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Association of Baseline Urinary Metabolic Biomarkers with ADPKD Severity in TAME-PKD Clinical Trial Participants. | LitMetric

AI Article Synopsis

  • Recent studies suggest that altered cellular metabolism significantly contributes to the severity of autosomal dominant polycystic kidney disease (ADPKD), prompting the TAME-PKD clinical trial to evaluate the effects of metformin on ADPKD patients.
  • In this study involving 95 participants, urinary levels of proteins and metabolites were analyzed to see how they relate to kidney function and size, particularly focusing on height-adjusted total kidney volume (htTKV) and estimated glomerular filtration rate (eGFR).
  • Results indicated that higher htTKV was linked to lower eGFR, with certain urinary biomarkers, including protein excretion and specific glycolytic enzymes, showing correlations with ADPKD severity, especially in younger patients.

Article Abstract

Background: Recent work suggests that dysregulated cellular metabolism may play a key role in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD). The TAME-PKD clinical trial is testing the safety, tolerability, and efficacy of metformin, a regulator of cell metabolism, in patients with ADPKD. This study investigates the cross-sectional association of urinary metabolic biomarkers with ADPKD severity among TAME-PKD trial participants at baseline.

Methods: Concentrations of total protein, targeted metabolites (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 urinary creatinine or osmolality to estimate excretion, were correlated with patients' baseline height-adjusted total kidney volumes (htTKVs) by MRI and eGFR. Additional analyses were performed, adjusting for participants' age and sex, using multivariable linear regression.

Results: Greater htTKV correlated with lower eGFR (=-0.39; =0.0001). Urinary protein excretion modestly correlated with eGFR (negatively) and htTKV (positively). Urinary cAMP normalized to creatinine positively correlated with eGFR. Among glycolytic enzymes, PKM2 and LDHA excretion positively correlated with htTKV, whereas PKM2 excretion negatively correlated with eGFR. These associations remained significant after adjustments for age and sex. Moreover, in adjusted models, succinate excretion was positively associated with eGFR, and protein excretion was more strongly associated with both eGFR and htTKV in patients <43 years old.

Conclusions: Proteinuria correlated with ADPKD severity, and urinary excretion of PKM2 and LDHA correlated with ADPKD severity at baseline in the TAME-PKD study population. These findings are the first to provide evidence in human urine samples that upregulated glycolytic flux is a feature of ADPKD severity. Future analysis may reveal if metformin treatment affects both disease progression and the various urinary metabolic biomarkers in patients throughout the study.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8312696PMC
http://dx.doi.org/10.34067/KID.0005962020DOI Listing

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