Gut Microbiota and Tacrolimus Trough Variability in Kidney Transplant Recipients

肾移植受者的肠道微生物群和他克莫司谷变异性

• 批准号: 10575456
• 负责人: Hyunyoung Jeong
• 金额: $ 26.15万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2025-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10575456
• 关键词: Acute; Biological Markers; Blood; Clinical; Clinical Research; Collection; Development; End stage renal failure; Immunologics; Immunosuppressive Agents; In Vitro; Individual; Kidney Transplantation; Life; Measurement; Metabolism; Monitor; Oral Administration; Organism; Outcome; Parents; Patients; Pharmaceutical Preparations; Pilot Projects; Population; Predictive Factor; Procedures; Production; Research Design; Risk; Specimen; Study Section; Tacrolimus; Therapeutic; Therapeutic immunosuppression; Transplant Recipients; Transplantation; Work; bacterial metabolism; blood-based biomarker; donor-specific antibody; gut microbes; gut microbiome; gut microbiota; high risk; improved; in vivo; metagenomic sequencing; nephrotoxicity; neurotoxicity; novel strategies; patient variability; personalized approach; predictive marker; prevent; recruit; secondary analysis

PROJECT SUMMARY Kidney transplantation is a life-saving procedure for patients with end-stage renal disease. Tacrolimus is utilized to prevent rejection of the kidney transplant but has a narrow therapeutic window with subtherapeutic tacrolimus levels associated with acute rejection and supratherapeutic levels associated with nephrotoxicity and neurotoxicity. Importantly, kidney transplant recipients with tacrolimus trough variability, i.e. marked intra-patient variation in tacrolimus trough levels, are at increased risk for acute rejection and kidney transplant loss. The factors predicting intra-patient tacrolimus trough variability, however, are not well understood. Our preliminary studies support a relationship between gut bacterial metabolism of tacrolimus and tacrolimus trough variability. The overall objective of this study is to define the relationship between the gut microbiota and tacrolimus trough variability in kidney transplant recipients. Our central hypothesis is that specific gut microbial species are associated with metabolism of tacrolimus and intra-patient tacrolimus trough variability. The hypothesis is based upon and inspired by our pilot studies: (1) Faecalibacterium, Blautia, and other commensal organisms directly metabolize tacrolimus into M1, a lesser active tacrolimus metabolite (2) M1 production is present in the fecal specimens of kidney transplant recipients (3) blood M1 is detected in kidney transplant recipients after oral administration of tacrolimus (Guo et al., Drug Metabo Dispos 47(3):194-202, 2019; Guo et al., Transplant Direct 6(10):e601, 2020). In this study, we will recruit 80 kidney transplant recipients for serial collection of fecal specimens during the first 3 months following transplantation and will profile the gut microbiome using metagenomic sequencing. As in vivo biomarkers of bacterial tacrolimus metabolism, we will profile blood M1 (the bacterial tacrolimus metabolite) levels and quantitative fecal M1 production to assess their relationships with intra-patient tacrolimus trough variability as well as acute rejection and de novo donor specific antibody development against the kidney transplant. In Aim 1, we will identify the gut bacterial species associated with tacrolimus metabolism. In Aim 2, we will determine the gut bacterial and blood profiles associated with intra-patient tacrolimus trough variability. Significance. Our study will enable development of gut-based and blood-based biomarkers to identify kidney transplant recipients at high risk for tacrolimus trough variability. Our study will provide the framework for providing improved precision delivery of immunosuppressive therapies in kidney transplant recipients.

项目总结