학술논문
Rationale and Design of a Phase 2, Double-blind, Placebo-Controlled, Randomized Trial Evaluating AMP Kinase-Activation by Metformin in Focal Segmental Glomerulosclerosis.
Document Type
Academic Journal
Author
Barsotti GC; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Luciano R; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Kumar A; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Meliambro K; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Kakade V; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Tokita J; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Naik A; Division of Nephrology, Department of Internal Medicine, University of Michigan School of Medicine, Ann Arbor, Michigan, USA.; Fu J; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Peck E; Clinical Research Coordinator, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Pell J; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Reghuvaran A; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Tanvir EM; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Patel P; Investigational Drug Service, Department of Pharmacy Services, Yale New Haven Hospital, Connecticut, USA.; Zhang W; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Li F; Department of Biostatistics, Yale School of Public Health, New Haven, Connecticut, USA.; Moeckel G; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.; Perincheri S; Department of Pathology, Yale School of Medicine, New Haven, Connecticut, USA.; Cantley L; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Moledina DG; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; Wilson FP; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.; He JC; Division of Nephrology, Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, New York, USA.; Menon MC; Section of Nephrology, Department of Medicine, Yale University School of Medicine, New Haven, Connecticut, USA.
Source
Publisher: Elsevier Country of Publication: United States NLM ID: 101684752 Publication Model: eCollection Cited Medium: Internet ISSN: 2468-0249 (Electronic) Linking ISSN: 24680249 NLM ISO Abbreviation: Kidney Int Rep Subsets: PubMed not MEDLINE
Subject
Language
English
Abstract
Introduction: Focal segmental glomerulosclerosis (FSGS), the most common primary glomerular disease leading to end-stage kidney disease (ESKD), is characterized by podocyte injury and depletion, whereas minimal change disease (MCD) has better outcomes despite podocyte injury. Identifying mechanisms capable of preventing podocytopenia during injury could transform FSGS to an "MCD-like" state. Preclinical data have reported conversion of an MCD-like injury to one with podocytopenia and FSGS by inhibition of AMP-kinase (AMPK) in podocytes. Conversely, in FSGS, AMPK-activation using metformin (MF) mitigated podocytopenia and azotemia. Observational studies also support beneficial effects of MF on proteinuria and chronic kidney disease (CKD) outcomes in diabetes. A randomized controlled trial (RCT) to test MF in podocyte injury with FSGS has not yet been conducted.
Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies.
Results and Conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.
(© 2024 International Society of Nephrology. Published by Elsevier Inc.)
Methods: We report the rationale and design of phase 2, double-blind, placebo-controlled RCT evaluating the efficacy and safety of MF as adjunctive therapy in FSGS. By randomizing 30 patients with biopsy-confirmed FSGS to MF or placebo (along with standard immunosuppression), we will study mechanistic biomarkers that correlate with podocyte injury or depletion and evaluate outcomes after 6 months. We specifically integrate novel urine, blood, and tissue markers as surrogates for FSGS progression along with unbiased profiling strategies.
Results and Conclusion: Our phase 2 trial will provide insight into the potential efficacy and safety of MF as adjunctive therapy in FSGS-a crucial step to developing a larger phase 3 study. The mechanistic assays here will guide the design of other FSGS trials and contribute to understanding AMPK activation as a potential therapeutic target in FSGS. By repurposing an inexpensive agent, our results will have implications for FSGS treatment in resource-poor settings.
(© 2024 International Society of Nephrology. Published by Elsevier Inc.)