Changes in renal endothelin activity with cardiac, renal and other chronic diseases in dogs

Pathways that disrupt the cardiovascular-renal axis in dogs are incompletely defined. The renal endothelin (ET-1) system may play a key role because it regulates blood pressure and sodium homeostasis in the kidney, but also mediates vascular dysfunction and pro-fibrotic/inflammatory changes that increase cardiovascular risk in people. Urinary ET-1 (UET-1) is a marker of renal vascular and tubular ET-1 activity, and so could provide insight into changes in renal ET-1 signalling that contribute to cardiovascular-renal interactions in dogs. We hypothesised that renal ET-1 activity increases in advanced canine chronic cardiac and renal diseases. In this pilot study, we compared UET-1 and cystatin C (a marker of renal injury/dysfunction) concentrations in surplus urine from four groups of dogs presented to the R(D)SVS: healthy (n=18), chronic kidney disease (CKD; IRIS stages 2-4; serum creatinine 257µmol/l, IQR395; n=11) cardiac disease (ACVIM classification B1-C; n=39) and non-cardiorenal chronic disease (n=14). Urine was free-catch and owner-collected on the morning of appointment. Samples were excluded if they contained active sediment, and were stored at -80ºC before batch analysis. Both UET-1 and cystatin C were measured by commercial ELISAs and indexed to urinary creatinine concentration (enzymatic method). Comparisons by one-way ANOVA yielded non-transformable residuals so Kruskal-Wallis with Dunn’s post hoc tests were used (significance P<0.05). There was a marked increase in UET-1 excretion in dogs with stage C heart disease (0.69, IQR 1.61pg/mg; n=11) compared to healthy dogs (0.02pg/mg, IQR 0.11; P=0.02). UET-1 excretion was also increased in stage B2 heart disease (0.25pg/mg, IQR 1.70; P=0.03; n=19) although to a lesser degree. This was predominantly due to increases in dogs with MMVD (0.38pg/mg, IQR 1.75; P=0.046; n=7) rather than those with non-MMVD cardiac diseases (0.23pg/mg, IQR 0.91). Numerical increases in UET-1 in CKD and chronic disease groups were not statistically significant. By contrast, CKD markedly increased urinary cystatin C excretion from below limits of detection to (0.53ng/mg, IQR 2.44; P<0.0001), while only modest increases (P=0.03) were observed in dogs with chronic disease (0.02ng/mg, IQR 0.07), and none at all in heart disease stages B1-C. Renal ET-1 activity increases with congestive heart failure, but surprisingly, also increases in MMVD before congestion develops. Neither increase is associated with renal injury or is a consequence of a chronic disease state. Renal ET-1 may mediate pathophysiological cardiovascular-renal interactions in MMVD that are different to those in isolated CKD and the development of congestive heart failure.