Chronic dehydration in sickle cell disease: An actionable biomarker to prevent vaso-occlusive episodes

Approximately 100,000 Americans, primarily of African descent, live with sickle cell disease (SCD), a genetic red blood cell (RBC) disorder characterized by a mutated hemoglobin (HbS). HbS-containing RBCs sickle when exposed to low oxygen or hypertonic environments, precipitating acute, excruciatingly painful episodes of vascular obstruction. Vaso-occlusive episodes (VOEs) account for a 7 to 30-fold higher hospitalization rate and a 2- to 6-fold higher rate of emergency department visits, compared to age-specific rates for Black Americans without SCD, and adversely impact quality of life and survival. Current disease-modifying treatments for SCD such as hydroxyurea, voxelotor, and crizanlizumab only reduce hospitalizations for VOE by 50% at most. Thus, prevention of VOE by other means in combination with existing treatments remains crucial. Chronic dehydration is a quantifiable and potentially actionable biomarker, which may predict morbidity and mortality in patients with SCD. In emergency room settings, VOE is frequently accompanied by acute dehydration, which is managed by fluid replacement. However, the prevalence of chronic dehydration during “steady-state” conditions (i.e., non- crisis) is unknown, and it is uncertain whether mild, chronic dehydration predicts increased risk of SCD-related morbidity or mortality. Age-associated hyposthenuria (i.e., the inability to concentrate urine), is common in SCD, and could plausibly contribute to chronic dehydration. Although SCD is thought to induce compensatory polydipsia (i.e., increased thirst), conflicting reports also note impaired thirst regulation, which may be sex or age dependent. Of note, all large examinations of steady-state dehydration have been limited to infants and very young children, excluding adolescents or adults who may be more susceptible to chronic dehydration due to progressive renal dysfunction. Our hypothesis is that chronic dehydration is predictive of VOE, hospitalizations, and death, and of relevance, may be suitable for monitoring to prevent VOE. To analyze the relationship between chronic dehydration and subsequent VOE we will 1). Conduct an epidemiologic investigation, using data and specimens available from the Cooperative Study of Sickle Cell Disease (CSSCD) and the more contemporary Multicenter Study of Hydroxyurea (MSH), and 2). Conduct a prospective, clinical study enrolling 50 participants with SCD. The CSSCD and MSH are open BioLINCC studies with rich phenotyping, lengthy prospective follow up, and adjudicated clinical events. We will use available serum specimens from these cohorts to assay serum osmolality, a marker of dehydration. Our observations from the epidemiologic investigation will be complemented by the prospective clinical study, which will include more granular data collection and state-of-the-art measurements of dehydration. The knowledge to be gained from this project will establish whether chronic dehydration during steady-state conditions is predictive of morbidity and mortality in patients with SCD and has the potential to influence patient behavior and recommendations for care, such as at-home hydration monitoring to encourage fluid intake for VOE prevention. Project Number: 7R21HL169555-02 | Fiscal Year: 2025 | NIH Institute/Center: National Heart Lung and Blood Institute (NHLBI) | Principal Investigator: MELISSA CAUGHEY (+1 co-PI) | Institution: JOHNS HOPKINS UNIVERSITY, BALTIMORE, MD | Award Amount: $131,050 | Activity Code: R21 | Study Section: ZHL1-CSR-K(J1) View on NIH RePORTER: https://reporter.nih.gov/project-details/7R21HL16955502