BACKGROUND
Many different cystatin C–based equations exist for estimating glomerular filtration rate. Major reasons for this are the previous lack of an international cystatin C calibrator and the nonequivalence of results from different cystatin C assays.
METHODS
Use of the recently introduced certified reference material, ERM-DA471/IFCC, and further work to achieve high agreement and equivalence of 7 commercially available cystatin C assays allowed a substantial decrease of the CV of the assays, as defined by their performance in an external quality assessment for clinical laboratory investigations. By use of 2 of these assays and a population of 4690 subjects, with large subpopulations of children and Asian and Caucasian adults, with their GFR determined by either renal or plasma inulin clearance or plasma iohexol clearance, we attempted to produce a virtually assay-independent simple cystatin C–based equation for estimation of GFR.
RESULTS
We developed a simple cystatin C–based equation for estimation of GFR comprising only 2 variables, cystatin C concentration and age. No terms for race and sex are required for optimal diagnostic performance. The equation, eGFR=130×cystatin C−1.069×age−0.117−7, is also biologically oriented, with 1 term for the theoretical renal clearance of small molecules and 1 constant for extrarenal clearance of cystatin C.
CONCLUSIONS
A virtually assay-independent simple cystatin C–based and biologically oriented equation for estimation of GFR, without terms for sex and race, was produced.
Estimating GFR using formulae based on s-creatinine or s-cystatin C alone was equally accurate according to the NKF K/DOQI guidelines. A formula that combines both provided a greater accuracy. If Cystatin C, which is clearly more expensive, is used, the choice of the cystatin C determination method and an adjusted prediction equation is essential. Use of the IDMS-traceable MDRD seems to yield the best cost-benefit ratio for routine practice.
Cystatin C has been proposed as an endogenous marker for measuring glomerular filtration rate (GFR) and is regarded as being equivalent to or better than creatinine. However, there are no published data on the production rate (Cys(pr)) or on the non-renal clearance of cystatin C (CL(nr)) in humans, which are essential parameters for GFR calculation. GFR was determined by measuring the plasma clearance of iohexol. Cystatin C, creatinine, urea and albumin were determined on the same serum samples as iohexol; 381 patients with a GFR range of 12-151 ml/min/1.73 m2, and 70 patients on haemodialysis were evaluated. Renal clearance of cystatin C (CLr) equals GFR * S (the sieving coefficient). Plasma clearance (CL) = CLr + CLnr. The relationship between Cys(pr) and the elimination rate (CL * serum-cystatin C) can be expressed as Cys(pr) = (S * GFR+CLnr) * serum-cystatin C. Assuming that the unknown values of Cys(pr) and CLnr are independent of GFR, the equation can be solved from GFR (iohexol clearance) and serum cystatin C (s-Cys) patient data. For S=1, we found Cys(pr) = 0.124 +/- 0.023 mg/min/1.73 m2 and Cl(nr)=22.3 ml/min/1.73 m2. For S = 0.94, found in rats, the values will be Cys(pr) = 0.117 mg/min/1.73 m2 and Cl(nr) = 21 ml/min/1.73 m2 and S-Cys in 70 patients on chronic haemodialysis was found to be 5.74 +/- 1.15 mg/l, in agreement with a calculated value of 5.56 mg/l (s-Cys=124/22.3) for GFR=zero. The mean value of the calculated Cl(nr) for the 70 patients was 22.7 +/- 6.6 ml/min/1.73 m2, which confirms the calculated level and indicates its biological variation. We thus propose the following formula for calculating GFR using the values found for CLnr and Cys(pr) in this study: GFR=124/s - Cys - 22.3 ml/min/1.73 m2, where serum cystatin C concentration is given as mg/l.
The ideal all-purpose GFR prediction equation does not exist. LM Revised should be preferred in patients with suspected or known renal insufficiency, while CKD-EPI is most useful in settings where patients with no a priori suspicion of renal impairment are evaluated. Differences in creatinine measurements between laboratories may limit the generalizability of the present validation.
LMRCR and FASCR seem to be attractive alternatives to CKD-EPICR in estimating GFR by creatinine-based equations in older Europeans. Addition of cystatin C leads to important improvement in estimation performance.
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