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The benefits of renin–angiotensin blockade in hypertension are dependent on blood-pressure lowering

Nature Clinical Practice Nephrology volume 2, pages 542–543 (2006)Cite this article

Blockade of the renin–angiotensin system (RAS) by angiotensin-converting-enzyme (ACE) inhibitors and/or angiotensin-receptor blockers (ARBs), is widely postulated to provide class-specific blood-pressure-independent protection against hypertensive injury.1 The very large ALLHAT trial—which was designed to test this theory—failed to demonstrate, however, the blood-pressure-independent therapeutic superiority of ACE inhibitors over thiazide diuretics for most cardiovascular endpoints.2 Accordingly, current guidelines stress the primacy of blood-pressure reduction and, based on cost considerations, recommend thiazide diuretics as initial therapy for most patients with hypertension—despite their expected stimulation of the RAS.3 By contrast, RAS blockade is still considered the regimen of choice for renoprotection based on the 15–50% relative risk (RR) reductions in renal endpoints compared with other antihypertensive regimens that have been reported in diabetic and nondiabetic chronic kidney disease (CKD).1,3 If however, the secondary (but prespecified and extensive) renal outcome data from ALLHAT are included, as in a recent meta-analysis, the case for blood-pressure-independent renal benefits of RAS blockade becomes considerably weaker.4 Even if only the more favorable data from clinical trials specifically targeted to 'renal outcomes' are critically reviewed, the evidence of specific renoprotection by RAS blockade is more ambiguous and the magnitude of such effects much smaller than claimed.1,5

To illustrate the above point, a substudy published after the landmark trial of captopril in diabetic nephropathy conducted by the Collaborative Study Group has indicated that the original interpretations of the trial might have been seriously compromised by the disproportionately greater randomization of the nephrotic patients at the highest risk of renal endpoints into the placebo group (66 vs 42 in the captopril group; P <0.002). This likely accounted for most of the excess of endpoints observed for the placebo group compared with the captopril group (43 vs 25; P <0.007).1 Of broader concern, such trials have either used dihydropyridine calcium-channel blockers (CCBs) in the control group to substitute for the antihypertensive effects of RAS blockade, and/or have failed to achieve equivalent blood-pressure reductions between treatment groups (blood pressure is typically 2–6 mmHg lower in the RAS blockade groups than in the control groups).4,5 CCBs impair renal autoregulation, which normally protects the glomerular capillaries against the transmission of systemic hypertension, and these capillaries are the primary site of injury in progressive CKD.1,5,6 Thus, CCBs might not provide renoprotection that is proportionate to the achieved blood-pressure reductions in patients with advanced proteinuric renal disease, unless normotension is achieved.6

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Authors and Affiliations

  1. Professor of Medicine and Director of the Division of Nephrology and Hypertension at Loyola University Medical Center, Maywood, IL, USA

    Anil K Bidani

  2. Professor of Medicine and Chief of the Section of Nephrology at Edward Hines Veterans Administration Hospital, Hines, IL, USA

    Karen A Griffin

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  1. Anil K Bidani
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Correspondence to Anil K Bidani.

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Bidani, A., Griffin, K. The benefits of renin–angiotensin blockade in hypertension are dependent on blood-pressure lowering. Nat Rev Nephrol 2, 542–543 (2006). https://doi.org/10.1038/ncpneph0299

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