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.