Abstract: SA-PO0598
Prognostic Associations of Baseline Urinary Succinate and Protein Excretion with ADPKD Progression in TAME-PKD Study Participants
Session Information
- Cystic Kidney Diseases: Clinical Research
November 08, 2025 | Location: Exhibit Hall, Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidneys
- 1201 Genetic Diseases of the Kidneys: Monogenic Kidney Diseases
Authors
- Hallows, Kenneth R., University of Southern California, Los Angeles, California, United States
- Abebe, Kaleab, University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Lalama, Christina M., University of Pittsburgh, Pittsburgh, Pennsylvania, United States
- Li, Hui, University of Southern California, Los Angeles, California, United States
- Saitta, Biagio, University of Southern California, Los Angeles, California, United States
- Bae, Kyongtae Ty, The University of Hong Kong, Hong Kong, Hong Kong
- 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 Baltimore School of Medicine, Baltimore, Maryland, United States
- Watnick, Terry J., University of Maryland Baltimore School of Medicine, Baltimore, Maryland, United States
Background
Dysregulated cellular metabolism contributes to ADPKD pathogenesis. The TAME-PKD study tested effects of metformin therapy and evaluated targeted urinary metabolic biomarkers in adult ADPKD subjects on disease progression over 2 years. All baseline visit samples were taken with subjects fasting, but subsequent biomarker measurements were often not performed fasting, thus increasing variability and potentially obscuring meaningful prognostic associations. Herein we undertook a new prognostic biomarker analysis using only baseline measurements to determine whether any biomarkers positively or negatively correlated with disease progression as measured by changes in height-adjusted total kidney volume (htTKV) and estimated GFR (eGFR) in longitudinal analyses.
Methods
Baseline urinary concentrations of total protein (measured by Bradford assay), targeted metabolites (lactate, pyruvate, and succinate measured by enzymatic activity assays), and glycolytic enzymes (pyruvate kinase-M2, lactate dehydrogenase-A, and pyruvate dehydrogenase kinase-1 measured by ELISA or immunoblotting) were normalized by urinary creatinine and compared with longitudinal changes in ln(htTKV) and eGFR in TAME-PKD study subjects taking placebo using a Laird & Ware linear mixed model.
Results
Consistent with prior reports, baseline urinary protein excretion was strongly positively correlated with changes in ln(htTKV) (P=0.002) and negatively correlated with changes in eGFR (P=0.001) over time in our study population. Of novel significance, baseline urinary succinate excretion was negatively correlated with ln(htTKV) increases over time (P=0.01) but was not correlated with eGFR changes over time (P=0.71). No correlations with either ln(htTKV) or eGFR were observed with the other tested metabolic biomarkers.
Conclusion
Altogether, our TAME-PKD study population data confirm proteinuria as an important negative prognostic factor for ADPKD disease progression and provide new evidence that higher oxidative metabolic flux as measured by urine excretion of the Krebs cycle intermediate succinate has positive prognostic implications, correlating with a slower increase in htTKV over time, likely reflecting an underlying state of reduced cyst growth and cellular proliferation.
Funding
- Other U.S. Government Support