Abstract: TH-PO693
Feline Autosomal Dominant Polycystic Kidney Disease Model to Elucidate Genetic Modifiers of Cyst Progression
Session Information
- ADPKD: Genetic and Model Studies
October 25, 2018 | Location: Exhibit Hall, San Diego Convention Center
Abstract Time: 10:00 AM - 12:00 PM
Category: Genetic Diseases of the Kidney
- 1001 Genetic Diseases of the Kidney: Cystic
Authors
- Lyons, Leslie A., College of Veterinary Medicine, University of Missouri, Columbia, Missouri, United States
- Yu, Yoshihiko, College of Veterinary Medicine, University of Missouri, Columbia, United States
- Shumway, Kate, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, United States
- Matheson, Jodi Suzanne, College of Veterinary Medicine, University of Missouri, Columbia, Missouri, United States
- Kline, Timothy L., Mayo Clinic , Rochester, Minnesota, United States
Background
Autosomal dominant polycystic kidney disease (ADPKD) is the most common inherited renal disease in domestic cats. The feline PKD1 mutation (c.10063C>A) causes a stop codon in exon 29 (C3284X) and is the only known variant causing ADPKD in cats, specifically Persians and related-breeds. Many ADPKD cats remain subclinical though some show rapid disease progression, develop chronic kidney disease (CKD) and succumb to disease within seven years of life. Thus, cats are a useful model to investigate genetic modifiers that influence disease progression and severity. Also, because of the consistent genetic background of the breed and the solitary causal mutation, drug trials can be more accurately interpreted as to success and failure, without complications of genetic heterogeneity of either the patient or the causal gene mutation.
Methods
Two normal and eleven Persian-derived cats heterozygous for the PKD1 c.10063C>A variant were evaluated by ultrasound (US), computed tomography (CT) and magnetic resonance imaging (MRI). Glomerular filtration rate (GFR), complete blood count, serum chemistries, symmetric dimethylarginine (SDMA), and urine analyses were determined.
Results
Ten clinically normal cats had multiple bilateral cysts and classified as feline chronic kidney disease (CKD) stage 1. Most cysts were located in the cortex or at the corticomedullary junction, with far fewer in the medulla. The oldest cat, 8.1 yrs, had slightly elevated SDMA at 15 and creatinine at 16 and a slightly lowered urine specific gravity of 1.028, and tentatively classified as CKD stage 2. Three cats had GFRs below 2.5. CT-based fractional cyst volume (FCV in mls) ranged from 0.63 – 28.22% and increased with age (r = 0.94). One cat had fast progression when considering cystic development and age with 1.08 FCV/mo at 19 mo. The stage 2 cat had the highest FCV of 28.22% but its FCV/mo was 0.29 ml/mo.
Conclusion
CT and MRI modalities are sufficient in cats to determine TKV and FCV. TKV is not a prognostic indicator of disease in cats. FCV is highly correlated with age. Fast progressing cats can be identified and used for the analysis of genetic variants that modify disease progression. Whole genome sequencing of slow and fast progressing cats is underway to elucidate the modifying variants.
Funding
- NIDDK Support