; Blood Urea Nitrogen; Brain; Brain Ischemia; Chronic Disease; Dose-Response Relationship, Drug; Immunohistochemistry; Male; Neuroprotective Agents; Optic Nerve; Rats; Rats, Wistar; Tacrolimus; Time Factors; Transaminases

Topics: Acute Disease; Azathioprine; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Male; Middle Aged; Retrospective Studies; Tacrolimus

Mycophenolate mofetil (MMF) has been previously shown to prevent functional deterioration in an experimental model of chronic renal allograft rejection.. In this retrospective case-control study, patients with chronic rejection who were receiving cyclosporine or tacrolimus and who had MMF added to their immunosuppressive regimen were compared with patients with chronic rejection who were not receiving MMF. Patients were matched for serum creatinine levels and transplant duration at the time MMF was begun.. In the MMF group, the average dose of MMF was 1482 mg/day with an average duration of 19.3 months. Over 36 months, including 12 months before MMF and up to 24 months on MMF, there was no difference in serum creatinine levels between the two groups. Cyclosporine levels and dose were no different.. In this small, retrospective, preliminary study, adding MMF to maintenance immunosuppression provided no clear benefit to renal allograft recipients with established chronic rejection. Larger prospective randomized studies are needed.

Topics: Adult; Case-Control Studies; Chronic Disease; Creatinine; Cyclosporine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Mycophenolic Acid; Retrospective Studies; Tacrolimus; Treatment Failure

Interleukin 10 (IL-10) is a macrophage and T-cell-derived cytokine with potent immunosuppressive properties. To assess its role in liver allograft rejection, we evaluated the plasma level and in situ production of IL-10 after liver transplantation and designed in vitro studies to asses the effects of IL-10 on the allogeneic response. Normal controls and liver transplant recipients with acute rejection, chronic rejection, other complications (recurrent hepatitis C, biliary complications), or no complications were evaluated. The plasma IL-10 level was measured by an immunoenzymatic technique. IL-10 expression in the liver was detected on frozen liver biopsies by in situ hybridization and immunohistochemistry. Plasma IL-10 levels were not elevated during acute or chronic rejection, when compared with liver recipients with uncomplicated transplants. IL-10 mRNA and protein expressions in the liver graft were restricted to rare scattered sinusoidal cells of transplant recipients with acute or chronic rejection, as well as in those with no complications. In mixed lymphocyte cultures performed with peripheral blood mononuclear cells (PBMC) from normal subjects, IL-10 decreased the cell proliferation in a dose-dependent manner, and this immunosuppression was synergistic with that of cyclosporine or FK506. These findings indicate that IL-10 production is low during allograft rejection. Thus, IL-10 therapy in association with cyclosporine or FK506 might be proposed after liver transplantation.

Topics: Acute Disease; Azathioprine; Cells, Cultured; Chronic Disease; Cyclosporine; Graft Rejection; Humans; Immunosuppressive Agents; Interleukin-10; Liver Transplantation; Lymphocyte Culture Test, Mixed; Lymphocytes; Methylprednisolone; Tacrolimus; Transplantation, Homologous

Topics: Adult; Chronic Disease; Demyelinating Diseases; Electromyography; Female; Humans; Immunosuppressive Agents; Polyneuropathies; Prednisolone; Psoriasis; Recurrence; Tacrolimus

The orthotopic liver transplantation (OLT) program of the University of Liège was initiated in 1986. Between 1986 and December 1998, 150 adult OLT have been performed in our institution, including 18 liver retransplantations, 1 combined heart and liver transplantation and 3 combined liver and kidney transplantations. The aim of this study was to report the last 3 years of our experience. From January 1996 to November 1998, we performed 50 OLT on 49 patients. Three were retransplantations and two were combined liver and kidney transplantations. Fourty-three patients were transplanted for chronic liver disease and 6 for acute or subacute hepatopathy. Mean waiting time on the list was 4 weeks. Immunosuppression was based on triple therapy (cyclosporin A/tacrolimus, steroids, azathioprine), with steroid and azathioprine withdrawal in most of the patients after 3 months. In the chronic liver disease group, operative (< 30 days) survival was 95% (peroperative myocardial infarction in 2 patients). In the acute liver disease group, postoperative survival was 66%. No perioperative death occurred in 1997 and 1998. Actuarial one year survival was 87%. In our experience, OLT has become a safe procedure.

Topics: Actuarial Analysis; Acute Disease; Adrenal Cortex Hormones; Adult; Azathioprine; Belgium; Chronic Disease; Cyclosporine; Heart Transplantation; Humans; Immunosuppressive Agents; Kidney Transplantation; Liver Diseases; Liver Transplantation; Myocardial Infarction; Postoperative Complications; Reoperation; Survival Rate; Tacrolimus; Time Factors; Waiting Lists

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

Blood transfusions are common in patients with end-stage liver disease (ESLD), and their effects on sensitization, rejection, and liver graft survival are not well known. These effects were examined in 121 recipients of primary liver grafts, surviving > or = 30 days. Ninety-six (79%) patients received transfusions before transplantation. Transfusion recipients had significantly fewer severe or recurrent rejection episodes (18%), compared with patients who did not receive transfusions (42%, P=0.006), if the first transfusion was > or = 90 days before the transplant. Patients with alcoholic ESLD (n=49) had significantly fewer severe rejection episodes when compared with the nonalcoholic (n=72) patients (12% vs. 35%, P=0.004). The transfusion benefit was, however, more apparent and significant in the nonalcoholic (26% vs. 56% in nontransfused, P=0.02) than among the alcoholic recipients (6% vs. 25%, P=0.1). This finding is, most likely, due to a combination of a higher rate of severe rejection and the statistical power of the larger number of recipients in the nonalcoholic group. This finding is further corroborated by a multivariate analysis in which blood transfusions retained their benefit (P<0.05) independent of recipient's age and diagnosis. Graft and patient survival were not significantly different in the transfused versus nontransfused groups. Transfusion recipients had a higher panel antibody (11.4+/-23.4 vs. 2.7+/-8.1, P<0.02) but no increased risk of a positive crossmatch. In liver recipients, blood transfusions diminish the risk of rejection independent of recipient's age and the cause of ESLD.

Topics: Adult; Blood Transfusion; Chronic Disease; Cyclosporine; Female; Graft Rejection; Humans; Immunosuppressive Agents; Intraoperative Period; Liver Diseases, Alcoholic; Liver Failure; Liver Transplantation; Male; Middle Aged; Tacrolimus; Time Factors

Acute myocardial rejection refractory to treatment still contributes significantly to patient death after intrathoracic transplantation. A historical series of 25 patients who received OKT3 (5 mg/day for 10 days) was compared with our current experience with 14 patients treated with tacrolimus (0.1 mg/kg/day targeting whole blood concentrations of 13 to 18 ng/ml): all 39 patients having persistent rejection unresponsive to treatment at the time of conversion. Mean periods of follow-up were 842.9 days and 342.6 days, respectively. Actuarial 1-year patient survival rates were 64.0% and 76.2% for the OKT3 and tacrolimus treatment groups, with most of the deaths in the OKT3 group occurring early (p = 0.064). Causes of death for patients receiving OKT3 included acute rejection (n = 5), infection (n = 3), carcinoma (n = 2), multiorgan failure (n = 1) and graft vessel disease (n = 1). The two deaths in the tacrolimus treatment group were the result of infections. Eighty percent of patients treated with OKT3 subsequently experienced further rejection episodes, in many cases necessitating methotrexate therapy. In contrast, only one patient (7.1%) from the tacrolimus group was diagnosed with rejection after conversion (p < 0.001). In conclusion, when compared with OKT3 therapy, a switch in baseline immunosuppression from cyclosporine to tacrolimus seems to be markedly more effective, as well as being safe for the treatment of persistent acute rejection.

Topics: Actuarial Analysis; Acute Disease; Adult; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Female; Graft Rejection; Heart Transplantation; Heart-Lung Transplantation; Humans; Immunosuppressive Agents; Lung Transplantation; Male; Middle Aged; Muromonab-CD3; Opportunistic Infections; Survival Analysis; Tacrolimus; Treatment Outcome

In a consecutive case series (level V evidence) involving 10 recipients of unilateral lung transplantation (LT) with bronchiolitis obliterans, in conjunction with Fujisawa protocol 93-0-003, the physiologic responses to FK 506 (tacrolimus) "rescue" immunosuppression were assessed. Recipients were 22+/-18 months post-LT and demonstrated progressive allograft dysfunction that was refractory to pulsed-dose methylprednisolone therapy. All recipients received induction immunosuppression with Minnesota antilymphocyte globulin (10 to 15 mg/kg/d) for 5 to 10 days, cyclosporine (CsA) (whole-blood Abbott TDX fluorescence polarization immunoassay (Abbott Inc, Abbott Park, IL)=600 to 800 ng/mL), azathioprine (2 mg/kg/d), and prednisone (tapered to 0.2 mg/kg/d). The "rescue" regimen consisted of oral FK 506 adjusted to maintain a whole-blood Abbott IMX microparticle enzyme immunoassay (Abbott Inc, Abbott Park, IL) of 10 to 15 ng/mL with an initial increase in prednisone (1.0 mg/kg/d) during conversion that was subsequently tapered to 0.2 mg/kg/d. Spirometry was performed monthly in accordance with accepted American Thoracic Society criteria. Recipients were classified in accordance with the International Society for Heart and Lung Transplantation (ISHLT) "Working Formulation for Standardization of Nomenclature and for Clinical Staging of Chronic Dysfunction in Lung Allografts" as stages Ib (n=2), IIb (n=4), and IIIb (n=4) upon entry to the protocol. The deltaFEV1/month relationships during CsA- and FK 506-based regimens were analyzed by linear regression and compared by signed rank test (p<0.05).. The deltaFEV1/month slopes were -0.0687+/-0.0221 and +0.0300+/-0.033 L/mo (mean+/-SEM) for CsA and FK 506, respectively (p=0.037). Although no significant spirometric improvement was noted in most recipients, no further decline in FEV1 occurred after conversion to FK 506. Recipients with less severe chronic dysfunction (ie, obliterative bronchiolitis [OB] stages Ib and IIb) stabilized their spirometric indexes at higher levels. Two recipients with OB stage IIIb died of hypercapnic respiratory failure at 6 and 8 months after conversion.. The deltaFEV1/mo slopes stabilized after FK 506 conversion. Earlier conversion may be beneficial in stabilizing FEV1 at a higher plateau. Significant economic impact may be anticipated with FK 506 compared to alternative cytolytic strategies for OB. However, multicenter prospective controlled investigations are necessary to further address the potential role of FK 506 after LT (level I evidence). Furthermore, the ISHLT "Staging of OB Syndrome" may have significant clinical implications vis-à-vis prognosis and potential therapies.

Topics: Bronchiolitis Obliterans; Chronic Disease; Dose-Response Relationship, Drug; Drug Administration Schedule; Follow-Up Studies; Graft Rejection; Humans; Immunosuppressive Agents; Lung Transplantation; Postoperative Complications; Prevalence; Societies, Medical; Tacrolimus; Treatment Outcome

Topics: Actuarial Analysis; Adult; Aged; Biopsy; Chronic Disease; Female; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Survival Rate; Tacrolimus; Time Factors

Topics: Acute Disease; Adult; Azathioprine; Biopsy; Blood Glucose; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Female; Follow-Up Studies; Glycated Hemoglobin; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Male; Pancreas Transplantation; Prednisone; Tacrolimus; Transplantation, Homologous

Topics: Animals; Chronic Disease; Graft Rejection; Immunosuppressive Agents; Interleukin-4; Intestinal Mucosa; Intestines; Mast Cells; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Tacrolimus; Transplantation, Homologous; Transplantation, Isogeneic

Topics: Acute Disease; Animals; Biomarkers; Chronic Disease; Dogs; Gastrointestinal Hormones; Graft Rejection; Immunohistochemistry; Immunosuppressive Agents; Intestine, Small; Myenteric Plexus; Nerve Fibers; Neurons; Neuropeptides; Tacrolimus; Transplantation, Autologous; Transplantation, Homologous; Tyrosine 3-Monooxygenase

Topics: Antilymphocyte Serum; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Incidence; Liver Transplantation; Reoperation; Retrospective Studies; Survival Rate; Tacrolimus; Treatment Outcome

We have previously demonstrated that subclinical chronic rejection (CR) induces structural and functional alterations in enteric smooth muscle and nerves in a rat model of small intestinal transplantation. This study was designed to investigate the effect of prolonged FK506 rescue therapy on these sequelae of CR. Immunohistochemistry of BrdU-labeled muscle cells demonstrated that active proliferation of intestinal smooth muscle caused by CR was successfully aborted by FK506 rescue therapy after a period of 30 days (control = 0.14 +/- 0.09; CR = 30.4 +/- 1.73; rescue = 2.4 +/- 0.63 cells/jejunal cross-section, P < 0.01). However, FK506 did not reverse the already established increase in muscular thickness (control = 92 +/- 2.4; CR = 193 +/- 10.6; rescue = 188 +/- 8.1 microns) due to CR. Bethanechol stimulated circular muscle contractility was improved markedly with rescue therapy (maximal contractile force reached 39.5% of control values in CR grafts and 68.8% after rescue). Rescue therapy did not reverse the loss of NADPH-diaphorase positive myenteric ganglia (control = 37 +/- 1.4; CR = 28 +/- 2.9; rescue = 23 +/- 1.7 ganglia/cross-section). Despite the persistent loss of ganglia, inhibitory junction potentials (IJPs) improved significantly returning to control values with FK506 (control = 10 +/- 0.5; CR = 5 +/- 0.3; CR rescue = 10 +/- 0.7 mV; IJPs recorded at 1 pulse/150V/0.75 ms). Although structural changes in enteric smooth muscle and myenteric neurons induced by CR were not reversed, the progression of subclinical CR can be effectively curbed by FK506 rescue therapy. The improvement in muscular mechanics and inhibitory neural innervation is probably due to the cessation of infiltrating immunocytes and sprouting of remaining myenteric nerves.

Topics: Animals; Chronic Disease; Graft Rejection; Intestinal Mucosa; Intestine, Small; Male; Muscle Contraction; Muscle, Smooth; Neuromuscular Junction; Rats; Rats, Inbred ACI; Rats, Inbred Lew; Synaptic Transmission; Tacrolimus

Topics: Bronchiolitis Obliterans; Chronic Disease; Female; Graft Rejection; Heart-Lung Transplantation; Humans; Immunosuppression Therapy; Tacrolimus

Living renal transplantation (Tx) was carried out on a 41-year-old male undergoing hemodialysis for a six-month period because of end-stage renal failure due to chronic glomerulonephritis. Tacrolimus (FK 506) was used as one of immunosuppressants. The graft worked immediately after Tx. However, his blood sugar level rose extremely high and use of insulin (IS) was required. At the second postoperative day, 0.3 mg/kg/day of FK506 was administered and the trough level (TL) was as high as 65 ng/ml. The serum IS level decreased from the pre-Tx value of 22 microU/ml to 12 microU/ml. With decrease in the dose of FK506, the TL was normalized, and the dose of IS could be decreased. FK506 has been reported to inhibit IS secretion. Therefore, we must be careful to evaluate the blood glucose level in the use of FK506 for patients with poor glucose tolerance.

Topics: Adult; Chronic Disease; Diabetes Mellitus; Glomerulonephritis; Glucose Intolerance; Humans; Kidney Transplantation; Male; Renal Dialysis; Tacrolimus; Transplantation, Homologous

Topics: Bronchiolitis Obliterans; Chronic Disease; Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Lung Transplantation; Randomized Controlled Trials as Topic; Tacrolimus

Lewis rat recipients of long-term, surviving, orthotopic Brown-Norway rat intestinal allografts, initially treated with cyclosporin A (CyA) or FK 506, were evaluated for their functional capacity and morphology over 1 year after the immunosuppressive therapy had been discontinued. Functional parameters such as nitrogen and fat balances, maltose absorption, blood chemistry, hematologic studies, and the weight gained by the allografted animals did not differ from those of syngeneically grafted or age-matched normal animals. Immunohistochemical studies showed that the lamina propria of the allografts was repopulated with recipient MHC class II+ mononuclear cells and that a normal distribution of T helper, T suppressor/killer, and IgA+ plasma cells had occurred. However, fibrous replacement of the mesenteric lymph nodes and Peyer's patches were detected in all, and an inflammatory obliterative arteriolopathy developed in the mesenteric vasculature of half of the allografted animals. No such findings were observed in recipients of syngeneic grafts. These results demonstrate that the limited use of potent immunosuppressive agents immediately after transplantation averts rejection and is followed by recipient-type mucosal lymphocytic repopulation. Simultaneously, a clinically not recognizable chronic rejection evolves. This suggests that the timely diagnosis of chronic rejection may not be possible with the use of standard tests of gut function and random mucosal biopsies alone.

Topics: Animals; Chronic Disease; Cyclosporine; Graft Rejection; Graft Survival; Intestinal Mucosa; Intestine, Small; Leukocyte Count; Leukocytes, Mononuclear; Lymph Nodes; Male; Rats; Rats, Inbred BN; Rats, Inbred Lew; T-Lymphocyte Subsets; Tacrolimus; Transplantation, Homologous

Graft rejection remains a major problem in liver transplantation. The frequency of acute rejection is of the order of 50%. The first episode usually occurs around the 7th day. The diagnosis, suggested by clinical signs and biochemical abnormalities, is confirmed by histology. Three fundamental histological lesions are usually observed: portal infiltrate, biliary lesions and endothelitis. Chronic liver rejection is characterised by progressive reduction in the number of interlobular bile ducts. It affects 5 to 15% of transplant recipients, is refractory or poorly responsive to current immunosuppressant treatments and usually requires retransplantation. Prophylactic immunosuppression usually consists of a triple combination of cyclosporin-azathioprine-corticosteroids. FK 506 has been recently proposed. Corticosteroids inhibit the synthesis of interleukin 1 and reduce the synthesis of mediators of inflammation. Azathioprine is an antimetabolite which inhibits T lymphocyte cell division. Cyclosporin decreases lymphokine secretion. FK 506 can be used to treat acute rejection resistant to other immunosuppressants and may prevent chronic rejection. Cyclosporin is started at low doses and gradually increased until the desired serum concentration is obtained. Regular monitoring of serum cyclosporin levels is essential to reduce the adverse effects of this drug. The doses of corticosteroids are gradually decreased to achieve a maintenance dose (10-30 mg/day). Azathioprine is commenced postoperatively (0.5 to 1.5 mg/kg/day). In the long term, azathioprine should be suspended and the dosage of corticosteroids should be reduced. The initial treatment of rejection consists of bolus injections of corticosteroids: 10 to 15 mg/kg/day of i.v. methylprednisolone for 2 or 3 days.(ABSTRACT TRUNCATED AT 250 WORDS)

Topics: Acute Disease; Adrenal Cortex Hormones; Azathioprine; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Graft Rejection; Humans; Liver Transplantation; Postoperative Complications; Tacrolimus; Transplantation, Homologous

Intractable liver allograft rejection remains an important cause of graft loss. In this present study, we evaluated the role of oral FK 506 in 30 rejection episodes resistant to conventional cyclosporin-based triple immunosuppression in a series of 28 patients. Rejection was reversed in 11 (91.7%) of 12 patients for intractable acute rejection and in 10 (58.8%) of 17 patients for chronic rejection. A progressive decline in serum bilirubin was observed within 14 days in those successfully salvaged and a serum bilirubin of less than 200 micromol/l at the time of FK 506 conversion in the chronic rejection subgroup was found to be good predictor of response (specificity 100%, sensitivity 60%). New onset diabetes mellitus (29%) and reversible renal impairment (32%) were the commonest adverse events observed. Eleven (52%) of the responding patients successfully discontinued corticosteroid medication and are currently on FK 506 monotherapy. FK 506 therapy has a significant impact in the control of both intractable acute and chronic allograft rejection with an acceptable toxicity profile.

Topics: Acute Disease; Adult; Bilirubin; Chronic Disease; Cyclosporine; Drug Therapy, Combination; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Transplantation; Male; Middle Aged; Retrospective Studies; Tacrolimus; Transplantation, Homologous; Treatment Outcome

Twenty-seven liver transplant recipients with intractable, biopsy-proven, acute or chronic rejection (defined as vanishing bile duct syndrome) were converted from cyclosporin to FK506. Successful conversion was achieved in 9 of 15 patients with acute rejection and in 6 of 12 patients with vanishing bile duct syndrome. A normal bilirubin was achieved more quickly in those with acute rejection (within 1 month) than in those with chronic rejection (within 3 months). A preconversion total bilirubin of less than 12 mg/dl was considered significant with regard to a successful outcome (P = 0.002). Graft survival was 66.7% and patient survival 73% in the case of acute rejection, and 50% and 66.7%, respectively, in the case of chronic rejection. Nephrotoxicity, neurotoxicity, and gastrointestinal side effects were the most serious complications of FK506 conversion. Six of ten patients had a drop in GFR that was 50% or greater after a minimum of 1 month of FK506 exposure. The mean maintenance dose of FK506 to maintain FK506 serum levels of 0.5-1.5 ng/ml was 0.07 mg/kg per 12 h for adults (half the recommended dose), compared to 0.15 mg/kg per 12 h for pediatric patients. This study demonstrates that FK506 can be used successfully to convert patients with intractable acute and chronic rejection. Careful adjustments of FK506 dosages and levels are required to minimize side effects.

Topics: Acute Disease; Administration, Oral; Adult; Bilirubin; Child; Child, Preschool; Chronic Disease; Cyclosporine; Graft Rejection; Graft Survival; Humans; Injections, Intravenous; Liver Transplantation; Salvage Therapy; Tacrolimus; Transplantation, Homologous

Thirty-seven liver-grafted patients with steroid-resistant acute or chronic graft rejection or with cyclosporin-related complications were converted from CyA to FK 506. The clinical outcome of the patients primarily depended on the degree of liver dysfunction present at initiation of FK 506 treatment. In patients switched to FK 506 for treatment of acute or early chronic graft rejection, CyA nephrotoxicity, or CyA malabsorption, the FK 506 therapy was associated with a clear improvement in the clinical course. In contrast, in patients with advanced chronic graft rejection, a lower response rate to the conversion in immunosuppression was observed. The lower response rate was associated with a higher patient mortality. These studies demonstrate that FK 506 represents a valuable alternative immunosuppressant for liver-grafted patients. The conversion from CyA to FK 506 should take place before serious--and potentially irreversible--disturbances in liver function are observed.

Topics: Acute Disease; Adolescent; Adult; Aged; Chronic Disease; Cyclosporine; Drug Resistance; Glucocorticoids; Graft Rejection; Graft Survival; Humans; Infusions, Intravenous; Liver Transplantation; Middle Aged; Salvage Therapy; Survival Rate; Tacrolimus

Topics: Acute Disease; Age Factors; Analysis of Variance; Chronic Disease; Cyclosporine; Drug Resistance; Female; Graft Rejection; Humans; Immunosuppressive Agents; Liver Function Tests; Liver Transplantation; Male; Multivariate Analysis; Prognosis; Sex Characteristics; Survival Analysis; Tacrolimus

Topics: Acute Disease; Adult; Alprostadil; Apoptosis; Child; Chronic Disease; Female; Graft Rejection; Graft vs Host Disease; Humans; Intestine, Small; Male; Methylprednisolone; Monitoring, Physiologic; Tacrolimus; Transplantation, Homologous

Topics: Adult; Azathioprine; Chronic Disease; Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Liver Transplantation; Middle Aged; Retrospective Studies; Steroids; Tacrolimus; Time Factors

Topics: Acute Disease; Adult; Alanine Transaminase; Bilirubin; Chronic Disease; Creatinine; Cyclosporine; Female; Follow-Up Studies; Graft Rejection; Humans; Liver Transplantation; Male; Tacrolimus

The effect of conversion from cyclosporine-steroid immunosuppression to the new agent FK506 was studied in 96 liver allograft recipients who were experiencing graft dysfunction or cyclosporine toxicity. Patients were stratified according to the cause of graft dysfunction that ultimately led to conversion to FK506. Response to FK506 introduction was monitored pathologically and biochemically. The outcome of a switch from CsA to FK506 was highly favorable in patients experiencing acute and the early stages of chronic rejection, despite optimal conventional therapy. Patients with later stages of chronic rejection did not respond to conversion to FK506 and most eventually lost their liver grafts in this process. Patients in whom we had difficulty separating chronic rejection from chronic persistent or low-grade chronic active hepatitis were mostly unaffected by conversion to FK506. Active hepatitis was a poor indication for conversion, because most of the patients experienced graft failure or died from liver failure. As a group, there was no statistically significant change in renal function 180 days after conversion to FK506. These findings expand the experience with FK506 in human liver allograft recipients.

Topics: Adolescent; Adult; Aged; Biopsy; Chemical and Drug Induced Liver Injury; Child; Child, Preschool; Chronic Disease; Cyclosporine; Female; Graft Rejection; Hepatic Artery; Hepatitis; Humans; Immunity, Cellular; Infant; Liver; Liver Diseases; Liver Transplantation; Male; Middle Aged; Tacrolimus

Orthotopic liver transplantation is now a widely used treatment for patients with end-stage liver disease. Lifelong pharmacologic immunosuppression renders these patients susceptible to many infections. The purpose of this article is to provide guidelines for treating the patient with end-stage liver disease, both before and after transplantation. In addition, we shall discuss some of the medical implications associated with end-stage liver disease and their clinical presentations and appropriate presurgical management. Adverse side effects of long-term immunosuppression and their effect on the oral and maxillofacial region shall also be discussed. Last, a brief discussion of FK506, the latest immunosuppressant, will be presented together with the implications of its use on our surgical treatment of these patients.

Topics: Anti-Bacterial Agents; Candidiasis, Oral; Chronic Disease; Cyclosporins; Gingival Hyperplasia; Humans; Immunosuppression Therapy; Liver Diseases; Liver Transplantation; Partial Thromboplastin Time; Prothrombin Time; Tacrolimus

Topics: Acute Disease; Chronic Disease; Cyclosporine; Follow-Up Studies; Graft Rejection; Humans; Liver Transplantation; Middle Aged; Tacrolimus; Treatment Outcome

Topics: Acute Disease; Adult; Biopsy; Child; Chronic Disease; Follow-Up Studies; Graft Rejection; Graft Survival; Humans; Liver Transplantation; Tacrolimus; Treatment Outcome

Topics: Administration, Oral; Adult; Bone Marrow Transplantation; Child; Chronic Disease; Cyclosporins; Female; Graft Survival; Graft vs Host Disease; Humans; Immunosuppression Therapy; Male; Tacrolimus; Treatment Outcome

Topics: Acute Disease; Animals; Bone Marrow Transplantation; Chronic Disease; Graft Survival; Graft vs Host Disease; Male; Rats; Rats, Inbred Lew; Tacrolimus