Renal Function in Infants with Sickle Cell Anemia: Baseline Data from the BABY HUG Trial.

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.

The pattern of blood pressure and renal function among children with Sickle Cell Anaemia presenting in a tertiary health institution in Nigeria

“…Although in the early ages the eGFR values were predominantly normal in this study, evidence of glomerular hyper iltration as suggested by eGFR >140ml/min/1.73m 2 was seen across all the ages from 2-16 years. Similarly, hyper iltration has been seen as early as 9-19 months of age according to the Pediatric Hydroxyurea Phase III Clinical Trial (BABY HUG) study [30]. The compromise of the renal vasculature due to sickled red cells has been associated with glomerular hyper iltration, proteinuria and glomerular hypertrophy.…”

Genetic modifiers of sickle cell disease

“…Sickle cell anemia has many complications due to sickle vasoocclusion and hemolytic anemia, and HbF affects the rate of some complications more than others [17]. Table I [18–58] summarizes the relationships HbF concentration with the common complications of disease. High HbF is strongly associated with a reduced rate of acute painful episodes, fewer leg ulcers, and longevity.…”

“…Compared with low HbF cases, they had significantly higher minor allele frequencies of the two known trans‐acting elements associated with high HbF (see below), BCL11A and the intergenic interval between HBS1L and MYB (HMIP; 6q22‐23). Individuals with either sickle cell anemia or HbS‐ β 0 thalassemia from the Southwestern Province of Saudi had HbF levels lower that of the individuals from the Eastern Province, yet higher than that of the African American sickle cell patients [77]. Southwestern Province patients have the HbS gene on African HBB haplotypes, usually the Benin type; in contrast to African Americans, they rarely have priapism or leg ulcers [78].…”

Robust clinical and laboratory response to hydroxyurea using pharmacokinetically guided dosing for young children with sickle cell anemia

“…It has proven benefits for the reduction of morbidity and mortality, in both adults and children . Untreated SCA results in significant progressive damage to nearly all organs, most notably the spleen, kidneys, heart, lungs, and brain, beginning as early as the first year of life. With decades of clinical research involving patients with SCA, there is no reason to suggest that hydroxyurea has short‐ or long‐term risks that outweigh its benefits, with improvement noted in nearly all clinical outcomes and even reduced mortality …”