Urinary active transforming growth factor β in feline chronic kidney disease

J.S Lawson,H.M Syme,C.P.D Wheeler-Jones,J Elliott

doi:10.1016/j.tvjl.2016.02.004

Abstract

The cytokine transforming growth factor beta 1 (TGF-β1) has been widely implicated in the development and progression of renal fibrosis in chronic kidney disease (CKD) in humans and in experimental models. The aims of this study were to assess the association between urinary active TGF-β1 and (a) development of CKD in a cross-sectional study, (b) deterioration of renal function over 1 year in a longitudinal study, and (c) renal histopathological parameters in cats. A human active TGF-β1 ELISA was validated for use in feline urine.Cross-sectional analysis revealed no significant difference in urinary active TGF-β1:creatinine ratio (aTGF-β1:UCr) between groups with differing renal function. Longitudinally, non-azotaemic cats that developed CKD demonstrated a significant (P = 0.028) increase in aTGF-β1:UCr approximately 6 months before the development of azotaemia, which remained elevated (P = 0.046) at diagnosis (approximately 12 months prior, 8.4 pg/mg; approximately 6 months prior, 22.2 pg/mg; at CKD diagnosis, 24.6 pg/mg). In the histopathology study, aTGF-β1:UCr was significantly higher in cats with moderate (P = 0.02) and diffuse (P = 0.005) renal fibrosis than in cats without fibrosis. Cats with moderate renal inflammation had significantly higher urinary active aTGF-β1 concentrations than cats with mild (P = 0.035) or no inflammatory change (P = 0.004). The parameter aTGF-β1:UCr was independently associated with Log urine protein:creatinine ratio in a multivariable analysis of clinicopathological parameters and interstitial fibrosis score in a multivariable analysis of histopathological features. These results suggest that urinary aTGF-β1 reflects the severity of renal pathology. Increases in urinary aTGF-β1 followed longitudinally in individual cats may indicate the development of CKD.

Highlights

Chronic kidney disease (CKD) is common in ageing cats, with a prevalence of 28–50% (Lulich et al, 1992; Marino et al, 2014)
The active TGFβ1 peptide must be liberated from the large latent complex (LLC) to exert a biological effect, a process that is initiated by a variety of molecules implicated in extra-cellular matrix (ECM) disruption (Annes et al, 2003)
For the cross-sectional study, cases were classified based upon baseline status and subsequent renal function, resulting in three groups: non-azotaemic cats that remained non-azotaemic for 24 months (NA), non-azotaemic cats that developed azotaemia within 24 months (NA-A), and cats with renal azotaemia at baseline (A)

Summary

Introduction

Chronic kidney disease (CKD) is common in ageing cats, with a prevalence of 28–50% (Lulich et al, 1992; Marino et al, 2014). The cytokine transforming growth factor beta one (TGF-β1) is the most studied pro-fibrotic mediator in human and experimentallyinduced kidney disease. TGF-β1 is secreted as an inactive precursor combined with the latency associated pro-peptide and latent TGF-β binding protein as the large latent complex (LLC). The active TGFβ1 peptide must be liberated from the LLC to exert a biological effect, a process that is initiated by a variety of molecules implicated in extra-cellular matrix (ECM) disruption (Annes et al, 2003). Urinary total TGF-β1 excretion increases in various human renal diseases (De Muro et al, 2004) as a result of increased renal production (Sharma et al, 1997)

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