SUBMITTED 30 MAY 22 1 REVISION REQ. 6 JUL 22; REVISION RECD. 1 AUG 22 2 ACCEPTED 31 AUG 22 3 ONLINE-FIRST: September 2022 4 DOI: https://doi.org/10.18295/squmj.9.2022.056 5 6 The Role of Hyposthenuria in Enuresis among Paediatric Patients 7 with Sickle Cell Disease 8 *Jasim N. Al‑Asadi,1 Alyaa M. Radhi,2 Dhuha S. Jumaa,2 Meaad K. 9 Hassan2 10 11 Departments of 1Family & Community Medicine and 2Pediatrics, College of 12 Medicine, University of Basrah, Basrah, Iraq 13 *Corresponding Author’s e-mails: jnk5511@yahoo.com and 14 jasim.naeem@uobasrah.edu.iq 15 16 Abstract 17 Objectives: Enuresis in children with sickle cell disease (SCD) is common. Many risk 18 factors have been postulated but its relation to hyposthenuria is debatable. This study 19 aims to determine the prevalence of enuresis inchildren with SCD in Basrah, Iraq and 20 to examine its relation with hyposthenuria. Methods: A cross-sectional 21 epidemiological study was performed on children with SCD who met the inclusion 22 criteria at the Basrah Center for Hereditary Blood Diseases over the period from the 23 first of December 2020 through May 2021. A questionnaire was used to collect 24 relevant data. Blood samples were tested for hemoglobin genotype, certain blood 25 indices, and serum hemoglobin. Urine was tested for albumin and creatinine, and the 26 specific gravity was measured using urine dipsticks. The relationships between 27 enuresis and various sociodemographic and clinical variables were assessed. Binary 28 logistic regression analysis was done to examine the independent risk factors of 29 enuresis. Results: Out of 200 eligible children, 161 were studied after exclusion of 39 30 based on the exclusion criteria, yielding an 80.5% response rate, 60.9% of them were 31 males. The mean age of the participants was 10.9 ± 2.9 years. Enuresis was reported 32 in 50 (31.1%) patients. The independent risk factors for enuresis were; family history 33 mailto:jnk5511@yahoo.com mailto:jasim.naeem@uobasrah.edu.iq of enuresis (OR, 5.94; 95% CI, 2.54-13.89; P<0.001), hyposthenuria (OR, 3.76, 95% 34 CI, 1.25-11.30; P= 0.018), and sleep disorders (OR, 2.90; 95% CI, 0.19-7.06; P= 35 0.019). Conclusion: Enuresis is common among children with SCD. Hyposthenuria 36 was significantly associated with enuresis. Family history of enuresis, and sleep 37 disorders were also found to be significantly related to enuresis. 38 Keywords: Enuresis, sickle cell disease, children, prevalence, hyposthenuria 39 40 Advances in Knowledge 41 - Enuresis is prevalent in sickle cell disease children (SCD). The role of hyposthenuria 42 as a determinant of enuresis is controversial. This study revealed hyposthenuria as 43 significant predictor of enuresis in children with SCD. 44 45 - To the best of the authors’ knowledge, this study is the first in Iraq that attempts to 46 examine the association between hyposthenuria and enuresis in SCD children. 47 48 Application to Patient Care 49 The results of this study may help understand the mechanisms underlying the enuresis 50 in children with SCD. 51 52 Introduction 53 Sickle cell disease (SCD), an autosomal-recessive hemoglobin disorder, is one of the 54 most common heritable diseases in the world.1 Some Eastern Mediterranean countries, 55 including Iraq, have also reported the disease. In Basrah, Iraq, 6.48% of the 56 population has the sickle cell trait. 2 Enuresis is more common in children with SCD 57 than in those with normal hemoglobin; however, prevalence rates vary widely, 58 ranging from 26.4% to 51% depending on study methodology and enuresis definition 59 criteria.3 60 61 SCD is a multisystem disease, with one of the most typically afflicted organs being 62 the kidneys due to medullary ischemia and infarction. The underlying etio- 63 pathogenesis of enuresis in SCD is not fully known. It has been related to tubular 64 dysfunction manifested as defects in urinary concentration (hyposthenuria) and 65 acidification, 4 low functional bladder capacity and high overnight urine volume, 3,5 66 glomerular hyperfiltration caused by increased prostaglandin production. 6 Eneh et al, 67 on the other hand, revealed that enuresis in children with SCD is related to other 68 causative variables that are common in the general population rather than 69 hyposthenuria. 7 Similarly, other studies revealed that potential mechanisms 70 underlying nocturnal enuresis in patients with normal hemoglobin genotype 71 (hemoglobin AA) are equally relevant in SCD patients. 5,8 72 73 The debatable role of hyposthenuria as a predictor of enuresis in SCD patients, as well 74 as the lack of studies on the subject in Basrah, Iraq justified the conduct of this study, 75 which aimed to verify the role of hyposthenuria in enuresis among SCD children. 76 77 Methods 78 Study setting, design, and patients 79 This was an analytical cross-sectional study including a non-probability convenient 80 sample of 200 children with steady state SCD consecutively attending the Basrah 81 Center for Hereditary Blood Diseases during the period from the first of December 82 2020 through May 2021. Subjects having diabetes mellitus, epilepsy, features of 83 urinary tract infection, isolated daytime incontinence, known renal dysfunction/ 84 impairment, diabetes insipidus, and on desmopressin or diuretic medication were 85 excluded from the study. Of the 200 eligible children, 34 children were excluded 86 because they either reported a history of recurrent urinary tract infection or were 87 proven to have it by urine analysis. Other exclusion criteria led to the exclusion of 88 five more children. The final studied sample size is made up of the remaining 161 89 children (80.5%). 90 91 Data collection & definition of variables 92 Patients and / or their parents were interviewed using a structured questionnaire that 93 was developed for this study and completed by one of the researchers. It consisted of 94 two parts; the first part contained information about the child's and parents' 95 sociodemographic features (age, sex, and birth order of the child, exposure to stressful 96 life event such as death or divorce of parents, number of siblings, parental level of 97 education, and monthly family income). Parents were asked if any of the following 98 life events had occurred in the family within the last 12 months; death or divorce of 99 parent, death of someone in close proximity, child moving to another address or 100 school, conflicts with neighbors or friends, financial problems.9 The second part 101 sought information on enuresis (type, time, and frequency or severity of enuresis), 102 family history of enuresis, and medical history of the child including sleep disorders 103 including disorders in initiating and maintaining sleep (like snoring, difficult arousal, 104 sleep breathing disorders, and insomnia). Parents were told that any information 105 received would be kept private and anonymous. Two pediatric experts and two 106 community medicine consultants in the field of research methodology validated the 107 questionnaire. 108 109 The type of SCD was recorded for all patients depending on baseline hemoglobin 110 electrophoresis and / High Performance Liquid Chromatography (HPLC) results. 111 Blood samples were collected for complete blood count using Automated Hematology 112 Analyzer. The urine samples sent for analysis were the first-voided morning, clean- 113 catch mid-stream samples. Specific gravity was measured using dipstick urinalysis 114 (ACON Laboratories, Inc., USA). A urinalysis was done to check for urinary tract 115 infection, and those with positive results were sent for urine culture and sensitivity. 116 Urine albumin was determined using immunoturbidimetric assay. Urinary creatinine 117 was measured by the alkaline picrate method. The urinary albumin/creatinine ratio 118 (ACR) was computed and classified as normal when it was less than 30mg/g, 119 microalbuminuria (ACR= 30-300 mg/g), or macroalbuminuria (ACR more than 300 120 mg/g). - 10 121 122 The way of urine collection was explained to the parents/ caregivers and older 123 participants. 124 125 Enuresis was applied when the child has a "repeated involuntary or unintentional 126 urine voiding into the bed or clothes that occurs exclusively during sleeping periods 127 and not related to medication by the age of five years or older, with a minimum 128 frequency of once monthly for at least three consecutive months" 3,11,12 Secondary 129 enuresis is reserved for children who have been dry for more than 6 months. 130 Otherwise, it is referred to as primary enuresis. 12 Hyposthenuria was defined as urine 131 specific gravity <1.010 on dipstick analysis. 13 132 133 Statistical analysis 134 Data were compiled and analyzed by the SPSS version 23.0 software (IBM Corp, 135 Armonk, New York, USA). The t-test, Chi square test, or Fisher’s Exact test were 136 used for comparison of covariates where applicable. Binary logistic regression 137 analysis was done to look for the possible independent risk factors associated with 138 enuresis. The level of significance was chosen at a P-value of <0.05. 139 140 Ethical consideration 141 The Ethical Committee of the College of Medicine, University of Basrah authorized 142 this study. Before the children were included in the research, their parents provided 143 informed consent. 144 145 Results 146 Out of 200 eligible children, 161 were studied after exclusion of 39 based on the 147 exclusion criteria, yielding an 80.5% response rate, with 98 (60.9%) males and 63 148 (39.1%) females; their mean age was 10.9±2.9 years (10.9±2.8 for males and 11.0±3.1 149 for females). Of the participants, children 50 (31.1%) were found to have enuresis. Of 150 enuretic children, 45 (90%) had primary enuresis and 5 (10%) had secondary enuresis. 151 Diurnal enuresis was reported in 4 (8%), nocturnal in 33 (66%), and both diurnal and 152 nocturnal in 13 (26%). Daily enuresis was found in 22 (44%) children, several 153 times/week in 15 (30%), once/week in 5 (10%), and once or more per month in 8 154 (16%). [Table 1] 155 156 No significant difference was noticed between children with and without enuresis 157 regarding age, sex, birth order, family income, stressful life events, and parents' level 158 of education. However, family history of enuresis, and higher number of siblings were 159 found to be significantly associated with enuresis [Table 2]. 160 161 All children included in the study have sickle cell anemia and sickle/ β- thalassemia. 162 None was found to have other types of SCD. In univariate analysis, children with 163 enuresis exhibited a significantly higher proportion of hyposthenuria than those 164 without enuresis (24.0% vs. 6.3%, P=0.002). Although enuretic children had a higher 165 percentage of sleep disorders and hospitalization rate and frequency during the 166 previous 12 months than non-enuretic, the difference was not found to be significantly 167 different. Furthermore, hemoglobin genotype, albuminuria, and serum hemoglobin 168 level, and red blood indices values (MCH, MCV, and MCHC values) were not 169 significantly different between the two groups [Table 3]. 170 171 Among SCD studied patients, three variables were found to be independent predictors 172 of enuresis. These were family history of enuresis (odd ratio (OR), 5.94; 95% CI, 173 2.54-13.89; P<0.001), hyposthenuria (OR, 3.76; 95% CI, 1.25-13.30; P=0.018) and 174 sleep disorders (OR, 2.90; 95%CI, 1.19-7.06; P= 0.019) [Table 4]. In contrast, none 175 of the other investigated variables was shown to be independent predictors of 176 enuresis. 177 178 Discussion 179 Our study has revealed that prevalence rate of enuresis was 31.1% among sickle cell 180 disease pediatric patients. Other studies have reported varying rates of enuresis in this 181 group of patients; in the United Kingdom, London (35.7%), 14 Sudan (38%), 15, 182 Saudi Arabia (48.6%), 16 and Nigeria (49.4%). 11 Such variation in the prevalence 183 rates might be due to disparities in the definition of enuresis, sampling method, 17 184 socio-cultural differences, and study design whether population or health institute 185 based studies. 18 Earlier studies in Iraq showed lower prevalence of enuresis among 186 children without SCD, which ranges from 7.5% - 29.5%. 18-20 Many studies have 187 consistently found a strong relationship between sickle cell disease and enuresis. 21,22 188 Sickle cell disease significantly affects renal structure and function, reflected in a 189 variety of renal syndromes and diseases including abnormal hemodynamics, 190 glomerulopathies, and hyposthenuria (impaired urinary concentrating ability). 23 191 192 The logistic regression analysis showed that hyposthenuria was independently and 193 significantly associated with enuresis (OR, 3.76; 95% CI, 1.25-11.30; P= 0.018). A 194 long before, 24 hyposthenuria-induced nocturnal polyuria was thought to be the cause 195 of nocturnal enuresis in sickle cell anemia (SCA) patients. This theory is reinforced 196 by the fact that hyposthenuria is a common and early infarction-related renal 197 complication. 25 Ugwu et al. later demonstrated the same results. 26 However, Eneh et 198 al. 7 and Readett et al. 27 found no association between enuresis and hyposthenuria, 199 and after water deprivation, SCD children with enuresis had the same maximum 200 voided urine volume as those without enuresis. They attributed enuresis to reduced 201 functional bladder capacity and other factors such as social and environmental 202 influences and decreased arousal during sleep. 7,27 203 204 Factors other than hyposthenuria were found to be significantly and independently 205 associated with enuresis. Family history of enuresis was found to be an independent 206 predictor of enuresis with an adjusted odds ratio of 5.94 (95% CI, 2.54-13.89; 207 P<0.001). A result, that has been reported before. 18,28 Such association highlights the 208 importance of genetic roots in the etiology of enuresis. 28 209 210 Although the rate of sleep disorders was higher in enuretic children (30.0%) compared 211 to 17.1% in non-enuretic children in univariate analysis, the difference was not 212 significant (P=0.064). However, after adjustment for other variables, sleep disorders 213 were observed to be an independent predictor for enuresis (adjusted OR, 2.90; 95% 214 CI, 1.19-7.06; P=0.019). Other studies have found that children with SCD are more 215 likely to have sleep difficulties, which cause them to be unable to awaken from sleep 216 in response to a full bladder, resulting in enuresis. 29,30 A variety of factors, including 217 pain, environmental, psychological, and treatment factors (which were not 218 investigated in this study), have been reported to influence sleep disorders. 31 These 219 factors might confound such relationship. The precise relationship between sleep 220 disorders and enuresis needs to be further investigated. Furthermore, the absence of 221 polysomnography and parents' reported data made defining sleep problems difficult. 222 Lehmann et al who reported an association between sleep disorders and enuresis 223 recommended that children with SCD and enuresis have to be referred to the 224 pulmonologist for the evaluation of sleep- disordered breathing. 32 225 226 Nocturnal enuresis in individuals with airway obstruction is thought to be caused by 227 increased synthesis of atrial natriuretic peptide, which raises the arousal threshold 228 during sleep. 33 229 230 The aggregation of two or all of the three independent risk factors mentioned above 231 was significantly higher in enuretic children than in non-enuretic children. In the 232 enuretic children, 37 (74.0%) had 0-1 risk factor of the three independent risk factors, 233 11 (22.0%) had 2 risk factors, and 2 (4.0%) had all three factors, compared to 109 234 (98.2%) who had 0-1 risk factor, 2 (1.8%) had 2 risk factors, and none (0.0%) had all 235 three factors (P <0.001). 236 237 Family income, parents' level of education, and birth order did not affect the 238 association with enuresis, a result that agrees with many previous studies.20,34 239 However, other studies reported a significant impact of socio-economic status on 240 enuresis prevalence rates. 15,35 Thus, it seems that there is no agreement on the 241 significance of socio-economic status as a risk factor for enuresis. This could be 242 attributed to the relative inaccuracy of social basic facilities in determining social rank 243 or it might reflect the increased knowledge and awareness regarding health and 244 health-related issues among all socioeconomic groups. 27 245 246 Our findings revealed that the well-documented decrease in enuresis prevalence with 247 age in children without SCD 20,36 was less evident in children with SCD, implying 248 that some SCD-related morbidities, such as intravascular sickling and vaso-occlusion, 249 improved less spontaneously in children with SCD. 25,37 This result is consistent with 250 what other researchers have found. 11,37 Although enuresis is frequently reported to be 251 more prevalent in boys than girls in children without SCD, 34 gender was not 252 associated with enuresis in our study. This finding is consistent with the findings of 253 Esezobor et al. 11 According to one possible theory, several sickle cell-related 254 characteristics may be related to enuresis. Readett et al. 27 observed a higher rate of 255 enuresis in children with hemoglobin SS, as well as a lower fetal hemoglobin level. In 256 agreement with Esezobor et al., 11 no association was identified between enuresis and 257 history of hospitalization during the 12 months preceding the study. 258 259 Though the number of siblings had a significant association with enuresis in 260 univariate analysis (P= 0.018), the logistic regression analysis revealed no effect after 261 adjusting for other variables. This result is consistent with that reported by others. 38 262 Our study is limited in that it was a cross-sectional study; thus, no causal relationships 263 between variables could be established. Furthermore, polysomnography was not done 264 to assess the pattern of sleep disordered breathing. Recall bias cannot be entirely 265 eliminated. The form and content of questions, as well as connecting exposure to 266 specific life events, may all have an impact on recall accuracy. SCD impacts the 267 psychosocial and quality of life in general, therefore, parents who have children with 268 the disease are more likely to recall previous exposure of their children. 269 270 The study's strength is that it is the first in Iraq to measure the prevalence and 271 determinants of enuresis in children with SCD, with special emphasis on the most 272 controversial determinant, hyopsthenuria. 273 274 Conclusions 275 Enuresis is common in pediatric patients with sickle cell disease. Hyposthenuria, 276 family history of enuresis, and sleep disorders were significant independent predictors 277 of enuresis. Children with sickle cell disease, especially those with a family history of 278 enuresis, should be assessed frequently for enuresis and kidney function. 279 280 Authors’ Contributions 281 JN, MK and AM designed and planned the study. AM and DS collected the data. JN 282 and MK contributed to the data analysis and drafting of the manuscript. All authors 283 reviewed and approved the final version of the manuscript. 284 285 Conflict of Interest 286 The authors declare no conflicts of interest. 287 288 Funding 289 No funding was received for this study. 290 291 RERFERENCES 292 1. Xu JZ, Thein SL. The carrier state for sickle cell disease is not completely 293 harmless. Haematologica 2019; 104: 1106–11.doi: 10.3324/haematol.2018.206060. 294 2. Hassan MK, Taha JY, Al-Naama LM, Widad NM, Jasim SN. Frequency of 295 haemoglobinopathies and glucose-6-phosphate dehydrogenase deficiency in Basra. 296 East Mediterr Health J 2003;9:45–54. 297 3. Uwaezuoke SN, Eneh CI, Ezenwosu OU, Ndu IK. 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Saudi J Kidney Dis 406 Transplant 2011;22:167–73. 407 408 Table 1: Types of enuresis reported among studied SCD patients 409 Variable No. % Onset of enuresis Primary Secondary 45 5 90 10 Time of enuresis Diurnal Nocturnal Both 4 33 13 8 66 26 Frequency Daily Several times/ week Once/week Once or more/month 22 15 5 8 44 30 10 16 Total 50 100 410 Table 2: Association of enuresis with socio-demographic characteristics 411 Variable Enuresis No enuresis P- value Age (years), Mean ±SD 10.4±2.8 11.2±2.9 0.119 Age (years) 6-7 8-9 10-11 12-13 14-15 9 (18.0) 11 (22.0) 10 (20.0) 11 (22.0) 9 (18.0) 21 (18.9) 13 (11.7) 20 (18.0) 24 (21.6) 33 (29.7) 0.369 Male sex, No. (%) 34 (68.0) 64 (57.7) 0.228 No. of siblings, No. (%) 0 1 2 3 4 5 & more 4 (8.0) 2 (4.0) 5 (10.0) 9 (18.0) 12 (24.0) 18 (36.0) 1 (0.9) 11 (9.9) 21 (18.9) 33 (29.7) 18 (16.2) 27 (24.3) 0.018 Birth order, No. (%) First Second Third Fourth 12 (24.0) 11 (22.0) 12 (24.0) 5 (10.0) 37 (33.3) 33 (29.7) 22 (19.8) 7 (6.3) 0.316 Fifth or higher 10 (20.0) 12 (10.8) Family history of enuresis, No. (%) Yes No 24 (48.0) 26 (52.0) 16 (14.4) 95 (85.6) <0.001 Per capita family monthly income (IQD), No. (%) <2500,000 250,000 -500,000 > 500,000 33 (66.0) 15 (30.0) 2 (4.0) 84 (75.2) 22 (19.8) 5 (4.5) 0.402 Father's education (years) < 12 ≥ 12 41 (82.0) 9 (18.0) 83 (74.8) 28 (25.2) 0.418 Mother's education (years) < 12 ≥ 12 37 (74.0) 13 (26.0) 89 (80.2) 22 (19.8) 0.412 Stressful life's event Yes No 15 (30.0) 35 (70.0) 20 (18.0) 91 (82.0) 0.101 Total 50 (31.1) 111 (68.9) No.= number, IQD= Iraqi Dinar 412 413 Table 3: Association of enuresis with certain clinical characteristics 414 Variable Enuresis n= 50 No enuresis n= 111 P- value Hemoglobin genotype, No. (%) SCA SC/ thalassemia 23 (46.0) 27 (54.0) 52 (46.8) 59 (53.2) 0.999 Hyopsthenuria, No. (%) 12 (24.0) 7 (6.3) 0.002 Sleep disorders, No. (%) 15 (30.0) 19 (17.1) 0.064 Hospitalization during the last year, No. (%) 42 (84.0) 78 (72.2) 0.115 Frequency of hospitalization, No. (%) No 1-3 times 4-6 times >6 times 8 (16.0) 13 (26.0) 14 (28.0) 15 (30.0) 33 (29.7) 33 (29.7) 29 (26.1) 16 (14.5) 0.068 Albuminuria (mg/g), No. (%) < 30 30 -300 >300 43 (86.0) 2 (4.0) 5 (10.0) 89 (80.2) 13 (11.7) 9 (8.1) 0.296 Hb (g/dl) 9.4 ± 1.7 9.4 ± 0.9 0.954 MCH (pg/cell), Mean± SD 25.5±5.0 26.9±3.6 0.579 MCV (fl), Mean± SD 75.5±11.4 80.8±9.7 0.408 MCHC (gm/dl), Mean± SD 33.5±1.7 33.2±1.2 0.742 No.= number, SCA= sickle cell anemia, SC= sickle cell, Hb= hemoglobin, MCH= 415 mean corpuscular hemoglobin, MCV= mean corpuscular volume, MCHC= mean 416 corpuscular hemoglobin concentration 417 418 Table 4: Logistic regression analysis 419 Parameter β Coefficient OR 95% CI for OR P-value Lower Upper Family history of enuresis 1.781 5.94 2.54 13.89 <0.001 Hyposthenuria 1.326 3.76 1.25 11.30 0.018 Sleep disorders 1.066 2.90 1.19 7.06 0.019 420