Approximately 2 million children in the United States have hypertension although most of them remain undiagnosed. With the current epidemic of obesity and physical inactivity in our youth, these numbers are certain to increase. While lifestyle modification has always been recommended early on in children with hypertension, the most recent recommendations suggest using either an angiotensin‐converting enzyme (ACE) inhibitor or angiotensin receptor blocker (ARB) in children with hypertension, especially when they have diabetes or chronic kidney disease (CKD) with proteinuria. Most of the evidence for this recommendation in children is extrapolated from data with adults, where we know that blockade of the renin‐angiotensin system (RAS) with an ACE inhibitor or ARB delays the progression of renal failure in those with CKD. The overall risks and benefits of ACE inhibitor and/or ARB use in children and the optimal blood pressure (BP) target for renal protection remain unclear.
To investigate if aggressive BP control slows the progression of CKD in children on RAS background therapy, researchers conducted an investigator‐initiated, international, multicenter trial conducted in 33 pediatric nephrology units in Europe. This study was designed to determine if intensified 24‐hour BP control would delay the progression of chronic renal disease in children with a variety of underlying kidney disorders. Originally planned as a 3‐year study with a single interim analysis after the first 2 years, the Effect of Strict Blood Pressure Control and ACE Inhibition on the Progression of Chronic Renal Failure in Pediatric Patients (ESCAPE) trial was extended to 5 years after a slower overall rate of progression to renal failure occurred than was originally planned.
From April 1998 through December 2001, investigators enrolled 468 children 3–18 years of age with stage II–IV CKD (ie, glomerular filtration rate [GFR] of 15–80 mL per minute per 1.73 m2 of body surface area) whose 24‐hour mean arterial BP (24‐hour AMBP) was either elevated (above the 95th percentile) or controlled by antihypertensive medication. Patients were excluded if they had known renal artery stenosis, had undergone kidney transplantation, were on immunosuppressive medications, had major cardiac, hepatic, or gastrointestinal disorders, or were unstable clinically. Eligible patients underwent 24‐hour AMBP at screening and were seen every 2 months for the first 6 month run‐in period. Treatment with an RAS antagonist was stopped at least 2 months before the end of the run‐in period when the active phase of the study began. A total of 385 patients met the eligibility criteria, underwent baseline examinations, and were randomly assigned to either conventional (196) or intensified (189) BP control.
Baseline characteristics including duration of CKD (mean 6.5 years), etiology of CKD (264 with renal hypoplasia‐dysplasia with or without obstructive or reflux uropathy, 52 with glomerulopathies, and 69 with congenital or hereditary nephropathies), baseline GFR, number with GFR reduction >3 mL/year, mean 24‐hour mean protein excretion, 24‐hour mean arterial pressure, and the number and class of antihypertensive agents required at baseline were similar in both groups. Randomization was stratified according to their underlying etiology of renal dysfunction and the annualized decrease in the GFR during the run‐in period (fast decrease, ≥3 mL per minute per 1.73 m2 per year; slow decrease, <3 mL per minute per 1.73 m2 per year). Eligible subjects were randomly assigned to either a conventional BP target (50th to 90th percentile of 24‐hour mean arterial BP for age) or an intensified BP target (below the 50th percentile for age). All children received the ACE inhibitor ramipril at the highest adult‐approved dose of 10 mg per day adapted for body size, 6 mg/m2 of body‐surface area per day, which was gradually increased during the first 2 months of the study.
Every 2 months, in the clinic, BP was measured using an auscultatory or oscillometric device, and GFR and urinary protein excretion were assessed using 24‐hour urine samples through a central lab. 24‐hour AMBP was performed at screening, before randomization, and every 6 months using a Spacelabs 90,207 oscillometric device (Spacelabs Healthcare, Issaquah, WA). Antihypertensive therapy from a suggested but noncompulsory protocol was selected to achieve the target BP levels, but the addition of an additional agent that blocked the RAS was prohibited. The primary endpoint was the time to the first event of the composite endpoint, defined as a 50% reduction in GFR or progression to end‐stage renal disease (ESRD) (GFR <10 mL per minute per 1.73 m2 or start of renal replacement therapy). Secondary endpoints included changes in BP, changes in GFR, and changes in proteinuria.
A total of 46 of 182 patients (29.9%) in the intensified‐control group and 69 of 190 (41.7%) in the conventional‐control group progressed to the primary endpoint (hazard ratio, 0.65; confidence interval, 0.44–0.94; P=.02), corresponding to an actuarial 5‐year rate of delay in the progression of renal disease of 70.1% vs 58.3%. Several covariates at baseline were associated with an increased risk of reaching the primary endpoint, including a low GFR, a greater degree of proteinuria, a higher 24‐hour mean arterial pressure, and older age. The reduction in risk achieved with intensified BP control remained significant even after adjustment for these covariates. An initial 50% reduction in proteinuria within the first 2 months after beginning ramipril was associated with a delay in the progression of renal disease. ACE inhibitor therapy before the start of the study did not influence the effect of the intervention on the delay in progression of renal disease.
Mean office systolic BP after 2 months decreased to 108.2 mm Hg and 110.2 mm Hg (P=.22) and mean office diastolic BP decreased to 63.8 mm Hg and 64.8 mm Hg (P=.50) in the intensified‐control and conventional‐control groups, respectively. In the cohort as a whole, at the 6‐month examination, 24‐hour mean systolic and diastolic BP and mean arterial pressure decreased from 119.2 mm Hg, 73.4 mm Hg, and 89.3 mm Hg to 111.4 mm Hg, 66.1 mm Hg, and 81.9 mm Hg (P<.0001 for all comparisons), respectively. In the cohort as a whole, the 24‐hour mean arterial BP continued to be reduced over the 5‐year study period (P<.001). The mean dose of ramipril was similar in both BP‐control groups as was adherence to therapy. However, after the 6‐month examination, the mean number of antihypertensive medications prescribed per patient in addition to ramipril was 0.9 in the intensified group as compared to 0.5 in the conventional group (P=.003). In the intensified‐control group, the target 24‐hour mean arterial pressure (<50th percentile) was reached by 60% of the patients at 12 months, 73% at 24 months, 71% at 36 months, 72% at 48 months, and 74% at 60 months. Even in the conventional therapy group, 24‐hour mean arterial pressure dropped below the 50th percentile with ramipril monotherapy in more than 50% of patients. The 2 groups differed in 24‐hour mean arterial pressure by 3.8 mm Hg at 12 months, 3.1 mm Hg at 24 months, 2.7 mm Hg at 36 months, 3.9 mm Hg at 48 months, and 2.9 mm Hg at 60 months (P=.002–.03). The time‐integrated mean arterial pressure within the target range was attained by 63.8% in the intensified‐control group and by 49.1 % in the conventional‐control group.
In the study cohort as a whole, the annualized reduction in the GFR changed from 3.3 mL/min/1.73 m2/y during the 6 month run‐in period to 2.4 mL/min/1.73 m2/y between month 2 and the last observation (P=.11). There was no difference in change in GFR between the 2 groups. In the study cohorts as a whole, mean urinary protein excretion was reduced from 0.82 gram protein/gram of creatinine to 0.36 gram protein/gram of creatinine at 6 months. Interestingly, despite persistent excellent BP control throughout the study, proteinuria gradually rebounded over time, resulting in a level of proteinuria after 36 months that did not differ significantly from that at baseline.
Intensified BP control on a background of RAS blockade with 24‐hour BP levels in the low range of normal confers a benefit on renal function in children with CKD. Reappearance of proteinuria in children achieving intensified BP control while receiving long‐term ACE inhibition is common and the mechanism for this observation needs to be further explored.—The Escape Trial Group. Strict blood pressure control and progression of renal failure in children. New Engl J Med. 2009;361:1639–1650.
Comment
Children make up less than 1% of all those with CKD and when it occurs, it is usually secondary to congenital renal malformations, urinary tract disorders, or genetic disorders. Hypertension is present in 50% of children with CKD. Although the role of antagonizing the RAS in adults for preventing ESRD in those with hypertensive and diabetic nephropathy is well evidenced, similar randomized studies in children have been anxiously awaited as only small, nonrandomized, case‐control, observational studies have been conducted until now.
The present 5‐year ESCAPE trial, which randomized children 3–18 years of age with CKD (GFR of 15–80 mL/min), all of whom were receiving high‐dose ACE inhibitor therapy with ramipril, demonstrated that intensive BP control (below the 50th percentile for age) when compared to a conventional BP level (between the 50th and 90th percentile for age) delays the progression to more severe renal disease. This occurred despite a difference of only 3–4 mm Hg in 24‐hour mean arterial pressure from the end of the first year to the completion of the 5‐year study. In the overall cohort, achieving the intensified target was associated with a 35% reduction in the relative risk of losing 50% of renal function or progressing to ESRD. Of note, in subgroup analysis, this benefit was observed among children with an underlying glomerulopathy or renal hypoplasia or dysplasia, but not among those with other congenital or hereditary nephropathies. Perhaps the fact that up to one‐third of the subjects in the study had been on ACE‐inhibitor therapy prior to enrollment allowed the antifibrotic and antiinflammatory effects of long‐term ACE inhibition to have different effects on the various etiologies of CKD in these children.
Why have other studies evaluating different BP targets (especially in adults) been unable to show a benefit on renal protection in patients with CKD? Perhaps this study was able to do so because the etiology of renal disease in children is often vastly different from those in the adult. Furthermore, the ability to follow these patients for 5 years is longer than the usual follow‐up of most adult trials. In fact, no difference between the treatment groups would have been detected if the trial had been stopped after 3 years as originally planned. In addition, adherence to therapy was greater and the drop‐out rate of 5.5% per year was considerably lower in this study than in previous studies, which also might have contributed to outcome improvement.
While treatment with ramipril was associated with a reduction in proteinuria (average decrease of 50%) within the first 6 months of the study and initial reduction in proteinuria was predictive of a long‐term benefit on renal function, this early antiproteinuric effect was lost by the 3rd year of follow‐up, despite the persistent BP‐lowering effect achieved throughout the trial. The authors propose that this observation may be related to the “aldosterone breakthrough” phenomenon that has been observed in up to 40% of adults receiving long‐term ACE inhibitor therapy, presumably due to upregulation of other enzymes such as chymase or urinary endothelin‐1 excretion that parallel the rise in proteinuria; they suggest that combination therapy with a direct renin inhibitor may overcome this “escape.” Additionally, the potential effect of using a higher dose of ACE inhibitor than that used in ESCAPE, 6 mg/m2 of body‐surface area per day, remains unknown. Clearly, further studies are necessary to better explain the rebound loss of proteinuria reduction and determine its significance in this patient population.
Although not directly studied in this trial, based largely on results of clinical trials in adults, it is generally assumed that high‐dose, ACE‐inhibitor therapy slows the progression of CKD in children. This study demonstrates that once a child with CKD is on ACE inhibitor therapy, targeting BP control to the low range of normal has an additive effect on slowing the progression of renal disease, at least among those with renal dysfunction due to glomerulopathies or renal hypoplasia‐dysplasia. The long‐term gradual increase in proteinuria observed despite optimal BP control and high dose ACE inhibition is concerning and needs to be further studied. How best to maximize long‐term renal protection in children with CKD in terms of maximizing RAS blockade and achieving long‐term proteinuric reduction needs to be evaluated in future trials.