Estimation of glomerular filtration rate using serum cystatin C and creatinine in adults with sickle cell anemia
Authors: Marianne E. M. Yee, Peter A. Lane, David R. Archer, Clinton H. Joiner, James R. Eckman, Antonio Guasch
Journal: American Journal of Hematology (2017)

Renal damage in sickle cell anemia (SCA) is a chronic morbidity that begins with hyperfiltration and albuminuria. With progressive glomerular injury, glomerular filtration rate (GFR) declines to "normal range," followed by renal insufficiency in adulthood. Progression to renal failure is an independent predictor of early death. Monitoring GFR changes is difficult in SCA, as traditional creatinine-based equations tend to overestimate true GFR while direct measurement of GFR is time-consuming and not practical for the clinical setting. The National Heart Lung and Blood Institute (NHLBI) Expert Panel Report on health maintenance in sickle cell disease (SCD) identified a need for more evidence regarding the natural decline in renal function, optimal screening methods, and GFR reference values for people with SCD.1 Cystatin C, which is eliminated exclusively by glomerular filtration, correlates with GFR in both chronic kidney disease (CKD) and patients with SCA.2 We evaluated the bias, precision, and accuracy of several equations that estimate GFR from serum creatinine (Cr) and cystatin C, as compared to the gold standard GFR measurement of iohexol clearance. Adults with hemoglobin SS, on hydroxyurea therapy, and persistent albuminuria were enrolled in a single-arm trial of losartan. GFR was measured by differential solute clearance of iohexol at three time points per patient, by intravenous infusion of iohexol 50 mg/kg followed by continuous infusion. Following a 60-minute equilibration, timed urine and blood specimens were collected every 30 minutes until 240 minutes post infusion. Iohexol concentration was measured by high-performance liquid chromatography (HPLC), and GFR was calculated as the average of four urinary iohexol clearances. Serum cystatin C and Cr were measured via the clinical laboratory at the times of GFR measurements in order to compare various equations of estimated GFR (eGFR) to measured GFR (mGFR). Patients with eGFR <60 mL/minute/1.73 m2 were excluded. The trial was approved by the Institutional Review Board (IRB) of Emory University and is registered with ClinicalTrials.gov, identifier NCT01989078. GFR was estimated using the 3 CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations (serum Cr only, cystatin C only, and combined Cr and cystatin C), 2 equations derived in the Jamaican Sickle Cell Cohort Study (JSCCS Cr, JSCCS Cystatin C),3, 4 Modification of Diet in Renal Disease (MDRD), and Cockcroft-Gault (Supporting Information Table 1). GFR was categorized as hyperfiltration (>130 mL/minute/1.73 m2), normal, or below-normal (<90 mL/minute/1.73 m2) per KDIGO consensus guidelines. To determine the agreement between eGFR and mGFR, the intraclass correlation coefficient (ICC) and linear regression (correlation) were calculated for each of the equations examined. There were 14 SCA subjects (10 males; 12 black, 2 Hispanic) with 33 GFR measurements. Mean mGFR was 106.6 mL/minute/1.73 m2 (range 68.0–147.0 mL/minute/1.73 m2), reflecting 5 (15%) studies with hyperfiltration and 7 (21%) with low GFR. Bias (mean difference of eGFR – mGFR), precision (standard deviation of bias), and accuracy (percentage prediction error within 10% (P10) and 30% (P30) of mGFR) for each eGFR equation are shown in Table 1. All Cr-based equations derived in non-SCA populations (CKD-EPI, MDRD, Cockcroft-Gault) had significant positive bias, while the JSCCS equations derived in SCA had moderate negative bias. This bias resulted in GFR categorization errors in the majority of studies for the Cr-based equations. The only equation in which bias was not statistically significant and ICC suggested fair reliability (>0.4) was the CKD-EPI cystatin C equation (bias = −0.2 mL/min/1.73 m2, P = .96). Previous studies have compared eGFR to technetium-99m-diethylene-triamine-pentaacetate (99mTc-DTPA) nuclear scan for GFR determination in SCA; however DTPA measurements may underestimate GFR due to plasma protein binding,5 thus the iohexol clearance provides the most accurate measurement of GFR and should be favored over other techniques when available. Arlet et al. previously compared iohexol-GFR to Cr-based eGFR in SCA, but did not assess cystatin C estimates of GFR.6 Our results support that serum Cr should not be utilized when aiming to accurately estimate GFR in SCA. Although the CKD-EPI equations have improved accuracy over simpler Cr-based formulas (MDRD and Cockcroft-Gault), both Cr-based CKD-EPI equations demonstrated significant positive bias in SCA, such that GFR was mis-categorized in the majority of cases with these equations. The Cr-based equations including CKD-EPI all require modification for patients of black race (the majority of SCA patients), indicating that these equations have limited accuracy in this population, which cannot be fully corrected with a modifying coefficient. Bias and accuracy were greatly improved with the cystatin C-only CKD-EPI equation, which eliminates error from serum Cr. Accuracy, bias, and classification were also improved with both equations derived in SCA adults in the JSCCS population (Cr-based and cystatin C-based), although these tended to underestimate GFR. The ability to estimate GFR from serum measurements is desirable because decline in renal function is a considerable problem in SCA that warrants accurate monitoring. Cystatin C has been shown to have better correlation with GFR in SCA, and the CKD-EPI Cystatin C equation here is shown to have negligible bias and fair correlation to mGFR. Cystatin C should be considered in situations in which accurate GFR estimation is needed, however in scenarios in which GFR determination is critical (eg, renal function assessment prior to bone marrow transplantation), we recommend that direct measurement of GFR via urinary and/or plasma clearance techniques (eg, iohexol) be considered in order to achieve the most accurate GFR results. This study was limited by small sample size and restriction to patients with albuminuria, thus may not be generalizable to SCA patients without albuminuria, those who are not on hydroxyurea therapy, and those with either greater hyperfiltration or greater renal insufficiency (ie, GFR <60 mL/minute/1.73 m2). Thus there is a need for larger studies of GFR measurement in SCA to develop eGFR equations with greater accuracy that can be used on a routine basis in the SCA population. The authors have no conflicts of interest to disclose. This work was supported by the Doris Duke Charitable Foundation Grant #2011099. The authors would like to acknowledge the Pediatric Research Alliance Biostatistics Core of Emory University School of Medicine for statistical support. Additional Supporting Information may be found online in the supporting information tab for this article. Supporting Information. Please note: The publisher is not responsible for the content or functionality of any supporting information supplied by the authors. Any queries (other than missing content) should be directed to the corresponding author for the article.