Methods
Study Population : We identified children and adolescents with SCD enrolled in two cohort studies at St. Jude Children’s Research Hospital: The Evaluation of Nocturnal Enuresis and Barriers to Treatment among Pediatric Patients with Sickle Cell Disease (PEESC; NCT01959958) and the Sickle Cell Clinical Research and Intervention Program (SCCRIP, NCT02098863)12. PEESC is a single center study of the epidemiologic, psychosocial, medical, and sociodemographic determinants of nocturnal enuresis and barriers to successful intervention among children and adolescents with SCD aged 6-17 years. SCCRIP is a longitudinal clinical cohort study of sickle cell patients which collects data to determine the incidence, prevalence, and severity of SCD complications and adverse health conditions within SCD12. The SCCRIP study does not collect data on nocturnal enuresis but does prospectively collect laboratory data of kidney function. The PEESC study identified patients with nocturnal enuresis and SCCRIP provided longitudinal follow-up on laboratory data before and after nocturnal enuresis was diagnosed.
Participants provided informed consent for these two studies, both of which were approved by the Institutional Review Board at St. Jude Children’s Research Hospital. Eligibility criteria for PEESC enrollment were a diagnosis of SCD and age 6-17 years.
Definitions: For our primary outcome measure, we identified patients enrolled in PEESC who met the Diagnostic and Statistical Manual of Mental Disorders (DSM-5) criteria for nocturnal enuresis1. We analyzed patients according to two groups: 1) “Lifetime Enuresis” if either caregiver or patient reported the patient having nocturnal enuresis in the past and/or currently and 2) “Current Enuresis” (a subset of Lifetime Enuresis) if the caregiver or patient reported the patient having nocturnal enuresis at the time of enrollment. We categorized participants as having or not having nocturnal enuresis in each of these groups.
For our predictor variables, we obtained patient age, sickle cell disease type, and exposure to sickle cell modifying therapy (hydroxyurea and chronic transfusion therapies) prior to age 3 years. We collected the mean values of height, weight, and laboratory results from annual visits between three and five years of age. We determined mean white blood cell count, hemoglobin, platelet count, absolute reticulocyte count, lactose dehydrogenase (LDH) and serum creatinine from these visits. The eGFR was determined by the mean eGFR measured at 3.0-4.9 years old using the Schwartz formula13. We defined hyperfiltration as a mean eGFR >75thpercentile in this cohort10; which resulted in an eGFR threshold of > 133 cc/min/1.73m2 for eGFR. Hyposthenuria was defined by a random urine specific gravity < 1.0109, 14. For our longitudinal analysis, we abstracted calculated eGFR, urine specific gravity, and hemoglobin from every annual visit.
Statistical analysis: The descriptive statistics of this study were summarized using frequencies for categorical variables and mean and standard deviation (SD) for continuous variables. Normality of data was evaluated by the Shapiro-Wilk test. Continuous data were compared by either two-sample t-tests or the Wilcoxon rank sum tests and categorical data were compared between the two groups by the Fisher exact test. Univariate and multivariate logistic regression models were used to assess the associations between covariates and lifetime enuresis or current enuresis. The generalized estimating equation (GEE) was used to assess the association of hyperfiltration and hyposthenuria with current enuresis for repeated data analysis. For the 45 patients with current enuresis, we included age, sex, and SCD type in the GEE model. For all analyses, p <0.05 was considered statistically significant.