Mailing Address
Gianluigi Ardissino,
Unit of Pediatric Nephrology, Dialysis and Transplantation, Department of Pediatrics,
Via Commenda 9, I-20122 Milano, Italy
Phone: +39.02.57992886 - Fax: +39.02.55011488 - E-mail: italkid@italkid.org
Abstract
Chronic kidney diseases (CKD) tend to progress
to end-stage renal failure (ESRF) in adults and children. As it has been demonstrated
that angiotensin-converting enzyme inhibitors (ACEi) have a renoprotective
effect in adults with proteinuric disease, and may be effective in reducing
hyperfiltration and proteinuria, they are frequently also used as anti-progression
agents in pediatric patients with CKD despite the absence of data confirming
their renoprotective role in the nephropathies peculiar to children. The aim
of this study was to investigate whether patients with hypodysplastic CKD (the
most common cause of ESRF in children) treated with ACEi show a significantly
slower decline in creatinine clearance (Ccr) than matched control patients.
The analysis was based on the information available in the database of the
ItalKid Project, a nationwide, population-based registry of chronic renal insufficiency
(CRI) in children in Italy. Of the 822 patients with CRI due to hypodysplasia,
we selected those who had been continuously treated with ACEi; the control
patients, who had never received ACEi, were identified from the same diagnostic
group and matched for gender, age and baseline Ccr (three controls for each
case). Progression was analysed as the slope of Ccr over time in a total of
164 patients: 41 cases with a mean age of 9.0(4.1 years and baseline Ccr of
50.9(16.0 mL/min/1.73 m2, and 123 matched controls with a mean age of 9.0(3.9
years and baseline Ccr of 51.2(16.5 mL/min/1.73 m2. There were no significant
between-group differences in blood pressure, the duration of follow-up, or
the pre-study slope of Ccr (-0.31(2.26 vs -0.33(3.58 mL/min/1.73m2/yr; p: ns).
After an average of 4.9(2.3 years, the mean slope of Ccr was not significantly
different between the cases and controls: -1.08(2.08 vs -1.80(4.42 mL/min/1.73
m2/yr (p: ns). The same finding was confirmed regardless of the severity of
renal impairment, and also when the analysis was restricted to the patients
with a FU of more than five years. We conclude that ACEi treatment does not
significantly modify the naturally progressive course of hypodysplastic nephropathy
in children, and that well- designed, prospective and randomised studies are
necessary before such treatment is routinely used for anti-progression purposes
in children with CKD.
Key words:
Progression; hypodysplastic nephropathy; renal insufficiency; angiotensin-
converting enzyme inhibitors
INTRODUCTION
A number of experimental studies have demonstrated that angiotensin-converting
inhibitors (ACEi) delay the progression of renal disease in patients with chronic
renal insufficiency (CRI), but this renoprotective effect was found in adult
patients with mainly diabetic [1] and non-diabetic [2-7] glomerular nephropathies.
It is not clear whether and to what extent it is mediated by the anti-proteinuric
or anti-hypertensive (systemic or intraglomerular) properties of ACEi, or by
an intrinsic (anti-fibrogenic) effect, or by all three mechanisms.
The accumulating evidence of the beneficial effect of ACEi in adults has generated
considerable expectations concerning the possibility of delaying the progression
of CRI in children, and this has been followed by their generalised pediatric
use. However, the diseases responsible for chronic kidney diseases (CKD) in
children are very different from those found in adults: in particular, glomerular
diseases are uncommon causes of CKD (6%), whereas primarily non-proteinuric
diseases such as hypodysplasia, with or without urological abnormalities account
for as many as 57% of cases [8]. On the basis of these epidemiological premises,
the efficacy of ACEi on the progression of CRI in children is questionable.
On the other hand, as these diseases are typically associated with a congenital
reduction in nephron mass with consequent hyperfiltration, ACEi use certainly
have a potentially strong rational [9]. Although ACEi are frequently used as
anti-hypertensive and anti-proteinuric agents in children too, no single study
has assessed their effect on the progressive decline of glomerular filtration
rate in this age group, probably because of the low prevalence of the disease
and the consequently small series of patients available in even specialised
centres. The aim of this study was to investigate the efficacy of ACEi as anti-progression
agents in children with CKD associated with primarily non-proteinuric diseases
using the information available in the large database of a nationwide registry
of childhood CRI (the ItalKid Project).
PATIENTS AND METHODS
The data used in the present study come from the Italian Pediatric Registry
of CRI (ItalKid Project), which includes all patients diagnosed as having a
creatinine clearance (Ccr) of <90 ml/min/1.73 m2 (calculated according to
Schwartz's formula [10]) before the age of 20 years. The general methodology
of the ItalKid Project (its organisational structure, reporting procedures
and data quality control) has been described in detail elsewhere [8].
As of 1 January 2003, a total of 1352 children had been registered. This study
considered 162 patients with CRI due to hypodysplastic nephropathy with or
without urological abnormalities (out of a total of 822) who started ACEi treatment
during the follow-up (FU) period. After excluding the patients with an age
of <2 years (n: 4), a baseline Ccr of <15 ml/min/1.73 m2 (n: 10) and
a FU duration on ACEi of <2 years (n: 65), as well as those for whom critical
data were incomplete (n: 42), the analysed sample consisted of 41 subjects
(33 males). Three patients who had never received ACEi, matched by diagnosis,
gender, age and baseline Ccr, were selected as controls for each of the 41
cases (n: 123; 99 males). The primary renal diseases responsible for CRI in
the population as a whole were hypodysplasia with associated urological abnormalities
(n=141) [vescicouretheral reflux (n=89), posterior urathral valves (n=35),
other urinary abnormalities (n=17)] and isolated hypodysplasia (n=23).
The demographic, clinical and biochemical parameters considered for the analysis
were age, systolic and diastolic arterial blood pressure (BP) and Ccr. BP was
analysed for the 30 cases and 74 controls for whom data were available as the
gender- and age-specific standard deviation score (SDS) using the reference
values of the 1987 Task Force on BP Control in Children [11].
The primary outcome measure was the rate of progression of CRI, which was calculated
as the slope of Ccr over time excluding the year in which ACEi treatment was
started. To exclude the possibility of a selection bias among the ACEi-treated
patients (i.e. the patients showing faster progression may have been more likely
to be prescribed ACEi), the pre-study slope of Ccr was calculated in the 24
cases and 66 controls for whom at least three pre-study Ccr determinations
were available.
The severity of CRI was classified as mild (60-89 mL/min), moderate (30-59
mL/min) or severe (15-30 mL/min) on the basis of the NKF definition [12]. Fast
progressors were defined as the patients with a Ccr slope of less than -3 mL/min/1.73
m2/yr; slow progressors as those with a Ccr slope of between -3 and 0 mL/min/1.73
m2/yr; and non-progressors as those who showed no loss or a gain in Ccr during
the FU [13].
RESULTS
The baseline clinical and laboratory parameters of the study population are
shown in Table 1. There were no differences between the cases and controls
in terms of the length of FU, age, Ccr or arterial BP, nor in terms of gender
or primary nephropathy distributions. In particular, 7.3% of the cases and
11.4% of the controls were hypertensive (systolic and/or diastolic BP >95th
centile for gender and age). Thirteen patients (3 cases and 10 controls)
were treated with an anti-hypertensive drug other than an ACEi (a calcium
or beta blocker) during the study period.
The pre-study Ccr calculated over a mean FU of 4.6(2.4 yrs was not significantly
different between the cases and controls: -0.31(2.26 vs -0.33(3.58 mL/min/1.73
m2/yr. One year after baseline, the decline in Ccr was significant in the ACEi-treated
group (from 50.9(16.0 to 47.9(17.9 mL/min/1.73 m2; p<0.005), but not in
the control group (from 51.2(16.5 to 49.9(18.3 mL/min/1.73 m2; p ns). The ACEi-treated
group but not the controls showed a significant decrease in systolic arterial
BP after one year and during FU (Fig. 1A), and in diastolic BP only during
FU (Fig. 1B).
At the end of the FU period, there was no significant difference in the Ccr
slope (excluding the first year) between the cases and controls: -1.08(2.08
vs -1.80(4.42 mL/min/1.73 m2/yr (Figs. 2 and 3). The same was true when the
analysis was restricted to the 22 cases with more than five years' FU and their
matched controls (n: 66): -1.20(1.37 vs-2.10(4.66 mL/min/1.73 m2/yr.
Analysis of the contingency table by treatment type (ACEi and controls) and
disease progression (fast progressors, slow progressors and non-progressors
as defined in methods) did not reveal any significant distribution in favour
of ACEi efficacy (Tab. 2). Furthermore, when the cases and controls were divided
into three groups on the basis of the initial severity of renal impairment
(Tab. 3), the corresponding Ccr slope was never significantly different between
the cases and controls although it was systematically steeper in the latter.
DISCUSSION
The results of our study suggest that ACEi treatment does not significantly
delay the progressive decline in renal function of pediatric patients with
hypodysplastic nephropathy, the most common cause of CRI in children [8].
Our analysis has a number of important limitations, but it may be useful
because of the absence of clinical trial results regarding the effect of
ACEi treatment on glomerular filtration rate in children with CKD.
Experimental data have demonstrated the efficacy of ACEi in reducing the progressive
loss of renal function, but clinical trials supporting this finding are still
limited to adult nephropathies [1-7] and it is well known that adult CKDs have
very different etiologies, clinical courses and outcomes than those peculiar
to children. The studies of the effects of ACEi in adults have mainly concentrated
on glomerular and highly proteinuric acquired nephropathies, whereas childhood
CKDs are commonly due to congenital nephropathies [8], more often show tubulo-interstitial
involvement (hypodysplasia with or without urological malformations account
for almost 2/3 of cases), and are frequently characterised by little or no
proteinuria [14]. As ACEi tend to be more effective in highly proteinuric adult
patients [15], it is perhaps not surprising that ACEi-treated children with
low proteinuric CKD do not show a significant improvement in terms of disease
progression.
It is also important to underline that hypertension is an important and common
feature of adult CKD and, together with proteinuria, has been identified as
a major contributor to progressive kidney damage [16]. In children, hypodysplastic
nephropathies are often associated with salt-losing syndrome and normal or
even low BP [17] and, when present, hypertension only develops during the most
advanced stages of CRI. The overall prevalence of hypertension in our study
population was as low as 10% (perhaps partially because of the exclusion of
patients with Ccr of <15 ml/min).
These differences between adult and pediatric CKDs (primary causes, proteinuria
levels and the prevalence of hypertension) may explain why we found ACEi to
be ineffective in children.
While reporting the results, we feel it is important to discuss the many limitations
of our study. First of all, the study is not prospective nor randomised, and
it may therefore be suspected that the patients addressed to ACEi treatment
may have had a faster progression rate (selection bias); however, given the
identical pre-study Ccr slopes in the cases and controls (Tab. 1), this concern
does not seem relevant. Secondly, our database lacks details concerning drug
types and dosages, and the patients' treatment compliance cannot be investigated.
However, the significant decrease in Ccr during the first year of FU (functional
effect of ACEi), and the decrease in both systolic and diastolic BP (Fig. 1)
not observed in the controls, provides indirect evidence that the cases were
actually receiving effective ACEi treatment.
A third weak point of the present analysis is related to the fact that the
ItalKid Project only records data on an annual basis, and so the calculation
of the slope of Ccr relies on limited observations. However, in our opinion,
the average 5-year FU was sufficiently long to ensure the reliability of the
results, which is further supported by the fact that the same finding of no
significant ACEi efficacy was confirmed when the analysis was restricted to
the patients with a FU of more than five years.
Another major limitation is the lack of information concerning proteinuria,
which was not systematically reported to the ItalKid database. As a consequence,
it was not feasible to test the possibility that the patients with higher proteinuria
levels may have benefitted from ACEi treatment. It is well known that ACEi
reduce urinary protein excretion in children with hypodysplastic nephropathy
[18] but, although often done in the case of adult nephropathies [19], the
use of proteinuria as a surrogate marker of disease progression may be misleading
because the ultimate target of anti-progression treatment should be to stabilise
the glomerular filtration rate rather than merely reduce urinary protein excretion.
Particularly in the case of CKDs characterised by low proteinuria levels, the
loss of urinary proteins may be an effect rather than the cause of disease
progression, and any intervention on the effect may well not lead to any benefit
on the cause.
The negative findings of the present study can be theoretically explained by
the poor sensitivity of the methodology used, which may have been incapable
of detecting a marginal efficacy of ACEi. Our study population clearly showed
a slow progression rate (a mean loss of Ccr of <2 mL/min/1.73 m2/yr) and
this may make detecting efficacy more difficult than in the case of a faster
decline in renal function. However, it is worth pointing out that our findings
indicate that any efficacy of ACEi is clearly not of paramount clinical importance,
and it can be speculated that, although delaying ESRF by a few years has an
important social and individual impact when managing older patients with a
short life expectancy, it is much less important in the case of children in
whom it will not substantially change their clinical outcome.
Interestingly, the accumulating evidence of the beneficial effect of ACEi in
adult patients with CKD has led pediatric nephrologists to make generalised
use of them in children, however, we could not identify any clear evidence
of short-term ACEi efficacy in reducing the progressive decline in the renal
function of children with hypodisplastic CKD. This suggests that using ACEi
for anti-progression purposes in such patients should be still considered an
experimental treatment and, as such, its prescription should continue to be
subject to essential safety and efficacy survelliance. The scientific pediatric
nephrology community should continue to encourage, promote and support well-designed
and prospective studies of this important aspect of CKD in children.
ACKNOWLEDGEMENTS
The ItalKid Project is supported by a research grant from the "Associazione
per il Bambino Nefropatico". This paper was written on behalf of all of the
members of the ItalKid Project, whose contribution was essential.
REFERENCES
| ACEi | Controls | p | |
| No. | 41 | 123 | |
| Gender (M/F) | 33/8 | 99/24 | n.s. |
| Age (yrs) | 9.0 ± 4.1 | 9.0 ± 3.9 | >n.s. |
| Follow up (yrs) | 5.1 ± 1.8 | <4.9 ± 2.5 | n.s. |
| SBP (SDS)* | 0.64±1.02 | 0.49±0.96 | n.s. |
| DBP (SDS)* | 0.52±0.89 | 0.44±1.11 | n.s. |
| Ccr (mL/min/1.73 m2) | 50.9 ± 16.0 | 51.2 ± 16.5 | n.s. |
| Pre-study Ccr slope (mL/min/1.73 m2/yr)* | -0.31 ± 2.26 | -0.33 ± 3.58 | n.s. |
Table 2: Distribution of patients treated with ACEi and controls by progression rate during follow-up
| Cases | Controls | X2= 0,581 p= 0.75 |
|
| Fast Progressors | 9 | 34 | |
| Slow Progressors | 22 | 59 | |
| Non Progressors | 10 | 30 |
Table 3: Slope of Ccr over time by initial level of Ccr in patients treated with ACEi and controls CRI ACEi Controls p
| CRI | ACEi | Controls | p |
| Mild (n:63) | -0.18 ± 1.93 | -0.38 ± 4.77 | 0.56 |
| Moderate (n:81) | -1.64± 2.10 | -2.76 ± 4.29 | 0.28 |
| Severe (n:20) | -1.70 ± 1.79 | -2.30 ± 2.17 | 0.86 |
CRI classification (12):
Mild: 60-89 ml/min/1.73 m2
Moderate: 30-59 ml/min/1.73 m2
Severe: (29 ml/min/1.73 m2
Figure 1: Systolic (A) and diastolic (B)
blood pressure at baseline, after one year and during follow-up in ACEi and
controls (data available for 30 cases and 60 controls)
Figure 2: Creatinine
clearance before (up to -1) and after the beginning of the study (>0)
in individual patients treated with ACEi (A) and controls (B).
Figure 3: Slope
of Ccr prior to study beginning in ACEi and control patients (*data
not available for all patients)
