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Indian Pediatr 2013;50:
923-928 |
|
Effect of Enalapril on Glomerular Filtration
Rate and Proteinuria in Children with Chronic Kidney Disease:
A Randomized Controlled Trial
|
Pankaj Hari, Jitender Sahu, Aditi Sinha, *Ravinder Mohan Pandey,
#Chandra Shekhar Bal and
Arvind Bagga
From the Departments of Pediatrics, *Biostatistics and #Nuclear
Medicine, All India Institute of Medical Sciences,
Ansari Nagar, New Delhi, India.
Correspondence to: Dr Pankaj Hari, Professor, Department of
Pediatrics, All India Institute of Medical Sciences, Ansari Nagar, New
Delhi 110 029, India.
Email: [email protected]
Received: January 08, 2013;
Initial review: January 28, 2013;
Accepted: February 21, 2013.
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Objective: To evaluate the efficacy of enalapril treatment on
decline in glomerular filtration rate and reduction in proteinuria in
children with chronic kidney disease (CKD).
Design: Open-label, randomized controlled trial.
Setting: Pediatric nephrology clinic at a
tertiary-care referral hospital.
Intervention: Children with GFR between 15-60 mL/min/1.73
m2 were randomized to receive either enalapril at 0.4 mg/kg /day or no
enalapril for 1 year.
Outcome measures: Change in GFR using 99mTc-DTPA
and urine protein to creatinine ratio. Secondary outcomes included
occurrence of composite outcome (30% decline in GFR or end stage renal
disease) and systolic and diastolic blood pressure SDS during the study
period.
Results: 41 children were randomized into two
groups; 20 received enalapril while 21 did not receive enalapril. During
1 year, GFR decline was not different in the two groups (regression
coefficient (r) 0.40, 95% CI -4.29 to 5.09, P=0.86). The mean
proteinuria reduction was 65% in the enalapril group, significantly
higher than control group. The difference was significant even after
adjustment for blood pressure was 198.5 (CI 97.5, 299.3; P<0.001).
3 (17.6%) patients in enalapril and 7 (36.8%) in non-enalapril group
attained the composite outcome.
Conclusions: Enalapril is effective in reducing
proteinuria in children with CKD and might be renoprotective in
proteinuric CKD.
Keywords: Chronic kidney disease, Enalapril, GFR, Proteinuria.
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Chronic kidney disease (CKD) with glomerular
filtration rate (GFR) below 60 ml/min/1.73 m 2
invariably progresses to end stage renal disease (ESRD). Causes of CKD
in children differ substantially from those in adults [1,2]. Large
studies in adults have demonstrated protective effect of angiotensin
converting enzyme inhibitor (ACEI) in retarding disease progression in
diabetic and other proteinuric nephropathies [3]. However, comparable
data from randomized controlled trials involving children are lacking.
While renin-angiotensin system (RAS) antagonists are used in 80% of CKD
children with glomerular etiology its use has been reported in 47% of
the non-glomerular CKD [4]. The Italian Pediatric Registry of chronic
renal insufficiency
concluded that it was unclear whether ACEI retarded progression of CKD
in hypodysplastic CKD [5].
Since these diseases are associated with reduction in nephron mass with
consequent hyperfiltration, there is a potential rationale for use of
ACEI for renoprotection. Although ACEI are frequently used as
antihypertensive and antiproteinuric agents in children, their efficacy
in slowing progression of renal disease has not been prospectively
examined. Recently, a large randomized controlled (ESCAPE) trial using
ACEI in children showed that intensified blood pressure control was
renoprotective as compared to conventional blood pressure control[6].
Since both groups received ramipril, the trial demonstrated benefits of
strict blood pressure control rather than efficacy of ACEI in retarding
progression of CKD.
The present study was conducted to evaluate whether
ACE inhibition by enalapril retards rate of decline in GFR and decrease
proteinuria in children with CKD.
Methods
This prospective, single-center, open-label,
randomized controlled trial was conducted at the Pediatric Nephrology
Clinic of a tertiary care hospital over 48-month period ending in
October 2008. The study protocol was approved by the Institute Ethics
Committee. Written informed consent was obtained from the parents before
inclusion in the study.
Children from 2 to 18 years of age with estimated GFR
between 15 and 60 mL/min/1.73 m 2
[7] with or without hypertension and proteinuria were screened for the
study. Those with radionuclide GFR between 15 and 60 ml/min/1.73 m2
were eligible for the study. Patients were
excluded if they had stage II hypertension, serum potassium >5.5 mEq/L,
renal artery stenosis, therapy with ACEI or angiotensin receptor
blockers (ARB) or non-steroidal anti-inflammatory drugs in the last 2
months, surgery for obstructive uropathy or therapy with
immunosuppressive agents in the last 6 months. Prior to inclusion, no
patient underwent washout of enalapril.
Initial evaluation included measurement of blood
pressure, blood counts and blood levels of creatinine, electrolytes,
urinary protein and creatinine, and estimation of radionuclide GFR.
Blood pressure was measured by auscultatory technique
and hypertension was defined based on criteria of the Fourth Report on
Hypertension[8]. GFR estimation was performed by two sample plasma
disappearance method after intravenous administration of 1 mCi 99mTc-DTPA, followed by collection
of blood samples at 60 and 180 minutes [9]. Urinary protein
concentration was measured using pyrogallol red-molybdate complex method
on autoanalyzer. Serum and urinary creatinine concentrations were
measured by modified Jaffé reaction [10]. Proteinuria was expressed as
the ratio of protein to creatinine (Up/Uc), as determined in spot urine
samples.
Eligible patients were randomized to either enalapril
or non-enalapril group. Enalapril was given in a single bedtime dose of
0.4 mg/kg for 12 months. Permuted block randomization was performed
using block size of four by an individual not involved in trial
implementation. The investigators were blinded to the randomization
schedule and allocation was concealed in opaque sealed envelopes.
Standard therapy for CKD was continued in both groups. Therapy with
antihypertensives other than ACEI, ARB and calcium channel blockers was
continued to maintain blood pressure <90 th
percentile for age, height and gender.
Follow up: Clinical evaluation, consisting of
physical examination, blood pressure, renal function tests,
electrolytes, complete blood count, Up/Uc were performed at the
beginning of the study and after 15 days, and 3, 6, and 12 months.
Compliance was assessed at each visit by pill count. DTPA GFR was
repeated at 6 and 12 months. Patients were withdrawn from the study if
two consecutive serum potassium levels were >6 mEq/L or serious adverse
events occurred.
The primary outcomes were decline in GFR and
percentage change in Up/Uc during 1 year. Secondary outcome measures
included occurrence of composite outcome and systolic and diastolic
blood pressure Standard deviation scores (SDS). Composite outcome was
defined as decline in GFR by >30% or attainment of ESRD. The end point
of the study was attainment of composite outcome or completion of 1-year
follow up.
Outcomes were also assessed in the subgroup of
children with proteinuria defined as Up/Uc >1.5 and without proteinuria
(Up/Uc <1.5).
Blood pressure values were normalized to SDS [7].
All adverse events and serious adverse events were
recorded.
Statistical analysis: In a previous study, the
mean monthly rate of decline of GFR in patients not treated with ACEI
was reported as 0.29 ml/min/1.73 m 2
[11]. Assuming a 50% difference in decline in GFR from
baseline between enalapril treated and untreated group, and considering
a drop-out rate of 10%, power of 0.80 and an
a error of 0.05 the
study required 20 patients in each group. This sample size was also
sufficient to detect 50% proteinuria reduction by ACEI [12]. Data are
presented as mean ± SD and analyzed using intention-to-treat principle.
The missing data for patients who were lost to follow up was computed
using the mean decline of GFR and percentage reduction of urine protein
to creatinine ratio as observed in the non-enalapril group. Since the
outcomes in the study were correlated and longitudinal, we used
generalized estimating equations for analysis [13]. P<0.05 was
considered significant.
Results
Sixty six patients with CKD stages 3 and 4 were
screened for inclusion in the study and 41 patients (2 girls) were
randomized into two groups (Fig.1). The baseline
characteristics of the two groups were similar (Table I).
The chief underlying causes of CKD were reflux nephropathy and
obstructive uropathy. At inclusion, 6 patients had systolic and/or
diastolic blood pressure above 95 th
percentile, and 4 were receiving antihypertensive drugs (amlodipine in
3, prazosin in 1). Twenty three patients had proteinuric and 18 had non-proteinuric
CKD. The baseline mean Up/Uc was significantly higher (5.1±3.8 vs
0.82±0.56, P<0.001) and the mean baseline GFR lower (28.9±8.7
vs 22.4 ±6.5 ml/min/1.73 m2,
P=0.01), in the proteinuric as compared to non-proteinuric
patients respectively.
|
Fig. 1 Flow of participants during the
study.
|
TABLE I Baseline Characteristics of Included Patients
|
Enalapril
|
Non-enalapril
|
|
(N=20) |
(N=21) |
Age, yr
|
8.4 ± 4.3 |
9.5 ± 4.7 |
Male sex (%)
|
20 (100) |
19 (90.5) |
Underlying renal disorder (%) |
|
|
Glomerulonephritis |
0 (0) |
3 (14.3) |
Reflux nephropathy
|
7 (35) |
6 (28.7) |
Obstructive uropathy |
6 (30) |
6 (28.7) |
Other, unknown |
7 (35) |
6 (28.7) |
Systolic BP (mm Hg) |
105 ± 9.0 |
109 ± 15.3 |
Diastolic BP (mm Hg) |
66 ± 8.8 |
69 ± 12.9 |
>95th percentile of BP (%)
|
|
|
Prior antihypertensive treatment (%) |
2
|
2
|
GFR (ml/min/1.73 m2)# |
26.5 ± 7.4 |
25.3 ± 8.8 |
Creatinine (mg/dL) |
1.8 ± 0.12 |
2.1 ± 0.23 |
Potassium (mEq/L) |
4.4 ± 0.08 |
4.3 ± 0.16 |
Up/Uc (mg/mg)* |
3.0 ± 2.7 |
2.8 ± 4.2 |
>1.5 Up/Uc |
13 (65) |
10 (47.6) |
Values are mean±SD; *Up/Uc - Urinary protein to creatinine
ratio; #99mTc-DTPA; *Urinary protein-to-creatinine ratio;
BP = Blood pressure. |
At 1 year, the rate of decline in GFR was 3.0±4.2 in
the enalapril and 4.2±5.1 mL/min/1.73 m2
in the non-enalapril group (P=0.51). The treatment
with enalapril was associated with slower GFR decline (regression
coefficient -0.78, 95% CI -3.59, 2.03; P=0.58), but not
statistically significant during 1-year period (Table III).
In the subgroup of patients with proteinuria (n=23), the rate of
GFR decline was 3.8±5.2 vs. 8.6±7.9 mL/min/1.73 m2
per year
in enalapril and non-enalapril group, respectively.
TABLE II Changes in the Parameters (mean±SD) During Treatment in Enalapril and Non-enalapril Groups
|
Enalapril |
Non-enalapril |
P value |
6 Months |
12 Months |
6 Months |
12 Months |
6 Months |
12 Months |
DTPA GFR (mL/min/1.73 m2 ) |
22.4±7.6
|
22.6±5.8 |
20.1±9.5 |
25.3±10.7 |
0.53 |
0.42 |
GFR decline (mL/min/1.73 m2)
|
|
3.0±4.2 |
|
4.2±5.1 |
|
0.51 |
Urine protein/creatinine (mg/mg) |
1.2±1.6 |
0.57±0.56 |
1.9±1.0 |
1.7±1.5 |
0.38 |
0.01 |
Percentage change in proteinuria |
57.3±40.1 |
65.8±40.5 |
-56.9±97 |
-199±345 |
0.01 |
0.0005 |
Systolic BP SDS |
0.54±1.0 |
0.56±0.89 |
1.29±1.26 |
1.16±0.82 |
0.05 |
0.07 |
Diastolic BP SDS |
0.68±0.85 |
0.81±0.81 |
1.26±0.95 |
1.45±0.68 |
0.06 |
0.03 |
Serum creatinine (mg/dL) |
2.2±0.9 |
2.1±0.9 |
2.5±1.7 |
2.5±1.5 |
0.44 |
0.46 |
Serum potassium (mEq/L) |
5.1±0.4 |
5.1±0.5 |
4.7±0.6 |
4.8±0.9 |
0.01 |
0.23 |
GFR: Glomorular filtration rate; BP: Blood pressure; SDS:
standard scores |
TABLE III Outcomes with Enalapril as Compared to Non enalapril Treatment (N=41)
Outcome |
*Regression
|
95% CI |
P
|
|
coefficient |
|
value |
|
± SE |
|
|
GFR decline
|
-0.78±1.43 |
-3.59, 2.03 |
0.58 |
Composite outcome |
-0.83±0.80 |
-2.40±0.73 |
0.29 |
Percentage change in proteinuria (unadjusted)
|
179.4±48.4 |
84.6, 274.3 |
<0.001 |
adjusted for blood pressure |
198.5±51.5 |
97.5, 299.3 |
<0.001 |
Systolic BP SDS |
- 0.54±0.27 |
-1.07, -0.01 |
0.04 |
Diastolic BP SDS
|
- 0.45±0.24 |
-0.92, 0.02 |
0.06 |
Serum potassium
|
0.23±0.13 |
-0.02, 0.49 |
0.07 |
The percentage change in proteinuria was
significantly higher in enalapril treated group as compared to non
enalapril group at both 6 months and 12 months (Table II).
Proteinuria reduction was correlated to baseline protein excretion
(r=0.72, P<0.001) and baseline GFR (r=-0.43, P=0.03). The
difference in proteinuria reduction remained significant after
adjustment for proteinuria and GFR at baseline (P=0.02). In the
subgroup with proteinuria, there was significantly higher percentage
reduction in proteinuria in enalapril group which remained significant
after adjustment for blood pressure (Web Table I). In the
subgroup with Up/Uc <1.5 (n=18) the percentage reduction in
proteinuria was also higher in the enalapril treated patients
(regression coefficient 200, 95% CI 21.4 to 379; P=0.03).
Secondary outcomes: The composite outcome was
assessed in 36 (87.8%) patients; 17 in enalapril and 19 in non-enalapril
group. Three (17.6%) patients in enalapril group and 7 (36.8%) in non-enalapril
group attained the composite outcome (Fig. 1). In the
proteinuric subgroup, 1 of 13 (7.7%) patients treated with enalapril and
6 of 10 (60%) patients in the non-enalapril group attained composite
outcome (P=0.01). Occurrence of composite outcome was
significantly lower in the proteinuric patients treated with enalapril (P=0.003)
and remained significant after adjustment for proteinuria and blood
pressure. However, the composite outcome was not significantly different
in the non-proteinuric group (regression coefficient 0.13, 95% CI -0.23
to 0.49, P=0.4).
At 3 months, mean reduction in systolic and diastolic
blood pressures from the baseline was 6.1±8.4 mm Hg and 5.5±5.8 mm Hg in
the enalapril group as compared to 1.7±1.5 mmHg and 0.8±0.7 mm Hg in the
non-enalapril group. The systolic and diastolic blood pressure SDS were
lower in the enalapril treated patients as compared to non-enalapril
group during the study (Table III). Serum potassium was
higher in enalapril treated patients during the study period (P=0.07);
the mean increase from baseline was 0.6±0.5 mEq/L at 1 year.
Adverse events were similar in the two groups. One
patient in the enalapril group was withdrawn due to hyperkalemia.
Discussion
Majority of patients had congenital abnormalities of
the kidney and urinary tract; about half of the patients had moderate
proteinuria (Up/Uc>1.5). ACE inhibition when started early in CKD may be
more renoprotective as compared to late CKD stages. Considering slow
decline in GFR in early CKD and short follow-up period of the study,
children with CKD stage II were unlikely to have outcome and hence were
not included in the study. The study was unable to demonstrate a
significant benefit of enalapril treatment in the rate of decline of GFR
or occurrence of composite outcome. However, occurrence of composite
outcome was significantly lower in subgroup of patients with proteinuria
treated with enalapril which persisted after adjustment for proteinuria
and blood pressure.
There is limited data on the efficacy of RAS
inhibition for renoprotection in children. Small uncontrolled studies
have shown beneficial effects of ACEI in children with proteinuric CKD
and hemolytic uremic syndrome [14,15]. Litwin, et al. [16] showed
add-on renoprotection with losartan added to ACEI in 11 patients with
CKD. A retrospective analysis of the Italkid project did not show
improved renal survival after an average 5-year follow-up with ACEI [5].
The major limitations of this study were selection bias and lack of
information on dosage of ACEI. Due to lack of data on proteinuria, the
study could not assess the benefits of ACEI in proteinuric CKD.
ACEI reduce the risk of doubling of serum creatinine
or ESRD by 30-40% in adults, which is related to the degree of
proteinuria [17,18]. Proteinuria and hyper-tension have been shown to be
independent predictors of decline in renal function in children with CKD
[19]. ESCAPE trial also showed that residual proteinuria was associated
with progression of renal failure [6].
There was a significant reduction in proteinuria in
the enalapril group in our study. Studies have shown reduction in
proteinuria ranging from 30-50% in children with CKD treated with ACEI
and ARB [6,20-22]. ESCAPE trial demonstrated equally effective reduction
in proteinuria with ramipril in children with glomerulopathy and
hypoplasia-dysplasia. However the proteinuria increased later to nearly
baseline level at three years. This late increase in proteinuria which
is attributed to "aldosterone breakthrough" phenomenon was not observed
in our study and proteinuria steadily decreased over 12-month period.
The renoprotection observed in the proteinuric
subgroup could be due to both antiproteinuric and antihypertensive
effect of enalapril. However, on multivariate regression, better renal
outcome in enalapril treated group with proteinuric CKD was independent
of blood pressure and proteinuria reduction. Diminished local release of
cytokines, inhibition of inflammatory pathways and reduced oxidative
stress could explain the renoprotective effect of RAS inhibitors
independent of proteinuria and blood pressure control [23].
More than 90% of the study subjects were males. This
could have been due to gender bias in seeking medical care, and also
preponderance of genitourinary anomalies, which are common in boys. The
sample size was small, which did not allow detection of smaller
differences in GFR decline in the two groups. As the number of patients
with glomerular disease was small, the effect of enalapril in children
with glomerular versus non-glomerular disease could not be
examined. The study included patients with GFR below 30 ml/min/1.73m2
who could potentially develop hyperkalemia with ACE inhibitors.
Therefore we used enalapril in submaximal doses which could have
obscured the renoprotective effect. However, it seems unlikely as the
antiproteinuric effect of enalapril was substantial. Single-center
trial, non-blinding and short follow-up period are other limitations of
the study. The subgroup analysis was not decided a priori and not
taken into consideration for the sample size calculation. Thus findings
of subgroup analysis are at best limited to hypothesis generation. We
conclude that enalapril appears to be effective in reducing proteinuria
in children with CKD and might retard progression to end stage renal
failure in proteinuric CKD. While proteinuria reduction with ACEI is a
fairly well established finding, its renoprotective efficacy needs to be
confirmed in non-proteinuric children with CKD by large well-designed
multi-centric trials.
Contributors: PH: conceived and designed the
study, interpreted the data and drafted the manuscript; JS: collected
the data and helped in manuscript writing; AS: helped in analysis of the
data and in manuscript writing; RMP: analysed the data and helped in
manuscript writing; CSB: conducted the laboratory test and interpreted
them; AB: designed the study and revised the manuscript for important
intellectual content. He will also act as guarantor of the study. The
final manuscript was approved by all authors.
Funding: None; Competing interest:
None stated.
What Is Already Known?
• Angiotensin converting enzyme inhibitors
slow decline in glomerular filtration rate and reduce
proteinuria in adults with chronic kidney disease.
What This Study Adds?
• Enalapril was found to be effective in
reducing proteinuria in children with CKD.
• Enalapril might retard progression in
proteinuric CKD which needs to be confirmed by large
well-designed multi-centric trial.
|
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