Fibrosis in Chronic Kidney Disease: Pathophysiology and Therapeutic Targets

Abstract

Chronic kidney disease (CKD) is a slowly progressive condition characterized by decreased kidney function, tubular injury, oxidative stress, and inflammation. CKD is a leading global health burden that is asymptomatic in early stages but can ultimately cause kidney failure. Its etiology is complex and involves dysregulated signaling pathways that lead to fibrosis. Transforming growth factor (TGF)-β is a central mediator in promoting transdifferentiation of polarized renal tubular epithelial cells into mesenchymal cells, resulting in irreversible kidney injury. While current therapies are limited, the search for more effective diagnostic and treatment modalities is intensive. Although biopsy with histology is the most accurate method of diagnosis and staging, imaging techniques such as diffusion-weighted magnetic resonance imaging and shear wave elastography ultrasound are less invasive ways to stage fibrosis. Current therapies such as renin-angiotensin blockers, mineralocorticoid receptor antagonists, and sodium/glucose cotransporter 2 inhibitors aim to delay progression. Newer antifibrotic agents that suppress the downstream inflammatory mediators involved in the fibrotic process are in clinical trials, and potential therapeutic targets that interfere with TGF-β signaling are being explored. Small interfering RNAs and stem cell-based therapeutics are also being evaluated. Further research and clinical studies are necessary in order to avoid dialysis and kidney transplantation.

Keywords: SGLT2 inhibitors; chronic kidney disease; inflammation; nuclear factor kappa B; renal fibrosis.

Figure 1

Schematic of the key elements in the process of kidney fibrosis. Injury to the kidney initiates activation of epithelium, proliferation of fibroblasts, and inflammation with infiltration of macrophages. Transforming growth factor- β (TGF-β) and other cytokines are released by kidney cells, stimulating transdifferentiation of epithelial cells to myofibroblasts, macrophages to myofibroblasts, and fibroblasts to myofibroblasts. TGF-β activates a cascade of pro-fibrotic downstream signaling pathways. Myofibroblasts are the cell type primarily responsible for production of excessive extracellular matrix, which leads to scarring, structural damage, and kidney fibrosis.