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

PROJECT SUMMARY
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.

Grant Number: 7R21HL169555-02
NIH Institute/Center: NIH
Principal Investigator: MELISSA CAUGHEY