Abstract
BackgroundThe lifetime incidence of kidney stones is about two times greater in men compared to women. Extracellular vesicles (EVs) shed from activated cells are present in the urine and may reflect or even mediate renal physiology and/or pathology. This study was designed to standardize methodology to characterize urinary EVs by digital flow cytometry and to identify possible sex differences in EVs in persons with and without their first symptomatic kidney stones.MethodsTwenty-four-hour urine collections were obtained from persons presenting with their first kidney stone episode (n = 50 women, 60 men; age 19–76 years) and sex- and age-matched controls from the general population (n = 24 women, 36 men).ResultsStandardization: Size of EV was variable within all groups. EV positivity was verified with two fluorophores for surface phosphatidylserine and/or using two different protein markers specific for renal-specific cells. The number of phosphatidylserine- and exosome marker-positive EVs did not correlate with urine osmolality and were similar in fresh vs. frozen and between two sequential urine collections from the same individual. Sex differences: Urine from women controls contained greater (P < 0.05) numbers of EVs positive for phosphatidylserine, exosomes, inflammatory factors and adhesion molecules, and cell-specific markers from different segments of the nephron, renal pelvis, and bladder compared to control men. In contrast, urine from women with kidney stones contained significantly (P < 0.05) lower numbers of EVs derived from podocytes, parietal cells, proximal convoluted tubule, thin and thick loop of Henle, distal tubule, collecting duct, renal pelvis, and bladder compared to control women and contained similar quantities of these types of EVs in men with and without kidney stones. There were also no sex differences in EVs positive for cell adhesion (E-cadherin and inter-cellular adhesion molecule-1 [ICAM-1]) molecules.ConclusionsUnlike women who do not have kidney stones, EVs in urine from women with nephrolithiasis are similar to men with and without kidney stones. Thus, EVs may mediate or reflect aspects of kidney stone pathogenesis and perhaps provide clues regarding sex differences in kidney stone incidence rates.
Highlights
The lifetime incidence of kidney stones is about two times greater in men compared to women
Sex differences in populations of urinary Extracellular vesicles (EVs) between control women and men The total number of urinary EVs positive for the following markers were significantly (P < 0.05) greater in control women compared to men: phosphatidylserine, exosome (CD63) marker, inflammatory molecules (VCAM1, tissue factor, and monocyte chemotactic protein-1 (MCP-1)), podocin plus galactin-1, claudin-1, urate-anion exchanger
Women with and without their first episode of symptomatic kidney stones both shed significantly more CD63-positive EVs compared to men, whereas persons of both sexes with renal stones shed a similar number of annexin-V-positive EVs
Summary
The lifetime incidence of kidney stones is about two times greater in men compared to women. The exact series of events that connect super-saturation to formation of a kidney stone remain unclear. These stones are often referred to as “idiopathic” calcium oxalate stones. Injured and activated cells shed distinct populations of biologically active extracellular vesicles (EVs) that are involved in numerous pathophysiological processes by removal and exchange of excess and unwanted RNAs, proteins, receptors, and metabolites. Recent studies suggest that activated cell-derived EVs can help identify early and late pathophysiological processes and contribute to the diagnosis, prognostic assessment, and management of individuals with suspected renal diseases [13,14]. A detailed profile of cellular injury or markers of cellular activation that could elucidate potential mechanisms involved in stone formation has yet to be developed
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