Calibrating the impact of dual RAAS blockade on the heart and the kidney - balancing risks and benefits

Overactivity of the renin-angiotensin-aldosterone system (RAAS) plays a key role in the pathophysiology of heart failure (HF) and chronic kidney disease (CKD). RAAS antagonists can significantly improve clinical outcomes, but monotherapy blocks but one step of the RAAS and can be bypassed through compensatory mechanisms. Providing more complete RAAS blockade by deploying drugs with complementary actions seemed logical - hence the practice of using dual (or triple) RAAS inhibitors. However, RAAS antagonists also exhibit dose-limiting side effects, including acute kidney injury, hyperkalaemia and hypotension, which blunt their overall effectiveness. Despite achieving better RAAS blockade, several trials failed to show clinical outcome improvements. Patients with concomitant CKD and HF (cardiorenal syndrome) are at the greatest risk of these adverse events and therefore the least able to benefit, yet they also have the worst prognosis. This paradox, where those most in need have fewest therapeutic options, poses three questions which are the focus of this review: whether (i) novel therapies that prevent adverse effects can restore therapeutic benefits to patients who would otherwise be RAAS-therapy intolerant, (ii) there are any validated alternatives to their use and (iii) newer approaches to the detection of fluid congestion are ready for implementation.