Creatinine May Outperform Cystatin C in eGFR Calculations in SCD Free

Data presented at a poster session of the 66th American Society of Hematology Annual Meeting and Exposition suggest that creatinine-based equations to estimate glomerular filtration rate (GFR) may outperform cystatin C-based equations when evaluating patients with sickle cell disease (SCD) for kidney disease, but follow-up is needed.¹

Kidney GFR can be measured directly using radioactive tracers such as iothalamate, but such approaches are clinically impractical. Thus, health care providers have relied on specific equations using blood levels of certain waste products to get an estimate (eGFR). Creatinine, a waste product of muscle breakdown, was historically used in an equation that included a Black race variable.

Recently, professional societies have recommended that GFR values be calculated without this race variable, and they have encouraged the use of a different waste marker, cystatin C, made by virtually all nucleated cells.² Unlike creatinine, cystatin C is not affected by muscle mass or dietary protein intake. Although it can be affected by factors such as smoking, obesity, and inflammation, it has generally been considered a more accurate blood marker for eGFR calculations than creatinine.³

SCD can cause a variety of renal manifestations, and the disease tends to progressively impair kidney function. Hyperfiltration and microalbuminuria can begin in childhood, and these can evolve to progressive lowering of the GFR and macroalbuminuria. Proteinuria and reduced GFR are both risk factors for increased mortality in SCD.⁴

Emily Limerick, MD, an assistant research physician at the National Heart, Lung, and Blood Institute in Bethesda, Maryland, recruited 67 patients with SCD who were free of current vaso-occlusive disease, most of whom were on stable doses of hydroxyurea. Notably, the mean measured GFR was 129 mL/min/1.73 m², so most patients had relatively normal kidney function or hyperfiltration.

Dr. Limerick assessed the accuracy of calculated eGFR values using various equations from the Chronic Kidney Disease Epidemiology Collaboration and an eGFR equation using creatinine previously developed to apply specifically to patients with SCD using data from Jamaica.^2,5 She contrasted these calculated eGFRs with values of GFR measured with radioactive iothalamate using the Wilcoxson signed-rank test.

The creatinine-based equation from 2009 (which includes the race factor) was the most accurate in terms of lowest median absolute values of discrepancy (25.6 mL/min/1.73 m²). However, Dr. Limerick also noted that the creatinine-based equation from 2021 (which does not include race) performed similarly (26.4 mL/min/1.73 m²).

Cystatin C-based equations performed more poorly, tending to overestimate kidney function. The 2012 cystatin C-based equation (which does not include a race factor) was the least accurate (33.8 mL/min/1.73 m²) in patients with and without albuminuria, and the Jamaican creatinine-based eGFR was similar. Both equations substantially underestimated actual GFR. The 2021 creatinine-based equation was closer to actual measured GFR than the 2021 version that uses both creatinine and cystatin (both without race factor).

The data suggest that cystatin C-based eGFR equations may not be the most appropriate for adult patients with SCD, at least for patients whose kidneys have not significantly deteriorated. However, other studies have suggested that cystatin C may be a better marker than creatinine for pediatric patients with SCD, as Dr. Limerick initially hypothesized might be the case for adult SCD.⁶

“Larger datasets in SCD with lower measures of GFR and longitudinal evaluations may better define the most appropriate equations to assess kidney function in SCD,” Dr. Limerick concluded.

Any conflicts of interest declared by the authors can be found in the original abstract.

References

1. Limerick E. Race-based creatinine Egfr equations outperform nonrace-based and cystatin C-based equations in a population of adults with sickle cell disease. Abstract 3888. Presented at the 66th American Society of Hematology Annual Meeting and Exposition; December 9, 2024; San Diego, California.
2. Delgado C, Baweja M, Crews DC, et al. A unifying approach for GFR estimation: recommendations of the NKF-ASN Task Force on reassessing the inclusion of race in diagnosing kidney disease. Am J Kidney Dis. 2022;79(2):268-288.e1.
3. Fernando S, Polkinghorne KR. Cystatin C: not just a marker of kidney function. J Bras Nefrol. 2020;42(1):6-7.
4. Nath KA, Hebbel RP. Sickle cell disease: renal manifestations and mechanisms. Nat Rev Nephrol. 2015;11(3):161-171.
5. Asnani MR, Lynch O, Reid ME. Determining glomerular filtration rate in homozygous sickle cell disease: utility of serum creatinine based estimating equations. PLoS One. 2013;8(7):e69922.
6. Alvarez OA, Wright D, Lopez G, et al. Serum cystatin C is a better marker for renal function than serum creatinine in children with sickle cell disease. Blood. 2005;106(11):3774.