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Abstract: FR-PO260

Longitudinal Characterization of Mitochondrial and Metabolic Changes in Autosomal Dominant Polycystic Kidney Disease

Session Information

Category: Genetic Diseases of the Kidneys

  • 1101 Genetic Diseases of the Kidneys: Cystic


  • Zheng, Jamie, Mayo Clinic, Rochester, Minnesota, United States
  • Trask, Cassandra, Mayo Clinic, Rochester, Minnesota, United States
  • Hogan, Marie C., Mayo Clinic, Rochester, Minnesota, United States
  • Torres, Vicente E., Mayo Clinic, Rochester, Minnesota, United States
  • Harris, Peter C., Mayo Clinic, Rochester, Minnesota, United States
  • Eirin, Alfonso, Mayo Clinic, Rochester, Minnesota, United States
  • Irazabal, Maria V., Mayo Clinic, Rochester, Minnesota, United States

Metabolic dysregulations and mitochondria abnormalities are implicated in the pathogenesis of autosomal dominant polycystic kidney disease (ADPKD), but reports differ between studies, and there are no longitudinal studies that determine the timing of these alterations through the disease. This study aimed to determine the longitudinal mitochondrial and metabolic changes in a slowly progressive Pkd1 mouse model (Pkd1RC/RC) and patients with ADPKD.


We analyzed the kidney metabolome of Pkd1RC/RC mice and WT controls (n=5 males and 5 females/group) at 1, 2, 4, 6, 8, 12, and 16 months (m, renal failure) using 1HNMR and mitochondrial characteristics in kidneys and urine from the same animals at 1, 6, and 16m using electron microscopy, RNAseq, and qPCR. Disease severity and progression were evaluated by kidney weight/body weight (KW/BW), cystic index (CI), fibrotic index (FI), and BUN. We collected urine and blood from 40 well-characterized, young, early-stage (<40 years, eGFR>90 ml/min1.73m2) patients with ADPKD and 20 age and sex-matched controls for metabolomics and mtDNA analyses. Abdominal MRIs were acquired for kidney volume.


KW/BW and CI were higher in Pkd1RC/RC from 1m and FI from 4m, but BUN was similar until 8m. Metabolic changes were present throughout the disease, but the metabolic profile varied at different stages. At 1m, kidney mitochondria resembled the typical appearance of WT controls, but the mitochondria number was lower in Pkd1RC/RC. Changes in mitochondria area and matrix density became apparent as the disease progressed. The mitochondrial genetic profile in Pkd1RC/RC versus WT differed at 1, 6, and 16m. However, functional analysis revealed distinct changes at different stages of the disease. In urine, the mtDNA copy number was lower at 1m, but unexpectedly, it increased with disease progression. Analyses of human urine and plasma samples are still ongoing.


ADPKD is associated with metabolic dysregulations and mitochondria abnormalities throughout the disease. However, the abnormalities observed were different in the early, middle, and late stages of the disease. These findings have significant implications for treating patients with ADPKD and suggest that different therapeutic strategies might be beneficial throughout the disease.


  • NIDDK Support