Research in feline medicine currently focuses on the search for convenient and cost-effective methods to identify cats with early chronic kidney disease (CKD). Serum urea and creatinine are rather insensitive markers for glomerular filtration rate (GFR) and exceed the reference interval only in a late stage of the disease, limiting the therapeutic options. Earlier detection of kidney dysfunction will allow more rapid therapeutic intervention leading to better quality of life and probably prolonged lifetime. Determination of GFR is the best method to evaluate kidney function, but has several practical limitations to be routinely used. Therefore, an obvious need exists for new indirect markers to estimate GFR in order to diagnose CKD more timely, preferably in the non-azotemic stage. Cystatin C, symmetric dimethylarginine (SDMA) and fibroblast growth factor-23 (FGF-23) have been studied recently.

Cystatin C is a low-molecular-weight protein produced at constant rate by all nucleated cells that meets the criteria required for endogenous GFR markers. Serum Cystatin C has important advantages over serum creatinine to assess renal function, both in humans and in dogs.¹ Recently, the value of serum Cystatin C to detect feline CKD was investigated by our research group at Ghent University. Although the initial results of the analytical² and biological³ validation were promising, serum Cystatin C could not differentiate healthy cats from cats with CKD and was poorly correlated with GFR. So, serum Cystatin C measured with the available human assays (particle-enhanced nephelometric or turbidimetric immunoassay) is not a reliable marker to evaluate feline kidney function.⁴

SDMA, a byproduct of protein methylation that is released into circulation after proteolysis and excreted primarily (≥90%) by renal clearance, offers promise to detect early feline kidney dysfunction. SDMA correlates well with serum creatinine and GFR, remains stable under storage conditions used in practice and is nowadays available in many countries.^5-7 More importantly, SDMA appears to be a more sensitive biomarker for assessing renal dysfunction than serum creatinine. In a retrospective evaluation of cats developing CKD, SDMA exceeded the reference interval on average 17 months prior to serum creatinine.⁵ Therefore, non-azotemic cats with persistently increased SDMA concentrations (>14 µg/ dL) should be managed as CKD IRIS stage 1 patients. Further, SDMA is not influenced by muscle mass, which is a major advantage over serum creatinine.⁶ In cats with CKD that present with obvious muscle wasting, SDMA might give a more accurate estimate of kidney dysfunction than serum creatinine. Although SDMA appears to have many advantages, further studies are still needed, mainly to assess the influence of non-renal factors on SDMA concentrations.

FGF-23, a phosphaturic hormone secreted in response to hyperphosphatemia, predicts the development of azotemia in geriatric cats and progressively increases with more advanced CKD.^8,9 Additionally, elevated FGF-23 at diagnosis of CKD is associated with an increased risk of progression and mortality.¹⁰ Further studies will need to reveal the practical value of FGF-23 as a marker for early diagnosis or disease progression of feline CKD.

Another pathway to identify kidney disease is by assessment of urinary biomarkers for tubular or glomerular damage. Retinol-binding protein, N-acetyl-β-glucosaminidase activity, urinary Cystatin C, transforming growth factor-β1, interleukin-8, kidney injury molecule-1 and (micro)albuminuria are promising candidates as urinary biomarkers for cats. In humans, detection of microalbuminuria is an important screening tool for CKD. Also, careful selection of biomarkers will allow detection of site-specific changes (glomerular versus tubular). In contrast, the clinical significance of microalbuminuria in cats remains unclear and the measurement of urinary albumin:creatinine ratio lacks benefit over urinary protein:creatinine ratio. Whether other urinary biomarkers have benefit over routine variables to detect early feline CKD is currently unknown. Because most cats with CKD predominantly have tubulointerstitial lesions, tubular markers are most promising. Looking to the future, it is not unlikely that one or more urinary biomarkers will become part of the diagnostic panel for early detection of feline CKD.

References

1.  Ghys LFE, Paepe D, Smets P, et al. Cystatin C: a new GFR marker and its potential use in small animal medicine. J Vet Intern Med. 2014;28:1152–1164.

2.  Ghys LFE, Meyer E, Paepe D, et al. Analytical validation of a human particle-enhanced nephelometric assay for cystatin C measurement in feline serum and urine. Vet Clin Pathol. 2014;43:226–234.

3.  Ghys L, Paepe D, Duchateau L, et al. Biological validation of feline serum cystatin C: the effect of breed, age and sex and establishment of a reference interval. Vet J. 2015;204:168–173.

4.  Ghys LFE, Paepe D, Lefebvre HP, et al. Evaluation of Cystatin C for the detection of chronic kidney disease in cats. J Vet Intern Med. 2015 (In Press).

5.  Hall JA, Yerramilli M, Obare E, et al. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in cats with chronic kidney disease. J Vet Intern Med. 2014;28:1676–1683.

6.  Hall JA, Yerramilli M, Obare E, et al. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in healthy geriatric cats fed reduced protein foods enriched with fish oil, L-carnitine and medium-chain triglycerides. Vet J. 2014;202:588–596.

7.  Nabity MB, Lees GE, Boggess MM, et al. Symmetric dimethylarginine assay validation, stability, and evaluation as a marker for the early detection of chronic kidney disease in dogs. J Vet Intern Med. 2015;29:1036–1044.

8.  Finch NC, Geddes RF, Syme HM, Elliott J. Fibroblast growth factor 23 (FGF-23) concentrations in cats with early nonazotemic chronic kidney disease (CKD) and in healthy geriatric cats. J Vet Intern Med. 2013;27:227–233.

9.  Geddes RF, Finch NC, Elliott J, Syme HM. Fibroblast growth factor 23 in feline chronic kidney disease. J Vet Intern Med. 2013;27:234–241.

10. Geddes RF, Elliott J, Syme HM. Relationship between plasma fibroblast growth factor-23 concentration and survival time in cats with chronic kidney disease. J Vet Intern Med. 2015;29:1494–1501.