Abstract
A urine concentrating defect is quite common in sickle cell anemia (SCA), has its onset in early childhood, and may be reversible (with transfusion) until age 10 years. BABY HUG is an NHLBI-NICHD sponsored double-blind, placebo-controlled Phase III Clinical Trial (NCT00006400) designed to assess efficacy of hydroxyurea in preventing organ damage in young children with SCA (Hb SS or SβO thalassemia); primary endpoints are spleen function and glomerular filtration rate (GFR). Two hundred thirty-three infants, recruited without regard to disease severity, underwent eligibility screening. To assess urine concentrating ability as a secondary endpoint, parents were instructed to collect and save timed urine specimens from subjects after 4 to 10 hours of fluid deprivation (NPO) overnight for osmolality (OSM) determination. More prolonged deprivation was avoided due to safety concerns. A paired serum sample for OSM, urea nitrogen (BUN), and creatinine was obtained the next morning. All specimens were analyzed in a central laboratory. The analyses included 184 infants with a urine specimen and a reported period of fluid deprivation of at least four hours; 178 had concurrent sera. Mean age was 13.0±2.7 mo (range 7.5 – 17.9 mo) and mean duration of fluid deprivation was 7.4±2.4 hr (4–13 hr). Mean serum OSM was 286±6 mOsm/kg H2O and independent of age, height, weight, or duration NPO. Urine OSM (mean 410±152, median 433, range 58–794 mOsm/kg H2O) was significantly greater than serum osmolality (p<0.0001) and correlated with duration NPO (p=0.001). One hundred forty-two infants (77.2%) concentrated urine (urine OSM > [mean serum OSM + 1 SD]); twenty-two (12.0%) had urine/serum OSM ratio > 2 and 54 (29.4%) had urine OSM > 500 mOsm/L. In addition, five infants (2.7%) were isosthenuric (urine OSM within mean serum OSM ± 1 SD) and 37 (20.1%) hyposthenuric (> 1 SD below mean serum OSM) despite instructions to withhold fluid. Urine OSM was associated with increasing 99mTc-DTPA GFR (p=0.024) and BUN (p<0.0001), but not with serum OSM, age, height, weight or serum creatinine. We conclude that even with a variable, often limited, fluid deprivation challenge, 75 percent of young infants with SCD were able to concentrate urine. We anticipate that at the end of each infant’s two-year study drug treatment period parents will be more successful in achieving the recommended fluid deprivation and urine collection and that differences in concentrating ability between those taking hydroxyurea and those taking placebo will be discernable.
Angiotensin receptor signaling in sickle cell anemia has a reno-protective effect on urine concentrating ability but results in sickle glomerulopathy