Modification of cardiovascular and renal risk factors using antagonists of the endothelin system
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Date
28/11/2014Author
MacIntyre, Iain McGregor
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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.
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