Estimation of Glomerular Filtration Rate Using Cystatin C Improves Risk Classification Compared to Estimation Using Creatinine

EBM Focus - Volume 8, Issue 37

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Reference: (N Engl J Med 2013 Sep 5;369(10):932), (level 1 [mid-level] evidence)

Glomerular filtration rate (GFR) is a standard measure of kidney function that is used to stage chronic kidney disease (CKD). The KDIGO staging system defines CKD as GFR< 60 mL/minute/1.73 m2. CKD stages correspond to categories of GFR values, each with a range of 15 mL/minute/1.73 m2, with lower GFR values indicating higher stage (more severe) disease (KDIGO 2013 Jan PDF). Because direct measurement of GFR is difficult, it is usually estimated (eGFR) by an equation typically using age, sex, and biomarker parameters. Several different estimation methods (CKD-EPI, MDRD, Cockcroft-Gault) have used creatinine as the principle marker of renal function. Though data have been inconsistent across different patient populations, the CKD-EPI creatinine equation has been shown to be comparable to the commonly used MDRD equation (Scand J Clin Lab Invest 2011 Apr;71(2):129). Newer equations have recently been developed using cystatin C, either alone or in combination with creatinine, and they may be more accurate than creatinine-based equations. This is in part because the filtration rate of cystatin C is unaffected by age, race, gender or muscle mass. A recent large validation cohort study compared risk classification based on CKD-EPI equations using cystatin C or creatinine.

Individual data from 90,750 patients from 11 general-population cohorts who had had standardized baseline measurements of both serum creatinine and cystatin C were analyzed. eGFR was calculated for each patient using CKD-EPI equations using cystatin C or creatinine. At baseline, the prevalence of CKD was 13.7% using cystatin C equation and 9.7% using creatinine equation. All-cause mortality was 13.6% overall in mean follow-up of 7.7 years.

CKD staging using the cystatin C equation was compared to staging using the creatinine equation. Using cystatin C, 21.5% of patients were classified to a higher CKD stage, and 19.3% to a lower stage compared to their creatinine-based stage. Classification to a higher stage by the cystatin C equation was associated with significantly increased risk of mortality for each category of GFR values, with hazard ratios for risk of death ranging from 1.36 to 3.04 (p < 0.05 for each GFR category). Conversely, classification to a lower stage was generally associated with reduced risk or mortality, though these reductions were significant only for stages corresponding to GFR categories of 45-59 mL/minute/1.73 m2 and 30-44 mL/minute/1.73 m2.

The improvement in predictive performance using the CKD-EPI cystatin C equation was summarized by the net reclassification index (NRI), which assesses the relative rates of appropriate and inappropriate reclassification (with positive value indicating improvement). For all-cause mortality, the NRI was 23% (95% CI 18%-28%). The cystatin C equation also associated with improved performance for prediction of cardiovascular death (NRI 17%, 95% CI 11%-23%) and end-stage renal disease (NRI 10%, 95% CI 0%-21%). Performance of CKD-EPI equation using both cystatin C and creatinine was similar to that of the cystatin C only equation. Similar results were also obtained in additional analysis of 5 cohorts with 2,960 patients with chronic kidney disease at baseline.

For more information, see the Chronic kidney disease topic in DynaMed.


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