Abstract
Abstract
BABY HUG is an NHLBI/NICHD-sponsored Phase III randomized double-blinded placebo-controlled clinical trial (NCT00006400) to test the hypothesis that hydroxyurea can prevent chronic organ damage in very young children with sickle cell anemia (SCA). Renal and splenic function measures are the co-primary endpoints. Renal disease in SCA begins early in life with impaired urine concentration and acidification, along with glomerular hyperfiltration; some patients will progress to microalbuminuria, glomerulosclerosis, macroalbuminuria, and even renal failure. In BABY HUG, glomerular filtration rate (GFR) elevation was selected as a primary endpoint, to be measured quantitatively by plasma clearance of injected 99mTc-DTPA and also estimated by the Schwartz equation where GFR = (height × 0.55)/(serum creatinine), with creatinine measured by HPLC to .01 mg/dL precision. Of 233 enrolled subjects, 193 completed screening and were randomized to study treatment. Quantitative GFR measurement was successful in most cases: 176 of 182 (97%) of DTPA clearance studies were adequate and 157 subjects had both baseline DTPA and Schwartz GFR values available for analysis. The average age at GFR measurement was 13.7 ± 2.6 months (range 9–19 months) and 59% of subjects were female. Baseline mean (± 1SD) hematological parameters included hemoglobin = 9.0 ± 1.4 gm/dL, absolute reticulocytes = 295.3 ± 137.4 × 109/L, WBC = 14.3 ± 5.8 × 109/L, and fetal hemoglobin (HbF) = 25.6 ± 8.8%. Baseline past medical history included dactylitis (34%), splenic sequestration (7%), and acute chest syndrome (5%). The average baseline quantitative GFR measurement determined by DTPA clearance was elevated at 125.4 ± 34.4 mL/min/1.73m2, (range 40.2 – 300.9 mL/min/1.73m2, normal value 100 ± 20 mL/min/1.73m2). The average baseline GFR estimate by Schwartz equation was substantially higher at 193.9 ± 53.8 mL/min/1.73m2, range 65.8 – 350.0 mL/min/1.73m2. In univariate analysis, the DTPA GFR value was positively correlated with the Schwartz GFR estimate (r=0.22, p=0.0059, slope=0.145) as well as age, weight, height (all p≤.001) but not with hemoglobin, HbF, WBC, reticulocytes, previous sickle cell-related events, or measures of splenic function including liver-spleen scan and quantitation of pitted erythrocytes and micronuclei. The Schwartz GFR estimate was positively correlated with age, height, WBC, and splenic function, and negatively correlated with hemoglobin and HbF. Using a quantitative GFR threshold of 120 mL/min/1.73m2 and an age threshold of 15 months, higher GFR values were observed in older infants, p=0.026. These data indicate that
renal dysfunction measured by GFR elevation may begin early in life in SCA; quantitative GFR measurement is feasible but highly variable in this very young patient population;
(3) the Schwartz and DTPA GFR values are strongly correlated, but the Schwartz estimate is usually greater and only modestly agrees with the quantitative DTPA GFR value. These baseline GFR measurements in BABY HUG support the hypothesis of age- and disease-related glomerular hyperfiltration in SCA. BABY HUG should yield important information regarding the ability of hydroxyurea to prevent renal damage among infants with SCA.