Renal interstitial fibrosis: mechanisms and evaluation

Abstract

Purpose of review: Tubulointerstitial injury in the kidney is complex, involving a number of independent and overlapping cellular and molecular pathways, with renal interstitial fibrosis and tubular atrophy (IFTA) as the final common pathway. Furthermore, there are multiple ways to assess IFTA.

Recent findings: Cells involved include tubular epithelial cells, fibroblasts, fibrocytes, myofibroblasts, monocyte/macrophages, and mast cells with complex and still incompletely characterized cell-molecular interactions. Molecular mediators involved are numerous and involve pathways such as transforming growth factor (TGF)-β, bone morphogenic protein (BMP), platelet-derived growth factor (PDGF), and hepatocyte growth factor (HGF). Recent genomic approaches have shed insight into some of these cellular and molecular pathways. Pathologic evaluation of IFTA is central in assessing the severity of chronic disease; however, there are a variety of methods used to assess IFTA. Most assessment of IFTA relies on pathologist assessment of special stains such as trichrome, Sirius Red, and collagen III immunohistochemistry. Visual pathologist assessment can be prone to intra and interobserver variability, but some methods employ computerized morphometery, without a clear consensus as to the best method.

Summary: IFTA results from on orchestration of cell types and molecular pathways. Opinions vary on the optimal qualitative and quantitative assessment of IFTA.

Figure 1. Cellular mediators of fibrosis

Cells involved in fibrosis include the renal tubules, the renal vasculature, and inflammatory cells, including lymphocytes, monocyte/macrophages, mast cells, and dendritic cells. The renal tubules at least undergo changes that impart them with a epithelial-mesenchymal phenotype (EMP) and are possibly involved in a process of epithelial-mesenchymal transition (EMT). The endothelium is possibly involved in a process of endothelial-mesenchymal transition (EndoMT). Evidence shows that the inflammatory cells participate in both the process of EMT/EMP and EndoMT. Fibroblasts/mesenchymal cells mediate the production of fibrosis and extracellular matrix (ECM) deposition and also may undergo a transition to a myofibroblastic phenotype, further leading to the production of fibrosis and ECM deposition.

Figure 2. Important molecular mediators of fibrosis

Transforming growth factor (TGF-β) is released through interactions with the extracellular matrix (ECM) and matrix metalloproteinases (MMPs), plasmin, and integrin; and when released from inhibition by latent TGF-β binding protein (LTBP) and latency-associated peptide (LAP), TGF-β binds the transforming growth factor receptor (TGFR), activating intracellular signals such as the Smad, jagged/notch, Akt, Bcl-2, and NF-κB pathways. These lead to nuclear transcription, ultimately culminating in collagen and ECM production and possibly leading to epithelial to mesenchymal transition (EMT). Smads also act on the integrin-linked kinase (ILK), which acts through glycogen synthase kinase (GSK) to produce β-catenin, which traverses into the nucleus to also induce transcription. The integrins (typically with α and β components [e.g., α5β6 integrin]) also act through ILK in a similar manner. Bone morphogenic protein (BMP), when binding to the BMP receptor (BMPR) also works through Smad, a process inhibited by sclerostin domain-containing protein 1 (also known as uterine sensitization-associated gene 1 [USAG-1]).[Figure adapted from [1, 229, 230].]

Figure 3. Fibrosis morphometry

Stains used to assess fibrosis are shown, including: Trichrome, Collagen III immunohistochemistry, and Sirius Red [on the left] with their corresponding quantitation markup images shown [on right].