Analysis of human urinary extracellular vesicles reveals disordered renal metabolism in myotonic dystrophy type 1

Chronic kidney disease (CKD) and the genetic disorder myotonic dystrophy type 1 (DM1) each are associated with progressive muscle wasting, whole-body insulin resistance, and impaired systemic metabolism. However, CKD is undocumented in DM1 and the molecular pathogenesis driving DM1 is unknown to involve the kidney. Here we use urinary extracellular vesicles (EVs), RNA sequencing, droplet digital PCR, and predictive modeling to identify downregulation of metabolism transcripts Phosphoenolpyruvate carboxykinase-1, 4-Hydroxyphenylpyruvate dioxygenase, Dihydropyrimidinase, Glutathione S-transferase alpha-1, Aminoacylase-1, and Electron transfer flavoprotein B in DM1. Expression of these genes localizes to the kidney, especially the proximal tubule, and correlates with muscle strength and function. In DM1 autopsy kidney tissue, characteristic ribonuclear inclusions are evident throughout the nephron. We show that urinary organic acids and acylglycines are elevated in DM1, and correspond to enzyme deficits of downregulated genes. Our study identifies a previously unrecognized site of DM1 molecular pathogenesis and highlights the potential of urinary EVs as biomarkers of renal and metabolic disturbance in these individuals.