Interpretation of plasma renin concentration in patients receiving aliskiren therapy.

Aliskiren (Tekturna or Rasilez) is an orally active renin inhibitor approved for the treatment of hypertension.1 As with inhibition of the renin-angiotensin system by angiotensinconverting enzyme inhibitors or type 1 angiotensin II (Ang II) receptor blockers, aliskiren therapy is accompanied by a reactive rise in plasma renin concentration, although in contrast to angiotensin-converting enzyme inhibitor and angiotensin receptor blocker therapy, aliskiren reduces enzymatic plasma renin activity (PRA). A direct comparison of aliskiren and angiotensin receptor blocker therapies in hypertensive patients showed differences in the magnitude of the reactive renin response.2,3 In 1 study, 300 mg/d of aliskiren and 320 mg/d of valsartan were similarly hypotensive, whereas plasma renin concentration was 2-fold higher during aliskiren therapy.3 In a second study, 150 mg/d of aliskiren and 150 mg/d of irbesartan were similarly hypotensive, whereas plasma renin concentration was 1.4-fold higher during aliskiren therapy.2,4 Moreover, the renin response to 300 mg of aliskiren was 1.6-fold higher than the response to 320 mg of valsartan in sodium-replete normotensive volunteers.5 Sealey and Laragh6 proposed that the exaggerated renin response may limit aliskiren’s ability to reduce blood pressure by counteracting the effect of renin inhibition on Ang II levels and may thereby account for the failure of 600 mg of aliskiren to reduce blood pressure at 300 mg of aliskiren. They also proposed the renin response to aliskiren therapy may paradoxically increase blood pressure in patients with a highly reactive renin concentration (renovascular, advanced, and malignant hypertension).6 Another concern expressed by several authors was the possible action of the increased renin concentrations on the putative renin receptor.2,7–10 How should the exaggerated renin response to aliskiren therapy be interpreted? Renin secretion is subject to tonic negative feedback inhibition by Ang II, and the reactive increase in renin concentration provides a valuable, although indirect, measure of the reduction of Ang II levels by aliskiren therapy.2,5,11–14 The renin response may also be due to unloading of the renal and extrarenal baroreceptors, although several studies show that aliskiren is not more hypotensive than angiotensin receptor blocker therapy.2,3,6,15 The kidney is an important site of the uptake of renin inhibitors,16,17 and autoradiographic studies show localization of aliskiren in the renal glomeruli, renal arteries, and capillaries but not in the renal tubules.17 It is, therefore, possible that aliskiren may act directly on the renin-secreting juxtaglomerular cell to influence prorenin processing and renin release by a mechanism independent of Ang II levels, although there is as yet no evidence for this. The reactive renin response may also reflect an effect of aliskiren on renin clearance,2 but no information is available that addresses this possibility. Finally, aliskiren may interfere with the renin assay by binding to prorenin and causing an overestimation of the renin concentration.2,7,18,19 In this brief review, I summarize some of the properties of aliskiren and the mechanisms that may account for the exaggerated renin response to aliskiren therapy. I review evidence that an important contributor to the exaggerated renin response is the interference by the renin inhibitor in the renin assay causing overestimation of the renin concentration.2,7,18,19 Contrary to the suggestion of Sealey and Laragh6 that the reactive renin response may limit the effect of aliskiren therapy on Ang II levels,6 the exaggerated renin response may not represent an increase in enzymatically active renin molecules in plasma. An important consequence of the overestimation of renin concentration is that the impact of the renin inhibitor on angiotensin peptide formation in vivo may be less than that indicated by the renin response.