No clear evidence of ACEi efficacy on the progression of chronic kidney disease in children with hypodysplastic nephropathy

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

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Table 1 Baseline characteristics of patients treated with ACEi and controls
  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.
Legends: ACEi: angiotensin-converting enzyme inhibitors; SBP and DBP: systolic and diastolic blood pressure; SDS: standard deviation score; Ccr = creatinine clearance. * The reported mean values are not based on the whole population because of missing data (see Patients and Methods)

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
Legend: Progression classes based on Ccr slopes over time:
Fast progressors : less than -3 mL/min/1.73 m2/yr,
Slow progressors : between -3 and -0.01 mL/min/1.73 m2/yr
Non-progressors : more than -0.01 mL/min/1.73 m2/yr

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)