Intensive lowering of blood pressure is beneficial in children with chronic kidney disease

Article Outline

• Question
• Design
• Setting
• Participants
• Intervention
• Outcomes
• Main Results
• Conclusions
• Commentary
• Copyright

Wühl E, Trivelli A, Picca S, Litwin M, Peco-Antic A, Zurowska A, et al. for the ESCAPE Trial Group. Strict blood-pressure control and progression of renal failure in children. N Engl J Med 2009;361:1639-50.

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Question 

Among children with chronic kidney disease (CKD), does intensified blood pressure control with a regimen including an angiotensin-converting enzyme (ACE) inhibitor, compared with standard care, delay the progression of kidney failure?

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Design 

Randomized controlled trial.

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Setting 

A total of 333 pediatric nephrology centers in Europe.

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Participants 

A total of 385 children, 3 to 18 years of age, with stage 2 to 4 CKD (glomerular filtration rate of 15 to 80 mL per minute per 1.73 m² of body surface area).

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Intervention 

All patients received ramipril at a dose of 6 mg/m² of body-surface area per day. The treatment group received intensified blood-pressure control (target 24-hour mean arterial pressure <the 50th percentile); the others received conventional blood-pressure control (mean arterial pressure in the 50th to 95th percentile), achieved by the addition of antihypertensive therapy that did not target the renin-angiotensin system; patients were followed up for 5 years.

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Outcomes 

The primary end point was the time to a decline of 50% in the glomerular filtration rate or progression to end-stage renal disease. Secondary end points included changes in blood pressure, glomerular filtration rate, and urinary protein excretion.

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Main Results 

Approximately 29.9% of the patients in the intensive treatment group reached the primary end point, as assessed by means of a Kaplan-Meier analysis, as compared with 41.7% in the conventional management group (hazard ratio, 0.65; confidence interval, 0.44 to 0.94; P = .02; number needed to treat = 9). The 2 groups did not differ significantly with respect to the type or incidence of adverse events or the cumulative rates of withdrawal from the study (28.0% vs 26.5%). Proteinuria eventually increased during ongoing ACE inhibition after an initial 50% decrease, despite persistently good blood-pressure control. Achievement of blood-pressure targets and a decrease in proteinuria were significant independent predictors of delayed progression of kidney disease.

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Conclusions 

Intensified blood-pressure control provides a substantial benefit with respect to renal function among children with CKD. Reappearance of proteinuria after initial successful pharmacologic blood pressure control is common among children who are receiving long-term ACE inhibition.

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Commentary 

This is a landmark study in several respects. First, blood pressure (BP) management was guided by 24-hour ambulatory BP monitoring (ABPM), a technique that is proving to be increasingly important in evaluation of BP and cardiovascular risk in children with CKD. Recent studies, for example, have demonstrated significant associations between abnormal ABPM profiles and the development of left ventricular hypertrophy in children with CKD. The ESCAPE trial adds further impetus to routine performance of ABPM in children with CKD. Second, all subjects in the study received a fixed dose of ramipril, an ACE inhibitor. ACE inhibitors have been associated with improved BP control in patients with CKD, but are often underused in clinical practice, perhaps because of a fear of hyperkalemia, a complication that occurred rarely in the ESCAPE cohort. Although the subjects in the ESCAPE trial may have been uniquely responsive to ACE inhibition because of a high percentage of dysplastic/structural forms of CKD, the improvement in BP with ramipril was impressive and argues strongly for more widespread use of ACE inhibitors in patients with CKD. Finally, subjects who achieved the lower BP goal of the 50th percentile on ABPM experienced deterioration in renal function less often than those who were treated to the usual BP goal (90th percentile). This held true even though proteinuria, which initially declined, later rebounded despite continued good BP control. Although some questions remain regarding the mechanism of the increase in proteinuria, the message of this study is clear: children with CKD should undergo routine ABPM, should receive an ACE inhibitor as part of their antihypertensive regimen, and may progress to end-stage renal disease more slowly if their BP is maintained at or below the 50th percentile.