Detrimental effects of dual ACEI-ARB therapy: is the (pro)renin receptor the culprit?

Chan et al. report increased mortality with angiotensin-converting enzyme inhibitors and angiotensin type 1 receptor blockers in hemodialysis patients, supporting emerging evidence that such dual therapy may be detrimental. We speculate that effects of reactive renin and prorenin release on the (pro)renin receptor may explain this apparent paradox, either through membrane-bound generation of angiotensin II or via stimulation of signal transduction pathways. Potential benefits of direct renin inhibitors and yet-to-be-developed (pro)renin receptor blockers are discussed.