Overview of the cellular and molecular basis of kidney fibrosis

Abstract

The common pathogenetic pathway of progressive injury in patients with chronic kidney disease (CKD) is epitomized as normal kidney parenchymal destruction due to scarring (fibrosis). Understanding the fundamental pathways that lead to renal fibrosis is essential in order to develop better therapeutic options for human CKD. Although complex, four cellular responses are pivotal. (1) An interstitial inflammatory response that has multiple consequences-some harmful and others healing. (2) The appearance of a unique interstitial cell population of myofibroblasts, primarily derived from kidney stromal cells (fibroblasts and pericytes), that are the primary source of the various extracellular matrix proteins that form interstitial scars. (3) Tubular epithelial cells that have variable and time-dependent roles as early responders to injury and later as victims of fibrosis due to the loss of their regenerative abilities. (4) Loss of interstitial capillary integrity that compromises oxygen delivery and leads to a vicious cascade of hypoxia-oxidant stress that accentuates injury and fibrosis. In the absence of adequate angiogenic responses, a healthy interstitial capillary network is not maintained. The fibrotic 'scar' that typifies CKD is an interesting consortium of multifunctional macromolecules that not only change in composition and structure over time, but can be degraded via extracellular and intracellular proteases. Although transforming growth factor beta appears to be the primary driver of kidney fibrosis, a vast array of additional molecules may have modulating roles. The importance of genetic and epigenetic factors is increasingly appreciated. An intriguing but incompletely understood cardiorenal syndrome underlies the high morbidity and mortality rates that develop in association with progressive kidney fibrosis.

Keywords: extracellular matrix; interstitial capillaries; kidney fibrosis; macrophages; myofibroblasts.

Figure 1

Schematic overview of the primary fibrogenic events. The upper figure depicts the key elements of the tubulointerstitium in normal kidneys. The myeloid cell population may be designated as dendritic cells rather than macrophages. The lower panel represents the key changes that are discussed further in this review: de novo appearance of an interstitial population of unique fibroblastic cells that also express alpha smooth muscle actin and are the primary source of the expanded extracellular matrix that leads to destructive interstitial scarring; an interstitial inflammatory response composed of primarily of blood-borne lymphohematopoietic cells (macrophages in particular are key drivers of both fibrosis and tissue repair); and progressive renal parenchymal loss due to interstitial capillary rarefaction and tubular atrophy. Graphs illustrate the statistically significant histopathological indicators of renal survival (free of end-stage kidney disease or serum creatinine doubling) with follow-up (shown in months) in a study of 313 patients with biopsy-confirmed lupus nephritis. The severity scores for (a) interstitial inflammation, (b) tubular atrophy, and (c) interstitial fibrosis were based of the following: 0 (nil), normal; 1+ (mild), <25% of the interstitial area affected; 2+ (moderate), 25–50% of the tubulointerstitial are involved; 3+ (severe), >50% of the interstitial area involved. (The graphs are reproduced with permission from Macmillan Publishers Ltd: Yu F et al. Kidney Int 2010;77:820–829.)