Therapeutic Efficacy of Hydrochlorothiazide in the Primary Monosymptomatic Nocturnal Enuresis of Children

Primary monosymptomatic nocturnal enuresis (PMNE), as a symptom means the involuntary urination at least 2 nights a month in children older than 5 years of age; this is despite the fact that most children gain voiding control at night from the age of 3 and these capabilities are earlier in females than males (1, 2). As a common childhood problem, it has a prevalence of 1.6% to 15%; 10% in 6-year old, and 5% in 14-year children still wet the bed at night (3, 4). Children who have never gained urination control (about 75% of cases) are defined as primary NE, and other children with development of incontinence at least in 6 months (25% of cases) are the secondary NE (5, 6). Moreover, NE without daytime urinary symptoms is defined as monosymptomatic, and NE with daytime urinary symptoms is defined as nonmonosymptomatic NE, which is accompanied by daytime urinary symptom (7). Idiopathic hypercalciuria (IHC) is a cause of urinary problems in children such as nephrolithiasis (6). Also, various manifestations of clinical urinary disorders such as recurrent abdominal pain, hematuria, urinary tract infections (UTIs), urgency, dysuria, and urinary incontinence are common in children with IHC (8, 9). The influence of genetic factors hypothesized as another etiology of PMNE also identified as autosomal dominant patterns for it (10, 11). Since children with NE do not have a psychiatric disorder, control of bladder may be lost by a stressful life, also physiology of sleep condition may play a role in the etiology of NE, with a commonly noted high arousal threshold. Detrusor muscle malfunction with a tendency for involuntary contractions and small amounts of urine in bladder are considered as another possible etiology (8, 12). NE may be associated with reduction of bladder capacity commonly observed in children with chronic constipation that leads to large dilated of distal colon impinging on bladder as another etiology of NE (4, 13, 14).

According to a recent observation, there is a significant correlation between urination volume (polyuria) in night and excretion of calcium (6, 15, 16). To treat this condition thiazide diuretics are used as drugs that are easy to use, have few complications, are inexpensive, widely available, and acceptable (17). Thiazides induce calcium reabsorption in distal tubules of kidney and ameliorate hypercalciuria (18-20). Based on the context, it was found that idiopathic hypercalciuria was a strong cause of NE, and hydrochlorothiazide (HCT) significantly improved hypercalciuria condition; therefore, it was suggested to evaluate the therapeutic effects of HCT on the improvement of NE condition. The current study considered the effect of HCT on the treatment of PMNE in children, males and females, in order to find a better treatment.

Totally, out of the 57 patients with PMNE in the case group, 34 patients were male (7/59%) and 23 patients were female (3/40%), and out of the 53 patients in the control group 27 patients were male (9/50%) and 26 patients were female (1/49%); based on this about gender of children there was no significant differences between the groups (P = 0.359). The mean age of children in the case and control groups were 8.35 ± 1.94 and 8.21 ± 1.99 years, respectively (P = 0.802). In addition, the youngest child was 6 years old and the oldest one was 13 years old (Table 1). As shown in Table 1, the age of children was not significantly different between the 2 groups (P = 0.223).

Also, as shown in Table 2, the mean of episodes of wet-night in the 1st (P <0.001), 2nd (P = 0.001), and 3rd (P = 0.001) months of examinations were significantly different between the control and case groups. The mean of episodes of wet-night, considering age (P = 0.899) and gender (P = 0.607) variables, was not significantly different between the control and case groups (Table 3). In the current study, HCT caused no complications in the subjects of the case group and no one developed intolerance to HCT.

In the current study, PMNE improved in the case group who receiving HCT. Alawwa et al. studied the therapeutic effect of HCT on NE. This study was conducted on 40 children with NE and they used placebo and 1 mg/kg/day oral HCT; clinical responses of children were studied during a period of 3 months. It was observed that HCT reduced episodes of wet night better than placebo, but both of them were statistically effective on reducing the mean of wet nights; the current study also came to the same conclusion (21). Yousefichaijan et al. in a study on the therapeutic effect of HCT on PMNE only in males, compared the case (HCT and conservative treatment) and control (conservative treatment) groups. They concluded that HCT was an effective therapeutic option; hence, it can be prescribed in the treatment of PMNE (17). Jang et al. in a study showed that the impact of HCT, which induced hypocalciuria in hypercalciuric rats, was associated with increased expression of transient receptor potential vanilloid 5 (TRPV5) protein; TRPV5 may also have a significant effect on the regulation of calcium excretion from the urinary system (22). Mechanisms of the relationship between HCT and NE explained by Park et al. (23) confirmed the current study results. Porter et al. reported that due to low cost, ease of use, easy to access, and low side effects of HCT, HCT can be used as an effective drug to treat NE in children (24). In addition, Hoenderop concluded that reabsorption of calcium reduced throughout the down-regulation of TRPV5 that became a factor for calcium loss from urinary system and caused hypercalciuria (25). Raes et al. (15) concluded that there was a correlation between polyuria, hypercalciuria, low urinary osmolality, and increased excretion of sodium in samples, in the urine of night time (15), but these 2 factors were not evaluated in the current study.

However, based on the following reasons, further studies are needed before the administration of HCT as an alternative or adjuvant treatment in NE: 1) Clinical studies on the impact of HCT in NE are few, 2) Laboratory studies on the effect of HCT on the treatment of NE are few and molecular mechanisms are not completely identified, and 3) The effects of different doses of HCT in various forms of NE including primary or secondary with and without monosymptomatic are not found yet. Limitation of the current study was that the 3-month follow-up of children and HCT as a non-routine drug to treat NE may lead to parental noncompliance. In addition, some children and their parents missed follow-up visits during the current study (new patients were replaced). It was explained to the parents that HCT is a cheap and safe drug for their children, in order to increase their cooperation with the study.

Therefore, due to the low number of clinical studies and unknown mechanism of this association, we recommend to further studies with larger sample sizes and studies that evaluated different dose of HCT on nocturnal enuresis.