Fibrosis and Metabolic Dysregulation in Feline CKD: Understanding the Hidden Progression Pathways

Chronic kidney disease in cats is increasingly understood as more than a decline in glomerular filtration. It is a progressive biological process driven by metabolic imbalance, oxidative stress, vascular dysfunction, and ultimately fibrosis. Among these, tubulointerstitial fibrosis remains the most consistent histopathological finding and is strongly associated with azotemia severity, anemia, proteinuria, and disease progression¹. This makes fibrosis a central determinant of irreversible renal damage rather than a secondary consequence. 

Early Metabolic Disruption: Role of FGF-23 

One of the earliest systemic changes in CKD is disruption of phosphate homeostasis, collectively known as CKD-mineral and bone disorder (CKD-MBD). Fibroblast growth factor-23 (FGF-23), produced by osteocytes and osteoblasts, plays a key role in this process by regulating phosphate and calcitriol metabolism. It increases urinary phosphate excretion and reduces intestinal phosphate absorption through suppression of calcitriol¹. 

Importantly, FGF-23 rises early in CKD, often before hyperphosphatemia or parathyroid hormone changes become evident¹. In cats, elevated FGF-23 is observed even in non-azotemic stages and increases with disease severity^1,2. It has also been detected in geriatric cats that later develop azotemia, suggesting its potential role as an early predictive marker¹. Additionally, increased FGF-23 is seen in cats with elevated SDMA despite normal phosphate levels, indicating early phosphate dysregulation³. These findings support FGF-23 as an early metabolic warning signal of CKD progression^1,4, although overlap between healthy and diseased cats limits individual diagnostic precision. 

Fibrosis as the Central Driver of Progression 

While metabolic changes occur early, fibrosis determines irreversible structural damage. Transforming growth factor-beta 1 (TGF-β1) is the most important profibrotic cytokine involved in this process. It is released in response to renal injury such as hypoxia, proteinuria, oxidative stress, and activation of the renin-angiotensin system. Once activated, it promotes extracellular matrix deposition, myofibroblast formation, and tubular epithelial apoptosis¹. 

In feline CKD, urinary TGF-β1 is significantly higher than in healthy cats and correlates with interstitial fibrosis severity. Serum levels do not reflect these changes, making urinary measurement more clinically relevant. Importantly, increased urinary TGF-β1 has been detected months before azotemia develops in non-azotemic cats that later progress to CKD¹. This indicates that fibrotic signaling is active well before conventional biomarkers detect disease. 

Procollagen type III amino-terminal propeptide (PIIINP) further reflects extracellular matrix remodeling. Increased urinary PIIINP in CKD cats correlates with renal stiffness and fibrotic burden, reinforcing its role as a structural damage marker⁵. 

Oxidative Stress and Vascular Changes 

Oxidative injury also contributes to early CKD progression. F2-isoprostanes, markers of lipid peroxidation, are elevated in early CKD stages in cats, suggesting active oxidative stress during disease initiation. However, levels decrease in advanced stages, likely due to loss of functional renal tissue. Hyperthyroidism can also elevate these markers, indicating systemic metabolic influence¹. 

Vascular endothelial growth factor (VEGF) is essential for maintaining renal microvascular integrity. In CKD cats, urinary VEGF is reduced compared to healthy cats, suggesting loss of vascular support. However, in hyperthyroid cats, VEGF increases and decreases after treatment, indicating complex regulation influenced by systemic disease¹. This suggests VEGF reflects both adaptive and degenerative vascular responses. 

Clinical Interpretation: A Multilayer Disease Model 

Together, these biomarkers highlight CKD as a continuum of metabolic, structural, and vascular injury rather than a single functional decline. 

FGF-23 identifies early phosphate dysregulation, TGF-β1 signals active fibrotic progression, PIIINP reflects extracellular matrix remodeling, F2-isoprostanes indicate oxidative injury, and VEGF reflects vascular integrity changes. 

A key clinical challenge is that all these markers show overlap between healthy, early CKD, and advanced disease groups. This limits their use as standalone diagnostic tools but supports their value in combined interpretation and longitudinal monitoring. 

Conclusion 

Feline CKD progression is driven by interconnected pathways involving metabolic imbalance, oxidative stress, vascular dysfunction, and fibrosis. Biomarkers such as FGF-23, TGF-β1, PIIINP, VEGF, and F2-isoprostanes provide complementary insights into these processes. 

Although none are yet definitive for individual diagnosis, together they represent a shift toward understanding CKD as an active biological process long before azotemia appears. This opens the door for earlier identification of at-risk cats and more targeted intervention strategies in clinical practice. 

References 

1. Kongtasai T, Paepe D, Meyer E, Mortier F, Marynissen S, Stammeleer L, Defauw P, Daminet S. Renal biomarkers in cats: A review of the current status in chronic kidney disease. Journal of veterinary internal medicine. 2022 Mar;36(2):379-96. https://academic.oup.com/jvim/article-pdf/36/2/379/66666729/jvim16377.pdf 

2. Liao YL, Chou CC, Lee YJ. The association of indoxyl sulfate with fibroblast growth factor-23 in cats with chronic kidney disease. Journal of Veterinary Internal Medicine. 2019 Mar;33(2):686-93. https://academic.oup.com/jvim/article-pdf/33/2/686/66659645/jvim15457.pdf 

3. Sargent HJ, Jepson RE, Chang YM, Biourge VC, Bijsmans ES, Elliott J. Fibroblast growth factor 23 and symmetric dimethylarginine concentrations in geriatric cats. Journal of veterinary internal medicine. 2019 Nov;33(6):2657-64. https://academic.oup.com/jvim/article-pdf/33/6/2657/66656463/jvim15590.pdf 

4. van den Broek DH, Chang YM, Elliott J, Jepson RE. Prognostic importance of plasma total magnesium in a cohort of cats with azotemic chronic kidney disease. Journal of veterinary internal medicine. 2018 Jul 1;32(4):1359-71. https://academic.oup.com/jvim/article-pdf/32/4/1359/66670955/jvim15141.pdf 
5. Thanaboonnipat C, Sutayatram S, Buranakarl C, Choisunirachon N. Renal shear wave elastography and urinary procollagen type III amino-terminal propeptide (uPIIINP) in feline chronic kidney disease. BMC veterinary research. 2019 Feb 11;15(1):54. https://link.springer.com/content/pdf/10.1186/s12917-019-1801-4.pdf