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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2011  |  Volume : 22  |  Issue : 5  |  Page : 976-981
Clinical correlation between hypercalciuria and nocturnal enuresis

1 Jondishapur University of Medical Sciences, Ahvaz, Iran
2 Iran University of Medical Sciences, Tehran, Iran

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Date of Web Publication6-Sep-2011


Hypercalciuria may present with dysuria, urinary incontinence and nocturnal enuresis (NE). To determine the frequency of hypercalciuria in NE patients and normally continent children, we studied 122 consecutive pre- school children with NE referred to our nephrology clinic during two years, from September 2007 to August 2009. We measured the 24- hour urinary calcium. Furthermore, we compared the response to nasal desmopressin in hypercalciuric and normocalciuric patients. Hypercalciuria was found in 26 (21.3 %) of the NE patients as compared with five (4.5%) of 110 continent children [(P < 0.001), OR = 5.68 (95% CI, 2.1-15.4)]. In addition, the mean 24- hour urine calcium/body weight ratio (24h- U- Ca/Bw) was higher in NE patients, 3.04 ± 1.54 vs. 2.57 ± 0.9, respectively (P = 0.005). Wet nights per week in both NE patients with and without hypercalciuria at the first visit ranged from two to seven (median: 6 and 7, respectively), and the mean overall success rate of the nasal desmopressin therapy was 83.3% and 90%, respectively (P > 0.05). The response to desmopressin above 90% occurred within one month of therapy without a significant change in the levels of hypercalciuria. We conclude that these results suggest that hypercalciuria has a significant association with NE and does not interfere with the desmopressin therapy.

How to cite this article:
Valavi E, Ahmadzadeh A, Hooman N, Aminzadeh M. Clinical correlation between hypercalciuria and nocturnal enuresis. Saudi J Kidney Dis Transpl 2011;22:976-81

How to cite this URL:
Valavi E, Ahmadzadeh A, Hooman N, Aminzadeh M. Clinical correlation between hypercalciuria and nocturnal enuresis. Saudi J Kidney Dis Transpl [serial online] 2011 [cited 2023 Jan 29];22:976-81. Available from: https://www.sjkdt.org/text.asp?2011/22/5/976/84461

   Introduction Top

Nocturnal enuresis (NE) is a common problem in childhood and early adolescence, and is characterized by urine loss during the night in children over the age at which bladder control is expected to be achieved. Although this condition has a high rate of spontaneous remission, bed- wetting has significant negative impacts on a child's self- image and causes many limitations and psychosocial effects on both children and their families. [1],[2]

High urine output at night, lack of increment in plasma vasopressin at night, uninhibited nocturnal detrusor muscle contractions and lack of arousal mechanisms have been proposed as pathogenic factors in this multi- factorial condition. [3],[4] Hypercalciuria is a newly proposed factor that has a correlation with NE. [5],[6] Although, in some studies, hypercalciuria was not frequent in NE patients, several studies have shown that the frequency of hypercalciuria in NE patients is more than that in continent children, and ranges from 15.3% to 57%. [7],[8],[9],[10] However, in most of these studies, the diagnosis of hypercalciuria was not done with the measurement of 24- hour urinary calcium (Ca) content, which is more reliable than the random urine sampling (UCa/UCr ratio). [7]

The aim of this study is to determine the frequency of hypercalciuria in NE patients and normal continent children in addition to the response to nasal desmopressin in hypercalciuric and normocalciuric NE children.

   Patients and Methods Top

In this case-control analytical study, all consecutive pre- school children with NE referred to the Nephrology Clinic of Abuzar Children's Hospital in Ahvaz, Iran, were enrolled in the study from September 2007 to August 2009. The control group consisted of continent children referred for pre- school routine examination. At the initial visit, all the NE patients and their parents were interviewed for chief complaints, present and past medical history, daytime and nighttime voiding patterns, bowel emptying habits, encopresis status, urinary tract infection status and psychosocial and learning problems contributing to enuresis.

Enuresis was defined according to the International Children's Continence Society (ICCS), and all patients were above five years of age and experienced enuresis at least two times per week. [11] Continent children who had not experienced NE since age three were selected from an equal distribution of age- and gender- matched controls.

We excluded patients with NE associated with daytime symptoms, urgency, frequency, urinary incontinence, urinary tract anomalies or infections, history of chronic kidney disease, diabetes insipidus, diabetes mellitus, mental retardation, active neurological disease and adenoid hypertrophy.

Biochemical parameters included serum urea, creatinine, complete blood count, fasting blood sugar and electrolytes, urinalysis and culture, urinary electrolytes and creatinine levels and kidney and bladder ultrasound. Twenty- four- hour urine samples were collected for each individual for measurement of calcium levels. In NE patients, urine was collected by waking up the children by their parents periodically during the night.

Hypercalciuria was defined as ≥4 mg/kg/day urinary calcium. The patients were divided into hypercalciuric and normocalciuric groups on the basis of urinary calcium levels. Plasma calcium, phosphorus, alkaline phosphatase and venous blood gas levels were measured in all the hypercalciuric children. Wet and dry nights were tracked by the parents and the success rate for control of NE was defined monthly as percentage of dry nights per month. After one month, the children in the study were consequently classified as: low responders, if there was no decrease or less than a 30% decrease in the number of wet nights compared to baseline; partial responders, if there was a 30-90% decrease in the number of wet nights compared to baseline; good responders, if there was a 90% or more decrease in the number of wet nights.

All the patients were advised to empty their bladder, restrict fluid and fruit intake starting two hours prior to bedtime, restrict salt, sugar and heavy foods at night and earn small rewards for dry nights. The patients initially received 10-20 μg nasal desmopressin, which was gradually increased to a maximum of 40 μg if more than one wet night per week was experienced. This treatment was continued along the study and the patients were evaluated monthly.

This study was supported by the vice- chancellery research center of Jundishapour University of Medical Sciences (No: u- 87090) and the Ethical Committee of Ahvaz Jundishapour University of Medical Sciences approved the study protocol.

   Statistical Analysis Top

Data were analyzed using SPSS version 13.0 (SPSS Inc., Chicago, IL, USA). All the variables were compared using Student's "t" test, Mann- Whitney U- test and chi- square test (for quantitative and qualitative variables, respectively). Fisher's exact test was used to evaluate the relationship between two categorical variables when there were small cell frequencies. Quantitative variables were provided as mean (±SD). In addition, risk was expressed as OR with 95% confidence index (CI), and P- values <0.05 were considered statistically significant. Children were grouped according to age, and multivariate analysis was used to evaluate the effect of gender, age and age-gender interaction.

   Results Top

One hundred twenty- two children with NE were included in the study, and 110 continent children comprised the control group. There were no statistically significant differences between these groups in age and gender (P > 0.05). Hypercalciuria was found in 26 (21.3%) NE patients and five (4.5 %) continent children, (P < 0.001, OR = 5.68, 95% CI, 2.1-15.4). In addition; the mean 24- hour urine calcium/ body weight (Bw) ratio, 24h- U- Ca/Bw), was 3.04 ± 1.54 vs. 2.57 ± 0.9 in NE patients and continent children, respectively (P = 0.005), [Table 1].
Table 1: Clinical characteristics of normal continent children and nocturnal enuresis patients.

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The mean age in NE patients was 8.5 (SD = 2.4) years, and 65 (53.3 %) of them were boys. Wet nights per week ranged from two to seven (median: 7), and a family history of NE was found in 78.6%.

The study girls were younger than boys, and the mean age in boys and girls was 8.83 ± 2.37 and 7.53 ± 2.28 years, respectively (P= 0.014). However, there were no significant differences between both genders in the median wet nights per week, 24h- U- Ca/Bw ratio or ultimate response to therapy (P > 0.05).

The mean of Z- score in the NE patients was 1.01 ± 2.5, with 1.1 ± 2.3 in boys and girls, respectively, and it was significantly lower in the hypercalciuric group (P = 0.001).

[Table 2] shows the clinical characteristics of NE patients with and without hypercalciuria in both girls and boys.
Table 2: Clinical characteristics of nocturnal enuresis patients with and without hypercalciuria.

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The hypercalciuric NE patients were significantly younger than the normocalciuric group 7.53 ± 2.28 vs. 8.83 ± 2.37 years, P = 0.01. The frequency of hypercalciuria in boys and girls was 42.3% and 57.7%, respectively, (P > 0.05); however, the girls with hypercalciuria were younger (P < 0.001). Wet nights per week in both NE patients with and without hypercalciuria at the first visit ranged from two to seven (median: 6 and 7, respectively, and the mean of 24h- U- Ca/Bw was 5.03 vs. 2.3).

Among the NE patients, 97 (79.5%) were ten years of age or younger; boys comprised 49.5% of the younger age group and 68% of the older group, but there were no statistically significant differences in gender or frequency of hypercalciuria among these age groups (P > 0.05).

[Table 3] shows the response of children to the therapies. The overall success rate after one month of therapy was 89%, and there was no difference between the hypercalciuric and the normocalciuric NE patients (83.3% and 90%), respectively (P > 0.05). Good response (above 90% after one month) to therapy was observed in 50% and 67.9% of the hypercalciuric and the normocalciuria patients, respectively, but this difference was not statistically significant (P > 0.05).
Table 3: The response of nocturnal enuresis patients to the therapies.

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Electrolyte abnormalities were not observed during the long- term follow- up, and the mean serum sodium before and after one month desmopressin therapy were 139 ± 3.38 and 140 ± 4.31, respectively, (P > 0.05).

The mean of the follow- up period of the study patients was 4.5 months. Two patients with hypercalciuria had partial renal tubular acidosis and were excluded from the NE group, while the rest had idiopathic hypercalciuria. No serious adverse events were observed with desmopressin except nasal irritation in two patients.

   Discussion Top

NE is a frequent problem in children, and the current evaluation program for its management does not include routine detection of hypercalciuria. In the present study, we added the quantification of 24- hour urinary calcium to other current evaluations in NE patients. All laboratory analyses were performed on an outpatient basis and did not employ urinary catheterization. Hypercalciuria was common in our NE patients (21.3%), and had a significant association with NE.

The prevalence of hypercalciuria in the normal population is considerable, and the authors have reported rates between 3.0% and 7.0% among children. [12],[13] Microscopic hematuria, gross hematuria episodes, unusual abdominal pain and dysuria are the most commonly reported clinical symptoms. [14] However, nocturnal and/or diurnal enuresis, urinary urge incontinence and supra pubic pain or urethralgia are some other signs and symptoms that are infrequently associated with hypercalciuria. [15],[16],[17]

The importance of hypercalciuria in NE has been considered in several studies. Aceto et al found nocturnal hypercalciuria in 39.7% of their enuretic patients and a significant association of hypercalciuria with low anti- diuretic hormone (ADH) levels and nocturnal polyuria. [9]

Raes et al observed a significant correlation between calcium excretion and nocturnal polyuria, low urinary osmolality and increased sodium and osmolar excretion in the night time urine sampling, [18] and Valenti et al found a decreased aquaporin two expression levels and nocturnal polyuria in enuretic patients associated with hypercalciuria. [19] Furthermore, hypercalciuria in a recent study was proposed to cause an interference with the therapeutic effect of desmopressin. [7]

In our study, boys were not a predominant gender, but they were older than the girls with a lower frequency of hypercalciuria. However, the response to therapy or other criteria did not differ significantly between boys and girls. We also found a significantly decreased Z- score in hypercalciuric patients. This finding was observed in both boys and girls, and needs further investigation.

The treatment of NE includes some drugs and several behavioral modification techniques. We presented several techniques and drug therapy in all the NE children. The mean success rate after the therapy was 88.97%, but did not differ significantly between hypercalciuric and normocalciuric NE patients (83.3% and 90%, respectively). However, in the literature, the overall success rate for desmopressin treatment ranged from 35% to 65%. [20] Ferrara et al found a 62.9% decrease in wet nights after oral desmopressin administration, [21] and the success rate in a Chinese study was 52%. [22] Mohammadjafari et al found a lower incidence of full response (above 90%) to nasal desmopressin in hypercalciuric children than in normocalciuria enuretic children (47.4% vs. 64.8%, respectively), and concluded that hypercalciuria is responsible for poor treatment responses. [7]

Based on our findings, the low response to therapy was not correlated with hypercalciuria, which was similar to the findings of a recent Scandinavian study; [10] only two of 46 Danish children with desmopressin- resistant NE and nocturnal polyuria revealed hypercalciuria, not different from the controls. [10]

One of the limitations in this study was the difficulty of 24- hour urine collection, and, in some cases, the parents suffered from repeated urine collection of their young children. We also did not measure the urinary calcium levels after treatment with desmopressin. We conclude that our findings suggest that hypercalciuria has a significant association with NE and does not interfere with the desmopressin therapy; however, the screening for hypercalciuria in all NE patients seems to be reasonable.

   Acknowledgment Top

The authors would like to thank Jondishapur University of Medical Science for the grant that made this study possible.

   References Top

1.Schober JM, Lipman R, Haltigan JD, Kuhn PJ. The impact of monosymptomatic nocturnal enuresis on attachment parameters. Scand J Urol Nephrol 2004;38:47- 52.  Back to cited text no. 1
2.Theunis M, van Hoeke E, Pesbrugge S, Hoebeke P, Vande Walle J. Self- image and performance in children with nocturnal enuresis. Eur J Urol 2002;41:660- 7.  Back to cited text no. 2
3.Neveus T, Lackgren G, Tuvemo T, Hetta J, Hjalmas K, Stenberg A. Enuresis background and treatment. Scand J Urol Nephrol Suppl 2000;206:1- 44.  Back to cited text no. 3
4.Norgaard JP, Djurhuus JC, Watanabe H, Stenberg A, Lettgen B. Experience and current status of research into the pathophysiology of nocturnal enuresis. Br J Urol 1997;79:825- 35.  Back to cited text no. 4
5.Pace G, Aceto G, Cormio L, et al. Nocturnal enuresis can be caused by absorptive hypercalciuria. Scand J Urol Nephrol 1999;33:111- 4.  Back to cited text no. 5
6.Deen PM, Daht N, Caplan MJ. The aquaporin2 water channel in autosomal dominant primary nocturnal enuresis. J Urol 2002;167(3): 1447-50.  Back to cited text no. 6
7.Mohammadjafari H, Kosaryan M, Karami H, Dabaghzadeh A. Response of Enuretic Children with and without Hypercalciuria to Nasal Desmopressin. Iran j Pediatr 2009;19(1):5- 10.  Back to cited text no. 7
8.Valenti G, Larea A, Gouraud S. Low calcium diet in hypercalciuric children restores AQP2 excretion and improves clinical symptoms. Am J Physiol 2002;52:895- 903.  Back to cited text no. 8
9.Aceto G, Penza R, Coccioli MS, et al. Enuresis subtypes based on nocturnal hypercalciuria: A multicenter study. J Urol 2003;170:1670- 3.  Back to cited text no. 9
10.Kamperis K, Hagstroem S, Rittig S, Djurhuus JC. Urinary calcium excretion in healthy children and children with primary monosymptomatic nocturnal enuresis. J Urol. Aug 2006;176 (2):770- 3.  Back to cited text no. 10
11.Nevéus T, Gontard A, Hoebeke P. The standardization of terminology of lower urinary tract function in children and adolescents: Report from the standardisation committee of the international children's continence society. J Urol 2006;176:314- 24.  Back to cited text no. 11
12.Penido MG, Diniz JS, Moreira ML, et al. Idiopathic hypercalciuria presentation of 471 cases. J Pediatr (Rio J) 2001;77:101- 4.  Back to cited text no. 12
13.Sargent JD, Stukel TA, Kresel J, Klein RZ. Normal values for random urinary calcium to creatinine ratios in infancy. J Pediatr 1993;123: 393- 7.  Back to cited text no. 13
14.Stapleton FB, Roy S 3rd, Noe HN, Jerkins G. Hypercalciuria in children with hematuria. N Engl J Med 1984;310:1345- 8.  Back to cited text no. 14
15.Kaha A, Travis LB, Brouhard BD. The association of idiopathic hypercalciuria and asymptomatic gross hematuria in children. J Pediatr 1981;99:716- 20.  Back to cited text no. 15
16.Fivush B. Irritability and dysuria in infants with idiopathic hypercalciuria. Pediatr Nephro 1990;14:262- 3.  Back to cited text no. 16
17.Lopéz MM, Castillo LA, Chávez JB, Ramones C. Hypercalciuria and recurrent urinary tract infection in Venezuelan children. Pediatr Nephrol 1999;13:433- 7.  Back to cited text no. 17
18.Raes A, Dossche L, Hertegonne N, et al. Hypercalciuria is related to osmolar excretion in children with nocturnal enuresis. J Urol 2010; 183(1):297- 301.  Back to cited text no. 18
19.Valenti G, Laera A, Pace G, et al. Urinary Aquaporin 2 and calciuria correlate with the severity of enuresis in children. J Am Soc Nephrol 2000;11:1873- 81.  Back to cited text no. 19
20.Evans JH. Evidence based management of nocturnal enuresis. BMJ 2001;323:1167- 9.  Back to cited text no. 20
21.Ferrara P, Marrone G, Emmanuele V, et al. Homotoxicological remedies versus desmopressin versus placebo in the treatment of enuresis: a randomized, double-blind, controlled trial. Pediatr Nephrol 2008;23(2):269- 74.  Back to cited text no. 21
22.Fai-Ngo Ng C, Wong SN, Hong Kong Childhood Enuresis Study Group. Comparing alarms, desmopressin, and combined treatment in Chinese enuretic children. Pediatr Nephrol 2005;20(2):163- 9.  Back to cited text no. 22

Correspondence Address:
Ehsan Valavi
Division of Nephrology, Pediatric Department, Abuzar Children's Hospital, Ahvaz
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Source of Support: None, Conflict of Interest: None

PMID: 21912028

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  [Table 1], [Table 2], [Table 3]

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