Estimating GFR using serum cystatin C alone and in combination with serum creatinine: a pooled analysis of 3,418 individuals with CKD

Abstract

Background: Serum cystatin C was proposed as a potential replacement for serum creatinine in glomerular filtration rate (GFR) estimation. We report the development and evaluation of GFR-estimating equations using serum cystatin C alone and serum cystatin C, serum creatinine, or both with demographic variables.

Study design: Test of diagnostic accuracy.

Setting & participants: Participants screened for 3 chronic kidney disease (CKD) studies in the United States (n = 2,980) and a clinical population in Paris, France (n = 438).

Reference test: Measured GFR (mGFR).

Index test: Estimated GFR using the 4 new equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both with age, sex, and race. New equations were developed by using linear regression with log GFR as the outcome in two thirds of data from US studies. Internal validation was performed in the remaining one third of data from US CKD studies; external validation was performed in the Paris study.

Measurements: GFR was measured by using urinary clearance of iodine-125-iothalamate in the US studies and chromium-51-EDTA in the Paris study. Serum cystatin C was measured by using Dade-Behring assay, standardized serum creatinine values were used.

Results: Mean mGFR, serum creatinine, and serum cystatin C values were 48 mL/min/1.73 m(2) (5th to 95th percentile, 15 to 95), 2.1 mg/dL, and 1.8 mg/L, respectively. For the new equations, coefficients for age, sex, and race were significant in the equation with serum cystatin C, but 2- to 4-fold smaller than in the equation with serum creatinine. Measures of performance in new equations were consistent across the development and internal and external validation data sets. Percentages of estimated GFR within 30% of mGFR for equations based on serum cystatin C alone, serum cystatin C, serum creatinine, or both levels with age, sex, and race were 81%, 83%, 85%, and 89%, respectively. The equation using serum cystatin C level alone yields estimates with small biases in age, sex, and race subgroups, which are improved in equations including these variables.

Limitations: Study population composed mainly of patients with CKD.

Conclusions: Serum cystatin C level alone provides GFR estimates that are nearly as accurate as serum creatinine level adjusted for age, sex, and race, thus providing an alternative GFR estimate that is not linked to muscle mass. An equation including serum cystatin C level in combination with serum creatinine level, age, sex, and race provides the most accurate estimates.

Figure 1. Performance in the pooled dataset by level of estimated GFR

Difference is calculated as (measured GFR-estimated GFR). Solid horizontal line indicates no difference. Solid black curve is a non-linear regression of the mean difference, which measures bias. Dashed grey lines are quantile regressions of the 5^th and 90^th percentiles of the differences, which measures precision. The grey dotted vertical line indicates 60 ml/min per 1.73 m². To convert GFR from mL/min/1.73 m² to mL/sec per 1.73 m², multiply by 0.01666. GFR, glomerular filtration rate.

Appendix Figure. Chronic Kidney Disease-Epidemiology Collaboration (CKD-EPI) Datasets

Figure shows allocation of studies to category 1 (development and interval validation) and category 2 (external validation) datasets, and availability of serum samples for cystatin C at the time of this analysis. ScysC, serum cystatin C; Scr, serum creatinine.