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Renoprotective effects of renin-angiotensin-system inhibitors

2006; Elsevier BV; Volume: 367; Issue: 9514 Linguagem: Inglês

10.1016/s0140-6736(06)68372-4

1474-547X

Amanda Adler, Irene Stratton, Brian Shine,

Sodium Intake and Health

The meta-analysis by Juan Casas and colleagues (Dec 10, p 2026)1Casas JP Chua W Loukogeorgakis S et al.Effect of inhibitors of the renin-angiotensin system and other antihypertensive drugs on renal outcomes: systematic review and meta-analysis.Lancet. 2005; 366: 2026-2033Summary Full Text Full Text PDF PubMed Scopus (608) Google Scholar addresses the question of whether inhibitors of the renin-angiotensin system (angiotensin-converting-enzyme [ACE] inhibitors and angiotensin-II-receptor blockers [ARBs]) delay the progression of renal disease in individuals with and without diabetes, independent of blood pressure changes. We wish to make the following points. Casas and colleagues excluded trials with no mention of changes in blood pressure from the meta-regression analyses, but they did not report the proportion of trials this represented. They chose to categorise blood pressure changes into tertiles, which, although convenient for graphical representation, might have resulted in a loss of power and residual confounding. The lowest tertile of blood pressure change (original figure 4) reflected worse blood pressure control among patients on ACE inhibitors or ARBs. Given that “systemic blood pressure is a major determinant of the progression of renal disease”, one would expect to see an increase in the risk of end-stage renal disease associated with ACE inhibitors and ARBs. No difference was noted. Inclusion in meta-analyses of studies that differ substantially from the other included studies is not appropriate.2Hearst N Grady D Barron HV Kerlikowske K Research using existing data: Secondary data analysis, ancillary studies, and systematic reviews.in: Hulley S Cummings SR Browner WS Grady D Hearst N Newman TB Designing clinical research. Lippincott Williams & Wilkins, Philadelphia2001Google Scholar ALLHAT contributed disproportionately to the overall effect measure, yet participants in that trial were about an eighth as likely to have developed end-stage renal disease as those in the other trials. If there were an interaction between the factor inspiring these differences and the effect of blockade of the angiotensin system, the results of this meta-analysis would be biased. Patients in ALLHAT assigned an ACE inhibitor had higher blood pressure during the trial than those assigned a calcium-channel blocker or diuretic, a difference unlikely to be addressed adequately if blood pressure changes are modelled categorically. It was not clear which studies contributed more than one endpoint, or which trials selectively published endpoints out of potentially many measured.3Williamson PR Gamble C Altman DG Hutton JL Outcome selection bias in meta-analysis.Stat Methods Med Res. 2005; 14: 515-524Crossref PubMed Scopus (136) Google Scholar Whereas albuminuria and changes in glomerular filtration rate probably reflect distinct renal pathophysiology, creatinine concentration, doubling of creatinine, and estimated glomerular filtration rate probably do not. Notably, in this meta-analysis, use of an ACE inhibitor or ARB was associated with improved renal function when plasma creatinine was included as a continuous endpoint (considered more robust), but not as a binary (doubling) endpoint. Casas and colleagues write: “Treatment decisions for hypertension in renal disease should be based on the blood-pressure-lowering effect…”. However, most patients with diabetes, and an even greater proportion of patients with diabetes and renal disease, die of cardiovascular disease,4Adler AI Manley SE Bilous RW Cull CA Holman RR Development and progression of nephropathy in type 2 diabetes: the United Kingdom Prospective Diabetes Study (UKPDS 64).Kidney Int. 2003; 63: 225-232Crossref PubMed Scopus (1329) Google Scholar which ACE inhibitors have been shown to delay. In the pharmacopoeia for type 2 diabetes, it is improbable that an ACE inhibitor or ARB could be excluded, if only because of the need for several treatments to control hypertension.5UKPDS GroupTight blood pressure control and risk of macrovascular and microvascular complications in type 2 diabetes: UKPDS 38. UK Prospective Diabetes Study Group.BMJ. 1998; 317: 703-713Crossref PubMed Google Scholar ACE inhibitors, by contrast with β blockers and thiazides, do not worsen glycaemia. Although Casas and colleagues have not shown ACE inhibitors and ARBs to be better than other agents, nor have they shown them to be worse. Hence, all other things being equal, these observations support prescription of ACE inhibitors and ARBs. We declare that we have no conflict of interest. Renoprotective effects of renin-angiotensin-system inhibitors – Authors' replyThe results of ALLHAT challenged widely held beliefs about the renoprotective effect of renin-angiotensin-system (RAS) inhibition and so it is unsurprising that each of the correspondents raises this as an issue. However, it is the largest randomised double-blind trial with the longest follow-up of the effects of antihypertensive drugs on renal outcomes and it fulfilled our prespecified inclusion criteria. Exclusion of ALLHAT from our analysis would, quite rightly, have prompted great criticism since the trial provides around half the available evidence on renal outcomes. Full-Text PDF