Abstract
Nephropathy is a well-recognized complication of sickle cell anemia (SCA) that is associated with considerable morbidity and mortality. Sickle nephropathy begins early in life, with glomerular damage characterized by hyperfiltration and glomerulomegaly, as well as tubular damage characterized by hyposthenuria. School-aged children can develop proteinuria and one-third of patients will eventually develop chronic renal failure as adults. Among the earliest markers of sickle nephropathy is glomerular hyperfiltration, typically measured as an elevated glomerular filtration rate (GFR). To date, however, no formal measurements of GFR have been published in young children with SCA, and its feasibility and interpretation in this age group have not been demonstrated. As part of a prospective, single-institution, IRB-approved open-label protocol using hydroxyurea in toddlers with SCA, the pre-treatment GFR was measured using plasma clearance of 99-Tc DTPA. The goal of this procedure was to determine the onset of hyperfiltration among young children with SCA, to identify risk factors associated with its onset, and to investigate the potential benefit of hydroxyurea in improving or preserving renal function. After intravenous injection of the DTPA radiotracer, 3–5 mL aliquots of venous blood were removed at 1 and 3 hours post-injection and analyzed for plasma radioactivity. Because DTPA is filtered at the glomerulus without substantial metabolism, secretion, or reabsorption, the plasma clearance allows an accurate and precise GFR measurement. The GFR was also estimated using the Schwartz equation, where GFR = height (cm) x k/serum creatinine, with k=0.55 for children between ages 1 and 12 years. A total of 13 children with HbSS (3 females, 10 males) were enrolled in this study, none of whom had laboratory evidence of renal disease at the time of evaluation. One child could not complete the DTPA study due to inadequate venous access. For the remaining 12 children, baseline GFR measurements were performed at age 3.0 ± 0.8 years (range 1.7 to 4.4 years) without complications. The average GFR measurement (mean ± SD) by DTPA clearance was 140.3 ± 20 mL/min/1.73m2, median 133 mL/min/1.73m2, range 117.9 to 172.7 mL/min/1.73m2 (normal 100 ± 20 mL/min/1.73m2). The baseline DTPA GFR measurement was elevated above 150 mL/min/1.73m2 in 5 of the 12 children, including 4 of 7 over age 3 years, although there was no signfiicant correlation between GFR and age or fetal hemoglobin. GFR estimates by the Schwartz equation were modestly correlated with the DTPA GFR measurements (R2 = 0.32, p = 0.055) but were typically slightly higher than the corresponding DTPA measurements. Three children who completed 24 months of hydroxyurea therapy had post-treatment DTPA clearance studies that revealed stable GFR measurements (average increase = 5.6 mL/min/1.73m2). These results illustrate that GFR measurement by DTPA clearance can be performed without difficulty in young children with SCA, requiring only peripheral intravenous access. Glomerular hyperfiltration as a manifestation of renal damage begins early in life for children with SCA, with elevated GFR values observed in the toddler age range. The Schwartz equation provides an estimate of GFR but probably cannot be used in lieu of the DTPA clearance study. Treatment with hydroxyurea may preserve renal function by abrogating further GFR hyperfiltration.
No Relationship Between Drug Transporter Genetic Variants and Tenofovir Plasma Concentrations or Changes in Glomerular Filtration Rate in HIV-Infected Adults
