Discussion
This study confirms prior epidemiologic reports that nocturnal enuresis
defined by DSM criteria is highly prevalent in children with SCD and
occurs more commonly in males.4, 5, 15-17 We currently
have a poor understanding of why nocturnal enuresis occurs with high
prevalence in patients with sickle cell anemia or what the potential
risk factors for nocturnal enuresis are and if they might lead to
targeted interventions. Therefore, we attempted to identify risk factors
occurring under age 5 that might predict the development of nocturnal
enuresis after age 5 years. Our primary hypothesis was that
hyperfiltration early in life would be associated with nocturnal
enuresis; however, we did not identify a difference in eGFR values
occurring at age 3-5 years between participants with and without
subsequent nocturnal enuresis. Interestingly, in univariate analysis of
the longitudinal evaluation of eGFR after age 5, we did find that
patients with enuresis had higher GFR levels. However, when including
the very strong predictor of sickle cell genotype in the model, this
association was no longer statistically significant. Nevertheless, these
results suggest the need for future research into the impact of
hyperfiltration, and other possible later renal effects that an early
extreme elevation of eGFR might case later in life. Also, questions
regarding the age at which pathologic differences in GFR occur and the
adequacy of current methodology in detecting early renal dysfunction
need to be addressed. Understanding the timing of when we can detect
differences in kidney function, especially in young patients, is
important for the design of future therapeutic interventions.
It is well-established that children with SCD develop
hyposthenuria9. While it seems plausible that poor
concentration of the urine is associated with enuresis, our study, using
urine specific gravity as a biomarker for hyposthenuria, did not find
this association. This result is consistent with a prior study that
found no difference in maximum urinary concentration in individuals with
SCD with and without enuresis5.
More severe anemia or tubular exposure to free heme is associated with
poor kidney outcomes18. We found that a lower
hemoglobin was associated with an increased probability of currently
having enuresis, when adjusted for age and sex. However, because
hemoglobin and SCD type are closely correlated, the association with
anemia was not significant when SCD type was included in the model.
Earlier studies have shown that acute anemic episodes are a risk factor
for the development of acute kidney injury in individuals with
SCD19 and hemolysis results in an increase in cell
free hemoglobin and heme, which are known
nephrotoxins20. It is possible that the release of
heme during episodes of red blood cell lysis perpetuates damage to the
nephron early in childhood, which later clinically presents as nocturnal
enuresis. As this study evaluated mean hemoglobin levels over a two-year
period, we could not determine the impact of acute anemic or hemolytic
events on the development of enuresis.
Children who reported ongoing symptoms of nocturnal enuresis were more
likely to have initiated hydroxyurea treatment at a younger age then
those who did not. Additionally, these children had a higher fetal
hemoglobin (HbF). These participants were probably initiated on
hydroxyurea at a younger age due to having more severe
disease21. A previous study noted that children on
regular transfusion therapy were less likely to report current enuresis
when compared to those not receiving transfusion22. We
also assessed whether transfusion therapy prior to age 3 years would
protect against enuresis but could not confirm it. Until a clear link
between sickle cell pathology in the kidney and outcomes is
demonstrated, the role of renoprotective interventions in ameliorating
enuresis will remain uncertain.
Our study had several limitations. First, we relied on participants and
family members to recall past symptoms of enuresis. We did not ask at
what age enuresis started and therefore did not have a comprehensive and
accurate trajectory of this symptom. Second, we did not assess the
specific gravity of the first morning urine after a water deprivation
test, but instead utilized a random urine sample at the time of a
patient visit. Future studies should evaluate hyposthenuria using a
water deprivation test; however, acceptance of this test may be limited
outside the setting of a clinical trial. Finally, in children without
sickle cell disease, nocturnal bladder overactivity, sleep disordered
breathing, neurological dysfunction and adverse psychological events are
associated with nocturnal enuresis6. One previous
report in children with sickle cell disease found that a lower
functional bladder capacity was associated with nocturnal
enuresis23. In our study, we did not evaluate these
associations; however, these measurements could be incorporated into
future studies as patients with sickle cell disease are known to have a
higher prevalence of pulmonary, central nervous system, and psychologic
complications.
Our study aimed to correlate early kidney findings with the development
of nocturnal enuresis. However, eGFR and urine specific gravity early in
life did not identify patients at risk for developing nocturnal
enuresis. Overall, sickle cell genotype and male gender remained the
strongest predictors of enuresis. Therefore, future research should
focus on additional mechanisms and risk factors that could contribute to
the high prevalence of nocturnal enuresis in children with sickle cell
anemia. Due to the overall high prevalence of nocturnal enuresis, we
recommend that children with SCD should be assessed for nocturnal
enuresis, particularly in males and those with severe anemia. Future
studies are still needed to determine the pathology of nocturnal
enuresis in sickle cell patients and whether treatment using sickle
cell-modifying therapies and additional behavioral interventions will
reduce the risk of this frequent problem.