High bias and low precision for estimated versus measured glomerular filtration rate in pediatric sickle cell anemia

Individuals with sickle cell anemia (SCA) develop glomerular injury that progresses to chronic kidney disease. Measured GFR (mGFR) is the gold standard test for monitoring glomerular function. Pediatric SCA research has used Tc-DTPA to determine the mGFR but this test is not feasible for annual monitoring because of its high cost and time commitment. A more convenient approach to track glomerular function is to measure serum creatinine (SCr) and/or cystatin C (CyC) and calculate the estimated glomerular filtration rate (eGFR). Several pediatric eGFR equations were validated in nonSCA populations; however, each of these equations has limitations and none has been validated in SCA. It is imperative to identify the eGFR equation with the least bias of eGFR relative to mGFR and highest precision for SCA clinical care and research. Bias defines the accuracy (eGFR minus mGFR) and standard deviation of this bias defines the precision of eGFR. The Institutional Review Board-approved Sickle Cell Clinical Research and Intervention Program (SCCRIP) requires annual eGFR and mGFR using Tc-DTPA every 3 to 6 years (NCT:020988635). To determine the accuracy and precision of five pediatric eGFR equations, we tested the hypotheses that: (i) in comparison to mGFR, estimates using the Chronic Kidney Disease in Children (CKiD) eGFR equation would have lowest bias and highest precision; (ii) bias would be similar by therapy and age; and (iii) the intrapatient variability for the bias would be low among patients with repeated measures. Among patients with eGFR and mGFR obtained within a 4-week period enrolled in the SCCRIP study, we performed an agreement analysis between five standard pediatric eGFR equations derived from either SCr, SCr and blood urea nitrogen (BUN), CyC, or SCr and CyC and mGFR by Tc-DTPA clearance. We excluded five participants with either chronic kidney disease or severe hyperfiltration (mGFR: <60 or >240, eGFR: >350 mL/min/1.73m). We determined eGFR and mGFR at outpatient appointments during clinician-determined steady state. We compared the bias (eGFR-mGFR) in patients with repeated measures and categorized patients as having low intrapatient variability if the absolute difference in the bias on repeated measures was <5 mL/min/1.73m. Summary statistics including mean and standard deviation (SD) for continuous variables and counts and percentages for categorical variables were reported and compared using statistical tests as appropriate. For the agreement analyses between mGFR and eGFR, mean bias (95% limits of agreement) and the SD of bias were calculated using Bland-Altman methods assuming constant variance. A t-test and F-test were used to compare bias and variance between the CKiD equation and four other pediatric eGFR equations. The Pearson correlation (r) or Spearman rank correlation (r), and Lin concordance correlation (CCC) with 95% confidence intervals are presented. The percentage difference between eGFR and mGFR and the percentage of values within ±10% (P10[%]) and ±30% (P30[%]) are presented. A linear regression model was used to assess the effects of age, treatments and/or their interaction on bias between eGFR and mGFR. Next, we analyzed patients with repeated measurements. We performed generalized least squares models to assess the effects of age, treatments and/or their interaction on bias. We modeled the correlations of repeated measurements on the same subjects using a compound symmetry correlation structure. All P-values were two-sided and considered statistically significant when <0.05. Analyses were performed using SAS v9.4 (Cary, NC, USA) and R-3.5. 2 (Vienna, Austria). Three-hundred sixty-four Tc-DTPA mGFR examinations were performed in 198 subjects. Among the 198 individuals with an initial mGFR, 196 also had SCr and 124 had SCr and CyC measured within 4 weeks of mGFR. The median age of the 198 participants at the time of their initial mGFR was 8.2 years (range, 2.1-18.0). The mean (± SD) mGFR was 141± 26 mL/min/1.73 m. Eighty-nine (45%) participants were female. No difference was observed in the mean age of female and male participants (8.6 vs. 8.5 years, P=0.83). However, the mean mGFR (± SD) was significantly higher in males than females (145±26 vs. 137±26 mL/min/1.73 m, P=0.024). At the time of mGFR, participants were receiv-