MSACL 2024 Abstract

Urine Adenine: A Novel Precision Biomarker for Kidney and Heart Failure Identified by Orthogonal Metabolomics Platforms

Kumar Sharma1, Ian Tamayo1, Guanshi Zhang1, Leila Hejazi1, Nagarjunachary Ragi1, Hak Joo Lee1, Afaf Saliba1, M. Imran Aslam2, Jian-Jun Liu3, Varsha Karanam2, Bhupendra K. Gurung1, Soumya Maity1, Huili Zheng3, Su Chi Lim3, Ravi Iyengar4, Petter Bjornstad5, Katherine R. Tuttle6, Kenneth C. Bedi Jr.7, Kenneth B. Margulies7, Vasan Ramachandran2,8, Jean C. Bopassa9,
(1) Center for Precision Medicine, University of Texas Health San Antonio, (2) Division of Cardiology, University of Texas Health San Antonio, (3) Clinical Research Unit, Khoo Teck Puat Hospital, Singapore, (4) Department of Pharmacological Sciences and Institute for Systems Biomedicine, Icahn School of Medicine at Mount Sinai, Ney York, NY, (5) Division of Nephrology, Department of Medicine and Section of Endocrinology, Department of Pediatrics, University of Colorado Anschutz Medical Campus, Aurora, CO, (6) Department of Medicine, University of Washington, Seattle, WA, USA, Division of Nephrology, Department of Medicine, Kidney Research Institute, University of Washington, Seattle, Washington, (7)Cardiovascular Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, Pennsylvania, (8) School of Public Health University of Texas Health San Antonio and University of Texas San Antonio, (9) Department of Cellular and Integrative Physiology, University of Texas Health San Antonio, San Antonio, Texas.

Kumar Sharma, MD (Presenter) University of Texas Health San Antonio

Presenter Bio: Dr. Sharma has over 30 years of experience as a Physician-Scientist in the field of multi-omics for complex diseases. He received his M.D. at Albert Einstein College of Medicine and his clinical and research fellowship training at the University of Pennsylvania. He developed a new theory of mitochondrial dysfunction in diabetic complications which was guided by a metabolomic signature of diabetic kidney disease. His novel insights have been published in JCI, Science, Cell Metabolism, PNAS, JASN and Kidney International. He has an H-factor of 88 and over 220 publications. With support from the NIH Kidney Precision Medicine Project, Dr. Sharma leads a multi-institutional team to develop spatial metabolomics for human kidney biopsies. He is currently developing novel biomarkers for clinical applications in precision medicine across multiple diseases using a combination of spatial and bulk metabolomics as well as pre-clinical cell and experimental models of disease. He holds the L. David Hillis Distinguished Chair in Medicine, is the Chief of Nephrology and is the founding director of the Center for Precision Medicine at the University of Texas Health San Antonio.

Relevant Financial Disclosures (within past 24 months, reported on Feb 05, 2024) Honorarium/Expenses MedScape Grant/Research Support NIH, VA Merit Committee/Board/Advisory Board Texas Renal Coalition Stock/Bonds SygnaMap Salary Consultant fees from Cara Therapeutics Discussing Products? NO, presenter will NOT present educational content related to products/services of the ineligible company(ies) listed above. Conflict mitigation NOT REQUIRED.

Metabolomics has the potential to deliver precision medicine biomarkers for complex disease as it reflects the effects of genes, diet, lifestyle and medications and is often translatable to non-invasive measurements. Metabolites can also be disease drivers and trigger pathways and epigenetic changes that are either protective or contributory. Despite the potential of metabolomics for precision medicine the reliance on a singular modality such as blood or urine metabolomics is insufficient for true insight on the role of metabolites as potential disease drivers. To address these challenges a multi-omic approach with orthogonal platforms can overcome the difficulties with interpretation of individual platforms. Over the past few years, our group has used a multi-omic approach to show success in the development of several powerful new clinically important biomarkers. In recent studies we used bulk metabolomics with over 1500 urine samples from 3 clinical cohorts to identify a narrow set of 15 candidate metabolites that were potentially causative for kidney failure and heart failure. We then employed untargeted spatial metabolomics on human kidney biopsies and human heart samples to identify metabolites linked to pathologic features. With both methods, endogenous adenine was identified as a key biomarker that was potentially in the causal pathway of kidney and heart fibrosis with diabetes. Experimental validation was performed in a mouse model and a pathway contributing to endogenous adenine was found to be protective for both the kidney and heart. This led to a CLIA ready clinical urine assay for adenine/creatinine by LC-MS to predict kidney and heart failure 5-10 years prior to other clinical indicators. The CLIA ready urine assay by LC-MS is now available for clinical use in patients with diabetes to identify those at high risk for kidney and heart failure. These studies establish a path by which orthogonal approaches with multi-omics could provide confident targets for biomarkers and novel therapeutics and deliver on the promise of metabolomics for precision medicine.

Acknowledgements: Funded by NIH DP3 and UO1 grants