Modification of cardiovascular and renal risk factors using antagonists of the endothelin system

Abstract

Chronic kidney disease (CKD) is an important independent risk factor in the development of cardiovascular disease (CVD). Indeed, patients with CKD are far more likely to die from CVD than reach end stage renal disease. Conventional cardiovascular risk factors and co-morbidity contribute to this increased risk of CVD. However, emerging evidence suggests other novel factors including inflammation, oxidative stress, and a shift in the balance of the vasodilator nitric oxide and vasoconstrictor endothelin system, are also important contributors. Despite increasing evidence that the endothelin system plays an important role in the development of CKD and CVD, there has been little research examining possible therapeutic benefits of its modification in patients with CKD. The overall aims of the work presented within this thesis were to examine CVD risk in patients with renal impairment and then to see what impact chronic inhibition of the endothelin system would have on risk factors for CVD and CKD progression. In the first two studies I examined markers of arterial stiffness (AS) and endothelial function in a cohort of patients with immune-mediated renal disease. I was able to show in the acute setting that improvement in renal function following treatment for these conditions leads to significant improvements in AS. Interestingly, in patients who were in remission from their renal disease, only classical cardiovascular risk factors appear to be linked to AS. In the next study I was able to prove that sitaxsentan, a selective oral ETA antagonist, did not cause functional blockade of the ETB receptor in man. This was the first study of its kind to confirm that a “selective” endothelin antagonist truly is selective in vivo: a finding that will allow more accurate mechanistic investigation of the ET system. In the final studies, I showed that in subjects with stable non-diabetic proteinuric CKD, chronic selective ETA receptor antagonism reduces blood pressure and AS, and that these systemic benefits are associated with an increase in renal blood flow and reduction in proteinuria. The reduction in proteinuria is most likely haemodynamic and linked to a fall in GFR and filtration fraction, similar to what is seen with ACE inhibitors. Importantly, these benefits were seen in patients already taking maximally tolerated renin-angiotensin aldosterone system blockade, suggesting that chronic endothelin antagonism could be an important future therapy in the management of CKD. In summary, I have shown that renal impairment can directly affect markers of arterial function and by inference increase the risk of CVD. Chronic antagonism of the endothelin system with ETA receptor blockers would appear to improve many of these biomarkers, including reductions in BP, AS and proteinuria. There were no adverse effects reported in these studies, suggesting that selective ETA antagonism may be safe enough for clinical development in CKD patients. Further larger clinical trials are warranted.