tacrolimus and Atrophy

Atopic dermatitis (AD) requires long-term management, mainly with topical anti-inflammatory agents. Topical corticosteroids (TCS) and tacrolimus ointment (TAC-O) are recommended as first-line treatments for AD. However, the long-term use of TCS is limited by cutaneous adverse events such as skin atrophy. For TAC-O, Japanese and US labelings were updated in 2003 and 2006, respectively, to include a boxed warning about a theoretical risk of skin cancer and lymphoma in patients treated with topical calcineurin inhibitors. However, TAC-O has been used worldwide for longer than 15 years to treat adult and pediatric patients with AD. Available data suggest that TAC-O is effective and well tolerated, and can improve quality of life. TAC-O has successfully been used in the proactive management of AD consisting of long-term intermittent use to prevent, delay or reduce the occurrence of AD flares. Systemic drug absorption after TAC-O application is negligible and unlikely to result in systemic immunosuppression. There is currently no strong evidence of an increased rate of malignancy in treated patients, and observational data from postmarketing surveillance studies have shown no safety concerns. In the absence of robust evidence, the warning about the carcinogenic potential in the Japanese labeling for TAC-O does not appear justified and should be reconsidered. This mitigation of description would allow adult and pediatric patients with AD to receive the effective treatment more appropriately.

Topics: Administration, Cutaneous; Adult; Atrophy; Calcineurin Inhibitors; Child; Dermatitis, Atopic; Dermatologic Agents; Glucocorticoids; Humans; Ointments; Skin; Skin Neoplasms; Tacrolimus; Treatment Outcome

Targeting the renin-angiotensin system and optimizing tacrolimus exposure are both postulated to improve outcomes in renal transplant recipients (RTRs) by preventing interstitial fibrosis/tubular atrophy (IF/TA). In this multicenter, prospective, open-label controlled trial, adult de novo RTRs were randomized in a 2 × 2 design to low- vs standard-dose (LOW vs STD) prolonged-release tacrolimus and to angiotensin-converting enzyme inhibitors/angiotensin II receptor 1 blockers (ACEi/ARBs) vs other antihypertensive therapy (OAHT). There were 2 coprimary endpoints: the prevalence of IF/TA at month 6 and at month 24. IF/TA prevalence was similar for LOW vs STD tacrolimus at month 6 (36.8% vs 39.5%; P = .80) and ACEi/ARBs vs OAHT at month 24 (54.8% vs 58.2%; P = .33). IF/TA progression decreased significantly with LOW vs STD tacrolimus at month 24 (mean [SD] change, +0.42 [1.477] vs +1.10 [1.577]; P = .0039). Across the 4 treatment groups, LOW + ACEi/ARB patients exhibited the lowest mean IF/TA change and, compared with LOW + OAHT patients, experienced significantly delayed time to first T cell-mediated rejection. Renal function was stable from month 1 to month 24 in all treatment groups. No unexpected safety findings were detected. Coupled with LOW tacrolimus dosing, ACEi/ARBs appear to reduce IF/TA progression and delay rejection relative to reduced tacrolimus exposure without renin-angiotensin system blockade. ClinicalTrials.gov identifier: NCT00933231.

Topics: Adult; Allografts; Angiotensin II Type 1 Receptor Blockers; Angiotensin-Converting Enzyme Inhibitors; Atrophy; Delayed-Action Preparations; Drug Therapy, Combination; Female; Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Male; Middle Aged; Polyomavirus Infections; Prognosis; Prospective Studies; Renin-Angiotensin System; Tacrolimus; Virus Activation

High intrapatient variability (IPV) of tacrolimus concentrations is increasingly recognized as a predictor of poor outcome in solid organ recipients. How it relates to evolution of histology has not been explored. We analyzed tacrolimus IPV using the coefficient of variability (CV) from months 6-12 after transplantation in a cohort of 220 renal recipients for whom paired protocol biopsies at 3 mo and 2 years were available. Recipients in the highest CV tertile had an increased risk of moderate to severe fibrosis and tubular atrophy by 2 years compared with the low-IPV tertile (odds ratio [OR] 2.47, 95% confidence interval [CI] 1.09-5.60, p = 0.031; and OR 2.40, 95% CI 1.03-5.60, p = 0.043, respectively). Other predictors were donor age, severity of chronic lesions at 3 mo, and presence of borderline or subclinical rejection at 3 mo. Chronicity score increased significantly more in the high CV tertile group than in the middle and low tertiles (mean increase 1.97 ± 2.03 vs. 1.18 ± 2.44 and 1.12 ± 1.80, respectively; p < 0.05). CV did not predict evolution of renal function, which did not deteriorate within the 2-year follow-up period. These results indicate that high IPV is related to accelerated progression of chronic histologic lesions before any evidence of renal dysfunction.

Topics: Atrophy; Disease Progression; Female; Fibrosis; Follow-Up Studies; Glomerular Filtration Rate; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Failure, Chronic; Kidney Function Tests; Kidney Transplantation; Male; Middle Aged; Prognosis; Retrospective Studies; Risk Factors; Tacrolimus; Transplantation, Homologous

Concerns about adverse effects of calcineurin inhibitors (CNIs) have prompted development of protocols that minimize their use. Whereas previous CNI withdrawal trials in heterogeneous cohorts showed unacceptable rates of acute rejection (AR), we hypothesized that we could identify individuals capable of tolerating CNI withdrawal by targeting immunologically quiescent kidney transplant recipients. The Clinical Trials in Organ Transplantation-09 Trial was a randomized, prospective study of nonsensitized primary recipients of living donor kidney transplants. Subjects received rabbit antithymocyte globulin, tacrolimus, mycophenolate mofetil, and prednisone. Six months post-transplantation, subjects without de novo donor-specific antibodies (DSAs), AR, or inflammation at protocol biopsy were randomized to wean off or remain on tacrolimus. The intended primary end point was the change in interstitial fibrosis/tubular atrophy score between implantation and 24-month protocol biopsies. Serially collected urine CXCL9 ELISA results were correlated with outcomes. The study was terminated prematurely because of unacceptable rates of AR (4 of 14) and/or de novo DSAs (5 of 14) in the tacrolimus withdrawal arm. Positive urinary CXCL9 predated clinical detection of AR by a median of 15 days. Analyses showed that >16 HLA-DQ epitope mismatches and pretransplant, peripheral blood, donor-reactive IFN-γ ELISPOT assay results correlated with development of DSAs and/or AR on tacrolimus withdrawal. Although data indicate that urinary CXCL9 monitoring, epitope mismatches, and ELISPOT assays are potentially informative, complete CNI withdrawal must be strongly discouraged in kidney transplant recipients who are receiving standard-of-care immunosuppression, including those who are deemed to be immunologically quiescent on the basis of current clinical and laboratory criteria.

Topics: Adult; Aged; Antibodies; Atrophy; Calcineurin Inhibitors; Chemokine CXCL9; Early Termination of Clinical Trials; Female; Fibrosis; Graft Rejection; Histocompatibility Testing; HLA-DQ Antigens; Humans; Immunosuppression Therapy; Interferon-gamma; Kidney; Kidney Transplantation; Kidney Tubules; Male; Middle Aged; Nephritis; Prospective Studies; Tacrolimus; Withholding Treatment; Young Adult

There is no evidence on the incidence of subclinical inflammation and scaring lesions in patients receiving tacrolimus (TAC) minimization and elimination immunosuppressive regimens.. This study analyzed preimplantation, 3 and 24 months protocol biopsies and anti-HLA donor-specific antibodies (DSA) in 140 low immunological risk kidney transplant recipients receiving reduced TAC exposure, prednisone, and mycophenolate, randomized at 3 months to be converted or not to sirolimus (SRL).. Mean TAC concentrations were 6.0 ± 2.4 ng/mL and 5.8 ± 2.2 ng/mL at 3 and 24 months. The incidence of subclinical inflammation lesions at 3 months was 9.3%. The incidence of (interstitial fibrosis) IF/(tubular atrophy) TA at month 24 was 57.6%, higher in SRL compared to TAC group (68.8 vs 44.4%; P = 0.022). Patients converted to SRL showed higher incidence of acute rejection (7.3% vs 0%), proteinuria (59.6% vs 25%; P = 0.001), and DSA (17.8% vs 7.3%; P = 0.201), respectively. Biopsy-proven acute rejection (odds ratio [OR] 2.32, 95% confidence interval [95% CI], 0.979-5.518, P = 0.056), subclinical inflammation lesions at 3 months (OR, 11.75; 95% CI, 1.286-107.474; P = 0.029) and conversion to SRL (OR, 2.72; 95% CI, 1.155-6.383; P = 0.022) were associated with IF/TA at month 24. Black ethnicity (OR, 0.22; 95% CI, 0.058-0.873; P = 0.031), donor age (OR, 2.74; 95% CI, 1.329-5.649; P = 0.006), and conversion to SRL (OR, 2.34; 95% CI, 1.043-5.267; P = 0.039) were associated with inferior renal function at 24 months.. In kidney transplant recipients receiving reduced TAC exposure, subclinical inflammation lesions at 3 months were associated with IF/TA at 24 months. Conversion from TAC to SRL was associated with inferior renal function, higher incidence of IF/TA, and trends to higher incidence of DSA at 24 months.

Topics: Adult; Atrophy; Biomarkers; Biopsy; Calcineurin Inhibitors; Chi-Square Distribution; Drug Substitution; Female; Fibrosis; Graft Rejection; Graft Survival; Histocompatibility; HLA Antigens; Humans; Immunosuppressive Agents; Isoantibodies; Kidney; Kidney Transplantation; Logistic Models; Male; Middle Aged; Multivariate Analysis; Nephritis; Odds Ratio; Proteinuria; Risk Factors; Sirolimus; Tacrolimus; Time Factors; Treatment Outcome

New-onset diabetes after transplantation (NODAT) is one of the frequent complications following kidney transplantation. Patients were randomized to receive cyclosporine A- or tacrolimus-based immunosuppression. Fasting and oral glucose tolerance tests were performed, and the patients were assigned to one of the following three groups based on the results: normal, impaired fasting glucose/impaired glucose tolerance (IFG/IGT), or NODAT. NODAT developed in 14% of patients receiving cyclosporine A-based immunosuppression and in 26% of patients taking tacrolimus (p = 0.0002). Albumin levels were similar, but uric acid level (p = 0.002) and the age of the recipient (p = 0.003) were significantly different comparing the diabetic and the normal groups. Evaluation of tissue samples revealed that acute cellular rejection (ACR) and interstitial fibrosis/tubular atrophy (IF/TA) were significantly different in the NODAT group. The pathological effect of new-onset diabetes after kidney transplantation can be detected in the morphology of the renal allograft earlier, before the development of any sign of functional impairment.

Topics: Adult; Age Factors; Aged; Atrophy; Biopsy; Blood Glucose; Calcineurin; Calcineurin Inhibitors; Cyclosporine; Diabetes Mellitus; Fasting; Female; Fibrosis; Glucose Tolerance Test; Graft Rejection; Humans; Hungary; Immunosuppressive Agents; Incidence; Kidney; Kidney Transplantation; Male; Middle Aged; Risk Factors; Tacrolimus; Time Factors

Currently, there are no accurate and simple methods available to measure this risk of atrophy in patients treated with topical glucocorticosteroids. In the present clinical trial, we validated a new score (Dermaphot(®) score) to assess the atrophogenic potential of glucocorticosteroids. 36 healthy adult volunteers were included in an investigator-initiated, blinded, randomized, intra-individual comparison, vehicle controlled multi-centre study. Subjects were treated in a randomized manner for 3 weeks with pimecrolimus cream 1 %, mometasone furoate (1 mg/g), clobetasol propionate 0.05 % and vehicle. In addition, ultrasound examination for skin thickness was performed. Data demonstrated a direct correlation of the achieved Dermaphot(®) score and the ultrasound thickness measurements. Our study shows that the Dermaphot(®) score can be used as a simple method to evaluate the atrophogenic potential of glucocorticosteroids. Respectively, we showed that the new score is an easy, valid and sensitive new tool for early detecting and quantifying even subclinical glucocorticosteroid-induced skin damage. We demonstrated that the score is able to differentiate the extent of skin atrophy (damage) after 3 weeks of topical glucocorticosteroid application with different levels of skin transparency and levels of telangiectasia.

Topics: Adult; Atrophy; Clobetasol; Female; Glucocorticoids; Humans; Male; Middle Aged; Mometasone Furoate; Pregnadienediols; Reproducibility of Results; Severity of Illness Index; Skin; Tacrolimus; Telangiectasis; Young Adult

Calcineurin-inhibitor therapy is a contributing factor to the origin of interstitial fibrosis and tubular atrophy (IFTA).. We conducted a prospective randomized trial of conversion of tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal. We compared the chronic changes (IFTA and sum of Banff chronic scores--Total Score) on protocol biopsies at 1 month, 1 year, and 2 years in all randomized patients. We compared the outcomes between treatment groups and analyzed the impact of previous rejection on the chronic changes.. We randomized 122 patients, 62 to sirolimus and 60 to tacrolimus. The 1-year biopsy was performed in 54 patients (90%) of the tacrolimus group and 56 patients (90%) of the sirolimus group. The proportion of biopsies with IFTA more than or equal to 2 and the Total Score more than 2 increased over the 2 years but were not different between the study groups at any time point. On the 1-year biopsy, there was more IFTA, and the fraction with Total Score more than 2 was higher in the tacrolimus group with previous rejection. In the cohort without rejection, there was a significant progression of the IFTA and Total Score between 1 and 2 years in both the sirolimus and tacrolimus groups.. Conversion from tacrolimus to sirolimus at 1-month posttransplant in kidney transplant recipients on rapid steroid withdrawal does not decrease the progression of chronic changes on protocol biopsies during the first 2 years even in those patients without previous acute rejection.

Topics: Adult; Aged; Aged, 80 and over; Atrophy; Biopsy; Contraindications; Disease Progression; Female; Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Longitudinal Studies; Male; Middle Aged; Prospective Studies; Risk Factors; Sirolimus; Steroids; Tacrolimus; Transplantation, Homologous; Withholding Treatment

Topical corticosteroids are widely used to treat atopic dermatitis (AD), but their anti-inflammatory mode of action can be accompanied by several unwanted side effects including skin atrophy and telangiectasia. In this 8-week, investigator-blinded, intraindividual right-left comparison study with patients with mild-to-moderate AD, hydrocortisone 1% cream (HCT) was applied twice daily for 4 weeks on one side of forehead skin without clinical signs of AD and pimecrolimus 1% cream (PIM) on the other. Epidermal and dermal thickness were assessed by optical coherence tomography (OCT) and high-frequency ultrasound, respectively. Skin atrophy and telangiectasia were assessed by contact dermatoscopic photography (Dermaphot(®)). Treatment with HCT leads to a significant decrease in epidermal thickness after only 2 weeks of treatment, while the decrease in PIM-treated sites was less pronounced and was not statistically significant. By 4 weeks after the end of treatment, epidermal thickness returned to baseline values. No dermal thinning or development of telangiectasia could be observed by means of ultrasound or Dermaphot(®), respectively. In summary, this study indicates that a 2-week single course of topical treatment with a mildly potent steroid can cause transient epidermal thinning, an effect not seen in the PIM group. The slight decrease with PIM - although not significant - could be due to normalization of the increased skin thickness caused by a subclinical inflammation in AD. This study suggests that PIM may be safer for treatment of AD in sensitive skin areas like the face, especially when repeated application is required.

Topics: Adult; Atrophy; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Female; Humans; Hydrocortisone; Male; Middle Aged; Single-Blind Method; Skin; Tacrolimus; Tomography, Optical Coherence; Ultrasonography; Young Adult

Seven patients with Rasmussen encephalitis (RE) were treated with the immunosuppressant tacrolimus and followed for a median of 22.4 months. They were compared with 12 historical untreated RE patients (median follow-up 13.9 months). The tacrolimus-treated patients had a superior outcome regarding neurologic function and progression rate of cerebral hemiatrophy but no better seizure outcome. No treated patient, but 7 of 12 control patients, became eligible for hemispherectomy. Tacrolimus did not have any major side effects.

Topics: Adolescent; Adult; Anticonvulsants; Atrophy; Brain; Cerebral Cortex; Child; Child, Preschool; Drug Therapy, Combination; Encephalitis; Female; Follow-Up Studies; Humans; Immunosuppressive Agents; Male; Neuropsychological Tests; Paresis; Tacrolimus; Treatment Outcome

SDZ ASM 981 is a selective inhibitor of inflammatory cytokines released from T lymphocytes and mast cells, which has been developed for the treatment of inflammatory skin diseases.. In the present study, the atrophogenic potential of SDZ ASM 981 1% cream in humans was compared with that of medium and highly potent topical steroids, and vehicle.. Four different preparations, SDZ ASM 981 1% cream, the corresponding vehicle of SDZ ASM 981 1% cream, betamethasone-17-valerate 0.1% cream and triamcinolone acetonide 0.1% cream, were applied to the volar aspect of the forearms of 16 healthy volunteers, twice daily, 6 days a week, for 4 weeks. Skin thickness was evaluated by ultrasound examination, clinical signs of atrophy by stereomicroscopy, and epidermal thickness was assessed by histology.. Both topical corticosteroids induced a significant reduction in skin thickness, as compared with SDZ ASM 981 1% cream and vehicle, which were shown to be equivalent. The difference in skin thickness (measured by ultrasound examination) between patients treated with SDZ ASM 981 1% cream and those receiving either of the two topical steroids was significant from day 8 onwards. Histological analysis performed at day 29 showed significant epidermal thinning with topical steroids compared with SDZ ASM 981 1% cream or the vehicle. Conclusion The lack of atrophogenic properties of SDZ ASM 981 1% cream in this short-term study demonstrates its potential as long-term treatment for inflammatory skin diseases, thus overcoming a major drawback of topical steroids. This may also be important for the treatment of children, and sensitive areas of skin, such as the face and skin-folds.

Topics: Administration, Topical; Adult; Anti-Inflammatory Agents; Atrophy; Dermatologic Agents; Double-Blind Method; Enzyme Inhibitors; Female; Glucocorticoids; Humans; Male; Ointments; Skin; Tacrolimus; Ultrasonography

Topical calcineurin inhibitors are a family of drugs that have been touted for having high efficacy without the risks of cutaneous atrophy and systemic absorption seen with topical corticosteroids. They may play an important role in the elderly population, where preexisting cutaneous atrophy increases susceptibility to these adverse effects.

Topics: Administration, Topical; Aged; Atrophy; Calcineurin Inhibitors; Dermatitis, Atopic; Dermatologic Agents; Humans; Medicare; Tacrolimus; United States

Topics: Acne Vulgaris; Atrophy; Cicatrix; Connective Tissue Diseases; Erythema; Humans; Tacrolimus; Treatment Outcome

The overexpression of calcineurin leads to astrocyte hyperactivation, neuronal death, and inflammation, which are characteristics often associated with pathologic aging and Alzheimer's disease. In this study, we tested the hypothesis that tacrolimus, a calcineurin inhibitor, prevents age-associated microstructural atrophy, which we measured using higher-order diffusion MRI, in the middle-aged beagle brain (

Topics: Aging; Animals; Atrophy; Brain; Calcineurin Inhibitors; Dogs; Female; Male; Tacrolimus

Patients with high tacrolimus clearance are more likely to experience transient under-immunosuppression in case of a missed or delayed dose. We wanted to investigate the association between estimated tacrolimus clearance and development of graft interstitial fibrosis and tubular atrophy (IFTA) in kidney transplant recipients. Associations between estimated tacrolimus clearance [daily tacrolimus dose (mg)/trough concentration (μg/l)] and changes in IFTA biopsy scores from week 7 to 1-year post-transplantation were investigated. Data from 504 patients transplanted between 2009 and 2013 with paired protocol biopsies (7 weeks + 1-year post-transplant) were included. There were no differences in baseline biopsy scores (7 weeks) in patients with different estimated tacrolimus clearance. Increasing tacrolimus clearance was significantly associated with increased ci + ct score of ≥2 at 1 year, odds ratio of 1.67 (95% CI; 1.11-2.51). In patients without fibrosis (ci + ct ≤ 1) at 7 weeks (n = 233), increasing tacrolimus clearance was associated with development of de novo IFTA (i + t ≤ 1 and ci + ct ≥ 2) at 1 year, odds ratio of 2.01 (95% CI; 1.18-3.50) after adjusting for confounders. High tacrolimus clearance was significantly associated with development of IFTA the first year following renal transplantation.

Topics: Adult; Aged; Atrophy; Cytochrome P-450 CYP3A; Female; Fibrosis; Humans; Immunosuppressive Agents; Kidney; Kidney Transplantation; Kidney Tubules; Male; Metabolic Clearance Rate; Middle Aged; Retrospective Studies; Risk Factors; Tacrolimus

Allotransplantation of submandibular salivary glands (SMGs) could be an alternative treatment option for severe keratoconjunctivitis sicca in noncandidates for autologous SMG transplantation. This study was conducted to evaluate the effect of allogeneic mesenchymal stem cell (MSC) therapy on the survival of allotransplanted SMGs.. Thirty-six SMG allotransplantations (n = 6 per group) were performed in New Zealand white rabbits and randomly divided into the following groups: allograft control (Allo-Ctrl), low-dose FK506 (FK506-L), high-dose FK506 (FK506-H), allogeneic MSCs, MSCs+FK506-L, and MSCs+FK506-H. Rabbits were closely observed for 2 weeks. Gland viability and rejection were assessed by monitoring interleukin-2 levels by ELISA, sialoscintigraphy, M3-muscarinic acetylcholine receptor expression, histological evaluation, and apoptosis assay.. Intraoperatively, all glands showed patency and saliva flow except 1 gland. Sialoscintigraphy revealed significantly higher saliva production within the MSC-treated glands. Histologically, MSC-treated glands showed higher glandular tissue preservation and less acini atrophy. The MSCs+FK506-H group revealed significantly lower apoptosis percentage. The highest survival was observed in the MSCs+FK506-H group, followed by the FK506-H and MSCs+FK506-L groups, and lastly less in the FK506-L and MSCs groups.. Concurrent administration of MSCs with FK506-H (0.16 mg/kg) resulted in higher survival rate with greater glandular tissue preservation and salivary secretion. MSCs with FK506-L (0.08 mg/kg) could be an alternative to FK506-H (0.16 mg/kg) in salivary gland allotransplantation.

Topics: Allogeneic Cells; Animals; Apoptosis; Atrophy; Female; Graft Rejection; Graft Survival; Immunosuppressive Agents; Interleukin-2; Male; Mesenchymal Stem Cell Transplantation; Rabbits; Receptor, Muscarinic M3; Salivation; Submandibular Gland; Tacrolimus; Time Factors; Tissue Survival; Transplantation, Homologous

Topics: Anti-Bacterial Agents; Atrophy; Blepharoptosis; Doxycycline; Edema; Elastin; Female; Humans; Tacrolimus; Treatment Outcome; Young Adult

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

To determine the effect of tacrolimus trough concentrations on clinical outcomes in kidney transplantation, while assessing if African-American (AA) race modifies these associations.. Retrospective longitudinal cohort study of solitary adult kidney transplants.. Large tertiary care transplant center.. Adult solitary kidney transplant recipients (n=1078) who were AA (n=567) or non-AA (n=511).. Mean and regressed slope of tacrolimus trough concentrations. Subtherapeutic concentrations were lower than 8 ng/ml.. AA patients were 1.7 times less likely than non-AA patients to achieve therapeutic tacrolimus concentrations (8 ng/ml or higher) during the first year after kidney transplant (35% vs 21%, respectively, p<0.001). AAs not achieving therapeutic concentrations were 2.4 times more likely to have acute cellular rejection (ACR) as compared with AAs achieving therapeutic concentrations (20.8% vs 8.5%, respectively, p<0.01) and 2.5 times more likely to have antibody-mediated rejection (AMR; 8.9% vs 3.6%, respectively, p<0.01). Rates of ACR (8.3% vs 6.7%) and AMR (2.0% vs 0.9% p=0.131) were similar in non-AAs compared across tacrolimus concentration groups. Multivariate modeling confirmed these findings and demonstrated that AAs with low tacrolimus exposure experienced a mild protective effect for the development of interstitial fibrosis/tubular atrophy (IF/TA; hazard ratio [HR] 0.78, 95% confidence interval [CI] 0.47-1.32) with the opposite demonstrated in non-AAs (HR 2.2, 95% CI 0.90-5.1).. In contradistinction to non-AAs, AAs who achieve therapeutic tacrolimus concentrations have substantially lower acute rejection rates but are at risk of developing IF/TA. These findings may reflect modifiable time-dependent racial differences in the concentration-effect relationship of tacrolimus. Achievement of therapeutic tacrolimus trough concentrations, potentially through genotyping and more aggressive dosing and monitoring, is essential to minimize the risk of acute rejection in AA kidney transplant recipients.

Topics: Adult; Atrophy; Black or African American; Dose-Response Relationship, Drug; Female; Fibrosis; Graft Rejection; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Longitudinal Studies; Male; Middle Aged; Tacrolimus

The present study aimed to investigate the influence of topical corticosteroid therapy and tacrolimus on morphological indices of different skin phototypes and to optimize topical therapy using the OCT technique.. Twenty healthy volunteers aging from 20 to 30 (14 men and 6 women) took part in the study: 10 persons with skin phototype I, II and 10 persons with skin phototype V, VI. Morphological state of the skin was assessed before and during application of topical steroids of different strength and calciumneurin inhibitors for 49 days. Morphological state was studied in vivo using the optical coherence tomograph.. Morphological manifestations of skin atrophy with the use of clobetasol propionate appear earlier than with the use of hydrocortisone 17-butyrate; this process was faster in representatives of groups V, VI. Epidermal thinning in the zone of tacrolimus application was not recorded in any phototype.. Recording of early preclinical signs of epidermis thinning in the course of OCT follow-up may be an indication for changing the corticosteroid therapy by calciumneurin inhibitors, which will permit to individualize the therapy, to increase its efficacy, and to minimize the possibility of complications in each particular case.

Topics: Administration, Topical; Adrenal Cortex Hormones; Adult; Atrophy; Dermoscopy; Female; Humans; Immunosuppressive Agents; Male; Reference Values; Skin; Tacrolimus; Tomography, Optical Coherence

Chronic renal transplant dysfunction is histopathologically characterized by interstitial fibrosis and tubular atrophy. This study investigated the relative contribution of baseline donor, recipient, and transplant characteristics to interstitial fibrosis and tubular atrophy score at month 12 after renal transplantation.. This retrospective study includes all 109 consecutive recipients with adequate implantation and month 12 biopsies transplanted between April of 2003 and February of 2007. Immunosuppression regimen was tacrolimus and steroids (10 days) plus either sirolimus or mycophenolate mofetil.. Average interstitial fibrosis and tubular atrophy score increased from 0.70 to 1.65 (P<0.001). In an adjusted multiple linear regression analysis, interstitial fibrosis and tubular atrophy score at month 12 was significantly related to donor type (donors after cardiac death versus living donor had interstitial fibrosis and tubular atrophy score+0.41, 95% confidence interval=0.05-0.76, P=0.02), baseline interstitial fibrosis and tubular atrophy, and immunosuppression regimen. Because of interaction between the latter two variables (P=0.002), results are given separately: recipients with a baseline interstitial fibrosis and tubular atrophy score of zero had a 0.60 higher score at month 12 (95% confidence interval=0.09-1.10, P=0.02) when mycophenolate mofetil-treated, whereas recipients with a baseline interstitial fibrosis and tubular atrophy score more than zero had a 0.38 higher score at month 12 (95% confidence interval=0.01-0.74, P=0.04) when sirolimus-treated. A higher score at month 12 correlated with a lower estimated GFR (ρ=-0.45, P<0.001).. These findings suggest that histologic assessment of a preimplantation biopsy may guide choice of immunosuppresion to maximize transplant survival and its interaction with type of immunosuppression.

Topics: Adult; Aged; Atrophy; Biopsy; Drug Therapy, Combination; Female; Fibrosis; Graft Rejection; Graft Survival; Humans; Immunosuppressive Agents; Kidney Transplantation; Kidney Tubules; Linear Models; Male; Middle Aged; Multivariate Analysis; Mycophenolic Acid; Netherlands; Proteinuria; Retrospective Studies; Risk Assessment; Risk Factors; Sirolimus; Steroids; Tacrolimus; Time Factors; Treatment Outcome

Topics: Adrenal Cortex Hormones; Adult; Atrophy; Biomarkers, Tumor; Carcinoma, Renal Cell; Glomerulonephritis, Membranous; Humans; Immunocompromised Host; Immunosuppressive Agents; Kidney; Kidney Diseases, Cystic; Kidney Neoplasms; Kidney Transplantation; Male; Mucin-1; Mycophenolic Acid; Nephrectomy; Postoperative Complications; Reoperation; Tacrolimus

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

The principal risk factors for cardiovascular mortality posttransplantation are hyperglycemia, hypertriglyceridemia, obesity, and smoking.. Among 115 patients, we assessed the risk factors for new-onset diabetes (NODM) and dyslipidemia (NODL), and their effects on the function and histopathologic changes in the allografts at 1 year posttransplantation.. When evaluating the risk factors and the initial recipient data, we observed a significant difference in age when comparing normal vs NODM patients (P=.004), normal versus NODL patients (P=.002), and normal versus NODL + NODM patients (P=.0001). The difference in body mass index (BMI) was significant when comparing normal with NODM + NODL patients (P=.003). In regard to immunosuppressive therapy, NODM was significantly more frequent among/prescribed tacrolimus (tac; P=.005), whereas subjects who received cyclosporine (CsA) showed a significantly higher incidence of NODL (P=.001). The triglyceride levels were 3.02 ± 1.51 mmol/L among those on CsA versus 2.15 ± 1.57 mmol/L for (P=.004). The difference also proved to be significant for total cholesterol level: 5.43 ± 1.23 mmol/L versus 4.42 ± 1.31 mmol/L respectively (P=.001). In regard to allograft function a significant difference was noted at 1 year after transplantation between the NODM + NODL and the normal group in serum creatinine level (P=.02) as well as the estimated glomerular filtration rate (P=.004). Among diabetic patients, the serum creatinine level measured at posttransplant year 5 was significantly higher than that in 1 year (212.43 vs 147.00 μmol/L; P=.0003). When assessing morphologic changes in the kidney, we observed significantly more frequent interstitial fibrosis/tubular atrophy in all 3 groups compared with normal function patients.. Our clinical study suggested that at 1 year after transplantation allograft function is already impaired in the presence of both medical conditions (NODM and NODL). However, in regard to morphology, a single condition (NODM or NODL) was sufficient to produce histologic changes in the kidney.

Topics: Adult; Analysis of Variance; Atrophy; Biomarkers; Biopsy; Body Mass Index; Case-Control Studies; Chi-Square Distribution; Creatinine; Cyclosporine; Diabetes Mellitus; Dyslipidemias; Female; Glomerular Filtration Rate; Glycated Hemoglobin; Graft Survival; Humans; Hungary; Immunosuppressive Agents; Kidney; Kidney Transplantation; Lipids; Logistic Models; Male; Middle Aged; Retrospective Studies; Risk Assessment; Risk Factors; Tacrolimus; Time Factors; Treatment Outcome

Filamentous tau inclusions are hallmarks of Alzheimer's disease (AD) and related tauopathies, but earlier pathologies may herald disease onset. To investigate this, we studied wild-type and P301S mutant human tau transgenic (Tg) mice. Filamentous tau lesions developed in P301S Tg mice at 6 months of age, and progressively accumulated in association with striking neuron loss as well as hippocampal and entorhinal cortical atrophy by 9-12 months of age. Remarkably, hippocampal synapse loss and impaired synaptic function were detected in 3 month old P301S Tg mice before fibrillary tau tangles emerged. Prominent microglial activation also preceded tangle formation. Importantly, immunosuppression of young P301S Tg mice with FK506 attenuated tau pathology and increased lifespan, thereby linking neuroinflammation to early progression of tauopathies. Thus, hippocampal synaptic pathology and microgliosis may be the earliest manifestations of neurodegenerative tauopathies, and abrogation of tau-induced microglial activation could retard progression of these disorders.

Topics: Aging; Amygdala; Amyloid Neuropathies; Animals; Atrophy; Blotting, Western; Brain; Gliosis; Humans; Immunohistochemistry; Immunosuppressive Agents; Macrophage Activation; Mice; Microglia; Microscopy, Electron; Microtubules; Mossy Fibers, Hippocampal; Nerve Degeneration; Neurofibrillary Tangles; Phosphorylation; Solubility; Spinal Cord; Synapses; Tacrolimus; tau Proteins

Erosive pustular dermatosis (EPD) is a rarely reported condition that primarily involves the actinically damaged scalp of elderly women. Although the condition is well recognized in the United Kingdom and Europe, no US cases have heretofore been reported.. We sought to document the presence, and determine the clinical characteristics, of EPD in the US population.. Patients were recruited from the dermatology clinic at a university in California and from the private practices of dermatologists in the Northern California region.. Eleven patients with EPD were identified. Eight were women and 3 were men. The scalp was involved in 9 patients and the extremities in two patients. The involved skin was actinically damaged in 9 patients. The patients were elderly (66-90 years) but one patient was a 15-year-old boy. All lesions resolved or greatly improved with the application of high-potency steroids or tacrolimus.. Not all patients were examined personally by the authors of this article. The length of follow-up was relatively short.. EPD is a fairly common disease and is the most likely diagnosis in instances where chronic, nonhealing, shallow erosions occur on actinically damaged, or otherwise atrophic, skin. In spite of the name, intact pustules are rarely present. The histology is that of moderate to marked, nonspecific chronic inflammation. EPD responds well to high-potency topical steroids.

Topics: Administration, Topical; Adolescent; Aged; Aged, 80 and over; Atrophy; Calcineurin Inhibitors; Clobetasol; Extremities; Female; Follow-Up Studies; Glucocorticoids; Humans; Male; Photosensitivity Disorders; Scalp Dermatoses; Skin Diseases; Skin Diseases, Vesiculobullous; Steroids; Tacrolimus; Treatment Outcome

Topics: Atrophy; Humans; Immunosuppressive Agents; Skin; Tacrolimus

Anetoderma is circumscribed atrophy of the skin due to a localized deficiency in elastic tissue. It can follow inflammatory skin diseases of several types, and occasionally is present in the skin around neoplasms. There are a few reports of anetoderma in the lesional skin of cutaneous lymphoma. We report on two patients who presented with multiple lesions of anetoderma and who later proved to have low-grade cutaneous B-cell lymphomas. One patient (Patient 1) is a 39-year-old man and the other patient is a 26-year-old woman who is a renal transplant recipient (Patient 2). Some biopsy specimens from the anetodermic skin of Patient 1 appeared to show an urticarial reaction, although plasma cells were present. A large nodule showed lymphoid follicles surrounded by plasmacytoid lymphocytes, with loss of elastic tissue in the adjacent dermis. The plasmacytoid cells stained overwhelmingly for lambda light chain, and staining of the urticarial lesions from this patient also showed a marked majority of lambda positive cells. Immunoglobulin heavy chain gene (IgH) rearrangements showed a dominant clonal pattern in the nodular lesion. We classified the disease in Patient 1 as marginal zone lymphoma and the disease in Patient 2 as a post-transplant lymphoproliferative disorder. Because of the intimate association of anetoderma and cutaneous B-cell lymphoproliferative disorders in these two patients, it seems possible that anetoderma could result from either a local effect of the neoplastic cells or associated inflammatory cells, especially neutrophils as in Case 1. The infiltrates of Case 1 had many interstitial neutrophils and only a few clonal plasmacytoid lymphocytes, indicating that this presentation of B-cell lymphoma can be a diagnostic pitfall. Given these two cases and similar ones in the literature, biopsy of lesional skin in anetoderma should be performed to ensure that lymphomatous infiltrates are not present. Even if plasma cells are sparse, studies to detect clonality are appropriate. Cutaneous B-cell lymphoma can be added to the list of associations of elastolysis and cutaneous lymphoma, which includes granulomatous slack skin (T-cell lymphoma) and cutis laxa (myeloma).

Topics: Adult; Atrophy; Cutis Laxa; Cyclosporine; DNA; Elastic Tissue; Female; Fluorescein-5-isothiocyanate; Gene Rearrangement, B-Lymphocyte, Heavy Chain; Herpesvirus 4, Human; Humans; Immunocompromised Host; Immunohistochemistry; In Situ Hybridization; Kidney Transplantation; Leukemia, Lymphocytic, Chronic, B-Cell; Lymphoma, B-Cell; Lymphoproliferative Disorders; Male; Polymerase Chain Reaction; RNA, Viral; Skin Neoplasms; Tacrolimus

Autoimmune enteropathy is characterized by chronic secretory diarrhea, villous atrophy, associated autoantibodies, and a partial response to immunosuppression. Currently available therapy (including steroids and cyclosporine) has resulted in remission only in a subset of patients. We evaluated the effects of tacrolimus (FK506) in patients with autoimmune enteropathy refractory to steroids and cyclosporine. Three patients with diagnosed autoimmune enteropathy who continued to have intractable diarrhea despite treatment with steroids and/or cyclosporine were treated with oral tacrolimus. Despite documented histological villous atrophy and poor absorption of oral cyclosporine, therapeutic tacrolimus levels were easily achieved in all 3 patients. All patients showed clinical improvement as documented by decreased stool output and ability to be weaned off parenteral nutrition; response time ranged from 1 to 4 months after tacrolimus was begun. Histological improvement was noted in all patients, and the small bowel biopsy specimens of 2 of the 3 patients showed a return to normal. All patients have been followed up for at least 6 months and are in clinical remission; 1 has received a bone marrow transplant for underlying immunodeficiency. Tacrolimus is a useful drug in the treatment of autoimmune enteropathy, even in patients who have not responded to steroids or cyclosporine. No long-term follow-up of patients with autoimmune enteropathy treated with tacrolimus is currently available.

Topics: Administration, Oral; Atrophy; Autoimmune Diseases; Biopsy; Duodenum; Female; Humans; Immunosuppressive Agents; Infant; Intestinal Diseases; Male; Remission Induction; Tacrolimus

Topics: Adaptation, Physiological; Atrophy; Connective Tissue; Dexamethasone; Gestational Age; Humans; Hyperplasia; Immunosuppressive Agents; Intestinal Mucosa; Intestine, Small; Lymphocyte Activation; Microscopy, Phase-Contrast; Organ Culture Techniques; Pokeweed Mitogens; T-Lymphocytes; Tacrolimus