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.