Tubular Injury Biomarkers in Feline CKD: What Can NGAL, KIM-1 and L-FABP Tell You?

When feline CKD is already suspected, identifying reduced renal function is only part of the clinical picture. The next question is whether the renal tubules are actively injured. This is particularly relevant because tubulointerstitial nephritis is a common lesion in feline CKD and may contribute to the mild proteinuria often seen in affected cats. 

Urinary tubular biomarkers can provide different types of information. Many are low-molecular-weight proteins that are normally reabsorbed by the renal tubules. Tubular damage can increase their urinary concentrations through impaired reabsorption or increased release from injured tubular cells. 

NGAL: A Marker of Tubular Injury, but Not a Renal-Specific Signal^[1] 

Neutrophil gelatinase-associated lipocalin (NGAL) is produced by neutrophils and epithelial cells, including renal tubular cells. Circulating NGAL is filtered and reabsorbed in the proximal tubules, while damaged tubular cells can release additional NGAL. As a result, serum and urinary NGAL may reflect tubular injury. 

In cats, urinary NGAL-to-creatinine ratio (uNGAL/Cr) has shown inconsistent findings. One investigation involving 80 azotemic CKD cats found higher uNGAL/Cr than in 18 healthy cats, particularly in IRIS stages 3–4. However, another small investigation involving 9 CKD cats and 44 healthy cats found no significant difference. Differences between assays may partly explain these conflicting results. 

Interpretation also requires attention to urinary tract disease. Urinary tract infection and pyuria can increase uNGAL, meaning these conditions should be ruled out before attributing an increased result to renal tubular injury. Different molecular forms of NGAL may also provide additional clues: the monomeric form has been associated mainly with azotemic acute kidney injury and advanced CKD, whereas the dimeric form is predominantly associated with urinary tract infection and pyuria. Overall, uNGAL may reflect the severity of azotemia or renal impairment more reliably than the specific type or progression of renal disease. 

L-FABP: A Signal of Active Tubular Stress? 

Liver-type fatty acid-binding protein (L-FABP) is found in proximal tubular epithelial cells and is involved in fatty acid homeostasis and protection against lipid peroxidation products. Urinary L-FABP-to-creatinine ratio (uL-FABP/Cr) has therefore been investigated as a marker of tubular stress and injury. 

In cats, increased uL-FABP/Cr has been reported in hyperthyroid cats and decreased after euthyroidism was achieved. In CKD, concentrations were higher in affected cats than in healthy cats, although there was considerable overlap. A uL-FABP/Cr concentration above 10 μg/g was reported in approximately 50% of azotemic CKD cats compared with 7% of nonazotemic CKD cats. A cutoff of 0.97 μg/g distinguished azotemic CKD cats from healthy cats with 100% sensitivity and 93% specificity^{[2],[3],[4],[5]}. 

These findings suggest that increased urinary L-FABP may indicate active tubular stress or injury. However, the possibility that increased L-FABP in nonazotemic cats predicts future kidney injury still requires confirmation. 

KIM-1: Useful Early, but Timing May Matter^[1] 

Kidney injury molecule-1 (KIM-1) is a membrane glycoprotein that is upregulated in proximal tubular cells following tubular damage. In cats with critical conditions associated with acute kidney injury, urinary KIM-1 has been detected, while it was undetectable in healthy cats. Experimental and naturally occurring acute kidney injury have also been associated with increased KIM-1 expression in proximal tubular cells. 

However, KIM-1 may not remain elevated throughout renal injury. In cats with more extensive tubular loss or fibrosis, the cells responsible for producing the biomarker may no longer be present in sufficient numbers. This could explain why some cats with CKD have shown negative KIM-1 findings. 

Practical Interpretation 

NGAL, L-FABP and KIM-1 offer information about tubular injury rather than simply renal filtration. But none should be interpreted in isolation. NGAL can be affected by urinary tract infection and pyuria, L-FABP requires further evaluation of nonrenal influences, and KIM-1 may depend on the timing and extent of tubular injury. 

For practicing veterinarians, these biomarkers are therefore promising tools for characterising tubular injury, but their clinical interpretation still depends on the overall renal and urinary findings. Their greatest value may come from understanding what type of renal injury is occurring and when, rather than treating an elevated urinary biomarker as a standalone diagnosis.

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. Wang IC, Hsu WL, Wu PH, Yin HY, Tsai HJ, Lee YJ. Neutrophil gelatinase-associated lipocalin in cats with naturally occurring chronic kidney disease. Journal of veterinary internal medicine. 2017 Jan;31(1):102-8. https://academic.oup.com/jvim/article-pdf/31/1/102/66667489/jvim14628.pdf
3. Wu PH, Hsu WL, Tsai PS, Wu VC, Tsai HJ, Lee YJ. Identification of urine neutrophil gelatinase-associated lipocalin molecular forms and their association with different urinary diseases in cats. BMC veterinary research. 2019 Aug 27;15(1):306. https://link.springer.com/content/pdf/10.1186/s12917-019-2048-9.pdf
4. Bland SK, Clark ME, Côté O, Bienzle D. A specific immunoassay for detection of feline kidney injury molecule 1. Journal of Feline Medicine and Surgery. 2019 Dec;21(12):1069-79. https://journals.sagepub.com/doi/pdf/10.1177/1098612X18812494
5. Habenicht LM, Webb TL, Clauss LA, Dow SW, Quimby JM. Urinary cytokine levels in apparently healthy cats and cats with chronic kidney disease. Journal of feline medicine and surgery. 2013 Feb;15(2):99-104. https://journals.sagepub.com/doi/pdf/10.1177/1098612X12461007