Renal Fibrosis in Lupus Nephritis

Abstract

Fibrosis can be defined as a pathological process in which deposition of connective tissue replaces normal parenchyma. The kidney, like any organ or tissue, can be impacted by this maladaptive reaction, resulting in persistent inflammation or long-lasting injury. While glomerular injury has traditionally been regarded as the primary focus for classification and prognosis of lupus nephritis (LN), increasing attention has been placed on interstitial fibrosis and tubular atrophy as markers of injury severity, predictors of therapeutic response, and prognostic factors of renal outcome in recent years. This review will discuss the fibrogenesis in LN and known mechanisms of renal fibrosis. The importance of the chronicity index, which was recently added to the histological categorization of LN, and its role in predicting treatment response and renal prognosis for patients with LN, will be explored. A better understanding of cellular and molecular pathways involved in fibrosis in LN could enable the identification of individuals at higher risk of progression to chronic kidney disease and end-stage renal disease, and the development of new therapeutic strategies for lupus patients.

Keywords: interstitial fibrosis; lupus nephritis; renal fibrosis; systemic lupus erythematosus; tubular atrophy.

Figure 1

Representation of the TGF-β/Smad signaling. TGF-β1 binds to its receptors and induces a cascade of signal transductions via both canonical (blue) and noncanonical (red) signaling. When TGF-β1 binds to its receptors, it triggers the phosphorylation and activation of Smad2/3, which translocate to the nucleus, inducing the transcription of TGF-β1-responsive genes and a pro-fibrotic response. This process can be blocked by Smad7, who inhibits Smad2/3. On the other hand, when BMP7 binds to its receptors triggers the phosphorylation on Smad1/5/8, which induce an anti-fibrotic response. In addition, TGF-β also activates the noncanonical signaling pathways able to influence renal inflammation and fibrosis. In this case, renal fibrosis is caused by the activation of pathways such as MAP kinase, PI3K/Akt, and Rho kinase, and is triggered by mediators such as angiotensin II and advanced glycation end products (AGEs) [Created with Biorender (https://biorender.com), accessed on 7 November 2022].

Figure 2

Main mechanisms involved in the pathogenesis of renal fibrosis in LN. Abbreviations: CIC—circulating immune complex; CKD—chronic kidney disease; ECM—extracellular matrix; EMT—epithelial-to-mesenchymal transition; ESRD—end-stage renal disease; GEC—glomerular endothelial cell; HIF—hypoxia-inducing factor; IC—immune complex; RMC—renal mesangial cell; TEC—renal tubular epithelial cell [Created with Biorender (https://biorender.com) accessed on 7 November 2022].