Changes in Renal Cortisol Metabolism are Associated with the Development of Canine Congestive Heart Failure

Within the distal nephron, the enzyme 11-beta hydroxysteroid dehydrogenase 2 (11βHSD2) protects the mineralocorticoid receptor (MR) from activation by cortisol, allowing it to interact with aldosterone. In humans, mutations of 11βHSD2 cause apparent mineralocorticoid excess, characterised by sodium and water retention with resultant hypertension. Sodium and water retention is also a hallmark of canine congestive heart failure (CHF). This could partly be explained by dysregulation of renal 11βHSD2 activity, exposing MR to activation by cortisol. The aim of this study was to investigate the activity of renal 11βHSD2 in canine CHF by measuring the concentration of cortisol and its metabolites in the urine from affected dogs. Owners collected urine in a home environment from healthy adult dogs (n = 7), and from dogs prior to presentation with noncardiac chronic disease (n = 6), and dogs with cardiac disease (ISACHCIb, n = 4; ISACHCII or III, n = 5). Levels of cortisol (F) and cortisone (E) excreted in urine were measured by mass spectrometry. Urinary cortisol was normalised to creatinine to account for variations in glomerular filtration rate. Cortisol was also measured in plasma obtained from all unhealthy dogs. Plasma cortisol levels (p = 0.75) and urinary cortisol:creatinine ratio (p = 0.22) did not differ between groups. However, the F/E ratio, was increased in dogs with class II–III heart failure (p = 0.048). An increased F/E ratio, in the presence of unchanged plasma cortisol, implies decreased renal 11βHSD2 activity and enhanced MR activation by cortisol in canine CHF. This data suggests that changes in renal cortisol metabolism in canine CHF cannot be explained by chronicity of disease, that the urinary F/E ratio has potential as a biomarker for canine CHF and that renal 11βHSD2 could offer a therapeutic target in its management. Further studies investigating 11βHSD2 expression and bioactivity in canine CHF are ongoing.