Abstract: PO1568
Correlation of Baseline Urinary Metabolic Biomarkers with ADPKD Severity in the TAME-PKD Study Participants
Session Information
- Cystic Kidney Diseases: Emerging Concepts, Biomarkers, and Clinical Trials
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1001 Genetic Diseases of the Kidneys: Cystic
Authors
- Hallows, Kenneth R., University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Althouse, Andrew D., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Li, Hui, University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Saitta, Biagio, University of Southern California Keck School of Medicine, Los Angeles, California, United States
- Abebe, Kaleab, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Bae, Kyongtae Ty, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Miskulin, Dana, Tufts Medical Center, Boston, Massachusetts, United States
- Perrone, Ronald D., Tufts Medical Center, Boston, Massachusetts, United States
- Seliger, Stephen L., University of Maryland School of Medicine, Baltimore, Maryland, United States
- Watnick, Terry J., University of Maryland School of Medicine, Baltimore, Maryland, United States
Background
Recent work suggests that dysregulated cellular metabolism plays a key role in autosomal dominant polycystic kidney disease (ADPKD) pathogenesis, with increased glycolytic metabolism (Warburg effect) and impaired oxidative metabolism. The TAME-PKD double-blind, placebo-controlled RCT is underway, testing the safety, tolerability and efficacy of metformin, a regulator of cell metabolism and activator of AMP-activated kinase, in ADPKD patients. The purpose of this study was to analyze the degree to which various baseline urinary biomarker values of key metabolites and metabolic enzymes correlate with ADPKD disease severity parameters in this study population.
Methods
Concentrations of total protein, key metabolites (creatinine, lactate, pyruvate, succinate, and cAMP), and key glycolytic enzymes (pyruvate kinase M2 (PKM2), lactate dehydrogenase A (LDHA), and pyruvate dehydrogenase kinase 1 (PDK1)) were measured by ELISA, enzymatic assays and immunoblotting in baseline urine specimens of 95 TAME-PKD participants. These analytes normalized by creatinine were correlated with patients’ baseline height-adjusted total kidney volumes (htTKV) by MRI and estimated GFR (eGFR) by CKD-EPI in unadjusted analyses. Additional analyses were performed adjusting for participants’ age and sex.
Results
As expected, a very significant negative correlation was found between htTKV and eGFR (r = -0.385; p = 0.0001) in this population, with a modest positive correlation between urinary total protein excretion and htTKV (r = 0.201; p = 0.052). None of the metabolites correlated with htTKV or eGFR. Among metabolic enzymes, PKM2 and LDHA both positively correlated with htTKV (r = 0.286; p = 0.005 and r = 0.233; p = 0.025, respectively). All of these correlations remained generally consistent in multivariable regression models adjusting for patient age and sex.
Conclusion
To varying degrees, proteinuria, lactate, PKM2, and PDK1 urinary concentrations correlated with ADPKD severity at baseline in the TAME-PKD study population, consistent with the idea that upregulated glycolytic flux is a feature of ADPKD severity. Future analysis will reveal how treatment with metformin may affect both disease progression and the various urinary metabolic biomarkers in patients throughout the study.
Funding
- Other U.S. Government Support