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Potential urinary biomarkers of feline CKD

Whitehouse W, Quimby J, et al. Urinary F2-Isoprostanes in Cats with International Renal Interest Society Stage 1–4 Chronic Kidney Disease . J Vet Intern Med. 2017;31:449–456.

F2-isoprostanes are an established biomarker of oxidative injury in humans.  They produced locally in the kidneys, formed by non-enzymatic, free radical catalyzed lipid peroxidation of arachidonic acid.  Within the human population, most studies of patients with chronic disease indicate that urinary levels are considered equivalent to plasma measurements.  F2-isoprostanes have potent bioactivity, including renal arterial vasoconstriction.

The authors hypothesized that urinary F2-isoprostanes would increase by IRIS stage in cats, as they have been noted to in humans.  The authors proposed that urinary F2-isprostanes might serve as a biomarker of chronic kidney disease (CKD) progression in cats, as well as a potential target for therapeutic intervention.
The study design was prospective observational.  Five groups of cats were included in the study, those over 5 years of age without evidence of CKD (n=11), and those with CKD in IRIS stages 1 (n=8), 2 (n=38), 3 (n=21) and 4 (n=10).

Urinary F2-isoprostanes were normalized to urine creatinine (IsoP).  The levels were compared among groups and assessed for correlation with blood pressure, proteinuria, serum creatinine and urine specific gravity.  The IsoPs were compared between cats with and without hypertension, those with and without proteinuria and in cats fed standard versus renal diets.

The authors found that urinary IsoPs were increased in cats with stage I CKD compared to mature control cats.  This increase was not statistically significant.  Cats with IRIS stage 1 CKD had significantly increased IsoP values compared to cats in stage 2, stage 3 and stage 4.  Cats with IRIS Stage 2 had significantly increased IsoPs compared to cats in stage 3 and stage 4.  The IsoP levels were significantly lower in cats in Stage 3 and 4 compared with normal healthy controls.  The urinary IsoP was found to be inversely correlated with serum creatinine, and positively correlated with USG.

There was no statistically significant difference in urinary IsoPs between hypertensive and non-hypertensive CKD cats, proteinuric and non-proteinuric CKD cats and CKD cats on standard versus renal diets.  No correlation was found between urinary IsoP and systolic blood pressure or urinary IsoP and UPC.

The authors concluded that their initial hypothesis was proven incorrect.  It would appear that IsoPs do not increase with increasing IRIS stage, but seem to be highest early in disease.  This study assumed that urinary and plasma F2-isoprostanes measurements are equivalent in most patients with chronic disease.  A caveat to this assumption is that this may not be the case in patients with CKD, which could result in misinterpretation of the significance of urinary IsoPs.

In general, however, it appears that IsoP is inversely correlated with serum creatinine and positively correlated with USG, suggestive that renal oxidative stress may be highest in the early stages of CKD in cats.  This finding may be useful in the ongoing search for biomarkers of early feline CKD, as well as targets for therapeutic intervention in feline CKD. The authors suggest several additional studies including those with larger study groups in each of the areas of interest.  A study of the relevance of fatty acid supplements and/or renal diets is also suggested. Controlling for variability in fatty acid levels in various diets would be challenging at best.  Body condition and muscle condition, as well as SDMA levels might be taken into consideration in future studies to better control for variables which impact renal health and IRIS staging. (KSD)

See also:
Reynolds BS, Lefebvre HP. Feline CKD: Pathophysiology and risk factors–what do we know? J Feline Med Surg. 2013 Sep;15 Suppl 1:3-14.