Proteomic Analysis of Urinary Microvesicles and Exosomes in Medullary Sponge Kidney Disease and Autosomal Dominant Polycystic Kidney Disease

Background and objectives Microvesicles and exosomes are involved in the pathogenesis of autosomal dominant polycystic kidney disease. However, it is unclear whether they also contribute to medullary sponge kidney, a sporadic kidney malformation featuring cysts, nephrocalcinosis, and recurrent kidney stones. We addressed this knowledge gap by comparative proteomic analysis. Design, setting, participants, & measurements The protein content of microvesicles and exosomes isolated from theurine of 15patientswithmedullarysponge kidney and15patientswithautosomaldominant polycystic kidney diseasewasdeterminedbymass spectrometryfollowedbyweightedgene coexpressionnetworkanalysis, support vector machine learning, and partial least squares discriminant analysis to compare the profiles and select the most discriminative proteins. The proteomic data were verified by ELISA. ResultsAtotal of 2950 proteinswere isolated frommicrovesicles and exosomes, including 1579 (54%) identified in all samples but only 178 (6%) and 88 (3%) specific formedullary sponge kidneymicrovesicles and exosomes, and 183 (6%) and 98 (3%) specific for autosomal dominant polycystic kidney disease microvesicles and exosomes, respectively. The weighted gene coexpression network analysis revealed ten modules comprising proteins with similar expression profiles. Support vector machine learning and partial least squares discriminant analysis identified 34proteins thatwere highlydiscriminativebetweenthediseases. Amongthese, CD133wasupregulated in exosomes from autosomal dominant polycystic kidney disease and validated by ELISA. Conclusions Our data indicate a different proteomic profile of urinary microvesicles and exosomes in patients with medullary sponge kidney comparedwith patientswith autosomal dominant polycystic kidney disease. The urine proteomic profile of patients with autosomal dominant polycystic kidney disease was enriched of proteins involved in cell proliferation and matrix remodeling. Instead, proteins identified in patients with medullary sponge kidney were associated with parenchymal calcium deposition/nephrolithiasis and systemic metabolic derangements associated with stones formation and bone mineralization defects.