Leveraging extracellular vesicle biology for novel tests and therapeutics for kidney fibrosis

Kidney fibrosis is mechanistically characterised by tissue injury followed by development of a fibrogenic niche. The fibrogenic niche involves chronic inflammation, vascular rarefaction, glomerulosclerosis, tubular atrophy, interstitial accumulation of extracellular matrix which replaces functional kidney parenchyma-culminating in reduced kidney function. Extracellular vesicles are bilipid membrane-encased nanoparticles that play critical roles as cell-to-cell messengers and waste management mechanisms. Extracellular vesciels communication has been demonstrated within the glomerulus, within the tubular compartment and, between tubular and glomerular compartments. Diverse extracellular vesicle cargoes interact with key pathways regulating cell facte and inflammation to mediate kidney fibrosis. Extracellular vesicles cargos can be leveraged as biomarkers to develop minimally invasive tests for kidney fibrosis and pinpoint active pathobiological processes to guide personalised mechanism-driven care. Mesechymal cell-derived extracellular vesicles, extracellular vesicles from bioengineered cells, post-modified extracellular vesicles and suppression of extracellular vesicle uptake have demonstrated promise in preclinical studies for preventing kidney fibrosis. Roadblocks to clinical implementation of extracellular vesicles as biomarkers include lack of standardised collection, measurement, normalisation and data processing protocols; as well as dearth of highly specific biomaker panels. Roadblocks to extracellular vesicle therapeutics include extracellular vesicle heterogeneity, sensitivity to small changes in production parameters, absence of standardised characterisation protocols, technological limitations and knowledge gaps on extracellular vesicle mechanisms of action. This review will contextualise kidney extracellular vesicle pathobiology with principles of clinical implementation to highlight extracellular vesicle potential as minimally invasive biomarkers and novel therapeutics for kidney fibrosis. Strategies to address roadblocks to clinical implementation of extracellular vesicles for kidney fibrosis and chronic kidney disease management will also be explored in this review. KEY POINTS: Extracellular vesicles (EVs) are bilipid membrane-encased nanoparticles that play critical roles as cell-to-cell messengers and waste management mechanisms. EV cargos can be leveraged as biomarkers to develop minimally invasive tests for kidney fibrosis and guide personalised mechanism-driven care. Mesenchymal cell-derived EVs, EVs from bioengineered cells, post-modified EVs and suppression of EV uptake have demonstrated promise for preventing kidney fibrosis.