Glomerular Hyperfiltration and Microalbuminuria in Children with Sickle Cell Anemia.

Glomerular hyperfiltration is an early manifestation of sickle cell nephropathy, and has been observed in children with sickle cell anemia (SCA) as young as 12 months of age with an age-dependent increase until the second decade of life. Over time, some children with SCA will develop microalbuminuria or frank proteinuria, but predictors of this complication are not currently available. The first aim of this study was to compare glomerular filtration rate (GFR) measured quantitatively by plasma clearance of injected 99-technetium diethylenetriaminepentaacetate (^99mTC-DTPA) to GFR estimates using serum creatinine and cystatin C in children with SCA. A second aim was to identify predictors of elevated GFR and microalbuminuria/proteinuria among children with SCA.

The Hydroxyurea Study of Long-Term Effects (HUSTLE) is a prospective observational study (NCT00305175) with the goal of describing the long-term cellular, molecular, and clinical effects of hydroxyurea therapy in SCA. At treatment initiation, patients have routine laboratory studies plus serum cystatin C, urine microalbumin, and GFR measurement by ^99mTC-DTPA clearance. The GFR was also estimated using the following published equations:

1. Schwartz standard formula with GFR = (height × 0.55) / serum creatinine;

2. Modified Schwartz formula with GFR = 39.1 [height (m) /serum creatinine (mg/dl)] × [1.8/cystatin C (mg/L)]^0.294[30/BUN 9mg/dl)]^0.169[1.099]^male[height(m)/1.4]^0.188;

3. Cystatin C formula 1 with GFR = −4.32 + (80.35 / cystatin C); and

4. Cystatin C formula 2 with GFR = anti log {1.962 + [1.123*log (1/cystatin C)]}.

Correlations between continuous variables were measured using Pearson's Correlation Coefficient and medians between patient groups were compared using the Wilcoxon-Mann-Whitney test.

A total of 65 children with SCA (41 males) enrolled in the HUSTLE study before starting treatment with hydroxyurea. The mean age of the patients was 9.4 ± 4.6 years (range 2.0–18.0 years). All patients were normotensive with mean systolic and diastolic blood pressure measurements of 107 and 61 mmHg, respectively. The mean serum creatinine was 0.34 ± 0.10 mg/dL (range 0.1 – 0.6 mg/dL); mean serum cystatin C was 0.76 ± 0.14 mg/L (range 0.57–1.22 mg/L). The mean ^99mTC-DTPA GFR value was elevated at 155.8 ± 38.9 mL/min/1.73m² (range: 91–308 mL/min/1.73m², normal for age 104 ± 20 mL/min/1.73m²). GFR values were not significantly different according to gender or age, although older teenagers had the lowest GFR values. Correlations between ^99mTC-DTPA-GFR and the four estimated GFR values were all significant, but the best correlation was with the modified Schwartz formula (Pearson Correlation Coefficient = 0.45, p = 0.0014). The ^99mTC-DTPA GFR values had a statistically significant negative correlation with serum cystatin C levels (Pearson Correlation Coefficient = −0.32, p = 0.0246) and a positive correlation with both systolic and diastolic blood pressure measurements (Pearson Correlation Coefficient = 0.27, p < 0.033 for both). A total of 63 patients had quantitative microalbumin measurements: 7 (11.1%) had microalbuminuria (30–299 mg protein/gm creatinine) and two (3.2%) had frank proteinuria (≥ 300 mg protein/gm creatinine). Mean ^99mTC-DTPA GFR values were higher in the 9 patients with microalbuminuria or proteinuria as compared to 54 without microalbuminuria (184.2 versus 152.7 mL/min/1.73m², p = 0.077). Conversely, cystatin C values were significantly lower in patients with microalbuminuria or proteinuria (0.63 mg/mL versus 0.78 mg/mL, p = 0.0028). The presence of microalbuminuria or proteinuria was also significantly associated with a higher systolic and diastolic BP, as well as lower WBC and ANC.

This prospective study confirms elevated GFR values in children with SCA, but documents only modest correlations with published formulas for GFR estimation in the setting of glomerular hyperfiltration. GFR elevation is associated with lower cystatin C levels, and higher systolic and diastolic blood pressure measurements. Microalbuminuria/proteinuria was present in 14.3% of this pediatric cohort and was associated with lower cystatin C, higher blood pressure values, and lower WBC and ANC. Serial monitoring of cystatin C may be useful as an early marker of sickle cell nephropathy.

Off Label Use: Hydroxyurea for children with sickle cell anemia.