Objectives To examine the feasibility and accuracy of GFR measurements in infants with sickle cell anemia (SCA). Study design The NHLBI/NICHD-sponsored Phase III randomized double-blinded placebo-controlled trial (BABY HUG) tests the hypothesis that hydroxyurea can prevent chronic organ damage in SCA. Glomerular filtration rate (GFR) elevation is a co-primary endpoint, measured quantitatively by 99mTc-DTPA plasma clearance and estimated by the Schwartz equation using height and creatinine. Results DTPA GFR measurement was attempted in 191 infants; 176 of 184 completed studies (96%) were interpretable. Average age (mean ± 1SD) was 13.7±2.6 months. Average DTPA GFR was 125.2±34.4 (range 40.2–300.9, normal 91.5±17.8 mL/min/1.73m2), and Schwartz estimates were higher at 184.4±55.5 mL/min/1.73m2. DTPA GFR was correlated with Schwartz GFR (r2=0.0658, p=0.0012); also with age, weight, height, and kidney volume (all p<0.002); but not with hemoglobin, HbF, WBC, reticulocytes, medical events, or splenic function. Conclusions Quantitative GFR measurement is feasible but variable among infants with SCA. Schwartz GFR estimates are not highly correlated with quantitative DTPA GFR values. Baseline GFR measurements suggest that renal dysfunction in SCA, evidenced by glomerular hyperfiltration, begins during infancy.
Silent brain infarcts occur in a small but significant number of infants with SCA as early as a year of age. This finding indicates a need for thorough evaluation of the CNS very early in life in children with SCA in order to develop timely intervention strategies.
Evidence of the laboratory benefits of hydroxyurea and its clinical efficacy in reducing acute vaso-occlusive events in adults and children with sickle cell anemia has accumulated for more than 15 years. A definitive clinical trial showing that hydroxyurea can also prevent organ damage might support widespread use of the drug at an early age. BABY HUG is a randomized, double-blind placebo-controlled trial to test whether treating young children ages 9 to 17 months at entry with a liquid preparation of hydroxyurea (20 mg/kg/day for two years) can decrease organ damage in the kidneys and spleen by at least 50%. Creation of BABY HUG entailed unique challenges and opportunities. Although protection of brain function might be considered a more compelling endpoint, preservation of spleen and renal function has clinical relevance, and significant treatment effects might be discernable within the mandated sample size of two hundred. Concerns about unanticipated severe toxicity and burdensome testing and monitoring requirements were addressed in part by an internal Feasibility and Safety Pilot Study, the successful completion of which was required prior to enrolling a larger number of children on the protocol. Concerns over recruitment of potentially vulnerable subjects were allayed by inclusion of a research subject advocate, or ombudsman. Finally, maintenance of blinding of research personnel was aided by inclusion of an unblinded primary endpoint person, charged with transmitting endpoint data and monitoring blood work locally for toxicity. (ClinicalTrials.gov number,NCT00006400)
Background-Transcranial Doppler ultrasonography (TCD) is used to predict stroke risk in children with sickle cell anemia (SCA), but has not been adequately studied in children under age 2 years.
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.
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