Current study could confirm previous reports about an increased excretion of tubular NAG enzyme in children treating common anti-epileptic treatment regimens. Our study showed that mean value of NAG/Cr index was increased 3.7-fold following administration of VPA over the median values of the epileptic children before treatment. Elevation of this index after the treatment with CBZ was 2.3-fold following administration of VPA over the median values of epileptic ones before treatment. However, the measure of NAG/Cr index was not significantly different between the two untreated groups. The adverse impact of mono and combined therapies on NAG/Cr index and therefore on renal tubular function has been observed in several previous studies, while some others demonstrated the clinical efficiencies of these drugs in epileptic children. In a study by Otsuka et al. the level of urinary excretion of NAG was high in 29% of all patients, in 47% of VPA group, and in 38% of CBZ group. In their study, a significant positive correlation was observed between NAG/Cr index and serum concentration of VPA [
9]. In another study by Tseng et al. VPA administration was accompanied with the highest incidence of abnormal urinary NAG/Cr index (in about 78% of treated children) that was significantly higher than that in the CBZ group with the incidence of 26%. However, the incidence of high urinary NAG index in the poly-therapy group and that in mono-therapy group was significantly similar [
10]. These adverse effects were also approved in studies on animal models. Some experimental studies revealed high NAG level in rats with partial ureteral obstruction and hydronephrotic atrophy [
11,
12]. Contrarily, in Hurkacz et al. study, increasing of NAG/Cr activity index was shown with concomitant therapy, but that was in the normal range and therefore tubular dysfunction was not approved following their treatment schedule [
7]. Also, in another study by Korinthenberg et al. those on anti-epileptic treatment with therapeutic drug levels demonstrated minor signs of tubular dysfunction [
13]. In earlier investigations, it has been hypothesized that following administration and absorption of some anti-epileptic drugs, the lysosomal contents of the tubular cells might be secreted into the lumen of the urinary tract to eliminate indigestible residues that are left after hydrolysis of high molecular weight material recaptured from the glomerular filtrate [
14]. In addition, NAG is a lysosomal hydrolasis that plays an important role in the catabolism of both glycoproteins and glycosaminoglycans [
15‐
17]. This mechanism is mainly occurred in the proximal tubulus and therefore can be interpreted as an indicator of functional disturbance of tubuls [
13]. Thus, according to our study results as well as other previous findings, NAG/Cr index can be used as a sensitive indicator of renal tubular disease activity, and it might be a suitable screening test for early diagnosis of renal disturbance.
In our survey, duration of treatment in all study groups was similar. It was suggested that distribution of NAG index of patients depended significantly on the length of therapy so that the level of urinary excretion of NAG was significantly higher in those who were taking long-term treatment (>10 years) with VPA, CBZ and combined therapy than those taking therapy shorter than 10 years [
18]. Even, after 1 to 2 years of the beginning of treatment, these patients may show persistence of the changes found after 6 months of therapy [
19]. Therefore, in the necessity of long-term administrating these drugs particularly VPA in epileptic children, a suitable dose of drug as well as appropriate treatment time should be primarily considered for minimizing their probable side effects.