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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2017  |  Volume : 28  |  Issue : 3  |  Page : 566-570
A randomized controlled trial of the effects of hydrochlorothiazide on overactive bladder and idiopathic hypercalciuria


1 Department of Pediatric Nephrology, Arak University of Medical Sciences, Arak, Iran
2 Department of Pediatrics, Arak University of Medical Sciences, Arak, Iran
3 Department of Biostatistics, Arak University of Medical Sciences, Arak, Iran
4 Department of Basic Sciences, Clinical Research Office, Amir Almomenin Hospital, Arak University of Medical Sciences, Arak, Iran
5 Faculty of Medicine, Arak University of Medical Sciences, Arak, Iran

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Date of Web Publication18-May-2017
 

   Abstract 

Overactive bladder is a stressful condition which affects around 15%—20% of 5- year-old and up to 2% of young adults. One of the most common causes of overactive bladder is hypercalciuria. Our study investigated the effect of hydrochlorothiazide (HCTZ) on overactive bladder and hypercalciuria. This randomized controlled trial was conducted on 88 patients with overactive bladder and idiopathic hypercalciuria. They were randomly divided into the intervention group receiving 1 mg/kg/day of HCTZ for 3 months, and the control group receiving training without any intervention. Treatment compliance and response were reviewed monthly in each patient using a 30-day bedwetting diary. In the 1st month, the mean of bedwetting was 14.47 ± 7.06 and 12.61 ± 7.57 in the intervention and control groups, respectively (P = 0.23). In the 2nd month, it was 10.04 ± 6.32 and 10.79 ± 7.83 in the intervention and control groups, respectively (P = 0.62); and in the 3rd month, it was 6.49 ± 7.13 and 7.64 ± 7.95 in the intervention and control groups, respectively (P = 0.59). There was no significant difference between the two groups. Thus, use of HCTZ was not found to be better than urine retention control training. Therefore, one may conclude that treating hypercalciuria with HCTZ had no demonstrable effect on overactive bladder.

How to cite this article:
Yousefichaijan P, Dorreh F, Rafiei M, Naziri M, Azimnejad A. A randomized controlled trial of the effects of hydrochlorothiazide on overactive bladder and idiopathic hypercalciuria. Saudi J Kidney Dis Transpl 2017;28:566-70

How to cite this URL:
Yousefichaijan P, Dorreh F, Rafiei M, Naziri M, Azimnejad A. A randomized controlled trial of the effects of hydrochlorothiazide on overactive bladder and idiopathic hypercalciuria. Saudi J Kidney Dis Transpl [serial online] 2017 [cited 2019 Dec 14];28:566-70. Available from: http://www.sjkdt.org/text.asp?2017/28/3/566/206458

   Introduction Top


Children with an overactive bladder typically have increased urinary frequency, urgency, and urge incontinence. Often, a girl will squat down on her foot to try to prevent incontinence (termed Vincent’s curtsy). The bladder in these children is functionally although not anatomically, smaller than normal and exhibits strong uninhibited contractions. Nearly 25% of children with nocturnal enuresis also have symptoms of an overactive bladder. Many children do not feel the need to urinate, till just before they become urinary incontinent. In girls, a history of recurrent urinary tract infection (UTI) is common, but incontinence may persist long time even after infections are adequately controlled. In these cases, it is not clear if the voiding dysfunction is a sequela of the UTIs or if the voiding dysfunction predisposes to recurrent UTIs. In girls, voiding cystourethrography often shows a dilated urethra and narrowed bladder neck with bladder wall hypertrophy. The urethral finding results from inadequate relaxation of the external urinary sphincter. Constipation is common and should be treated, particularly with any child with Bristol Stool Score 1 or 2.[1],[2],[3],[4],[5],[6]

Overactive bladder is a stressful condition which affects around 15%—20% of five-year olds and up to 2% of young adults. Hyper- calciuria has been proposed as an important cause of bedwetting. According to a recent observation, there was a significant correlation between calcium excretion and nocturnal diuresis volume, low urinary osmolality, and increased sodium excretion in nighttime urine samples.[7] Recent researches show that transient receptor potential cation channel subfamily V member 5 protein (TRVP5) in kidney distal convoluted tubule has an important role in regulating the calcium secretion rate[8] in a way that the protein downregulation reduces calcium reabsorption and increases urination.[9]

Research by Jang and et al, indicates that hydrochlorothiazide (HCTZ) increases TVRP5 receptors in distal convoluted tubule and can make effect on the urinary calcium volume.[8] HCTZ is a calcium-sparing diuretic from thiazides. This is a cheap drug and can be used once in a day and has a reasonable safety profile. Hence, considering the effectiveness of this medicine in regulating hypercalciuria, it might be useful in the treatment of enuresis.

Alawwa’s research had indicated that HCTZ as an effective and safe treatment for enuresis.[10]


   Objectives Top


This study was designed to analyze HCTZ treatment for overactive bladder and idiopathic hypercalciuria; and also whether overactive bladder can be treated by treating hyper- calciuria.


   Materials and Methods Top


In this clinical trial study, 88 patients, with overactive bladder and idiopathic hypercal- ciuria referred to the pediatric clinic of Amirkabir Hospital in Arak city. Patients were between six and 16 years of age. Our inclusion criteria were no organic disease and discontinuing other treatment for the last four weeks. Our inclusion criteria included all children with idiopathic hypercalciuria; at the baseline, Bartter syndromes and RTAs or each kind of secondary hypercalciuria was excluded from the study. The patients and parents were well- informed about the nature and objectives of the study and signed the informed consent.

At first, organic causes of the disorder were recorded by biography, clinical examination, and paraclinical test. Then, patients were randomly categorized as the intervention and control groups. All patients with calcium to creatinine ratio of more than 0.2 were treated by 0.1 mg HCTZ. Patients of the intervention group (44 cases) were given HCTZ (1 mg/kg/ day), 10 hours before they sleep at nights, and they also were receiving training.

Hypercalciuria is defined as random calcium/ creatinine ratio >0.2. These children were checked for polyuria, concentrating defects, and their fluid intake. The renal functions in all patients were checked and if there was any decrease in renal function, they were excluded from the study.

The urine calcium/creatinine ratio in these patients was measured after two weeks, if they were normocalciuric, they would continue their treatment, but if they were still hyper- calciuric, then they would be excluded from the study. The control group (44 cases) did not receive any medication but only received training. The treatment period has continued for three months, and the number of children with bedwetting in both groups was recorded and compared at the beginning and the end of each month.

We called the patients several times during the treatment period, to verify the method of drug use and make sure that they were following the clinical orders. Possible side effects and the number of bedwetting appearances during a month have been asked and recorded. To record the data, a checklist has been provided, and patients or their parents have been asked to mark the paper daily, from the beginning of the study and during the treatment, if the patient bed is dry or wet. Papers have been collected at the end of the month, and a comparison has been made between the two groups before and after treatment. Necessary recommendations to parents:

  1. Proper usage of fruit and vegetables
  2. High usage of liquids as much as to turn urine white
  3. Avoiding extra salt or salty snacks
  4. Drinking enough liquid to satisfy thirst, which should be limited after 6 pm
  5. Making sure about children urinating before going to sleep
  6. Avoiding extra sugar, caffeine, and salt after 4 pm
  7. Waking the child up to ask him to urinate at least once in a night sleep.


Data were analyzed using the Statistical Package for the Social Sciences (SPSS) software version 18.0, (SPSS Inc., Chicago, IL, USA). Paired /[1]-test and independent test were used when they were appropriate to use. P <0.05 were considered statistically significant.

Ethical codes such as participating in research with consent or leaving it voluntarily, keeping the information secure and keep the collected data confidential have been considered, and the approved laws of University’s Ethical Committee have been observed in all stages of the research.


   Results Top


A total of 88 suitable patients were enrolled in the trial. They were randomly allocated to treatment group or control group.

The mean age of the patients in the treatment group was 8.02 ± 1.67 years, and in control group was 8.47 ± 1.64 years (P = 0.20). There was no statistical significance between two groups. In both groups, there were 25 boys (56.8%) and 19 girls (43.2%) participated in the study, so both groups were the same according to age and sex. The mean and the standard deviation of bedwetting in both groups for three months have been illustrated in [Table 1].
Table 1: The mean ± standard deviation of bedwetting in the study groups in three months.

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   Discussion Top


Both groups received training and a reduction in bedwetting appearances have been seen at the end of the three months, but there was no considerable difference between two groups in the number of children with bedwetting.

Alawwa et al assessed 40 children suffering from primary enuresis. Patients were randomized into two groups, group one first received placebo for three months, and group two received HCTZ for the same period. After a two weeks wash out period, both groups were crossed over in their medication and treatment continued for another three months. Both HCTZ and placebo were statistically effective in reducing the average percentage of wet nights. HCTZ resulted in a significantly better reduction than placebo.[10] Hypercalciuria has not been examined in Alawwa’s research, but in our research, patients suffering from enu- resis and hypercalciuria have been participated. Choi et al in their researches showed that HCTZ in low dose (0.5 mg/kg/day) may be safe and effective in controlling renal hyper- calciuria in children.[11] Naseri and Sadegh evaluated the role of high dose HCTZ (1–2 mg/kg/day) in pediatric calculus formers with hypercalciuria and showed 52.6% of 19 patients have become normocalciuric.[12]

In this study, HCTZ 1 mg/kg/d has been used, and all patients who became normo- calciuric continued to participate in the study. In Yousefichaijan et al study, patients with hypercalciuria and urine infection received HCTZ 1 mg/kg/d, but it could not prevent the infection.[6] However, in another research by the same researcher, the same drug dose has reduced abdominal pain in patients affected by hypercalciuria and abdominal pain.[13]

In a research, Deshpande et al has explored studies in curing bedwetting that has used medicines other than desmopressin and tri- cyclic and concluded that although medicines such as indomethacin or diclofenac were better than placebo in controlling bedwetting, they were not better than desmopressin and also they had some side effects; no medication was effective in reducing disorders; however, a combination of medicines and behavior therapy were somewhat effective.[14]

In another research published in 2007, the side effects and safety of desmopressin have been studied. This study expresses that according to the global use of this pills in the last 30 years and enormous data and local reports of its side effects, this medicine is generally safe and considering its indications and following treatment dose, no particular side effects were observed.[15]

It has been reported that Desmopressin may not be effective for nocturnal enuresis associated with polyuria and hypercalciuria.[16] In a study about different ways of curing bed- wetting that was published in 2010, the usage of nonmedical methods such as start chart, reward system, dry bed training, bedwetting alarm as well as medications such as desmo- pressin, anticholinergic drugs and tricyclic compounds have all been explored. But failure in some nonmedical methods and/or lack of cooperation of families in using them and in addition, the side effects of desmopressin (such as hyponatremia, headache, gastrodynia, and changes of behavior), oxybutynin and tricyclic compounds (such as mouth dryness, headache, constipation, urinary retention, behavior changes, nightmares, and possible cardiac arrhythmias) makes patients to stop practising these methods and also taking these medicines.[17]

In another research by Caldwell et al, it was shown that simple behavioral therapy such as rewarding, waking children up during the night to empty their bladder, bladder training, and liquid limitation are more effective than treatments that have been already done, but they are less effective than alarm therapy and some medications; and behavior therapy has been recommended to be the highest priority rather than other treatments.[18] In addition, in our research, simple advises such as liquid limitation and getting up during the night reduced bedwetting in both groups.

Finally, considering the lack of researches exploring HCTZ influence on bedwetting alongside hypercalciuria, more investigations with larger sample sizes and longer-term use of HCTZ are recommended.


   Conclusion Top


HCTZ was not better than training to control bedwetting in the treatment of overactive bladder and idiopathic hypercalciuria. Hence, overactive bladder can not be treated by only treating hypercalciuria.


   Acknowledgments Top


The article was taken from Ms. Atefeh Azimnejad thesis (711: Number thesis) and we hereby express our sincere appreciation for her efforts; and also special thanks to Amir Kabir Research Center. (IRCT2013110813366N2).

Conflict of interest: None declared.

 
   References Top

1.
Yousefichaijan P, Salehi B, Firouzifar MR, Sheikholeslami H. The correlation between attention deficit hyperactivity disorder and enuresis in children with nocturnal enuresis. J Isfahan Med Sch 2012;30:1-8.  Back to cited text no. 1
    
2.
Yousefichaijan P, Firouzifar MR, Cyrus A. Correlation between sacral ratio and primary enuresis. J Nephropathol 2012;1:183-7.  Back to cited text no. 2
    
3.
Yousefichaijan P, Firouzifar MR, Dorreh F. Growth and development in 6 years old children with and without primary nocturnal enuresis. J Med Univ Zanjan 2011;20:97-100.  Back to cited text no. 3
    
4.
Yousefichaijan P, Salehi B, Rafiei M, Ghadimi N, Taherahmadi H, Hashemi SM. Emotional disorders in children with monosymptomatic primary nocturnal enuresis. J Pediatr Nephrol 2015;3:22-5.  Back to cited text no. 4
    
5.
Yousefichaijan P, Salehi B, Rafiei M, Firouzifar MR, Mousavinejad SA. Parents function and behavioral disorders in children with/without diurnal voiding dysfunction: A comparative study. Zahedan J Res Med Sci 2014; 16(9) 1-4.  Back to cited text no. 5
    
6.
Yousefichaijan P, Firouzifar MR, Cyrus A. Does hydrochlorothiazide prevent recurrent urinary tract infection in children with idio- pathic hypercalciuria? J Pediatr Urol 2013 ;9(6 Pt A):775-8.  Back to cited text no. 6
    
7.
Raes A, Dossche L, Hertegonne N, et al. Hypercalciuria is related to osmolar excretion in children with nocturnal enuresis. J Urol 2010;183:297-301.  Back to cited text no. 7
[PUBMED]    
8.
Jang HR, Kim S, Heo NJ, et al. Effects of thiazide on the expression of TRPV5, calbindin-D28K, and sodium transporters in hypercalciuric rats. J Korean Med Sci 2009;24 Suppl:S161-9.  Back to cited text no. 8
[PUBMED]    
9.
Hoenderop JG, van Leeuwen JP, van der Eerden BC, et al. Renal Ca+2 wasting, hyper- absorption, and reduced bone thickness in mice lacking TRPV5. J Clin Invest 2003;112:1906-14.  Back to cited text no. 9
[PUBMED]    
10.
Alawwa IA, Matani YS, Saleh AA, Al-Ghazo MA. A placebo-controlled trial of the effects of hydrochlorothiazide on nocturnal enuresis. Urol Int 2010;84:319-24.  Back to cited text no. 10
    
11.
Choi JN, Lee JS, Shin JI. Low-dose thiazide diuretics in children with idiopathic renal hypercalciuria. Acta Paediatr 2011 ;100:e71-4.  Back to cited text no. 11
    
12.
Naseri M, Sadeghi R. Role of high-dose hydrochlorothiazide in idiopathic hyper-cal- ciuric urolithiasis of childhood. Iran J Kidney Dis 2011;5:162-8.  Back to cited text no. 12
    
13.
Yousefichaijan P, Cyrus A, Dorreh F, Gazerani N, Sedigh HR. Effect of hydro- chlorothiazide on reducing recurrent abdominal pain in girls with idiopathic hyper- calciuria. J Res Med Sci 2011;16 Suppl 1: S433-6.  Back to cited text no. 13
    
14.
Deshpande AV, Caldwell PH, Sureshkumar P. Drugs for nocturnal enuresis in children (other than desmopressin and tricyclics). Cochrane Database Syst Rev 2012;12:CD002238.  Back to cited text no. 14
    
15.
Vande Walle J, Stockner M, Raes A, N0rgaard JP. Desmopressin 30 years in clinical use: A safety review. Curr Drug Saf 2007;2:232-8.  Back to cited text no. 15
    
16.
Aceto G, Penza R, Coccioli MS, et al. Enuresis subtypes based on nocturnal hypercalciuria: A multicenter study. J Urol 2003;170(4 Pt 2): 1670-3.  Back to cited text no. 16
    
17.
National Clinical Guideline Center. Nocturnal Enuresis: The Management of Bedwetting in Children and Young People. London: National Clinical Guideline Center; 2010. Available from: http://www.nice.org.uk.  Back to cited text no. 17
    
18.
Caldwell PH, Nankivell G, Sureshkumar P. Simple behavioural interventions for nocturnal enuresis in children. Cochrane Database Syst Rev 2013;7:CD003637.  Back to cited text no. 18
    

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Correspondence Address:
Mahdyieh Naziri
Department of Base Science, Clinical Research Office, Amir AlMomenin Hospital, Arak University of Medical Sciences, Arak
Iran
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DOI: 10.4103/1319-2442.206458

PMID: 28540894

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