Liquid Biopsy at the Frontier of Kidney Diseases: Application of Exosomes in Diagnostics and Therapeutics

Abstract

In the era of precision medicine, liquid biopsy techniques, especially the use of urine analysis, represent a paradigm shift in the identification of biomarkers, with considerable implications for clinical practice in the field of nephrology. In kidney diseases, the use of this non-invasive tool to identify specific and sensitive biomarkers other than plasma creatinine and the glomerular filtration rate is becoming crucial for the diagnosis and assessment of a patient's condition. In recent years, studies have drawn attention to the importance of exosomes for diagnostic and therapeutic purposes in kidney diseases. Exosomes are nano-sized extracellular vesicles with a lipid bilayer structure, composed of a variety of biologically active substances. In the context of kidney diseases, studies have demonstrated that exosomes are valuable carriers of information and are delivery vectors, rendering them appealing candidates as biomarkers and drug delivery vehicles with beneficial therapeutic outcomes for kidney diseases. This review summarizes the applications of exosomes in kidney diseases, emphasizing the current biomarkers of renal diseases identified from urinary exosomes and the therapeutic applications of exosomes with reference to drug delivery and immunomodulation. Finally, we discuss the challenges encountered when using exosomes for therapeutic purposes and how these may affect its clinical applications.

Keywords: biomarkers; kidney diseases; liquid biopsy; therapeutics; urinary exosomes.

Figure 1

Extracellular vesicle classification. A depiction of the four different classes of extracellular vesicles indicating their modes of biogenesis and release. Exosomes are generated through the endocytosis of multivesicular bodies and are released via exocytosis, are spherical in shape, and vary in size. Microvesicles are generated and released through budding/shedding from plasma membrane, are irregular in shape, and vary in size. Apoptotic bodies are released through blebbing by cells undergoing apoptosis. Migrasomes (pomegranate-like structures) grow on and are released from the tips or intersections of retraction fibers, which mark the path of migrating cells.

Figure 2

Exosome biogenesis. Exosomes are generated in a process that involves the double invagination of the plasma membrane in the early endosomes, resulting in the formation of intracellular multivesicular bodies (MVBs) that possess cell surface proteins and soluble proteins associated with the extracellular environment and the plasma membrane of the parent cell. Within these MVBs, inward invaginations occur, resulting in the formation of intraluminal vesicles (ILVs) in late endosomes following cargo sorting. Both ESCRT-dependent and ESCRT-independent driven pathways participate in creating multivesicular bodies. Exocytic MVBs fuse with the plasma membrane in Rab-GTPases-regulated manner. ILVs eventually become exosomes when secreted to the extracellular microenvironment. Exosome content depends on the cell type and the physiological and pathological condition of the cell.

Figure 3

Hallmarks of exosomes. Exosomes contain a wide variety of molecules, such as nucleic acids, proteins, and lipids. The contents of the exosome are a representation of the cell of origin and of the physiological state of the cell from which the exosome is released from.

Figure 4

Exosome–recipient cell communication. Exosomes communicate with and modulate recipient cell signaling via multiple routes. Upon reaching the target cell, (1) ligands on the exosome surface membrane and receptors on the plasma membrane of the target cell can interact, inducing downstream signaling cascade in the recipient cell. (2) Exosome membrane can fuse with the plasma membrane and release its contents directly into the cytosol of the recipient cell. (3) Exosomes are internalized by the recipient cell and follow the endosomal pathway for cargo release/recycling.