Update on biomarkers in feline chronic kidney disease

Main Article Content

Kakanang Piyarungsri


Chronic kidney disease (CKD) is one of the most commonly found in geriatric cats. The gold standard for identifying renal function is measurement of glomerular filtration rate (GFR), but it is difficult to perform and rarely done in veterinary practice. To assess the renal function, increased serum creatinine and blood urea nitrogen (BUN) or decreased urine specific gravity (USG) are routinely diagnosed kidney disease in cats. However, the kidney disease was detected from these diagnoses when kidney function had decreased more than 75%. Therefore, the assessment of renal function need for the diagnostic tools which early identify performance charge of kidney function. This article reviews the reports of feline CKD biomarkers and discusses their use in early detecting feline CKD. The renal biomarkers may replace the difficult procedure for the assessment of progressive kidney disease and early identify kidney damage

Article Details

How to Cite
Piyarungsri, K. (2017). Update on biomarkers in feline chronic kidney disease. Veterinary Integrative Sciences, 15(3), 207–211. Retrieved from https://he02.tci-thaijo.org/index.php/vis/article/view/145719
Review Article


Al-Ghazlat, S.A., Langston, C.E., Greco, D.S., Reine, N.J., May, S.N., Shofer, F.S., 2011. The prevalence of microalbuminuria and proteinuria in cats with diabetes mellitus. Top. Companion Anim. Med. 26, 154–157.

Arata, S., Ohmi, A., Mizukoshi, F., Baba, K., Ohno, K., Setoguchi, A., Tsujimoto, H., 2005. Urinary transforming growth factor-beta1 in feline chronic renal failure. J. Vet. Med. Sci. 67, 12531255.

Bishop, S.A., Lucke, V.M., Stokes, C.R., Gruffydd-Jones, T.J., 1991. Plasma and urine biochemical changes in cats with experimental immune complex glomerulonephritis. J. Comp. Pathol. 104, 65–76.

Bourbouze, R., Baumann, F.C., Bonvalet, J.P., Farman, N., 1984. Distribution of N-acetyl-beta-Dglucosaminidase isoenzymes along the rabbit nephron. Kidney Int. 25, 636-642.

Braff, J., Obare, E., Yerramilli, M., Elliott, J., Yerramilli, M., 2014. Relationship between serum symmetric dimethylarginine concentration and glomerular filtration rate in cats. J. Vet. Intern. Med. 28, 1699-1701.

Brown, S.A., 2004. Pathogenesis and pathophysiology of renal disease. Proceeding of 3rd-5th Hill’s European Symposium on Chronic Renal Disease, 14-23.

Chakrabarti, S., Syme, H.M., Brown, C.A., Elliott, J., 2013. Histomorphometry of feline chronic kidney disease and correlation with markers of renal dysfunction. Vet. Pathol. 50, 147-155.

Conti, M., Moutereau, S., Zater, M., Lallali, K., Durrbach, A., Manivet, P., Eschwège, P., Loric, S., 2006. Urinary cystatin C as a specific marker of tubular dysfunction. Clin. Chem. Lab. Med. 44, 288-291.

Eddy, A.A., Giachelli, C.M., 1995. Renal expression of genes that promote interstitial inflammation and fibrosis in rats with protein-overload proteinuria. Kidney Int. 47, 1546-1557.

Elliot, J., Barber, P., 1998. Feline chronic renal failure: clinical findings in 80 cases diagnosed between 1992 and 1995. J. Small Anim. Pract. 39, 78-85.

Elliott, J., Rawlings, J.M., Markwell, P.J., Barber, P.J., 2000. Survival of cats with naturally occurring chronic renal failure: effect of dietary management. J. Small Anim. Pract. 41, 235-242.

Fernández-Fresnedo, G., Ramos, M.A., González-Pardo, M.C., de Francisco, A.L., López-Hoyos, M., Arias, M., 2000. B lymphopenia in uremia is related to an accelerated in vitro apoptosis and dysregulation of Bcl-2. Nephrol. Dial. Transplant. 15, 502-510.

Finch, N.C., Geddes, R.F., Syme, H.M., Elliott, J., 2013. 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. 27, 227-233.

Geddes, R.F., Elliott, J., Syme, H.M., 2013. The effect of a feeding renal diet on plasma fibroblast growth factor 23 concentrations in cats with stable azotemic chronic kidney disease. J. Vet. Intern. Med. 27, 1354-1361.

Ghys, L.F., Meyer, E., Paepe, D., Delanghe, J., Daminet, S., 2014. Analytical validation of a human particle-enhanced nephelometric assay for cystatin C measurement in feline serum and urine. Vet. Clin. Pathol. 43, 226-234.

Habenicht, L.M., Webb, T.L., Clauss, L.A., Dow, S.W., Quimby, J.M., 2013. Urinary cytokine levels in apparently healthy cats and cats with chronic kidney disease. J. Feline Med. Surg. 15, 99-104.

Hall, J.A., Yerramilli, M., Obare, E., Yerramilli, M., Jewell, D.E., 2014. Comparison of serum concentrations of symmetric dimethylarginine and creatinine as kidney function biomarkers in cats with chronic kidney disease. J. Vet. Intern. Med. 28, 16761683.

Hall l, J.A., Yerramilli, M., Obare, E., Yerramilli, M., Yu, S., Jewell, D.E., 2015. 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 mediumchain triglycerides. J. Vet. Intern. Med. 29, 10361044.

Hall, J.A., Yerramilli, M., Obare, E., Li, J., Yerramilli, M., Jewell, D.E., 2017. Serum concentrations of symmetric dimethylarginine and creatinine in cats with kidney stones. PLoS One. 12, e0174854.

Hao, J., Ju, H., Zhao, S., Junaid, A., Scammell-La Fleur, T., Dixon, I.M., 1999. Elevation of expression of Smads 2, 3, and 4, decorin and TGF-beta in the chronic phase of myocardial infarct scar healing. J. Mol. Cell. Cardiol. 31, 667-678.

Harte, J.G., Markwell, P.J., Moraillon, R.M., Gettinby, G.G., Smith, B.H.E., Wills, J.M., 1994. Dietary Management of Naturally Occurring Chronic Renal Failure in Cats. J. Nurt. 124, 2660S-2662S.

Hattori, T., Shindo, S., Kawamura, H., 1998. Apoptosis and expression of Bax protein and Fas antigen in glomeruli of a remnant-kidney model. Nephron. 79, 186–191.

Hofmann-Lehmann, R., Holznagel, E., Ossent, P., Lutz, H., 1997. Parameters of disease progression in long-term experimental feline retrovirus (feline immunodeficiency virus and feline leukemia virus) infections: hematology, clinical chemistry, and lymphocyte subsets. Clin. Diagn. Lab. Immunol. 4, 33-42.

Hsu, W.L., Lin, Y.S., Hu, Y.Y., Wong, M.L., Lin, F.Y., Lee, Y.J., 2014. Neutrophil gelatinase-associated lipocalin in dogs with naturally occurring renal diseases. J. Vet. Intern. Med. 28, 437-442.

Huang, L., Haylor, J.L., Hau, Z., Jones, R.A., Vickers, M.E., Wagner, B., Griffin, M., Saint, R.E., Coutts, I.G., El Nahas, A.M., Johnson, T.S., 2009. Transglutaminase inhibition ameliorates experimental diabetic nephropathy. Kidney Int. 76, 383-394.

Inker, L.A., Schmid, C.H., Tighiouart, H., Eckfeldt, J.H., Feldman, H.I., Greene, T., Kusek, J.W., Manzi, J., Van Lente, F., Zhang, Y.L., Coresh, J., Levey, A.S., 2012. Estimating glomerular filtration rate from serum creatinine and cystatin C. N. Engl. J. Med. 367, 20-29.

Jepson, R.E., Brodbelt, D., Vallance, C., Syme, H.M., Elliott, J., 2009. Evaluation of predictors of the development of azotemia in cats. J. Vet. Intern. Med. 23, 806-813.

Jepson, R.E., Syme, H.M., Vallance, C., Elliott, J., 2008. Plasma asymmetric dimethylarginine, symmetric dimethylarginine, l-arginine, and nitrite/nitrate concentrations in cats with chronic kidney disease and hypertension. J. Vet. Intern. Med. 22, 317-324.

Jepson, R.E., Vallance, C., Syme, H.M., Elliott, J., 2010. Assessment of urinary N-acetyl-beta-Dglucosaminidase activity in geriatric cats with variable plasma creatinine concentrations with and without azotemia. Am. J. Vet. Res. 71, 241247.

Johnson, T.S., El-Koraie, A.F., Skill, N.J., Baddour, N.M., El Nahas, A.M., Njloma, M., Adam, A.G., Griffin, M., 2003. Tissue transglutaminase and the progression of human renal scarring. J. Am. Soc. Nephrol. 14, 2052-2062.

Kai, K., Yamaguchi, T., Yoshimatsu, Y., Kinoshita, J., Teranishi, M., Takasaki, W., 2013. Neutrophil gelatinase-associated lipocalin, a sensitive urinary biomarker of acute kidney injury in dogs receiving gentamicin. J. Toxicol. Sci. 38, 269277.

Kjeldsen, L., Cowland, J.B., Borregaard, N., 2000. Human neutrophil gelatinase-associated lipocalin and homologous proteins in rat and mouse. Biochim. Biophys. Acta. 1482, 272-283.

Kralova-Kovarikova, S., Leva, L., Knotek, Z., Toman, M., 2016. Changes in lymphocyte function and subset counts in cats with spontaneous chronic kidney disease. Vet. Med. (Praha). 61, 553-559.

Krofic Zel, M., Tozon, N., Nemec Svete, A., 2014. Plasma and erythrocyte glutathione peroxidase activity, serum selenium concentration, and plasma total antioxidant capacity in cats with IRIS stages I-IV chronic kidney disease. J. Vet. Intern. Med. 28, 130-136.

Lapointe, C., Bélanger, M.C., Dunn, M., Moreau, M., Bédard, C., 2008. N-acetyl-beta-Dglucosaminidase index as an early biomarker for chronic kidney disease in cats with hyperthyroidism. J. Vet. Intern. Med. 22, 11031110.

Lawler, D.F., Evans, R.H., Chase, K., Ellersieck, M., Li, Q., Larson, B.T., Satyaraj, E., Heininger, K., 2006. New perspectives the aging feline kidney: a model mortality antagonist. J. Feline Med. Surg. 8, 363-371.

Lee, Y.J., Hu, Y.Y., Lin, Y.S., Chang, C.T., Lin, F.Y., Wong, M.L., Kuo-Hsuan, H., Hsu, W.L., 2012. Urine neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute canine kidney injury. BMC Vet. Res. 8, 248.

Lund, E., Armstrong, P.J., Kirk, C.A., Kolar, L.M., Klausner, J.S., 1999. Health status and population characteristics of dogs and cats examined at private veterinary practices in the United States. J. Am. Vet. Med. Assoc. 214, 13361341.

Marescau, B., Nagels, G., Possemiers, I., De Broe, M.E., because, I., Billiouw, J.M., Lornoy, W., De Deyn, P.P., 1997. Guanidino compounds in serum and urine of nond ialyzed patients with chronic renal insufficiency. Metabolism. 46, 1024-1031.

Mayer-Roenne, B., Goldstein, R.E., Erb, H.N., 2007. Urinary tract infections in cats with hyperthyroidism, diabetes mellitus and chronic kidney disease. J. Feline. Med. Surg. 9, 124132.

Minkus, G., Reusch, C., Hörauf, A., Breuer, W., Darbès, J., Kraft, W., Hermanns, W., 1994. Evaluation of renal biopsies in cats and dogs-histopathology in comparison with clinical data. J. Small Anim. Pract. 35, 465-472.

Mishra, J., Dent, C., Tarabishi, R., Mitsnefes, M.M., Ma, Q., Kelly, C., Ruff, S.M., Zahedi, K., Shao, M., Bean, J., Mori, K., Barasch, J., Devarajan, P., 2005. Neutrophil gelatinase-associated lipocalin (NGAL) as a biomarker for acute renal injury after cardiac surgery. Lancet. 365, 1231-1238.

Mishra, J., Mori, K., Ma, Q., Kelly, C., Barasch, J., Devarajan, P., 2004. Neutrophil gelatinaseassociated lipocalin: a novel early urinary biomarker for cisplatin nephrotoxicity. Am. J. Nephrol. 24, 307-315.

Miyazaki, M., Kamiie, K., Soeta, S., Taira, H., Yamashita, T., 2003. Molecular cloning and characterization of a novel carboxylesterase-like protein that is physiologically present at high concentrations in the urine of domestic cats (Felis catus). Biochem J 370, 101-110.

Miyazaki, M., Soeta, S., Yamagishi, N., Taira, H., Suzuki, A., Yamashita, T., 2007. Tubulointerstitial nephritis causes decreased renal expression and urinary excretion of cauxin, a major urinary protein of the domestic cat. Res. Vet. Sci. 82, 76-79.

Miyazaki, M., Yamashita, T., Hosokawa, M., Taira, H., Suzuki, A., 2006. Species-, sex-, and agedependent urinary excretion of cauxin, a mammalian carboxylesterase. Comp Biochem Physiol B Biochem Mol Biol. 145, 270-277.

Nath, K.A., 1992. Tubulointerstitial changes as a major determinant in the progression of renal damage. Am. J. Kidnary Dis. 20, 1-17.

Newman, D.J., Thakkar, H., Edwards, R.G., Wilkie, M., White, T., Grubb, A.O., Price, C.P., 1995. Serum cystatin C measured by automated immunoassay: a more sensitive marker of
changes in GFR than serum creatinine. Kidney Int. 47, 312-318.

Orphanides, C., Fine, L.G., Norman, J.T., 1997. Hypoxia stimulates proximal tubular cell matrix production via a TGF-beta1-independent mechanism. Kidney Int. 52, 637-647.

Paepe, D., Ghys, L.F., Smets, P., Lefebvre, H.P., Croubels, S., Daminet, S., 2014. Routine kidney variables, glomerular filtration rate and urinary cystatin C in cats with diabetes mellitus, cats with chronic kidney disease and healthy cats. J. Feline Med. Surg. 17, 880-808.

Piyarungsri, K., Pusoonthornthum, R., 2017. Risk and protective factors for cats with naturally occurring chronic kidney disease J. Feline Med. Surg. 19, 358-363.

Piyarungsri, K., Pusoonthornthum, R., 2016. Changes in reduced glutathione, oxidized glutathione, and glutathione peroxidase in cats with naturally occurring chronic kidney disease. Comp. Clin. Path. 25, 655-662.

Poli, A., Tozon, N., Guidi, G., Pistello, M., 2014. Renal alterations in feline immunodeficiency virus (FIV)-infected cats: a natural model of lentivirusinduced renal disease changes. Viruses. 4, 1372-1389.

Polzin, D.J., 2011. Chronic kidney disease in small animals. Vet Clin North Am Small Anim Pract. 4, 15-30.

Pusoonthornthum, R., Pusoonthornthum, P., Krishnamra, N., 2010. Calcium-phosphorus homeostasis and changes in parathyroid hormone secretion in cats with various stages of spontaneous chronic renal failure. Comp. Clin. Path. 19, 287-293.

Rodriguez, J., Blais, M.C., Lapointe, C., Arsenault, J., Carioto, L., Harel, J., 2014. Serologic and urinary PCR survey of leptospirosis in healthy cats and in cats with kidney disease. J. Vet. Intern. Med. 28, 284-293.

Sánchez-Lara, A.C., Elliott, J., Syme, H.M., Brown, C.A., Haylor, J.L., 2015. Feline chronic kidney disease is associated with upregulation of transglutaminase 2: a collagen cross-linking enzyme. Vet. Pathol. 52, 513-523.

Sato, R., Soeta, S., Syuto, B., Yamagishi, N., Sato, J., Naito, Y., 2002. Urinary excretion of N-acetylbeta-D-glucosaminidase and its isoenzymes in cats with urinary disease. J. Vet. Med. Sci. 64, 367-371.

Shin, D.M., Jeon, J.H., Kim, C.W., Cho, S.Y., Lee, H.J., Jang, G.Y., Jeong, E.M., Lee, D.S., Kang, J.H., Melino, G., Park, S.C., Kim, I.G., 2008. TGFbeta mediates activation of transglutaminase 2 in response to oxidative stress that leads to protein aggregation. FASEB J. 22, 2498-2507.

Shweke, N., Boulos, N., Jouanneau, C., Vandermeersch, S., Melino, G., Dussaule, J.C., Chatziantoniou, C., Ronco, P., Boffa, J.J., 2008. Tissue transglutaminase contributes to interstitial renal fibrosis by favoring accumulation of fibrillar collagen through TGF-beta activation and cell infiltration. Am. J. Pathol. 173, 631-342.

Smets, P.M., Meyer, E., Maddens, B., Duchateau, L., Daminet, S., 2010. Effect of sampling method and storage conditions on albumin, retinolbinding protein, and N-acetyl-ß-Dglucosaminidase concentrations in canine urine samples. J. Vet. Diagn. Invest. 22, 896-902.

Szekanecz, Z., Haines, G.K., Harlow, L.A., Shah, M.R., Fong, T.W., Fu, R., Lin, S.J., Rayan, G., Koch, A.E., 1995. Increased synovial expression of transforming growth factor (TGF)-beta receptor endoglin and TGF-beta 1 in rheumatoid arthritis: possible interactions in the pathogenesis of the disease. Clin. Immunol. Immunopathol. 76, 187194.

Vallance, P., Leone, A., Calver, A., Collier, J., Moncada, S., 1992. Accumulation of an endogenous inhibitor of nitric oxide synthesis in chronic renal failure. Lancet. 339, 572-575. van Hoek, I., Daminet, S., Notebaert, S., Janssens, I., Meyer, E., 2008. Immunoassay of urinary retinol binding protein as a putative renal marker in cats. J. Immunol. Methods. 329, 208–213.

Veis, D.J., Sorenson, C.M., Shutter, J.R., Korsmeyer, S.J., 1991. Bcl-2-deficient mice demonstrate fulminant lymphoid apoptosis, polycystic kidneys, and hypopigmented hair. Cell. 75, 229– 240.

Viau, A., El Karoui, K., Laouari, D., Burtin, M., Nguyen, C., Mori, K., Pillebout, E., Berger, T., Mak, T.W., Knebelmann, B., Friedlander, G., Barasch, J., Terzi, F., 2010. Lipocalin 2 is essential for chronic kidney disease progression in mice and humans. J. Clin. Invest. 120, 4065-4076.

Wang, I.C., Hsu, W.L., Wu, P.H., Yin, H.Y., Tsai, H.J., Lee, Y.J., 2017. Neutrophil gelatinase- associated lipocalin in cats with naturally occurring chronic kidney disease. J. Vet. Intern. Med. 31, 102–108.

Watson, A., 2001. Indicators of renal insufficiency in dogs and cats presented at a veterinary teaching hospital. Aust. Vet. Pract. 31, 54-58.

Webb, C.B., Falkowski, L., 2009. Oxidative stress and innate immunity in feline patients with diabetes mellitus: the role of nutrition. J. Feline Med. Surg. 11, 271-276.

White, J.D., Malik, R., Norris, J.M., Malikides, N., 2010. Association between naturally occurring chronic kidney disease and feline immunodeficiency virus infection status in cats. J. Am. Vet. Med. Assoc. 236, 424-429.

White, J.D., Norris, J.M., Baral, R.M., Malik, R., 2006. Naturally occurring chronic renal disease in Australian cats: a prospective study of 184 cases. Aust. Vet. J. 84, 188-194. Wolf, G., 2006. Renal injury due to renin-angiotensinaldosterone system activation of the transforming growth factor-beta pathway. Kidney Int. 70, 1914-1919.

Wu, F., Dassopoulos, T., Cope, L., Maitra, A., Brant, S.R., Harris, M.L., Bayless, T.M., Parmigiani, G., Chakravarti, S., 2007. Genome-wide gene expression differences in Crohn's disease and ulcerative colitis from endoscopic pinch biopsies: insights into distinctive pathogenesis. Inflamm Bowel Dis. 13, 807-821.

Yabuki, A., Mitani, S., Fujiki, M., Misumi, K., Endo, Y., Miyoshi, N., Yamato, O., 2010. Comparative study of chronic kidney disease in dogs and cats: Induction of myofibroblasts. Res. Vet. Sci. 88, 294-299.

Yamamoto, T., Noble, N.A., Cohen, A.H., Nast, C.C., Hishida, A., Gold, LI., Border, W.A., 1996. Expression of transforming growth factor-beta isoforms in human glomerular diseases. Kidney Int. 49, 461-469.

Yang, B., Johnson, T.S., Thomas, G.L., Watson, P.F., Wagner, B., Skill, N.J., Haylor, J.L., El Nahas, A.M., 2001. Expression of apoptosis-related genes and proteins in experimental chronic renal scarring. J. Am. Sos. nephrol. 12, 275-288.

Zhou, X., Ma, B., Lin, Z., Qu, Z., Huo, Y., Wang, J., Li, B., 2014. Evaluation of the usefulness of novel biomarkers for drug-induced acute kidney injury in beagle dogs. Toxicol. Appl. Pharmacol. 280, 30-35.