Renin-angiotensin-aldosterone system inhibition exacerbates anemia in sickle cell disease

ABSTRACT: Renin-angiotensin-aldosterone system inhibitors (RAASi) are suggested for treating albuminuria in patients with sickle cell disease (SCD). RAASi may exacerbate anemia in the general population and those with diabetes through unclear mechanisms. The impact of RAASi on anemia in chronic hemolytic disorders, such as SCD, is unknown. In a cross-sectional analysis of 658 Walk-PHaSST participants, RAASi use was independently associated with lower hemoglobin concentrations, adjusting for age, sex, SCD genotype, estimated glomerular filtration rate, and erythroid-stimulating agent and hydroxyurea use (β, -0.46 ± 0.21; P = .032). In 2 longitudinal cohorts (University of Illinois Chicago, n = 24; multicenter losartan clinical trial, n = 32), RAASi therapy led to a reduction in hemoglobin concentrations compared with pretreatment values by -0.44 ± 0.14 g/dL (P = .006) and -0.53 ± 0.17 g/dL (P = .005), respectively. SCD mice treated with losartan demonstrated lower hemoglobin concentrations after 6 and 14 weeks (P< .001) and lower absolute reticulocyte counts by 14 weeks (P = .03) vs control mice without changes in circulating erythropoietin, interleukin-12p70 (IL-12p70), IL-3, or insulin-like growth factor 1 levels. Bone marrow cells from losartan-treated SCD mice had lower colony-forming units (P ≤ .09) with rescue of erythroid colony formation after exogenous erythropoietin supplementation (P = .02). Bone marrow histopathology demonstrated reduced erythroid relative to myeloid ratios in losartan-treated vs untreated SCD mice. Hemoglobin levels should be closely monitored when using RAASi in this high-risk population.