Fast track — ArticlesBlood-pressure control for renoprotection in patients with non-diabetic chronic renal disease (REIN-2): multicentre, randomised controlled trial
Introduction
In diabetic and non-diabetic chronic nephropathies, high blood pressure is a major determinant of disease progression, and blood-pressure reduction is renoprotective.1 Reducing blood pressure with drugs that inhibit the renin-angiotensin system has the additional benefit of lowering glomerular hypertension,2 which in turn, ameliorates glomerular-sieving properties.3 In animals, at comparable levels of blood-pressure control, angiotensin-converting-enzyme (ACE) inhibitors or angiotensin-II-receptor blockers are more renoprotective than conventional antihypertensive drugs.2, 3, 4 Work done in patients accords with this finding.5, 6, 7, 8, 9, 10 In individuals with non-diabetic renal disease, the Ramipril Efficacy In Nephropathy (REIN) trial5, 6, 7 showed that—at comparable levels of blood-pressure control—the ACE inhibitor ramipril slowed decline in glomerular filtration rate (GFR) and reduced progression to end-stage renal disease by 50% compared with conventional drugs.
Can blood-pressure reduction to levels lower than in the REIN study (diastolic <90 mm Hg) help to further retard or even prevent dialysis? Results of the Modification of Diet in Renal Disease study11, 12 showed that in patients with non-diabetic proteinuric renal disease, targeting treatment at blood-pressure levels of 125/75 mm Hg or less reduced GFR decline more effectively than if the target was 140/90 mm Hg.11 However, 48% of patients in the lower blood-pressure group received ACE-inhibitor therapy versus 28% in the usual blood pressure group.12 Thus, the benefit recorded in the low blood-pressure group was affected by use of ACE inhibitors. In the African American Study of Kidney Disease and Hypertension (AASK),9 targeting antihypertensive therapy at a mean blood pressure of 92 mm Hg, compared with usual targets of 102–107 mm Hg, did not slow progression of hypertensive nephrosclerosis. In this study, an identical proportion of patients in the usual or lower blood-pressure group was on ACE-inhibitor therapy.9 A meta-analysis of 11 randomised trials of ACE-inhibitor therapy in 1860 people with non-diabetic chronic kidney disease showed that systolic blood-pressure reduction to less than 120 mm Hg did not offer additional renoprotection compared with targets of 120–130 mm Hg, and reduction to 110 mm Hg or less even accelerated progression of renal disease.13 Thus, the additional benefit of blood-pressure reduction to lower than the original REIN study targets5, 6, 7 remains questionable and might even create safety issues, particularly in the setting of concomitant ACE-inhibitor therapy.13 With this background, the REIN 2 trial was designed to establish whether, on top of ACE inhibition, further blood-pressure lowering could be of benefit in chronic kidney disease. Our primary objective was to assess the effect of intensified versus conventional blood-pressure control on progression to end-stage renal disease. Secondary aims were to compare the effects of two different levels of blood-pressure control on GFR decline, residual proteinuria, and fatal and non-fatal cardiovascular events, and to investigate the relations between achieved blood-pressure reduction and main outcome variables.
Section snippets
Participants
Between June, 1999, and June, 2003, we screened men and women (age 18–70 years) who had non-diabetic nephropathy and persistent proteinuria and who had not received ACE-inhibition therapy for at least 6 weeks for inclusion in our study. We defined persistent proteinuria as urinary protein excretion exceeding 1 g per 24 h for at least 3 months without evidence of urinary-tract infection or overt heart failure (New York Heart Association class III–IV). Patients with proteinuria of 1–3 g per 24 h
Results
The first interim analysis, done as per protocol, showed that, despite more effective blood-pressure reduction in the intensified blood-pressure control arm, the cumulative incidence of end-stage renal disease, rate of GFR decline, and residual proteinuria were similar in the two arms. Moreover, none of the above outcome variables was affected to any great extent. On the basis of these findings, the independent adjudicating panel stated that the study had to be stopped for futility. All data
Discussion
We have shown that in patients with non-diabetic, proteinuric chronic nephropathies, intensified blood-pressure control with ramipril and felodipine reduced blood pressure more effectively than did conventional control with ramipril alone and was safe. However, this intensified regimen compared with conventional ACE inhibition alone had no additional benefits for residual proteinuria, GFR decline, and progression to end-stage renal disease. By multivariate analyses, further blood-pressure
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