University Associate Professor in Clinical Pathology University of Cambridge Cambridge, England, United Kingdom
Background: The pathogenesis of feline calcium oxalate urolithiasis remains enigmatic, although renal tubular injury secondary to endocytosis of intraluminal crystals is postulated to lead to formation of calcium oxalate uroliths in humans. Urinary extracellular vesicles (UEV) could act as a nidus for crystal formation, thus contributing to stone risk. Uromodulin is an inhibitor of crystal formation, hence reduced abundance of UEV-associated uromodulin might increase heterogeneous nucleation and stone risk. Hypothesis: UEV excretion rates are higher, and abundance of UEV-associated uromodulin is reduced, in cats with urolithiasis. Animals: 7 cats with presumed calcium oxalate urolithiasis and 13 control cats.
Methods: UEVs were isolated from frozen, 0.5-3mL urine samples by ultrafiltration and size exclusion chromatography. UEV concentrations were determined by nanoparticle tracking analysis and normalised to urine volume and urine creatinine concentration. UEV-associated uromodulin abundance was determined by liquid chromatography tandem mass-spectrometry. Data are presented as median [range].
Results: UEV excretion rates in female cats with uroliths were higher than in female controls (2.6x105 [1.3x105-7.3x105] UEVs/mL:µmol/L, n=5 vs. 5.13x104 [1.1x104-1.6x105] UEVs/mL:µmol/L, n=4; P=0.03). This was not apparent in male cats (with uroliths (n=2): 3.2x104 and 6.9 x104 UEVs/mL:µmol/L vs. without uroliths: 9.8x104 [1.1x104-6.0x105] UEVs/mL:µmol/L (n=9)). Uromodulin was detectable in UEVs of 5/10 control cats but in none of 4 cats with urolithiasis (P=0.22). Conclusions and clinical importance: These preliminary data suggest that UEV excretion rate and potentially the abundance of UEV-associated uromodulin could contribute to the pathogenesis of calcium oxalate urolithiasis in cats, although larger studies are needed to confirm these findings.
