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Principal Investigator: Hyunyoung Jeong
Organization: WEILL MEDICAL COLL OF CORNELL UNIV
Fiscal Year: 2024
Award: $201,725
Funding agency: National Institute of Allergy and Infectious Diseases
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.
Terms: <Acute><Anti-Rejection Therapy><Biological Markers><Blood><Blood Reticuloendothelial System><Clinical><Clinical Research><Clinical Study><Collection><Development><Drugs><ESRD><End stage renal failure><End-Stage Kidney Disease><End-Stage Renal Disease><GI microbiome><GI microbiota><Gastrointestinal microbiota><Immunochemical Immunologic><Immunologic><Immunological><Immunologically><Immunologics><Immunosuppressants><Immunosuppressive Agents><Immunosuppressive Therapy><Immunosuppressive drug><Immunosuppressive treatment><In Vitro><Individual><Intermediary Metabolism><Kidney Grafting><Kidney Transplantation><Kidney Transplants><Life><Measurement><Medication><Metabolic Processes><Metabolism><Monitor><Nephrotoxic><Oral Administration><Oral Drug Administration><Organism><Outcome><Parents><Patients><Personalized medical approach><Pharmaceutical Preparations><Pilot Projects><Population><Predictive Factor><Procedures><Production><Renal Grafting><Renal Transplantation><Renal Transplants><Research Design><Research Specimen><Risk><Specimen><Study Section><Study Type><Tacrolimus><Therapeutic><Therapeutic immunosuppression><Transplant Recipients><Transplantation><Work><artificial immunosuppression><bacteria metabolism><bacterial metabolism><bio-markers><biologic marker><biomarker><blood-based biomarker><blood-based marker><developmental><digestive tract microbiome><donor antibodies><donor-specific antibody><drug/agent><enteric microbial community><enteric microbiome><enteric microbiota><gastrointestinal microbial flora><gastrointestinal microbiome><gut commensal><gut community><gut flora><gut microbe community><gut microbes><gut microbial community><gut microbial composition><gut microbial consortia><gut microbial species><gut microbiome><gut microbiota><gut microbiotic><gut microflora><gut-associated microbiome><high risk><immune suppressive agent><immune suppressor><immunosuppression therapy><immunosuppressive substance><immunosuppressor><improved><in vivo><individualized approach><intestinal biome><intestinal flora><intestinal microbes><intestinal microbiome><intestinal microbiota><intestinal microflora><intestinal tract microflora><intraoral drug delivery><kidney toxicity><kidney tx><living system><metagenome sequencing><metagenomic sequencing><nephrotoxicity><neuron toxicity><neuronal toxicity><neurotoxicity><new approaches><novel approaches><novel strategies><novel strategy><parent><patient variability><patient variation><personalized approach><pilot study><precision approach><predictive biomarkers><predictive marker><predictive molecular biomarker><prevent><preventing><recruit><secondary analysis><study design><tailored approach><transplant><transplant patient><variability between patients><variation between patients>