Pathophysiology and Biomarkers of Renal Fibrosis

Renal fibrosis represents the common end point of chronic kidney injury irrespective of the initiating cause. It is characterised by an excessive deposition of extracellular matrix components, notably collagens and fibronectin, which leads to tubular atrophy, capillary rarefaction and progressive loss of renal function. The process is driven by resident fibroblasts, pericytes and epithelial cells that undergo transdifferentiation into myofibroblasts under the influence of profibrotic mediators such as transforming growth factor-β (TGF-β), angiotensin II and other signalling molecules. Inflammation, mediated by infiltrating immune cells and cytokines, amplifies the fibrotic response. Emerging evidence highlights a key role for cellular plasticity in the form of epithelial-to-mesenchymal transition (EMT) and endothelial-to-mesenchymal transition (EndMT). Non-invasive biomarkers have become central to early detection and monitoring. These include circulating and urinary molecules reflecting matrix turnover, such as collagen fragments, growth factors, chemokines and novel matrix-derived peptides. Advances in imaging and molecular profiling further promise to refine risk stratification and guide therapeutic interventions.

Research from Nature Portfolio

Investigations into collagen type VI cleavage have identified endotrophin, a bioactive fragment released during extracellular matrix remodelling, as a robust urinary marker of disease progression. Quantification of the endotrophin:creatinine ratio in chronic kidney disease cohorts localised this peptide to fibrotic regions and demonstrated that higher quartiles of urinary endotrophin predicted one-year decline in renal function and onset of end-stage disease. Addition of endotrophin measurements to standard risk models significantly improved reclassification metrics, supporting its potential utility as a non-invasive indicator of ongoing fibrosis and as a tool for personalised risk assessment.

Pathophysiology and Biomarkers of Renal Fibrosis publication trend

The graph below shows the total number of articles in pathophysiology and biomarkers of renal fibrosis across all publications each year (not limited to Nature Index journals).

Technical terms

Extracellular matrix: A network of proteins and glycoproteins, including collagens and fibronectin, that provides structural support to tissues and is excessively deposited in fibrosis.

Myofibroblast: A specialised cell expressing contractile proteins that synthesises large amounts of extracellular matrix during tissue repair and fibrosis.

Epithelial-to-mesenchymal transition (EMT): A process by which epithelial cells lose polarity and adhesion to acquire a mesenchymal phenotype, contributing to the pool of matrix-producing cells.

Endothelial-to-mesenchymal transition (EndMT): A form of cellular plasticity in which endothelial cells transform into mesenchymal cells, promoting fibrosis and vascular remodelling.

Biomarker: A measurable indicator of biological processes or pharmacological responses, used here to detect or predict renal fibrosis non-invasively.

Endotrophin: A cleavage fragment of collagen type VI released during matrix remodelling, serving as a pro-fibrotic mediator and urinary marker of disease progression.

Mitophagy: The selective degradation of damaged mitochondria by autophagy, which can regulate cellular survival and fibrotic activation under stress conditions.

Transforming growth factor-β (TGF-β): A cytokine that orchestrates fibrotic responses by inducing myofibroblast differentiation and promoting extracellular matrix synthesis.

References

1. Fibrosis in Chronic Kidney Disease: Pathogenesis and Consequences. International Journal of Molecular Sciences (2021).
2. Urinary endotrophin predicts disease progression in patients with chronic kidney disease. Scientific Reports (2017).
3. Rictor/mTORC2 signalling contributes to renal vascular endothelial‐to‐mesenchymal transition and renal allograft interstitial fibrosis by regulating BNIP3‐mediated mitophagy. Clinical and Translational Medicine (2024).
4. Biomarkers for the detection of renal fibrosis and prediction of renal outcomes: a systematic review. BMC Nephrology (2017).