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Monchaud C, Humeau A, Crépin S, Kawsarani L, Villeneuve C, Etienne I, Rerolle JP, Marquet P. Relationships Between Tacrolimus Exposure and Adverse Events in Renal Transplant Patients: The ExpoTac Study. Ther Drug Monit 2025; 47:152-160. [PMID: 39626094 DOI: 10.1097/ftd.0000000000001287] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2024] [Accepted: 10/24/2024] [Indexed: 01/11/2025]
Abstract
ABSTRACT In transplantation, the association of tacrolimus exposure with efficacy is better known than with adverse effects. The ExpoTac study explored the relationships between tacrolimus exposure and adverse events (AEs) in kidney transplant patients who benefited from at least 3 measurements of tacrolimus area under the curve (AUC) within 2 years of transplantation. The relationships between tacrolimus AUC, trough concentration C 0 , peak concentration C max , and AEs were explored using univariate analysis and Cox models in 386 patients (1281 sets of exposure biomarkers). Headaches and renal impairment potentially induced by tacrolimus were associated with significantly lower mean dose-standardized exposure biomarkers and a higher proportion of C max values above the median. Patients with tremor displayed significantly higher mean AUC 0-24 (343 ± 79 versus 308 ± 63 hours·mcg/L, P = 0.041). Cox analysis revealed a significant association between (1) the time to the first headache report and mean C max , mean AUC 0-24 , and the proportion of C max values above the median (hazard ratios [95% confidence interval] = 0.237 [0.007-0.538]; 7.499 [1.508-29.713]; 5.055 [1.577-17.137]) and (2) the time to first renal impairment report and the proportion of C 0 values above the median (0.401 [0.098-0.681]). Refining AUC, C max , and C 0 upper limits would help to refine tacrolimus therapeutic ranges and limit the risks of AEs after kidney transplantation.
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Affiliation(s)
- Caroline Monchaud
- Service de Pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, Limoges, France
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
| | - Antoine Humeau
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
| | - Sabrina Crépin
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
- Unité de Vigilance des Essais Cliniques, Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Limoges, France
| | - Lama Kawsarani
- Service de Pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, Limoges, France
| | - Claire Villeneuve
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
- Unité de Vigilance des Essais Cliniques, Service de Pharmacologie, Toxicologie et Pharmacovigilance, CHU Limoges, Limoges, France
| | - Isabelle Etienne
- Service de Néphrologie - Hémodialyse - Transplantation, CHU Rouen, Rouen, France ; and
| | - Jean-Philippe Rerolle
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
- Service de Néphrologie, Dialyse et Transplantation, CHU Limoges, France
| | - Pierre Marquet
- Service de Pharmacologie, toxicologie et pharmacovigilance, CHU Limoges, Limoges, France
- INSERM UMR-1248 Pharmacologie et Transplantation, Université Limoges, Limoges, France
- FHU SUPORT, Limoges, France
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2
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Dębska-Ślizień A, Kuźmiuk-Glembin I, Hożejowski R, Kamińska D, Krajewska M, Zawiasa-Bryszewska A, Kurnatowska I, Smykał-Jankowiak K, Głyda M, Kozioł L, Karczewski M, Ciechanowski K, Kwiatkowska E. Renal Allograft Function and the Tacrolimus C/D Ratio: Insights from a Prospective Study on MeltDose Tacrolimus. J Clin Med 2024; 13:6241. [PMID: 39458191 PMCID: PMC11508752 DOI: 10.3390/jcm13206241] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2024] [Revised: 10/14/2024] [Accepted: 10/15/2024] [Indexed: 10/28/2024] Open
Abstract
Background: The tacrolimus concentration-to-dose (C/D) ratio is valuable for optimizing nephrotoxicity-related renal outcomes. Prospective data on the C/D ratio in kidney transplant recipients newly treated with MeltDose tacrolimus are limited. We analyzed the C/D ratio pattern of MeltDose tacrolimus and its effect on posttransplant renal function, comparing it with the literature data on immediate-release tacrolimus (IR-Tac). Methods: In total, 101 adult kidney transplant recipients on a standard immunosuppressive regimen including MeltDose tacrolimus were enrolled in this prospective, multicenter cohort study and followed for 12 months. The C/D ratio classified patients as fast, intermediate, or slow metabolizers. Renal function was assessed via the estimated glomerular filtration rate (eGFR). MeltDose tacrolimus data were compared with previous IR-Tac data by bootstrapping. Results: The cohort exhibited a right-skewed C/D ratio distribution with a mean of 2.12 ng/mL × 1/mg, which was significantly greater than the 1.29 mean for IR-Tac (p < 0.001). Compared with fast metabolizers, slow metabolizers of MeltDose tacrolimus experienced greater eGFR gains at 6 months post-transplantation (median +7.9 vs. -3.6 mL/min; p = 0.005). A Bayesian linear mixed-effects model predicting the eGFR at month 12 identified the baseline eGFR, time from transplant, body mass index, and log-transformed C/D ratio as significant variables. A one-unit increase in the log-transformed C/D ratio corresponded to an approximate increase of 4.5 mL/min in the eGFR at month 12. Conclusions: Slow metabolizers of MeltDose tacrolimus had significantly better renal function outcomes than fast metabolizers. MeltDose tacrolimus is associated with slower metabolism than is IR-Tac, as evidenced by its higher C/D ratios.
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Affiliation(s)
- Alicja Dębska-Ślizień
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, 80-952 Gdansk, Poland; (A.D.-Ś.); (I.K.-G.)
| | - Izabella Kuźmiuk-Glembin
- Department of Nephrology, Transplantology and Internal Diseases, Medical University of Gdansk, 80-952 Gdansk, Poland; (A.D.-Ś.); (I.K.-G.)
| | - Roman Hożejowski
- Medical Department, Chiesi Poland Sp. z o.o., 02-305 Warsaw, Poland
| | - Dorota Kamińska
- Faculty of Medicine, Wroclaw University of Science and Technology, 51-377 Wroclaw, Poland
| | - Magdalena Krajewska
- Faculty of Medicine, Wroclaw University of Science and Technology, 51-377 Wroclaw, Poland
| | - Anna Zawiasa-Bryszewska
- Department of Internal Diseases and Transplant Nephrology, Medical University of Lodz, 90-153 Lodz, Poland (I.K.)
| | - Ilona Kurnatowska
- Department of Internal Diseases and Transplant Nephrology, Medical University of Lodz, 90-153 Lodz, Poland (I.K.)
| | | | - Maciej Głyda
- Department of Transplantology, Surgery and Urology, District Hospital, 60-479 Poznan, Poland
- Collegium Medicum in Bydgoszcz, Nicolaus Copernicus University, 85-067 Bydgoszcz, Poland
| | - Lidia Kozioł
- Department of General and Transplant Surgery, Poznan University of Medical Sciences, 60-352 Poznan, Poland
| | - Marek Karczewski
- Department of General and Transplant Surgery, Poznan University of Medical Sciences, 60-352 Poznan, Poland
| | - Kazimierz Ciechanowski
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, 70-111 Szczecin, Poland
| | - Ewa Kwiatkowska
- Department of Nephrology, Transplantology and Internal Medicine, Pomeranian Medical University, 70-111 Szczecin, Poland
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Fan TY, Yan Y, Lu Q, Li J, Chen H. Treatment of Hyperlipidemia With Alirocumab in a Liver Transplant Recipient With Poor Blood Lipid Control: Case Report. Transplant Proc 2024; 56:1169-1172. [PMID: 38876927 DOI: 10.1016/j.transproceed.2024.05.015] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2024] [Revised: 05/10/2024] [Accepted: 05/17/2024] [Indexed: 06/16/2024]
Abstract
The use of proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors, such as alirocumab, to treat drug-resistant hypercholesterolemia is increasing; however, to date there have been no studies on the use of alirocumab to treat the hyperlipidemia that follows liver transplantation. Here we report a case of successful management of hyperlipidemia, albeit without total reversal of elevated serum triglycerides, with alirocumab monotherapy in a liver transplantation patient who was resistant to rosuvastatin and fenofibrate. In terms of safety, only transient palpitations following the first few alirocumab injections were recorded. This case illustrates that alirocumab can be a viable option for patients who experience poor lipid control after liver transplantation.
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Affiliation(s)
- Tie-Yan Fan
- Hepatobiliary and Pancreatic Center of Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Yan Yan
- Department of Clinical Pharmacy of Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Qian Lu
- Hepatobiliary and Pancreatic Center of Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Jun Li
- Hepatobiliary and Pancreatic Center of Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China
| | - Hong Chen
- Hepatobiliary and Pancreatic Center of Beijing Tsinghua Changgung Hospital, School of Clinical Medicine, Tsinghua University, Beijing, China.
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Raja K, Panackel C. Post Liver Transplant Renal Dysfunction-Evaluation, Management and Immunosuppressive Practice. J Clin Exp Hepatol 2024; 14:101306. [PMID: 38274509 PMCID: PMC10806298 DOI: 10.1016/j.jceh.2023.101306] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/10/2023] [Accepted: 11/21/2023] [Indexed: 01/27/2024] Open
Abstract
Liver transplantation (LT) is an effective and lifesaving treatment for patients with end-stage liver disease and hepatocellular carcinoma. Significant improvement in intermediate and long-term survival has been possible due to advancements in immunosuppressive therapy, perioperative care, and surgical techniques. Despite these advances, metabolic complications, including diabetes mellitus, cardiovascular diseases, malignancies, and renal dysfunction, are challenging issues after LT. Acute kidney injury (AKI) and chronic kidney disease (CKD) after LT are common and result in significant morbidity and mortality. Early diagnosis of kidney injury after LT is challenging, and no technique has yet proven effective in prediction of renal dysfunction. The methods for assessing renal function range from formulas that predict glomerular filtration rate to non-invasive biomarkers. The universal adoption of the model for end-stage liver disease has a direct impact on the incidence of peri-transplant AKI and development of CKD in the long-term. Post-LT renal dysfunction is multifactorial and is usually a result of pre-transplantation comorbidities, occurrence of renal dysfunction on the waiting list, perioperative events, and post-transplant nephrotoxic immunosuppressive medication use. Early identification of patients at risk for renal dysfunction and adoption of preventive measures are crucial in the pre-transplant period. No data are currently available to suggest a surgical technique that reliably demonstrates renal protection. Nephroprotective strategies during LT follow accepted surgical practice guidelines, such as maintenance of intravascular volume and mean arterial pressure. The management of kidney disease following LT is challenging, as by the time the serum creatinine is significantly elevated, few interventions impact the course of progression. Early nephroprotective measures are strongly advised and they mostly center on delaying the administration of calcineurin inhibitors (CNIs) during the initial postoperative period, lowering CNI dosage and combining CNI with mycophenolate mofetil and everolimus. The reasons for renal failure following LT, the techniques used to diagnose it, and the therapies designed to preserve renal function both immediately and late after LT are all critically evaluated in this review.
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Affiliation(s)
- Kaiser Raja
- Department of Gastroenterology and Hepatology, King's College Hospital London, Dubai, United Arab Emirates
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Puri P. Renal Dysfunction After Liver Transplant: Is CNI Nephrotoxicity Overrated. J Clin Exp Hepatol 2023; 13:556-558. [PMID: 37440945 PMCID: PMC10333944 DOI: 10.1016/j.jceh.2023.05.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/10/2023] [Accepted: 05/12/2023] [Indexed: 07/15/2023] Open
Affiliation(s)
- Pankaj Puri
- Fortis Escorts Liver and Digestive Diseases Institute, Fortis Escorts Hospital, New Delhi, 110025, India
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López-Ibor JV, Citores MJ, Portoles J, Gómez-Bueno M, Sánchez-Sobrino B, Muñoz A, Cuervas-Mons V, Segovia-Cubero J. Role of TGF-β1 +869T>C polymorphism in renal dysfunction one year after heart transplantation. J Heart Lung Transplant 2022; 41:1672-1678. [PMID: 36210267 DOI: 10.1016/j.healun.2022.09.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2022] [Revised: 08/01/2022] [Accepted: 09/06/2022] [Indexed: 10/14/2022] Open
Abstract
BACKGROUND Chronic kidney disease is a major complication after heart transplantation with wide inter-individual variability. Calcineurin inhibitor nephrotoxicity, mediated by transforming growth factor-beta1 (TGF-β1), is an important contributing factor. Our objective was to evaluate the association between TGF-β1 polymorphisms and renal dysfunction 1-year after heart transplantation. METHODS Single-center observational study that included patients who received a first heart transplant between 1990-2013. According to the 1-year eGFR decline, patients were classified as "Stable" (decrease in eGFR<10% or eGFR>60 ml/min/1.73m2) or "Progressors" (decrease in eGFR>10% and eGFR<60 ml/min/1.73m2). "Progressors" were then subdivided by the degree of eGFR decrease in "Mild progressors" (10-30%) or "Rapid progressors" (>30%). The association between TGF-β1 +869T>C polymorphism and other risk factors with the eGFR outcome was analysed. RESULTS A total of 355 patients (78% male; 50.7 ± 11.8 years) were included. According to the 1-year eGFR decline, 220 patients (62%) were classified as "Stable" and 135 (38%) as "Progressors". TGF-β1+869CC genotype was more prevalent in "Stable" vs "Progressors" group (20% vs 8%, p = 0.009). In the multivariate analysis, female sex (p 0.02) and eGFR<60 ml/min/1.73 m2 at first month post-heart transplant (p = 0.004) remained as risk factors of eGFR decline, and TGF-β1 + 869CC genotype (p = 0.001) and renal dysfunction pre-heart transplant (p = 0.04) as protective factors. TGF-β1 + 869CC genotype was less frequently found in "Mild progressors" compared to "Rapid progressors" [p = 0.019; OR (95%CI) = 0.19 (.05-.76)]. CONCLUSIONS The TGF-β1 +869CC genotype is associated with a lower risk of calcineurin inhibitor nephrotoxicity after heart transplant. This genetic susceptibility could enable a more personalized patient treatment.
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Affiliation(s)
- Jorge V López-Ibor
- Department of Cardiology, Advanced Heart Failure and Heart Transplantation Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - María J Citores
- Department of Internal Medicine, Instituto de Investigación Puerta de Hierro-Segovia de Arana (IDIPHISA), Majadahonda, Madrid, Spain.
| | - Jose Portoles
- Department of Nephrology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Manuel Gómez-Bueno
- Department of Cardiology, Advanced Heart Failure and Heart Transplantation Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
| | - Beatriz Sánchez-Sobrino
- Department of Nephrology, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Alejandro Muñoz
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain
| | - Valentín Cuervas-Mons
- Department of Internal Medicine, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; Department of Medicine, Universidad Autónoma de Madrid, Spain
| | - Javier Segovia-Cubero
- Department of Cardiology, Advanced Heart Failure and Heart Transplantation Unit, Hospital Universitario Puerta de Hierro Majadahonda, Madrid, Spain; Centro de Investigación Biomédica en Red en Enfermedades Cardiovasculares (CIBERCV), Madrid, Spain
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Akalya K, Murali TM, Vathsala A, Teo BW, Low S, Dharmasegaran D, Koh LP, Bonney GK, Hong WZ, Da Y, Chua HR. Elevated Urinary Tissue Inhibitor Of Metalloproteinase-2 And Insulin-Like Growth Factor Binding Protein-7 Predict Drug-Induced Acute Kidney Injury. Curr Drug Metab 2022; 23:223-232. [PMID: 35469565 DOI: 10.2174/1389200223666220425111931] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2021] [Revised: 12/24/2021] [Accepted: 01/25/2022] [Indexed: 11/22/2022]
Abstract
BACKGROUND Urinary tissue inhibitor of metalloproteinase-2 (TIMP2) and insulin-like growth factor binding protein-7 (IGFBP7) predict severe acute kidney injury (AKI) in critical illness. Earlier but subtle elevation of either biomarker from nephrotoxicity may predict drug-induced AKI. METHODS A prospective study involving serial urine collection in patients treated with vancomycin, aminoglycosides, amphotericin, foscarnet, or calcineurin inhibitors was performed. Urinary TIMP2 and IGFBP7, absolute levels, normalized with urine creatinine were examined in days leading to AKI onset by KDIGO criteria in cases, or at final day of nephrotoxic therapy in non-AKI controls who were matched for age, baseline kidney function and nephrotoxic exposure. RESULTS Urinary biomarker analyses were performed in 21 AKI patients and 28 non-AKI matched-controls; both groups had comparable baseline kidney function and duration of nephrotoxic drug therapy. Significantly higher absolute, normalized, and composite levels of TIMP2 and IGFBP7 were observed in AKI cases versus controls as early as 2-3 days before AKI onset (all P<0.05); >70% of patients with corresponding levels above 75th percentile developed AKI. Normalized TIMP2 at 2-3 days pre-AKI predicted AKI with the highest average AUROC of 0.81, followed by that of composite [TIMP2]x[IGFBP7] (0.78) after cross-validation. [TIMP2]x[IGFBP7] >0.01 (ng/mL)2 /1000 predicted AKI with a sensitivity of 79% and specificity of 60%. CONCLUSION Elevated urinary TIMP2 or IGFBP7 predicts drug-induced AKI with a lead-time of 2-3 days; an opportune time for interventions to reduce nephrotoxicity.
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Affiliation(s)
- K Akalya
- Division of Nephrology, University Medicine Cluster, National University Hospital (Singapore)
| | - Tanusya Murali Murali
- Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - Anantharaman Vathsala
- Division of Nephrology, University Medicine Cluster, National University Hospital (Singapore).,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - Boon-Wee Teo
- Division of Nephrology, University Medicine Cluster, National University Hospital (Singapore).,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
| | - Sanmay Low
- Renal Unit, Department of Medicine, Ng Teng Fong General Hospital, Singapore
| | - Dharmini Dharmasegaran
- Division of Nephrology, University Medicine Cluster, National University Hospital (Singapore)
| | - Liang-Piu Koh
- Department of Haematology, National University Cancer Institute, Singapore
| | - Glenn Kunnath Bonney
- Liver Transplantation, National University Centre for Organ Transplantation, Singapore
| | - Wei-Zhen Hong
- Division of Nephrology, University Medicine Cluster, National University Hospital (Singapore)
| | - Yi Da
- Division of Nephrology, University Medicine Cluster, National University Hospital (Singapore)
| | - Horng-Ruey Chua
- Division of Nephrology, University Medicine Cluster, National University Hospital (Singapore).,Department of Medicine, Yong Loo Lin School of Medicine, National University of Singapore
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Pacheco MP, Carneiro-D'Albuquerque LA, Mazo DF. Current aspects of renal dysfunction after liver transplantation. World J Hepatol 2022; 14:45-61. [PMID: 35126839 PMCID: PMC8790396 DOI: 10.4254/wjh.v14.i1.45] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/24/2021] [Revised: 10/24/2021] [Accepted: 01/06/2022] [Indexed: 02/06/2023] Open
Abstract
The development of chronic kidney disease (CKD) after liver transplantation (LT) exerts a severe effect on the survival of patients. The widespread adoption of the model for end-stage liver disease score strongly impacted CKD incidence after the procedure, as several patients are transplanted with previously deteriorated renal function. Due to its multifactorial nature, encompassing pre-transplantation conditions, perioperative events, and nephrotoxic immunosuppressor therapies, the accurate identification of patients under risk of renal disease, and the implementation of preventive approaches, are extremely important. Methods for the evaluation of renal function in this setting range from formulas that estimate the glomerular filtration rate, to non-invasive markers, although no option has yet proved efficient in early detection of kidney injury. Considering the nephrotoxicity of calcineurin inhibitors (CNI) as a factor of utmost importance after LT, early nephroprotective strategies are highly recommended. They are based mainly on delaying the application of CNI during the immediate postoperative-period, reducing their dosage, and associating them with other less nephrotoxic drugs, such as mycophenolate mofetil and everolimus. This review provides a critical assessment of the causes of renal dysfunction after LT, the methods of its evaluation, and the interventions aimed at preserving renal function early and belatedly after LT.
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Affiliation(s)
- Mariana P Pacheco
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
| | - Luiz Augusto Carneiro-D'Albuquerque
- Division of Digestive Organs Transplant, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
| | - Daniel F Mazo
- Division of Clinical Gastroenterology and Hepatology, Department of Gastroenterology, University of São Paulo School of Medicine, Sao Paulo 05403-900, Sao Paulo, Brazil
- Division of Gastroenterology, Department of Internal Medicine, School of Medical Sciences of University of Campinas, Campinas 13083-878, Sao Paulo, Brazil
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Boggi U, Baronti W, Amorese G, Pilotti S, Occhipinti M, Perrone V, Marselli L, Barsotti M, Campani D, Gianetti E, Insilla AC, Bosi E, Kaufmann E, Terrenzio C, Vistoli F, Marchetti P. Treating Type 1 Diabetes by Pancreas Transplant Alone: A Cohort Study on Actual Long-term (10 Years) Efficacy and Safety. Transplantation 2022; 106:147-157. [PMID: 33909390 DOI: 10.1097/tp.0000000000003627] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/22/2022]
Abstract
BACKGROUND Physiologically regulated insulin secretion and euglycemia are achievable in type 1 diabetes (T1D) by islet or pancreas transplantation. However, pancreas transplant alone (PTA) remains a debated approach, with uncertainties on its relative benefits and risks. We determined the actual long-term (10 y) efficacy and safety of PTA in carefully characterized T1D subjects. METHODS This is a single-center, cohort study in 66 consecutive T1D subjects who received a PTA between April 2001 and December 2007, and were then all followed until 10 y since transplant. Main features evaluated were patient survival, pancreas graft function, C-peptide levels, glycemic parameters, and the function of the native kidneys. RESULTS Ten-year actual patient survival was 92.4%. Optimal (insulin independence) or good (minimal insulin requirement) graft function was observed in 57.4% and 3.2% of patients, respectively. Six (9.0%) patients developed stage 5 or 4 chronic kidney disease. In the remaining individuals bearing a successful PTA, estimated glomerular filtration rate (eGFR) decline per year was -2.29 ± 2.69 mL/min/1.73 m2. Reduction of eGFR at 1 y post-PTA was higher in those with pre-PTA hyperfiltration and higher HbA1c concentrations; eGFR changes afterward significantly correlated with diabetes duration. In recipients with normoglycemia at 10 y, 74% of normoalbuminuric or microalbuminuric subjects pre-PTA remained stable, and 26% progressed toward a worse stage; conversely, in 62.5% of the macroalbuminuric individuals albuminuria severity regressed. CONCLUSIONS These long-term effects of PTA on patient survival, graft function, and the native kidneys support PTA as a suitable approach to treat diabetes in selected T1D patients.
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Affiliation(s)
- Ugo Boggi
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Division of General and Transplant Surgery, Cisanello University Hospital, Pisa, Italy
| | - Walter Baronti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Gabriella Amorese
- Division of General and Transplant Surgery, Cisanello University Hospital, Pisa, Italy
| | - Silvia Pilotti
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Margherita Occhipinti
- Diabetes Unit, Versilia Hospital, Azienda ASL Area Vasta Nord-Ovest, Lido di Camaiore, Lucca, Italy
| | - Vittorio Perrone
- Division of General and Transplant Surgery, Cisanello University Hospital, Pisa, Italy
| | - Lorella Marselli
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Departmental Section of Endocrinology and Metabolism of Organ and Cellular Transplantation, Cisanello University Hospital, Pisa, Italy
| | | | - Daniela Campani
- Department of Surgical, Medical, Molecular Pathology and Critical Area, Division of Surgical Pathology, Pisa University Hospital, Pisa, Italy
| | - Elena Gianetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Andrea Cacciato Insilla
- Department of Surgical, Medical, Molecular Pathology and Critical Area, Division of Surgical Pathology, Pisa University Hospital, Pisa, Italy
| | - Emanuele Bosi
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Emanuele Kaufmann
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
| | - Chiara Terrenzio
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
| | - Fabio Vistoli
- Department of Translational Research and New Technologies in Medicine and Surgery, University of Pisa, Pisa, Italy
- Division of General and Transplant Surgery, Cisanello University Hospital, Pisa, Italy
| | - Piero Marchetti
- Department of Clinical and Experimental Medicine, University of Pisa, Pisa, Italy
- Departmental Section of Endocrinology and Metabolism of Organ and Cellular Transplantation, Cisanello University Hospital, Pisa, Italy
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10
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Fujino C, Sanoh S, Katsura T. Variation in Expression of Cytochrome P450 3A Isoforms and Toxicological Effects: Endo- and Exogenous Substances as Regulatory Factors and Substrates. Biol Pharm Bull 2021; 44:1617-1634. [PMID: 34719640 DOI: 10.1248/bpb.b21-00332] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
The CYP3A subfamily, which includes isoforms CYP3A4, CYP3A5, and CYP3A7 in humans, plays important roles in the metabolism of various endogenous and exogenous substances. Gene and protein expression of CYP3A4, CYP3A5, and CYP3A7 show large inter-individual differences, which are caused by many endogenous and exogenous factors. Inter-individual differences can cause negative outcomes, such as adverse drug events and disease development. Therefore, it is important to understand the variations in CYP3A expression caused by endo- and exogenous factors, as well as the variation in the metabolism and kinetics of endo- and exogenous substrates. In this review, we summarize the factors regulating CYP3A expression, such as bile acids, hormones, microRNA, inflammatory cytokines, drugs, environmental chemicals, and dietary factors. In addition, variations in CYP3A expression under pathological conditions, such as coronavirus disease 2019 and liver diseases, are described as examples of the physiological effects of endogenous factors. We also summarize endogenous and exogenous substrates metabolized by CYP3A isoforms, such as cholesterol, bile acids, hormones, arachidonic acid, vitamin D, and drugs. The relationship between the changes in the kinetics of these substrates and the toxicological effects in our bodies are discussed. The usefulness of these substrates and metabolites as endogenous biomarkers for CYP3A activity is also discussed. Notably, we focused on discrimination between CYP3A4, CYP3A5, and CYP3A7 to understand inter-individual differences in CYP3A expression and function.
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Affiliation(s)
- Chieri Fujino
- Laboratory of Clinical Pharmaceutics and Therapeutics, College of Pharmaceutical Sciences, Ritsumeikan University
| | - Seigo Sanoh
- Graduate School of Biomedical and Health Sciences, Hiroshima University.,School of Pharmaceutical Sciences, Wakayama Medical University
| | - Toshiya Katsura
- Laboratory of Clinical Pharmaceutics and Therapeutics, College of Pharmaceutical Sciences, Ritsumeikan University
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11
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Kou K, Sun X, Li M, Li T, Hu Y, Li S, Lv G. Beneficial effects of Wuzhi Capsule on tacrolimus blood concentrations in liver transplant patients with different donor-recipient CYP3A5 genotypes. J Clin Pharm Ther 2021; 47:200-210. [PMID: 34708436 DOI: 10.1111/jcpt.13533] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2021] [Revised: 09/02/2021] [Accepted: 09/14/2021] [Indexed: 12/27/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Tacrolimus (Tac) is an immunosuppressant that is widely used to prevent allograft rejection in patients after liver transplantation. Its metabolism mainly depends on the cytochrome P450 3A5 (CYP3A5), which has genetic polymorphisms. Recently, a Chinese herbal medicine known as Wuzhi Capsule (WZC) was shown to increase Tac blood concentrations by inhibiting the activity of CYP3A in animal studies in rats. To date, it remains unexplored whether WZC can be efficiently used to enhance the blood concentration of Tac in liver transplant patients with different donor-recipient CYP3A5 genotypes. METHODS A total of 185 liver transplant patients were enrolled and two-way ANOVA was carried out, then they were divided into four groups according to the combinations of donor-recipient CYP3A5 phenotypes. WZC was given to patients when the dose of Tac was ≥4 mg, and the dose-adjusted C0 (C0 /D) of Tac measured twice in succession was ≤1 ng/ml/mg. The blood trough concentration of Tac (C0 ), C0 /D, and dose- and body weight-adjusted C0 (C0 /D/W) was analysed on days 7 and 14 after liver transplantation. RESULTS The genotypes of donor and recipient or WZC had significant effects on C0, C0/D and C0/D/W. There were significant differences in the Tac blood concentrations between the groups. The recipient expression (*1)/donor expression (*1) (R+/D+) group had the lowest C0 , C0 /D and C0 /D/W among the four groups. Furthermore, a larger proportion of patients in the CYP3A5 expression groups required Tac dose adjustment to achieve a therapeutic effect and were given Tac with WZC. Notably, the use of WZC significantly increased the blood concentrations of Tac in the CYP3A5 expression groups and greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC in the CYP3A5 expression groups. What is more, WZC reduced the hospitalization cost of patients to a certain extent. WHAT IS NEW AND CONCLUSION WZC significantly increased the C0 , C0 /D and C0 /D/W in the CYP3A5 expression groups and reduced the hospitalization expenses of patients to a certain extent. What is more, greater increases in the C0 /D and C0 /D/W were significantly associated with higher doses of WZC.
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Affiliation(s)
- Kai Kou
- Department of Hepatobiliary surgery, Jilin University First Hospital, Changchun, China
| | - Xiaodong Sun
- Department of Hepatobiliary surgery, Jilin University First Hospital, Changchun, China
| | - Mingqian Li
- Department of Hepatobiliary surgery, Jilin University First Hospital, Changchun, China
| | - Ting Li
- Department of Hepatobiliary surgery, Jilin University First Hospital, Changchun, China
| | - Yuelei Hu
- Department of Hepatobiliary surgery, Jilin University First Hospital, Changchun, China
| | - Shuxuan Li
- Department of Hepatobiliary surgery, Jilin University First Hospital, Changchun, China
| | - Guoyue Lv
- Department of Hepatobiliary surgery, Jilin University First Hospital, Changchun, China
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12
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Furuse M, Hosomi S, Nishida Y, Itani S, Nadatani Y, Fukunaga S, Otani K, Tanaka F, Nagami Y, Taira K, Kamata N, Watanabe T, Watanabe K, Fujiwara Y. The impact of cytochrome P450 3A genetic polymorphisms on tacrolimus pharmacokinetics in ulcerative colitis patients. PLoS One 2021; 16:e0250597. [PMID: 33886687 PMCID: PMC8062093 DOI: 10.1371/journal.pone.0250597] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/31/2020] [Accepted: 04/09/2021] [Indexed: 12/17/2022] Open
Abstract
Tacrolimus (Tac) is an effective remission inducer of refractory ulcerative colitis (UC). Gene polymorphisms result in interindividual variability in Tac pharmacokinetics. In this study, we aimed to examine the relationships between gene polymorphisms and the metabolism, pharmacokinetics, and therapeutic effects of Tac in patients with UC. Forty-five patients with moderate-to-severe refractory UC treated with Tac were retrospectively enrolled. Genotyping for cytochrome P450 (CYP) 3A4*1G, CYP3A5*3, CYP2C19*2, CYP2C19*3, nuclear receptor subfamily 1 group I member 2 (NR1I2)–25385C>T, ATP-binding cassette subfamily C member 2 (ABCC2)–24C>T, ABCC2 1249G>A, and ABCC2 3972C>T was performed. Concentration/dose (C/D) ratio, clinical therapeutic effects, and adverse events were evaluated. The C/D ratio of Tac in UC patients with the CYP3A4*1G allele was statistically lower than in those with the CYP3A4*1/*1 allele (P = 0.005) and significantly lower in patients with CYP3A5*3/*3 than in those with CYP3A5*1 (P < 0.001). Among patients with the CYP3A4*1G allele, the C/D ratio was significantly lower in patients with CYP3A5*1 than in those with CYP3A5*3/*3 (P = 0.001). Patients with the NR1I2–25385C/C genotype presented significantly more overall adverse events than those with the C/T or T/T genotype (P = 0.03). Although CYP3A4*1G and CYP3A5*3 polymorphisms were related to Tac pharmacokinetics, CYP3A5 presented a stronger effect than CYP3A4. The NR1I2–25385C/C genotype was related to the overall adverse events. The evaluation of these polymorphisms could be useful in the treatment of UC with Tac.
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Affiliation(s)
- Maizumi Furuse
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shuhei Hosomi
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
- * E-mail:
| | - Yu Nishida
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shigehiro Itani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yuji Nadatani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Shusei Fukunaga
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koji Otani
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Fumio Tanaka
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Yasuaki Nagami
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Koichi Taira
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Noriko Kamata
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Toshio Watanabe
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
| | - Kenji Watanabe
- Department of Center for Inflammatory Bowel Disease, Division of Internal Medicine, Hyogo College of Medicine, Hyogo, Japan
| | - Yasuhiro Fujiwara
- Department of Gastroenterology, Osaka City University Graduate School of Medicine, Osaka, Japan
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13
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Leino AD, Pai MP. Maintenance Immunosuppression in Solid Organ Transplantation: Integrating Novel Pharmacodynamic Biomarkers to Inform Calcineurin Inhibitor Dose Selection. Clin Pharmacokinet 2020; 59:1317-1334. [PMID: 32720300 DOI: 10.1007/s40262-020-00923-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022]
Abstract
Calcineurin inhibitors, the primary immunosuppressive therapy used to prevent alloreactivity of transplanted organs, have a narrow therapeutic index. Currently, treatment is individualized based on clinical assessment of the risk of rejection or toxicity guided by trough concentration monitoring. Advances in immune monitoring have identified potential markers that may have value in understanding calcineurin inhibitor pharmacodynamics. Integration of these markers has the potential to complement therapeutic drug monitoring. Existing pharmacokinetic-pharmacodynamic (PK-PD) data is largely limited to correlation between the biomarker and trough concentrations at single time points. Immune related gene expression currently has the most evidence supporting PK-PD integration. Novel biomarker-based approaches to pharmacodynamic monitoring including development of enhanced PK-PD models are proposed to realize the full clinical benefit.
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Affiliation(s)
- Abbie D Leino
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Rm 3569, Ann Arbor, MI, 48109, USA
| | - Manjunath P Pai
- Department of Clinical Pharmacy, College of Pharmacy, University of Michigan, 428 Church Street, Rm 3569, Ann Arbor, MI, 48109, USA.
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14
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Wang Z, Zheng M, Yang H, Han Z, Tao J, Chen H, Sun L, Guo M, Wang L, Tan R, Wei JF, Gu M. Association of Genetic Variants in CYP3A4, CYP3A5, CYP2C8, and CYP2C19 with Tacrolimus Pharmacokinetics in Renal Transplant Recipients. Curr Drug Metab 2020; 20:609-618. [PMID: 31244435 DOI: 10.2174/1389200220666190627101927] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2019] [Revised: 05/05/2019] [Accepted: 05/31/2019] [Indexed: 12/11/2022]
Abstract
BACKGROUND Our study aimed to investigate the pharmacogenetics of cytochrome P3A4 (CYP3A4), CYP3A5, CYP2C8, and CYP2C19 and their influence on TAC Pharmacokinetics (PKs) in short-term renal transplant recipients. METHODS A total of 105 renal transplant recipients were enrolled. Target Sequencing (TS) based on next-generation sequencing technology was used to detect all exons, exon/intron boundaries, and flanking regions of CYP3A4, CYP3A5, CYP2C8, and CYP2C19. After adjustment of Minor Allele Frequencies (MAF) and Hardy-Weinberg Equilibrium (HWE) analysis, tagger Single-nucleotide Polymorphisms (SNPs) and haplotypes were identified. Influence of tagger SNPs on TAC concentrations was analyzed. RESULTS A total of 94 SNPs were identified in TS analysis. Nine tagger SNPs were selected, and two SNPs (rs15524 and rs4646453) were noted to be significantly associated with TAC PKs in short-term post-transplant follow-up. Measurement time points of TAC, body mass index (BMI), usage of sirolimus, and incidence of Delayed Graft Function (DGF) were observed to be significantly associated with TAC PKs. Three haplotypes were identified, and rs15524-rs4646453 was found to remarkably contribute to TAC PKs. Recipients carrying H2/H2 (GG-AA) haplotype also showed significantly high weight- and dose-adjusted TAC concentrations in posttransplant periods of 7, 14, and 30 days and 3 and 6 months. CONCLUSIONS Two tagger SNPs, namely, rs15524 and rs4646453, are significantly related to the variability of TAC disposition, and TAC measurement time points, BMI, usage of sirolimus, and incidence of DGF contribute to this influence. Recipients carrying H2/H2 (GG-AA) haplotype in rs15524-rs4646453 may require a low dosage of TAC during 1-year follow-up posttransplant.
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Affiliation(s)
- Zijie Wang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ming Zheng
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Haiwei Yang
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Zhijian Han
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Jun Tao
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Hao Chen
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Li Sun
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Miao Guo
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Libin Wang
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ruoyun Tan
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Ji-Fu Wei
- Research Division of Clinical Pharmacology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
| | - Min Gu
- Department of Urology, The First Affiliated Hospital of Nanjing Medical University, Nanjing 210029, China
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15
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Hao GX, Song LL, Zhang DF, Su LQ, Jacqz-Aigrain E, Zhao W. Off-label use of tacrolimus in children with glomerular disease: Effectiveness, safety and pharmacokinetics. Br J Clin Pharmacol 2020; 86:274-284. [PMID: 31725919 DOI: 10.1111/bcp.14174] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2019] [Revised: 10/21/2019] [Accepted: 11/04/2019] [Indexed: 12/13/2022] Open
Abstract
Glomerular diseases are leading causes of end-stage renal disease in children. Tacrolimus is frequently used off-label in the treatment of glomerular diseases. The effectiveness, safety and pharmacokinetic data of tacrolimus in the treatment of glomerular diseases in children are reviewed in this paper to provide evidence to support its rational use in clinical practice. The remission rates in previously published studies were different. In 19 clinical trials on children with nephrotic syndrome, the overall remission rate was 52.6-97.6%. In four clinical trials on children with lupus nephritis, the overall remission rate was 81.8-89.5%. In a pilot study with paediatric Henoch-Schönlein purpura nephritis patients, the overall remission rate was 100.0%. Infection, nephrotoxicity, gastrointestinal symptoms and hypertension are the most common adverse events. Body weight, age, CYP3A5 genotype, cystatin-C and daily dose of tacrolimus may have significant effects on the pharmacokinetics of tacrolimus in children with glomerular disease. More prospective controlled trials with long follow-up are needed to demonstrate definitely the effectiveness, safety and pharmacokinetics of tacrolimus in children with glomerular diseases.
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Affiliation(s)
- Guo-Xiang Hao
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China
| | - Lin-Lin Song
- Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Dong-Feng Zhang
- Department of Pediatric Nephrology, Children's Hospital of Hebei Province affiliated to Hebei Medical University, Shijiazhuang, China
| | - Le-Qun Su
- Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
| | - Evelyne Jacqz-Aigrain
- Department of Pediatric Pharmacology and Pharmacogenetics, Hôpital Robert Debré, APHP, Paris, France
| | - Wei Zhao
- Department of Clinical Pharmacy, School of Pharmaceutical Sciences, Shandong University, Jinan, China.,Department of Pharmacy, Shandong Provincial Qianfoshan Hospital, the First Hospital Affiliated with Shandong First Medical University, Jinan, China
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16
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Mendoza Rojas A, Hesselink DA, van Besouw NM, Baan CC, van Gelder T. Impact of low tacrolimus exposure and high tacrolimus intra-patient variability on the development of de novo anti-HLA donor-specific antibodies in kidney transplant recipients. Expert Rev Clin Immunol 2019; 15:1323-1331. [PMID: 31721605 DOI: 10.1080/1744666x.2020.1693263] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Introduction: De novo donor-specific antibodies (dnDSA) directed against HLA are a major contributing factor to the chronic deterioration of renal allograft function. Several factors, including the degree of HLA matching, younger recipient age, and past sensitization events have been shown to increase the risk for the development of dnDSA. The development of dnDSA is also strongly associated with modifications in the immunosuppressive regimen, non-adherence, and under-immunosuppression.Areas covered: Tacrolimus is widely used after solid organ transplantation (SOT) and in recent years, both a high intra-patient variability in tacrolimus exposure and low tacrolimus exposure have been found to be associated with a higher risk of dnDSA development in kidney transplant recipients. This article provides an overview of current findings published in the recent 5 years regarding the relationship between tacrolimus exposure and variation therein and the development of dnDSA.Expert opinion: In this review, we describe how combining data on tacrolimus intra-patient variability and mean pre-dose concentration may be an effective tool to identify kidney transplant recipients who are at higher risk of developing dnDSA.
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Affiliation(s)
- Aleixandra Mendoza Rojas
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Nicole M van Besouw
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Carla C Baan
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
| | - Teun van Gelder
- Department of Internal Medicine, Nephrology & Transplantation, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands.,Department of Hospital Pharmacy, Clinical Pharmacology Unit, Erasmus MC, Erasmus University Medical Center, Rotterdam, the Netherlands
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17
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Yan L, Yang ZQ, Shi YY, Ren J, Yang CL, Wan ZL, Bai YJ, Luo LM, Wang LL, Li Y. Effects of Wuzhi Capsules on Blood Concentration of Tacrolimus in Renal Transplant Recipients. Ann Transplant 2019; 24:594-604. [PMID: 31712547 PMCID: PMC6873908 DOI: 10.12659/aot.918980] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2019] [Accepted: 10/02/2019] [Indexed: 02/05/2023] Open
Abstract
BACKGROUND Tacrolimus is a widely used immunosuppressant in renal transplant recipients. It was demonstrated in rats and healthy volunteers that Wuzhi capsules could inhibit metabolism and maintain blood concentration of tacrolimus. However, there are no clinical studies of Wuzhi capsules in renal transplant recipients. This research aimed to assess the effect of Wuzhi capsules on the blood concentration of tacrolimus in renal transplant recipients. MATERIAL AND METHODS A total of 158 Chinese renal transplant recipients receiving tacrolimus with or without Wuzhi capsules were included in this retrospective study. The cohort study included 126 recipients, with 86 recipients receiving Wuzhi capsules (WZCs) and the other 40 recipients not receiving WZCs. Another 32 recipients were involved in a self-control study. RESULTS Dose- and body weight-adjusted trough concentrations (C0/D/W) of tacrolimus in the WZC group were found to be significantly higher than that in the non-WZC group (P<0.05). The improvement of C0/D/W by administration of Wuzhi capsules was more significant in CYP3A5 expressers than in non-expressers following subgroup analysis. Furthermore, the WZC group had a remarkably higher proportion of subjects who reached target tacrolimus concentration than in the non-WZC group, both in CYP3A5 expressers (P=0.01) and non-expressers (P<0.001). Multiple linear regression analysis and self-control analysis confirmed the positive impact of Wuzhi capsules on tacrolimus concentration (P<0.001). CONCLUSIONS Wuzhi capsules can increase tacrolimus trough concentration without adverse effects on allograft function, especially in CYP3A5 expressers. Efficient and convenient immunosuppressive effects on renal transplant recipients can be achieved by treatment including administration of Wuzhi capsules.
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Affiliation(s)
- Lin Yan
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
| | - Zhi-Qiang Yang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
| | - Yun-Ying Shi
- Department of Nephrology, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R. China
| | - Jing Ren
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
| | - Cui-Li Yang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
| | - Zheng-Li Wan
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
| | - Yang-Juan Bai
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
| | - Li-Mei Luo
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
| | - Lan-Lan Wang
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
| | - Yi Li
- Department of Laboratory Medicine, West China Hospital, Sichuan University, Chengdu, Sichuan, P.R.China
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18
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Haase VH. ARNT as a Novel Antifibrotic Target in CKD. Am J Kidney Dis 2018; 73:281-284. [PMID: 30343956 DOI: 10.1053/j.ajkd.2018.08.009] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2018] [Accepted: 08/19/2018] [Indexed: 01/15/2023]
Affiliation(s)
- Volker H Haase
- Department of Medicine, Vanderbilt University Medical Center; and Department of Molecular Physiology and Biophysics and Program in Cancer Biology, Vanderbilt University School of Medicine, Nashville, TN.
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Wettersten N, Maisel AS, Cruz DN. Toward Precision Medicine in the Cardiorenal Syndrome. Adv Chronic Kidney Dis 2018; 25:418-424. [PMID: 30309459 DOI: 10.1053/j.ackd.2018.08.017] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2018] [Revised: 08/21/2018] [Accepted: 08/27/2018] [Indexed: 11/11/2022]
Abstract
Although the field of oncology has made significant steps toward individualized precision medicine, cardiology and nephrology still often use a "one size fits all" approach. This applies to the intersection of the heart-kidney interaction and the cardiorenal syndrome as well. Recent studies have shown that the prognostic implications of worsening renal function (WRF) in acute heart failure are variable; thus, there is a need to differentiate the implications of WRF to better guide precise care. This may best be performed with biomarkers that can give the clinician a real-time evaluation of the physiologic state at the time of developing WRF. This review will summarize current cardiac and renal biomarkers and their status in the evaluation of cardiorenal syndrome. Although we have made progress in our understanding of this syndrome, further investigation is needed to bring precision medicine into routine clinical practice for the care of patients with cardiorenal syndrome.
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Yang L, de Winter BCM, van Schaik RHN, Xie RX, Li Y, Andrews LM, Shuker N, Bahmany S, Koch B, van Gelder T, Hesselink DA. CYP3A5 and ABCB1 polymorphisms in living donors do not impact clinical outcome after kidney transplantation. Pharmacogenomics 2018; 19:895-903. [PMID: 29991328 DOI: 10.2217/pgs-2018-0066] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/05/2023] Open
Abstract
Aim: To investigate the association between donor CYP3A5 and ABCB1 polymorphisms and tacrolimus (Tac)-induced nephrotoxicity and renal function in kidney transplant recipients. Methods: The CYP3A5 6986A>G and ABCB1 3435C>T polymorphisms were determined in 237 recipients and donors. Results: There was no significant association between Tac-related nephrotoxicity and donor CYP3A5 and ABCB1 genotype. The donor ABCB1 3435C>T polymorphism was associated with estimated glomerular filtration rate on day 7 and month 1. The combined donor–recipient ABCB1 genotype (3435C>T polymorphism) was significantly related with estimated glomerular filtration rate on day 3 and 7 in univariate analysis. However, these differences were no longer statistically significant in multivariate analysis. Conclusion: A genetic analysis of ABCB1 and CYP3A5 of kidney transplant donors is not helpful to improve renal transplant outcomes.
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Affiliation(s)
- Lin Yang
- Department of Pharmacy, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, PR China
| | - Brenda CM de Winter
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Ron HN van Schaik
- Department of Clinical Chemistry, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Rui-Xiang Xie
- Department of Pharmacy, Fujian Cancer Hospital & Fujian Medical University Cancer Hospital, Fuzhou, PR China
| | - Yi Li
- Department of Laboratory Medicine, West China Hospital of Sichuan University, Chengdu, PR China
| | - Louise M Andrews
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Nauras Shuker
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Soma Bahmany
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Birgit Koch
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Teun van Gelder
- Department of Hospital Pharmacy, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
- Department of Internal Medicine, Division of Nephrology & Transplantation, Rotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
| | - Dennis A Hesselink
- Department of Internal Medicine, Division of Nephrology & Transplantation, Rotterdam Transplant Group, Erasmus MC, University Medical Center Rotterdam, Rotterdam, The Netherlands
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Analysis of common polymorphisms within NR1I2 and NR1I3 genes and tacrolimus dose-adjusted concentration in stable kidney transplant recipients. Pharmacogenet Genomics 2017; 27:372-377. [DOI: 10.1097/fpc.0000000000000301] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Thölking G, Gerth HU, Schuette-Nuetgen K, Reuter S. Influence of tacrolimus metabolism rate on renal function after solid organ transplantation. World J Transplant 2017; 7:26-33. [PMID: 28280692 PMCID: PMC5324025 DOI: 10.5500/wjt.v7.i1.26] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/05/2016] [Revised: 11/22/2016] [Accepted: 01/14/2017] [Indexed: 02/05/2023] Open
Abstract
The calcineurin inhibitor (CNI) tacrolimus (TAC) is an integral part of the immunosuppressive regimen after solid organ transplantation. Although TAC is very effective in prevention of acute rejection episodes, its highly variable pharmacokinetic and narrow therapeutic window require frequent monitoring of drug levels and dose adjustments. TAC can cause CNI nephrotoxicity even at low blood trough levels (4-6 ng/mL). Thus, other factors besides the TAC trough level might contribute to CNI-related kidney injury. Unfortunately, TAC pharmacokinetic is determined by a whole bunch of parameters. However, for daily clinical routine a simple application strategy is needed. To address this problem, we and others have evaluated a simple calculation method in which the TAC blood trough concentration (C) is divided by the daily dose (D). Fast TAC metabolism (C/D ratio < 1.05) was identified as a potential risk factor for an inferior kidney function after transplantation. In this regard, we recently showed a strong association between fast TAC metabolism and CNI nephrotoxicity as well as BKV infection. Therefore, the TAC C/D ratio may assist transplant clinicians in a simple way to individualize the immunosuppressive regimen.
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Asada A, Bamba S, Morita Y, Takahashi K, Imaeda H, Nishida A, Inatomi O, Sugimoto M, Sasaki M, Andoh A. The effect of CYP3A5 genetic polymorphisms on adverse events in patients with ulcerative colitis treated with tacrolimus. Dig Liver Dis 2017; 49:24-28. [PMID: 27717793 DOI: 10.1016/j.dld.2016.09.008] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/19/2016] [Revised: 07/30/2016] [Accepted: 09/11/2016] [Indexed: 02/08/2023]
Abstract
BACKGROUND Tacrolimus is an immunosuppressive agent, used in the remission induction therapy of ulcerative colitis (UC). AIMS We investigated the correlation between CYP3A5 genetic polymorphisms and the adverse events in patients with UC. The pharmacokinetics of tacrolimus after oral administration were also analyzed. METHODS We enrolled 29 hospitalized patients with UC received oral tacrolimus. Genotyping for CYP3A5 A6986G (rs776746) was performed using Custom TaqMan® SNP genotyping assays. Adverse events, concentration and dose (C/D) ratios and clinical outcomes were investigated. RESULTS CYP3A5 expressers and non-expressers were 16 and 13, respectively. C/D ratios of CYP3A5 expressers were significantly lower compared to non-expressers. The response rate in CYP3A5 non-expressers was relatively higher in the early phase of treatment compared to expressers, but not statistically significant. The incidence of overall adverse events was significantly higher in CYP3A5 expressers than in non-expressers (P=0.034, chi-squared test). In particular, the incidence of nephrotoxicity was significantly higher in CYP3A5 expressers compared to non-expressers (P=0.027, chi-squared test). All of the nephrotoxicity were reversible and resolved by discontinuation or dose reduction of tacrolimus. CONCLUSION The adverse events especially nephrotoxicity were frequently observed in CYP3A5 expressers. CYP3A5 expressers should be paid attention to the onset of nephrotoxicity.
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Affiliation(s)
- Ayumi Asada
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Shigeki Bamba
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan.
| | - Yukihiro Morita
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | | | - Hirotsugu Imaeda
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Atsushi Nishida
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Osamu Inatomi
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | | | - Masaya Sasaki
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
| | - Akira Andoh
- Department of Medicine, Shiga University of Medical Science, Otsu, Japan
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24
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Flahault A, Anglicheau D, Loriot MA, Thervet E, Pallet N. Clinical impact of the CYP3A5 6986A>G allelic variant on kidney transplantation outcomes. Pharmacogenomics 2016; 18:165-173. [PMID: 27977332 DOI: 10.2217/pgs-2016-0146] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
AIM Meta-analyses and large cohort studies provide confusing results on the association of the CYP3A5 6986A>G allelic variant and adverse outcomes in kidney transplant recipients under tacrolimus-based immunosuppressive regimen. A residual effect of CYP3A5 recipient genotype is unexpected if kidney transplant recipients have similar exposure of tacrolimus. PATIENTS & METHODS We have undertaken a population-based, observational study, to investigate all the consecutive patients who received a kidney transplant at the Necker hospital between 2005 and 2015, who were treated with tacrolimus and for whom the CYP3A5 genotype was available. RESULTS & CONCLUSION We analyzed 577 patients followed for up to 5 years. We found a significant association of CYP3A5 genotypes with tacrolimus daily dose as well as with tacrolimus dose-adjusted concentrations. We however found no association of CYP3A5 genotypes with histology scores on biopsies, measured renal function, biopsy-proven acute rejection episodes and graft survival.
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Affiliation(s)
- Adrien Flahault
- College de France, Laboratory of Central Neuropeptides in the Regulation of Body Fluid Homeostasis & Cardiovascular Functions, CIRB, INSERM U1050, Paris, France
| | - Dany Anglicheau
- Paris Descartes University, Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France.,Department of Nephrology & Kidney Transplantation, Necker Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Marie-Anne Loriot
- Paris Descartes University, Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France.,Clinical Chemistry Department, Hôpital Européen Georges Pompidou Assistance Publique Hôpitaux de Paris, Paris, France
| | - Eric Thervet
- Paris Descartes University, Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France.,Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France
| | - Nicolas Pallet
- Paris Descartes University, Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France.,Clinical Chemistry Department, Hôpital Européen Georges Pompidou Assistance Publique Hôpitaux de Paris, Paris, France
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25
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Barcelona Consensus on Biomarker-Based Immunosuppressive Drugs Management in Solid Organ Transplantation. Ther Drug Monit 2016; 38 Suppl 1:S1-20. [PMID: 26977997 DOI: 10.1097/ftd.0000000000000287] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
With current treatment regimens, a relatively high proportion of transplant recipients experience underimmunosuppression or overimmunosuppression. Recently, several promising biomarkers have been identified for determining patient alloreactivity, which help in assessing the risk of rejection and personal response to the drug; others correlate with graft dysfunction and clinical outcome, offering a realistic opportunity for personalized immunosuppression. This consensus document aims to help tailor immunosuppression to the needs of the individual patient. It examines current knowledge on biomarkers associated with patient risk stratification and immunosuppression requirements that have been generally accepted as promising. It is based on a comprehensive review of the literature and the expert opinion of the Biomarker Working Group of the International Association of Therapeutic Drug Monitoring and Clinical Toxicology. The quality of evidence was systematically weighted, and the strength of recommendations was rated according to the GRADE system. Three types of biomarkers are discussed: (1) those associated with the risk of rejection (alloreactivity/tolerance), (2) those reflecting individual response to immunosuppressants, and (3) those associated with graft dysfunction. Analytical aspects of biomarker measurement and novel pharmacokinetic-pharmacodynamic models accessible to the transplant community are also addressed. Conventional pharmacokinetic biomarkers may be used in combination with those discussed in this article to achieve better outcomes and improve long-term graft survival. Our group of experts has made recommendations for the most appropriate analysis of a proposed panel of preliminary biomarkers, most of which are currently under clinical evaluation in ongoing multicentre clinical trials. A section of Next Steps was also included, in which the Expert Committee is committed to sharing this knowledge with the Transplant Community in the form of triennial updates.
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26
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Influence of Donor and Recipient CYP3A4, CYP3A5, and ABCB1 Genotypes on Clinical Outcomes and Nephrotoxicity in Liver Transplant Recipients. Transplantation 2016; 100:2129-2137. [DOI: 10.1097/tp.0000000000001394] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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27
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Pallet N, Etienne I, Buchler M, Bailly E, Hurault de Ligny B, Choukroun G, Colosio C, Thierry A, Vigneau C, Moulin B, Le Meur Y, Heng AE, Legendre C, Beaune P, Loriot MA, Thervet E. Long-Term Clinical Impact of Adaptation of Initial Tacrolimus Dosing to CYP3A5 Genotype. Am J Transplant 2016; 16:2670-5. [PMID: 26990694 DOI: 10.1111/ajt.13788] [Citation(s) in RCA: 49] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2016] [Revised: 02/12/2016] [Accepted: 03/03/2016] [Indexed: 01/25/2023]
Abstract
Pretransplantation adaptation of the daily dose of tacrolimus to CYP3A5 genotype is associated with improved achievement of target trough concentration (C0 ), but whether this improvement affects clinical outcomes is unknown. In the present study, we have evaluated the long-term clinical impact of the adaptation of initial tacrolimus dosing according to CYP3A5 genotype: The transplantation outcomes of the 236 kidney transplant recipients included in the Tactique study were retrospectively investigated over a period of more than 5 years. In the Tactique study, patients were randomly assigned to receive tacrolimus at either a fixed dosage or a dosage determined by their genotype, and the primary efficacy end point was the proportion of patients for whom tacrolimus C0 was within target range (10-15 ng/mL) at day 10. Our results indicate that the incidence of biopsy-proven acute rejection and graft survival were similar between the control and the adapted tacrolimus dose groups, as well as between the patients who achieve the tacrolimus C0 target ranges earlier. Patients' death, cancer, cardiovascular events, and infections were also similar, and renal function did not change. We conclude that optimization of initial tacrolimus dose using pharmacogenetic testing does not improve clinical outcomes.
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Affiliation(s)
- N Pallet
- Clinical Chemistry Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.,Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.,Paris Descartes University, Paris, France.,Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France
| | - I Etienne
- Department of Nephrology-Clinical Immmunology, CHU Rouen, Rouen, France
| | - M Buchler
- Department of Nephrology, CHU Tours, Tours, France
| | - E Bailly
- Department of Nephrology, CHU Tours, Tours, France
| | | | - G Choukroun
- Department of Nephrology, CHU Amiens, Amiens, France
| | - C Colosio
- Department of Nephrology, CHU Reims, Reims, France
| | - A Thierry
- Department of Nephrology, CHU Poitiers, Poitiers, France
| | - C Vigneau
- Department of Nephrology, CHU Rennes, Rennes, France
| | - B Moulin
- Department of Nephrology, CHU Strasbourg, Strasbourg, France
| | - Y Le Meur
- Department of Nephrology, CHU Brest, Brest, France
| | - A-E Heng
- Department of Nephrology, CHU Clermont-Ferrand, Clermont-Ferrand, France
| | - C Legendre
- Department of Nephrology, Necker Hospital, Assistance Publique Hôpitaux de Paris, Paris, France
| | - P Beaune
- Clinical Chemistry Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.,Paris Descartes University, Paris, France.,Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France
| | - M A Loriot
- Clinical Chemistry Department, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.,Paris Descartes University, Paris, France.,Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France
| | - E Thervet
- Department of Nephrology, Hôpital Européen Georges Pompidou, Assistance Publique Hôpitaux de Paris, Paris, France.,Paris Descartes University, Paris, France.,Sorbonne Paris Cité, INSERM UMRS 1147, Paris, France
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28
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Which Genetic Determinants Should be Considered for Tacrolimus Dose Optimization in Kidney Transplantation? A Combined Analysis of Genes Affecting the CYP3A Locus. Ther Drug Monit 2016; 37:288-95. [PMID: 25271728 DOI: 10.1097/ftd.0000000000000142] [Citation(s) in RCA: 41] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
BACKGROUND Tacrolimus is established as immunosuppressant after kidney transplantation. Polymorphism of the cytochrome P450 3A5 (CYP3A5) gene contributes significantly to tacrolimus dose requirements. Recently, CYP3A4*22 was reported to additionally affect tacrolimus pharmacokinetics (PK). In addition, there are further polymorphic genes, possibly influencing CYP3A activity [pregnane x receptor NR1I2, P450 oxidoreductase (POR), and peroxisome proliferator-activator receptor alpha (PPARA)]. We aimed to investigate combined effects of these gene variants on tacrolimus maintenance dose and PK in patients with stable kidney transplantation of 2 study centers. METHODS A total of 223 white patients (German cohort, 136; Danish cohort, 87) was included and genotyped for CYP3A5 (rs776746), CYP3A4 (rs35599367), NR1I2 (rs2276707), POR (rs1057868), and PPARA (rs4253728). Dosage and trough concentration/dose ratios were considered separately. A subset was investigated for comprehensive PK parameters. RESULTS Tacrolimus dose, trough concentration, and trough concentration/dose ratio did not differ between the German and Danish cohort. CYP3A5*3 and CYP3A4*22 contributed to dose requirements only in the German and in the total cohort. Homozygous carriers of both variants required 4.8 ± 3.1 mg, whereas carriers of the wild types required 165% higher mean tacrolimus doses (12.5 ± 7.7 mg, P = 1.4 × 10). The PK investigation revealed only nonsignificant impact of CYP3A4 genotypes on AUC12h in CYP3A5 nonexpressers (P = 0.079, power = 57%). For the entire sample, the final multiple linear regression model for trough concentration/dose ratio included CYP3A5, CYP3A4, and age. It explained 18.3% of the interindividual variability of tacrolimus trough concentration/dose ratios (P = 8.8 × 10). CONCLUSIONS Therapeutic drug monitoring remains essential in clinical care of patients with kidney transplantation. Genotyping of CYP3A5 and CYP3A4, however, could facilitate rapid dose finding to adapt the appropriate immunosuppressant dose, whereas other genetic factors had only little or no effect.
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29
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Pharmacogenetic Biomarkers Predictive of the Pharmacokinetics and Pharmacodynamics of Immunosuppressive Drugs. Ther Drug Monit 2016; 38 Suppl 1:S57-69. [DOI: 10.1097/ftd.0000000000000255] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
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30
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Clark SL, Taylor A, Shaw KN, Copelovitch L. Making every drop count for pediatric kidney transplant patients. Hosp Pediatr 2015; 5:287-9. [PMID: 25934814 DOI: 10.1542/hpeds.2014-0146] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Affiliation(s)
- Stephanie L Clark
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and
| | - April Taylor
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and
| | - Kathy N Shaw
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
| | - Lawrence Copelovitch
- Department of Pediatrics, Children's Hospital of Philadelphia, Philadelphia, Pennsylvania; and Perelman School of Medicine at the University of Pennsylvania, Philadelphia, Pennsylvania
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31
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Naito T, Mino Y, Aoki Y, Hirano K, Shimoyama K, Ogawa N, Kagawa Y, Kawakami J. ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affect renal function in patients with rheumatoid arthritis. Clin Chim Acta 2015; 445:79-84. [PMID: 25817604 DOI: 10.1016/j.cca.2015.03.021] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2015] [Accepted: 03/18/2015] [Indexed: 01/16/2023]
Abstract
BACKGROUND This study aimed to evaluate the blood exposure of and clinical responses to tacrolimus based on genetic variants of CYP3A5 and ABCB1 in patients with rheumatoid arthritis. METHODS Seventy rheumatoid arthritis patients treated with oral tacrolimus once daily were enrolled. Blood concentrations of tacrolimus and its major metabolite 13-O-demethylate at 12h after dosing were determined. The relationships between the tacrolimus pharmacokinetics and efficacy, renal function, and CYP3A5 and ABCB1 genotypes were evaluated. RESULTS Dose-normalized blood concentration of tacrolimus was significantly higher in the CYP3A5*3/*3 group than in the *1 allele carrier group. A lower metabolic ratio of 13-O-demethylate to tacrolimus was observed in the CYP3A5*3/*3 group. The ABCB1 3435TT group had higher dose-normalized blood concentrations of tacrolimus and 13-O-demethylate. The blood tacrolimus concentration was inversely correlated with the estimated glomerular filtration rate (eGFR). ABCB1 C3435T but not CYP3A5 genotype had decreased eGFR. Patients lacking the CYP3A5*3 allele had a higher incidence of tacrolimus withdrawal. CONCLUSION CYP3A5*3 increased the blood exposure of tacrolimus through its metabolic reduction. ABCB1 C3435T led to a higher blood exposure of tacrolimus and its major metabolite. The ABCB1 genetic variant and its associated tacrolimus pharmacokinetics affected renal function in rheumatoid arthritis patients.
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Affiliation(s)
- Takafumi Naito
- Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan.
| | - Yasuaki Mino
- Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yuki Aoki
- Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan; Department of Clinical Pharmaceutics and Pharmacy Practice, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka, Japan
| | - Kumi Hirano
- Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Kumiko Shimoyama
- Department of Rheumatology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Noriyoshi Ogawa
- Department of Rheumatology, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
| | - Yoshiyuki Kagawa
- Department of Clinical Pharmaceutics and Pharmacy Practice, Graduate School of Pharmaceutical Sciences, University of Shizuoka, Shizuoka, Shizuoka, Japan
| | - Junichi Kawakami
- Department of Hospital Pharmacy, Hamamatsu University School of Medicine, Hamamatsu, Shizuoka, Japan
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Giri S, Bader A. A low-cost, high-quality new drug discovery process using patient-derived induced pluripotent stem cells. Drug Discov Today 2014; 20:37-49. [PMID: 25448756 DOI: 10.1016/j.drudis.2014.10.011] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2014] [Revised: 07/23/2014] [Accepted: 10/23/2014] [Indexed: 02/07/2023]
Abstract
Knockout, knock-in and conditional mutant gene-targeted mice are routinely used for disease modeling in the drug discovery process, but the human response is often difficult to predict from these models. It is believed that patient-derived induced pluripotent stem cells (iPSCs) could replace millions of animals currently sacrificed in preclinical testing and provide a route to new safer pharmaceutical products. In this review, we discuss the use of IPSCs in the drug discovery process. We highlight how they can be used to assess the toxicity and clinical efficacy of drug candidates before the latter are moved into costly and lengthy preclinical and clinical trials.
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Affiliation(s)
- Shibashish Giri
- Centre for Biotechnology and Biomedicine, Department of Cell Techniques and Applied Stem Cell Biology, Medical Faculty of University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany.
| | - Augustinus Bader
- Centre for Biotechnology and Biomedicine, Department of Cell Techniques and Applied Stem Cell Biology, Medical Faculty of University of Leipzig, Deutscher Platz 5, 04103 Leipzig, Germany
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Cuenca AB, Citores MJ, de la Fuente S, Duca AM, Escamilla N, Baños I, Cuervas-Mons V. TT genotype of transforming growth factor beta1 +869C/T is associated with the development of chronic kidney disease after liver transplantation. Transplant Proc 2014; 46:3108-3110. [PMID: 25420836 DOI: 10.1016/j.transproceed.2014.10.002] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023]
Abstract
BACKGROUND Chronic kidney disease (CKD) is a frequent complication in patients with liver transplantation (LT), and calcineurin inhibitor chronic nephrotoxicity, mediated by transforming growth factor beta1 (TGF-β1) is an important contributing factor. The aim of this study was to assess the influence of genetic polymorphisms of TGF-β1 in the development of CKD at 6 months after transplantation. METHODS One hundred sixty-four LT patients (63.4% male; overall mean age, 48.7 ± 11.6 years) were included in the analysis. CKD was considered at the 6th month after LT and was defined as an estimated glomerular filtration rate (eGFR) of <60 mL/min/1.73 m(2) as calculated on the basis of Modification of Diet in Renal Disease 4-variable equation. TGF-β1 +869 C/T and +915 G/C polymorphisms were analyzed with the use of hybridization with fluorescent probes and analysis by means of flow cytometry with the Luminex system. The association between the presence of CKD at 6 months and these polymorphisms, as well as with other known risk factors for CKD after LT, was considered. RESULTS In the univariate analysis, the TT genotype of TGF-β1 +869 (P = .036; odds ratio, 2.1; 95% confidence interval, 1.1-4.2), age at LT (P < .001), pre-transplantation serum creatinine levels (P = .03), eGFR (P < .001), CKD (P = .027), and immunosuppression with cyclosporine (P = .017) were associated with CKD at 6 months after transplantation. In the multivariate analysis, TGF-β1 +869TT genotype (P = .017), immunosuppression with cyclosporine (P = .002), age at LT (P = .024), and pre-transplantation CKD (P < .001) remained as independent variables associated with the development of CKD at 6 months after transplantation. CONCLUSIONS The genetic polymorphism TGF-β1 +869 C/T may be an independent risk factor for CKD after liver transplantation.
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Affiliation(s)
- A B Cuenca
- Departamento de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de investigación sanitaria Hospital Puerta de Hierro Majadahonda (IDIPHIM) Madrid, Spain.
| | - M J Citores
- Departamento de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de investigación sanitaria Hospital Puerta de Hierro Majadahonda (IDIPHIM) Madrid, Spain
| | - S de la Fuente
- Departamento de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de investigación sanitaria Hospital Puerta de Hierro Majadahonda (IDIPHIM) Madrid, Spain
| | - A M Duca
- Unidad de Trasplante Hepatico, Departamento de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de investigación sanitaria Hospital Puerta de Hierro Majadahonda (IDIPHIM), Madrid, Spain
| | - N Escamilla
- Unidad de Trasplante Hepatico, Departamento de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de investigación sanitaria Hospital Puerta de Hierro Majadahonda (IDIPHIM), Madrid, Spain
| | - I Baños
- Unidad de Trasplante Hepatico, Departamento de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de investigación sanitaria Hospital Puerta de Hierro Majadahonda (IDIPHIM), Madrid, Spain
| | - V Cuervas-Mons
- Unidad de Trasplante Hepatico, Departamento de Medicina Interna, Hospital Universitario Puerta de Hierro Majadahonda, Instituto de investigación sanitaria Hospital Puerta de Hierro Majadahonda (IDIPHIM), Madrid, Spain
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Tsuchimoto A, Shinke H, Uesugi M, Kikuchi M, Hashimoto E, Sato T, Ogura Y, Hata K, Fujimoto Y, Kaido T, Kishimoto J, Yanagita M, Matsubara K, Uemoto S, Masuda S. Urinary neutrophil gelatinase-associated lipocalin: a useful biomarker for tacrolimus-induced acute kidney injury in liver transplant patients. PLoS One 2014; 9:e110527. [PMID: 25329716 PMCID: PMC4203804 DOI: 10.1371/journal.pone.0110527] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/05/2014] [Accepted: 09/23/2014] [Indexed: 12/17/2022] Open
Abstract
Tacrolimus is widely used as an immunosuppressant in liver transplantation, and tacrolimus-induced acute kidney injury (AKI) is a serious complication of liver transplantation. For early detection of AKI, various urinary biomarkers such as monocyte chemotactic protein-1, liver-type fatty acid-binding protein, interleukin-18, osteopontin, cystatin C, clusterin and neutrophil gelatinase-associated lipocalin (NGAL) have been identified. Here, we attempt to identify urinary biomarkers for the early detection of tacrolimus-induced AKI in liver transplant patients. Urine samples were collected from 31 patients after living-donor liver transplantation (LDLT). Twenty recipients developed tacrolimus-induced AKI. After the initiation of tacrolimus therapy, urine samples were collected on postoperative days 7, 14, and 21. In patients who experienced AKI during postoperative day 21, additional spot urine samples were collected on postoperative days 28, 35, 42, 49, and 58. The 8 healthy volunteers, whose renal and liver functions were normal, were asked to collect their blood and spot urine samples. The urinary levels of NGAL, monocyte chemotactic protein-1 and liver-type fatty acid-binding protein were significantly higher in patients with AKI than in those without, while those of interleukin-18, osteopontin, cystatin C and clusterin did not differ between the 2 groups. The area under the receiver operating characteristics curve of urinary NGAL was 0.876 (95% confidence interval, 0.800–0.951; P<0.0001), which was better than those of the other six urinary biomarkers. In addition, the urinary levels of NGAL at postoperative day 1 (p = 0.0446) and day 7 (p = 0.0006) can be a good predictive marker for tacrolimus-induced AKI within next 6 days, respectively. In conclusion, urinary NGAL is a sensitive biomarker for tacrolimus-induced AKI, and may help predict renal event caused by tacrolimus therapy in liver transplant patients.
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Affiliation(s)
- Ayami Tsuchimoto
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Haruka Shinke
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Miwa Uesugi
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Mio Kikuchi
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
- Department of Pharmacy, Kagawa University Hospital, Kagawa, Japan
| | - Emina Hashimoto
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Tomoko Sato
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Yasuhiro Ogura
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Koichiro Hata
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Yasuhiro Fujimoto
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Toshimi Kaido
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Junji Kishimoto
- Department of Research and Development of Next Generation Medicine, Faculty of Medical Sciences, Kyushu University, Fukuoka, Japan
| | - Motoko Yanagita
- Department of Nephrology, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Kazuo Matsubara
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
| | - Shinji Uemoto
- Division of Hepatobiliary-Pancreatic Surgery and Transplantation, Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto, Japan
| | - Satohiro Masuda
- Department of Clinical Pharmacology and Therapeutics, Kyoto University Hospital, Kyoto, Japan
- * E-mail:
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Personalized tacrolimus dose requirement by CYP3A5 but not ABCB1 or ACE genotyping in both recipient and donor after pediatric liver transplantation. PLoS One 2014; 9:e109464. [PMID: 25310192 PMCID: PMC4195667 DOI: 10.1371/journal.pone.0109464] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/02/2014] [Accepted: 09/10/2014] [Indexed: 12/20/2022] Open
Abstract
Tacrolimus (TAC) is the backbone of an immunosuppressive drug used in most solid organ transplant recipients. A single nucleotide polymorphism (SNP) at position 6986G>A in CYP3A5 has been notably involved in the pharmacokinetic variability of TAC. It is hypothesized that CYP3A5 genotyping in patients may provide a guideline for TAC therapeutic regimen. To further evaluate the impact of CYP3A5 variants in donors and recipients, ABCB1 and ACE SNPs in recipients on TAC disposition, clinical and laboratory data were retrospectively reviewed from 90 pediatric patients with liver transplantation and their corresponding donors after 1 year of transplantation. The recipients with CYP3A5 *1/*1 or *1/*3 required more time to achieve TAC therapeutic range during the induction phase, and needed more upward dose during the late induction and the maintained phases, with lower C/D ratio, compared with those with CYP3A5 *3/*3. And donor CYP3A5 genotypes were found to impact on TAC trough concentrations after liver transplantation. No association between ABCB1 or ACE genotypes and TAC disposition post-transplantation was found. These results strongly suggest that CYP3A5 genotyping both in recipient and donor, not ABCB1 or ACE is necessary for establishing a personalized TAC dosage regimen in pediatric liver transplant patients.
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Rojas L, Neumann I, Herrero MJ, Bosó V, Reig J, Poveda JL, Megías J, Bea S, Aliño SF. Effect of CYP3A5*3 on kidney transplant recipients treated with tacrolimus: a systematic review and meta-analysis of observational studies. THE PHARMACOGENOMICS JOURNAL 2014; 15:38-48. [PMID: 25201288 DOI: 10.1038/tpj.2014.38] [Citation(s) in RCA: 104] [Impact Index Per Article: 9.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 12/16/2013] [Revised: 03/26/2014] [Accepted: 06/04/2014] [Indexed: 12/21/2022]
Abstract
The highly variable pharmacokinetics of tacrolimus can hamper the optimal management of kidney transplant patients. This variability has been attributed to the genetic polymorphism of CYP3A5 6986A>G, but the evidence is not clear. We conducted a meta-analysis of studies evaluating the effect of CYP3A5 polymorphism on kidney transplant recipients with tacrolimus plasma concentration divided by daily dose per body weight (C/D) and clinical outcomes. We searched in MEDLINE and EMBASE. We found evidence suggesting a significantly lower C/D among CYP3A5*1 allele carriers compared with carriers of the CYP3A5*3/*3 genotype at weeks 1 and 2, and months 1, 3, 6 and 12. We demonstrated that the expresser genotype might have higher risk of acute rejection and chronic nephrotoxicity. In conclusion, CYP3A5 6986A>G polymorphism can affect tacrolimus pharmacokinetics and the incidence of acute rejection and chronic nephrotoxicity on kidney transplant recipients. Patients at high risk of developing tacrolimus-related complications could be detected even before their kidney transplant.
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Affiliation(s)
- L Rojas
- 1] Department of Internal Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile [2] Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - I Neumann
- 1] Department of Internal Medicine, Faculty of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile [2] Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, Ontario, Canada
| | - M José Herrero
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - V Bosó
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - J Reig
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - J Luis Poveda
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - J Megías
- Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain
| | - S Bea
- Nephrology Department, Kidney transplant Unit, Hospital Universitari i Politècnic La Fe, Valencia, Spain
| | - S F Aliño
- 1] Pharmacogenetic Unit, Drug Clinical Area, Hospital Universitari i Politècnic, La Fe and Instituto de Investigación Sanitaria La Fe, Valencia, Spain [2] Clinical Pharmacology Unit, Drug Clinical Area, Hospital Universitari i Politècnic La Fe, Valencia, Spain [3] Department of Pharmacology, Faculty of Medicine, University of Valencia, Valencia, Spain
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Fujinaga K, Usui M, Yamamoto N, Ishikawa E, Nakatani A, Kishiwada M, Mizuno S, Sakurai H, Tabata M, Isaji S. Hypertension and Hepatitis C Virus Infection Are Strong Risk Factors for Developing Late Renal Dysfunction After Living Donor Liver Transplantation: Significance of Renal Biopsy. Transplant Proc 2014; 46:804-810. [PMID: 24767353 DOI: 10.1016/j.transproceed.2013.11.103] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 11/22/2013] [Indexed: 02/07/2023]
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38
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Xue F, Han L, Chen Y, Xi Z, Li Q, Xu N, Xia Y, Streicher K, Zhang J, Xia Q. CYP3A5 genotypes affect tacrolimus pharmacokinetics and infectious complications in Chinese pediatric liver transplant patients. Pediatr Transplant 2014; 18:166-76. [PMID: 24438215 DOI: 10.1111/petr.12216] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 12/02/2013] [Indexed: 12/01/2022]
Abstract
Little information is available regarding the impact of cytochrome P450 (CYP) 3A5 on the metabolism of TAC in infant LTx. Therefore, the CYP3A5 genotype of Chinese pediatric recipients (intestine) as well as donors (graft liver) was performed for the purpose of establishing an optimal dosage regimen in children. Sixty-four patients were divided according to CYP3A5 genotype (expression of *1 allele: EX and NEX) for each recipient (R) and donor (D), EX-R/EX-D (n = 21), EX-R/NEX-D (n = 8), NEX-R/EX-D (n = 8) and NEX-R/NEX-D (n = 27). Results indicated that initial TAC daily dose requirement was higher among EX-R/EX-D children compared with those who did not express CYP3A5 (0.28 ± 0.10 vs. 0.19 ± 0.08 mg/kg/day, p < 0.01). CYP3A5 expression contributed an overall of 38.35% to its C/D ratios, and graft liver was a key determinant. Additionally, the EX-R/EX-D group showed significantly higher incidence of infectious complications, lower immune response and was an independent risk factor for the development of infections (odds ratio 3.86, p = 0.025). Donor CYP3A5 expression partially explains TAC dose requirement, the effect of CYP3A5 variation may influence clinical outcomes; therefore, monitoring immune response may be important for preventing risks associated with under- and over-immunosuppression.
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Affiliation(s)
- Feng Xue
- Department of Liver Surgery and Liver Transplantation, Shanghai Jiao-tong University School of Medicine, Renji Hospital, Shanghai, China
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Stefan CP, Cunningham KW. Kch1 family proteins mediate essential responses to endoplasmic reticulum stresses in the yeasts Saccharomyces cerevisiae and Candida albicans. J Biol Chem 2013; 288:34861-70. [PMID: 24142703 DOI: 10.1074/jbc.m113.508705] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022] Open
Abstract
The activation of a high affinity Ca(2+) influx system (HACS) in the plasma membrane is required for survival of yeast cells exposed to natural or synthetic inhibitors of essential processes (secretory protein folding or sterol biosynthesis) in the endoplasmic reticulum (ER). The mechanisms linking ER stress to HACS activation are not known. Here we show that Kch1, a recently identified low affinity K(+) transporter in the plasma membrane of Saccharomyces cerevisiae, is up-regulated in response to several ER stressors and necessary for HACS activation. The activation of HACS required extracellular K(+) and was also dependent on the high affinity K(+) transporters Trk1 and Trk2. However, a paralog of Kch1 termed Kch2 was not expressed and not necessary for HACS activation in these conditions. The pathogenic yeast Candida albicans carries only one homolog of Kch1/Kch2, and homozygous knock-out mutants were similarly deficient in the activation of HACS during the responses to tunicamycin. However, the Kch1 homolog was not necessary for HACS activation or cell survival in response to several clinical antifungals (azoles, allylamines, echinocandins) that target the ER or cell wall. Thus, Kch1 family proteins represent a conserved linkage between HACS and only certain classes of ER stress in these yeasts.
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Affiliation(s)
- Christopher P Stefan
- From the Department of Biology, The Johns Hopkins University, Baltimore, Maryland 21218
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40
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Liu YY, Li C, Cui Z, Fu X, Zhang S, Fan LL, Ma J, Li G. The effect of ABCB1 C3435T polymorphism on pharmacokinetics of tacrolimus in liver transplantation: a meta-analysis. Gene 2013; 531:476-88. [PMID: 24042126 DOI: 10.1016/j.gene.2013.09.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2013] [Revised: 09/05/2013] [Accepted: 09/06/2013] [Indexed: 01/16/2023]
Abstract
OBJECTIVES The effect of ABCB1 C3435T SNP on the pharmacokinetics of immunosuppressive drug tacrolimus in different studies was conflicting. So a meta-analysis was employed to study the correlation of ABCB1 C3435T SNP and the pharmacokinetics of tacrolimus at different post-transplantation times. METHOD Several studies about ABCB1 C3435T polymorphism and the pharmacokinetics of tacrolimus were collected through the search on PubMed and the Cochrane Library. After the extraction of pharmacokinetic parameters from these studies, a meta-analysis was performed on the software STATA version 11.0. RESULTS A total of 9 studies were adopted including 558 liver transplant recipients. For the dose of tacrolimus, the subjects with wild-type CC had a significantly higher tacrolimus dose than homozygous mutated genotype TT within 1 week (WMD=0.01 (0.00, 0.02), P=0.014) and the similar result in recipients with heterozygous CT compared with TT after transplantation for 1 month (WMD=0.01 (0.00, 0.02), P=0.002). For the tacrolimus concentration/dose ratio, subjects with CT had higher C/D ratio than those with CC and TT at different post-transplantation times. A subgroup analysis based on different ethnic populations was also carried out. Donors' genotypes were also considered in this meta-analysis. CONCLUSION Through this meta-analysis for the including studies about the pharmacokinetics of tacrolimus and ABCB1 C3435T SNP, several significant associations were obtained. Particularly, the Caucasians showed more significant associations between the C/D ratio and ABCB1 C3435T polymorphism; however, the correlations were not steady at different post-transplantation times.
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Affiliation(s)
- Yuan-Yuan Liu
- Department of Health Statistics, School of Public Health, Tianjin Medical University, 22 Qi-Xiang-Tai Road, Heping District, Tianjin 300070, China
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Menon MC, Murphy B. Maintenance immunosuppression in renal transplantation. Curr Opin Pharmacol 2013; 13:662-71. [PMID: 23731524 DOI: 10.1016/j.coph.2013.05.004] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Accepted: 05/03/2013] [Indexed: 12/28/2022]
Abstract
The need to maintain allograft recipients on immunosuppression is nearly universal. Immunosuppressive agents used in organ transplantation target one or more steps of the host alloimmune response, specifically processes related to CD4-positive T lymphocytes. Calcineurin-inhibitor based steroid-containing regimens have been the mainstay of maintenance immunosuppression over the last two decades. Newer agents have shown efficacy in this role in recent trials with comparable allograft and patient outcomes. These agents have permitted calcineurin-inhibitor minimization and steroid-sparing strategies in selected groups of patients.
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Affiliation(s)
- Madhav C Menon
- Ichan School of Medicine at Mount Sinai, New York, United States
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Quaglia M, Terrazzino S, Boldorini R, Stratta P, Genazzani AA. Severe acute nephrotoxicity in a kidney transplant patient despite low tacrolimus levels: a possible interaction between donor and recipient genetic polymorphisms. J Clin Pharm Ther 2013; 38:333-6. [PMID: 23574377 DOI: 10.1111/jcpt.12066] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2012] [Accepted: 03/20/2013] [Indexed: 12/01/2022]
Abstract
WHAT IS KNOWN AND OBJECTIVE Tacrolimus has a narrow therapeutic index and shows large interindividual variations in pharmacokinetics, which may be partly explained by genetic variability in metabolic enzymes of the cytochrome P450 (mainly CYP3A4 and CYP3A5) and transport P-glycoprotein (encoded by the ABCB1 gene). Genetic variability in the expression of biotransformation enzymes and drug transporters may also predispose individuals to tacrolimus-induced nephrotoxicity. CASE SUMMARY We report a case of severe biopsy-proven Tacrolimus (TAC) nephrotoxicity that occurred 1 month after renal transplantation despite persistently low TAC levels. The donor genotype was CYP3A5*3/*3 (loss-of-function genotype), whereas that of the recipient was CYP3A5*1/*3. The donor and recipient genotypes did not differ with respect to either CYP3A4 rs35599367C>T (both were CC homozygotes) or ABCB1 gene polymorphisms (both TT homozygotes for the 1236C>T polymorphism and CT heterozygotes for the 3435C>T polymorphism). WHAT IS NEW AND CONCLUSION This case study suggests that donor/recipient genetic mismatch in metabolic enzymes may have an important role in modulating tacrolimus nephrotoxicity. It provides a possible explanation for the intriguing observation that for a subset of patients, cumulative TAC doses appear to correlate better with nephrotoxicity than trough levels.
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Affiliation(s)
- M Quaglia
- Nefrologia e Trapianto, Dipartimento di Medicina Traslazionale & Interdisciplinary Research Center Autoimmune Disease (IRCAD), Università del Piemonte Orientale A. Avogadro, Novara, Italy.
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