Sickle Cell Trait-Associated Dehydration Linked to Increased Risk of Death

Melissa C. Caughey, PhD

Dehydration may play a pivotal role in mortality risk among persons with sickle cell trait, according to findings from a population-based analysis.

In new research from the Atherosclerosis Risk in Communities (ARIC) trial—a 30-year population sample-based analysis of more than 16,000 adults from 4 different community backgrounds genotyped for hemoglobin S (HbS) and hemoglobin C (HbC) before being monitored for cardiovascular outcomes from 1987-1989 to present—a team of US investigators found an association between dehydration hospitalization, concurrent death and sickle cell trait among Black patients in the assessment.

Reported by a team led by Melissa C. Caughey, PhD, of the Joint Department of Biomedical Engineering, University of North Carolina and North Carolina State University, the investigators believe the association may indication a risk of more severe sickle cell trait-associated outcomes among persons lacking hydration.

Caughey and colleagues sought to observe the association between sickle cell trait and chronic dehydration or related adverse events in the Black general population. As they noted, most currently available evaluations are consisting of case reports looking at exercise-induced dehydration in military personnel or athletes with sickle cell trait.

“Less focus has been directed at hyposthenuria, or the inability to concentrate urine,” they wrote. “While hyposthenuria is a known complication of SCT, its functional consequences such as chronic dehydration have not been described in the adult SCT general population.”

The team used ARIC data including 4266 Black adults aged 45-64 years old in the baseline 1987-1989 assessment. Investigators observed an “excellent” retention of approximately 80% of all surviving participants in the 2019 annual survey for ARIC. The subanalysis population’s clinical characteristics were collected at baseline, with evidence of dehydration calculated from fasting blood examples.

Participants’ hospitalization and deaths were captured through active surveillance of the ARIC trial, with ICD-10 codes defining hospitalizations due to dehydration.

In Caughey and colleagues’ Black participant population, 4110 were successfully genotyped for HbS and HbC; 3719 were included for analysis and 228 (6%) were identified with sickle cell trait.

Patients with and without sickle cell trait reported “largely comparable” baseline characteristics—except for factors related to dehydration: participants with sickle cell trait reported greater mean plasma osmolality and a greater proportion of baseline classification of dehydration, even after controlling for risk factors (odds ratio [OR], 1.40; 95% CI, 1.06 - 1.85). In each participant arm, women were more likely to have baseline dehydration than men.

Investigators assessed participants over a mean follow-up period of 27 years. They observed 373 participants hospitalized for dehydration, and 2006 deaths overall. Those with sickle cell trait reported slightly greater death rates (57% vs 54%), though the cumulative incidence of dehydration hospitalization was similar across the 2 arms (10% vs 10%).

After adjusting for risk factors, investigators observed a 43% increased risk of death with baseline dehydration among participants with sickle cell trait (hazard ratio [HR], 1.43; 95% CI, 1.01 - 2.03). Among those without the trait, risk was increased by 10% (HR, 1.10; 95% CI, 1.00 - 1.21). Interestingly, investigators observed no significant link between baseline dehydration and subsequent dehydration-associated hospitalizations for either arm.

As the team noted, hyposthenuria is common among patients with sickle hemoglobinopathies including sickle cell trait. While mean plasma osmolality values were only “modestly higher” among participants with sickle cell trait, the greater plasma osmolality in the absence of fluid restriction may denote a more persistent form of dehydration that may worsen with exertion.

“Our study suggests a potential role for dehydration in heightened mortality among individuals with SCT, which underscores the need for adequate hydration in this population,” the team wrote. “However, we relied upon calculated rather than measured plasma osmolality, were unable to consider urine analysis, and hospitalizations for dehydration were based on unadjudicated discharge codes.”

Though the conclusion was considered speculative, the team concluded that there may be a risk association between persistent dehydration in the absence of fluid restriction and severe clinical outcomes among patients with sickle cell trait.

The study, “Prevalence and outcomes of dehydration in adults with sickle cell trait: the Atherosclerosis Risk in Communities (ARIC) study,” was published online in the British Journal of Hematology.