Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences

Abstract

Fibrosis is a process characterized by an excessive accumulation of the extracellular matrix as a response to different types of tissue injuries, which leads to organ dysfunction. The process can be initiated by multiple and different stimuli and pathogenic factors which trigger the cascade of reparation converging in molecular signals responsible of initiating and driving fibrosis. Though fibrosis can play a defensive role, in several circumstances at a certain stage, it can progressively become an uncontrolled irreversible and self-maintained process, named pathological fibrosis. Several systems, molecules and responses involved in the pathogenesis of the pathological fibrosis of chronic kidney disease (CKD) will be discussed in this review, putting special attention on inflammation, renin-angiotensin system (RAS), parathyroid hormone (PTH), fibroblast growth factor 23 (FGF23), Klotho, microRNAs (miRs), and the vitamin D hormonal system. All of them are key factors of the core and regulatory pathways which drive fibrosis, having a great negative kidney and cardiac impact in CKD.

Keywords: FGF23; Klotho; PTH; RAS; artificial intelligence; fibrosis; image analysis; inflammation; microRNAs; vitamin D.

Figure 1

Vitamin D receptor activators (VDRAs) reduced cardiac fibrosis in experimental chronic kidney disease (CKD). Cardiac fibrosis in rats with normal renal function (NRF) and chronic renal failure (CRF) analyzed by collagen deposition (Masson Trichrome and Sirius Red stainings) and Collagen I immunohistrochemistry. Modified from Panizo et al. Nephrol Dial Transplant 2013 28(11):2735-44 with permission of Oxford University Press.

Figure 2

Kidney biopsy showing an advanced stage of tubule interstitial and glomerular fibrosis (T2) in a patient with IgA nephropathy (Jones silver stain ×400).

Figure 3

Vitamin D and kidney fibrosis. Thick lines indicate direct interaction, thin lines indicate mediated interaction. PTH, parathyroid hormone; TGF-ß, transforming growth factor beta; EMT, epithelial to mesenchymal transition; ADAM17, tumor necrosis factor-alfa converting enzyme; TNF-α, tumor necrosis factor-alfa; RAS, renin-angiotensin system; Ang II, angiotensin II. Modified from Martinez-Arias et al. Nephrol Dial Transplant 2020 (in press), with permission of Oxford University Press.