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Renal Function and Patient-Reported Outcomes in Stable Kidney Transplant Patients Following Conversion From Twice-Daily Immediate-Release Tacrolimus to Once-Daily Prolonged-Release Tacrolimus: A 12-Month Observational Study in Routine Clinical Practice in Germany (ADAGIO).
Hugo, C, Weihprecht, H, Banas, B, Schröppel, B, Jank, S, Arns, W, Schenker, P, Rath, T, Hergesell, O, Feldkamp, T, et al
Transplantation proceedings. 2021;(5):1484-1493
Abstract
INTRODUCTION This 12-month, noninterventional study on routine clinical practice in Germany evaluated renal function in stable kidney transplant recipients converted from immediate-release tacrolimus (IR-T) to prolonged-release tacrolimus (PR-T). METHODS Renal function was assessed in 183 patients by estimated glomerular filtration rate using the modification of diet in renal disease-4 formula. Self-reported gastrointestinal health-related quality of life, adherence, satisfaction with PR-T, suspected rejection episodes, and safety were also assessed at conversion and at 3, 6, and 12 months. RESULTS Conversion from IR-T to PR-T resulted in stable kidney function over 12 months, with a difference in estimated glomerular filtration rate between the first and final visits of 0.1 mL/min/1.73 m2 (95% confidence interval, -1.6, 1.8). Eight patients experienced an acute rejection episode (4.4%). At each assessment, gastrointestinal health-related quality of life was low and adherence was high. Most patients reported that they were very satisfied (69.8%) or satisfied (28.1%) with PR-T at the final visit. Among patients reporting a preference, 78.4% preferred PR-T, 2.2% preferred IR-T, and 19.4% reported no preference. The safety profile of PR-T was consistent with that previously described. CONCLUSION Conversion of stable kidney transplant recipients from IR-T to PR-T provided stable kidney and graft function over 12 months (Verband Forschender Arzneimittelhersteller--registered study: NIS ADV-02).
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Efficacy of microneedling combined with tacrolimus versus either one alone for vitiligo treatment.
Ebrahim, HM, Albalate, W
Journal of cosmetic dermatology. 2020;(4):855-862
Abstract
BACKGROUND Combination therapies have reported to augment the repigmentation in vitiligo. Microneedling (Mn) facilitates drug delivery across the skin barrier. OBJECTIVE To evaluate and compare the efficacy and safety of Mn combined with tacrolimus vs Mn alone or tacrolimus 0.1% ointment for treatment of localized and stable vitiligo. PATIENTS AND METHOD Ninety patients with vitiligo were randomized into three groups: group I received microneedling with tacrolimus, group II microneedling only both at 2 weeks interval for twelve sessions, and group III applied tacrolimus ointment 0.1% twice daily for 6 months. Skin biopsies were taken at baseline and after treatment. RESULTS The overall improvement (76.6%) was significantly higher in the combined group compared with other groups. Repigmentation was excellent in 66.6 of group I vs 33.3% in the other two groups (P .03). A highly significant improvement of the extremities was observed in the combined group than in the other groups (P < .001). A fewer number of sessions have reported in the combined group (I) than in the microneedling group (II; P < .001). Immunohistochemical results showed a significantly higher expression of HMB-45 in group I than in other two groups (P .04). Side effects were mild and tolerable in all groups. CONCLUSION The combination group has shown promising results over the other two groups.
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Long-term, prolonged-release tacrolimus-based immunosuppression in de novo kidney transplant recipients: 5-year prospective follow-up of the ADHERE study patients.
Rummo, O, Carmellini, M, Kamar, N, Durrbach, A, Mousson, C, Caputo, F, Mathe, Z, Christiaans, MHL, Kuypers, DRJ, Klempnauer, J, et al
Transplant international : official journal of the European Society for Organ Transplantation. 2020;(2):161-173
Abstract
The objectives of this study were to assess long-term graft survival, patient survival, renal function, and acute rejections in de novo kidney transplant recipients, treated with once-daily prolonged-release tacrolimus-based therapy. The study was a 5-year non-interventional prospective follow-up of patients from the ADHERE study, a Phase IV 12-month open-label assessment of patients randomized to receive prolonged-release tacrolimus in combination with mycophenolate mofetil (MMF) (Arm 1) or sirolimus (Arm 2). From 838 patients in the randomized study, 587 were included in the long-term follow-up, of whom 510 completed the study at year 5. At 1 year post-transplant, graft and patient survival rates were 93.0% and 97.8%, respectively, and at 5 years were 84.0% and 90.8%, respectively. Cox proportional hazards analysis showed no association between graft loss, initial randomized treatment arm, donor age, donor type, or sex. The 5-year acute rejection-free survival rate was 77.4%, and biopsy-confirmed acute rejection-free survival rate was 86.0%. Renal function remained stable over the follow-up period: mean ± SD eGFR 4-variable modification diet in renal disease formula (MDRD4) was 52.3 ± 21.6 ml/min/1.73 m2 at 6 months and 52.5 ± 23.0 ml/min/1.73 m2 at 5 years post-transplant. These findings support the role of long-term once-daily prolonged-release tacrolimus-based immunosuppression, in combination with sirolimus or MMF, for renal transplant recipients in routine clinical practice.
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Expected and Observed Glomerular Filtration Rates in Kidney Transplant Patients Converted to Once Daily Tacrolimus: 10 Years of Follow-up.
Tinti, F, Schiaffini, G, Umbro, I, Zavatto, A, Poli, L, Pretagostini, R, Garofalo, M, Bachetoni, A, Lai, S, D'Alessandro, MD, et al
Transplantation proceedings. 2020;(5):1547-1551
Abstract
The decline of allograft kidney function in the long term remains a significant issue in renal transplantation, with drug nephrotoxicity and cardiovascular complications as important risk factors. Our study aimed to evaluate the estimated glomerular filtration rate (eGFR) trend and metabolic cardiovascular risk factors over 10 years in a cohort of kidney transplant (KT) recipients converted from twice-daily (TD) tacrolimus (Tac) to once-daily (OD)-Tac. We enrolled 55 consecutive KT recipients who had been at the outpatient clinic between 2009 and 2011. Thirty-seven reached the 10-year follow-up. We compared the observed eGFR with the expected eGFR trend described in KT-recipients and monitored blood pressure and metabolic cardiovascular risk factors. The observed eGFR remained stable throughout the complete follow-up (P = .188). The observed decline of eGFR was significantly lower compared with the expected decline for KT patients (P < .001). The blood pressure was maintained within target values. The monitoring of plasma glucose levels demonstrated the stability of median values (P = .686), as well as cholesterol level (P = .250), high-density lipoprotein (HDL) cholesterol (P = .294), and triglycerides (P = .592) throughout the follow-up. The monitoring of tacrolimus plasma level demonstrated that median trough levels remained constant (median values 4.4-5.5 ng/mL) throughout the entire follow-up period (P = .149). We suggest that the reasonable control of metabolic risk factors for cardiovascular disease over long-term follow-up may significantly contribute to the preservation of eGFR compared with the decline expected in KT recipients.
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Tacrolimus-induced diabetic ketoacidosis with subsequent rapid recovery of endogenous insulin secretion after cessation of tacrolimus: A case report with review of literature.
Maruyama, K, Chujo, D
Medicine. 2019;(36):e16992
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Abstract
RATIONALE Immunosuppressive agents such as tacrolimus (TAC) and cyclosporin might cause glycemic disorders by suppressing insulin production. However, only a few cases of diabetic ketoacidosis (DKA) with longitudinal evaluation of endogenous insulin secretion related to TAC administration have been reported. PATIENT CONCERNS A 59-year-old Asian woman, who received prednisolone and TAC 4.0 mg for the treatment of anti-aminoacyl-tRNA synthetase antibody-positive interstitial pneumonia, was admitted to our hospital due to impaired consciousness and general malaise. DIAGNOSES She had metabolic acidosis; her plasma glucose, fasting serum C-peptide immunoreactivity (CPR), and urinary CPR levels were 989 mg/dL (54.9 mmol/L), 0.62 ng/mL, and 13.4 μg/d, respectively. No islet-related autoantibodies were detected. Therefore, she was diagnosed with TAC-induced DKA. INTERVENTION Intravenous continuous insulin infusion and rapid saline infusion were administered. TAC was discontinued because of its diabetogenic potential. OUTCOMES Sixteen weeks after cessation of TAC administration, she showed good glycemic control without administration of insulin or any oral hypoglycemic agents; her serum CPR level also improved dramatically. These findings suggested that TAC-induced pancreatic beta cell toxicity is reversible. LESSONS We reported a case of TAC-induced DKA with subsequent recovery of pancreatic beta cell function after cessation of TAC, resulting in good glycemic control. As TAC is widely used, we should pay attention to patients' glucose levels even though the TAC concentrations used are within the target range. Furthermore, dose reduction or cessation of TAC should be considered if hyperglycemia is detected during administration of this agent.
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Safety and tolerability of high-intensity statin therapy in heart transplant patients receiving immunosuppression with tacrolimus.
Heeney, SA, Tjugum, SL, Corkish, ME, Hollis, IB
Clinical transplantation. 2019;(1):e13454
Abstract
BACKGROUND Following heart transplantation (HT), HMG CoA reductase inhibitors (statins) have been shown to reduce total and low-density lipoprotein (LDL) cholesterol, development of cardiac allograft vasculopathy (CAV), and mortality. Studies in HT patients have demonstrated the safety of low/moderate intensity statins; however, little data exist using high-intensity (HI) statins. The study aim was to evaluate the safety and efficacy of HI statins in HT recipients receiving tacrolimus. METHODS This single-center, retrospective analysis included adult HT recipients from January 1, 2005, to December 31, 2015, who received HI statin therapy during posttransplant follow-up. The primary outcome, tolerability, was defined as the absence of myalgias, hepatotoxicity, rhabdomyolysis, or HI statin dose reduction/discontinuation. The secondary end point was the mean reduction in total and LDL cholesterol. RESULTS Among the 24 patients included, one experienced myalgias and therapy discontinuation (4%; P > 0.99). No other HI statin dose reduction/discontinuation occurred, and no instances of rhabdomyolysis or hepatotoxicity were observed. The average reduction in total and LDL cholesterol after conversion to HI statin was 35 mg/dL (P = 0.02) and 19 mg/dL (P = 0.10), respectively. CONCLUSIONS High-intensity statin therapy appears safe and efficacious in HT recipients receiving tacrolimus and is a reasonable option for the treatment of refractory hyperlipidemia.
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Ocular allergy: update on clinical trials.
Bielory, L, Schoenberg, D
Current opinion in allergy and clinical immunology. 2019;(5):495-502
Abstract
PURPOSE OF REVIEW The purpose of this article is to provide an update on the advances made through recent clinical trials regarding the treatment of the signs and symptoms of allergic conjunctivitis and its associated conditions. RECENT FINDINGS Recent studies have demonstrated significant advancement in the various forms of immunotherapy treatments. Nutritional interventions such as probiotics have surfaced as a viable complementary treatment option. Novel delivery methods such as contact lenses have been further studied along with a new tacrolimus formulation to improve ocular levels of the drug. SUMMARY Currently, the primary advances in treatment for allergic conjunctivitis has shifted from new ophthalmic agents to immunotherapy and improvement of drug delivery. This includes the classic subcutaneous and sublingual and the novel epicutaneous and intralymphatic immunotherapy delivery systems as well as an edible rice vaccine. New targets for treatment have spurred research into new antagonist drugs such as (OC000459), a prostaglandin D2 antagonist. The Marinosolv formulation using tacrolimus shows promise and may be considered for other ophthalmic agents in the future. Other nonpharmacological treatments such as stenting and mechanical barrier gel have demonstrated their usefulness in treating ocular symptoms.
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Coenzyme Q10 alleviates tacrolimus-induced mitochondrial dysfunction in kidney.
Yu, JH, Lim, SW, Luo, K, Cui, S, Quan, Y, Shin, YJ, Lee, KE, Kim, HL, Ko, EJ, Chung, BH, et al
FASEB journal : official publication of the Federation of American Societies for Experimental Biology. 2019;(11):12288-12298
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The major side effect of tacrolimus (Tac) is nephrotoxicity. We studied whether supplementation of coenzyme Q10, (CoQ10) a potent antioxidant, can reduce Tac-induced nephrotoxicity via improving mitochondrial function. In an in vitro study, CoQ10 reduced the production of Tac-induced mitochondrial reactive oxygen species and abolished the loss of mitochondrial membrane potential in proximal tubular cell line. Assessment of mitochondrial function revealed that CoQ10 decreased oxygen consumption and mitochondrial respiration rate increased by Tac, suggesting improvement of mitochondrial function to synthesize ATP with CoQ10 treatment. The effect of the CoQ10in vitro study was observed in an experimental model of chronic Tac-induced nephropathy. CoQ10 attenuated Tac-induced oxidative stress and was accompanied by function and histologic improvement. On electron microscopy, addition of CoQ10 increased not only the number but also the volume of mitochondria compared with Tac treatment only. Our data indicate that CoQ10 improves Tac-induced mitochondrial dysfunction in kidney. Supplementary CoQ10 treatment may be a promising approach to reduce Tac-induced nephrotoxicity.-Yu, J. H., Lim, S. W., Luo, K., Cui, S., Quan, Y., Shin, Y. J., Lee, K. E., Kim, H. L., Ko, E. J., Chung, B. H., Kim, J. H., Chung, S. J., Yang, C. W. Coenzyme Q10 alleviates tacrolimus-induced mitochondrial dysfunction in kidney.
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Efficacy and safety of prolonged-release tacrolimus in stable pediatric allograft recipients converted from immediate-release tacrolimus - a Phase 2, open-label, single-arm, one-way crossover study.
Rubik, J, Debray, D, Kelly, D, Iserin, F, Webb, NJA, Czubkowski, P, Vondrak, K, Sellier-Leclerc, AL, Rivet, C, Riva, S, et al
Transplant international : official journal of the European Society for Organ Transplantation. 2019;(11):1182-1193
Abstract
There are limited clinical data regarding prolonged-release tacrolimus (PR-T) use in pediatric transplant recipients. This Phase 2 study assessed the efficacy and safety of PR-T in stable pediatric kidney, liver, and heart transplant recipients (aged ≥5 to ≤16 years) over 1 year following conversion from immediate-release tacrolimus (IR-T), on a 1:1 mg total-daily-dose basis. Endpoints included the incidence of acute rejection (AR), a composite endpoint of efficacy failure (death, graft loss, biopsy-confirmed AR, and unknown outcome), and safety. Tacrolimus dose and whole-blood trough levels (target 3.5-15 ng/ml) were also evaluated. Overall, 79 patients (kidney, n = 48; liver, n = 29; heart, n = 2) were assessed. Following conversion, tacrolimus dose and trough levels remained stable; however, 7.6-17.7% of patients across follow-up visits had trough levels below the target range. Two (2.5%) patients had AR, and 3 (3.8%) had efficacy failure. No graft loss or deaths were reported. No new safety signals were identified. Drug-related treatment-emergent adverse events occurred in 28 patients (35.4%); most were mild, and all resolved. This study suggests that IR-T to PR-T conversion is effective and well tolerated over 1 year in pediatric transplant recipients and highlights the importance of therapeutic drug monitoring to maintain target tacrolimus trough levels.
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Analysis of NFATc1 amplification in T cells for pharmacodynamic monitoring of tacrolimus in kidney transplant recipients.
Kannegieter, NM, Hesselink, DA, Dieterich, M, de Graav, GN, Kraaijeveld, R, Baan, CC
PloS one. 2018;(7):e0201113
Abstract
BACKGROUND Therapeutic drug monitoring (TDM) of tacrolimus, based on blood concentrations, shows an imperfect correlation with the occurrence of rejection. Here, we tested whether measuring NFATc1 amplification, a member of the calcineurin pathway, is suitable for TDM of tacrolimus. MATERIALS AND METHODS NFATc1 amplification was monitored in T cells of kidney transplant recipients who received either tacrolimus- (n = 11) or belatacept-based (n = 10) therapy. Individual drug effects on NFATc1 amplification were studied in vitro, after spiking blood samples of healthy volunteers with either tacrolimus, belatacept or mycophenolate mofetil. RESULTS At day 30 after transplantation, in tacrolimus-treated patients, NFATc1 amplification was inhibited in CD4+ T cells expressing the co-stimulation receptor CD28 (mean inhibition 37%; p = 0.01) and in CD8+CD28+ T cells (29% inhibition; p = 0.02), while this was not observed in CD8+CD28- T cells or belatacept-treated patients. Tacrolimus pre-dose concentrations of these patients correlated inversely with NFATc1 amplification in CD28+ T cells (rs = -0.46; p < 0.01). In vitro experiments revealed that 50 ng/ml tacrolimus affected NFATc1 amplification by 58% (mean; p = 0.02). CONCLUSION In conclusion, measuring NFATc1 amplification is a direct tool for monitoring biological effects of tacrolimus on T cells in whole blood samples of kidney transplant recipients. This technique has potential that requires further development before it can be applied in daily practice.