Estimated GFR and risk of death--is cystatin C useful?

Current estimates suggest that as many as one in six persons in North America have chronic kidney disease,1 a condition that may worsen over time and signal the need for continuous monitoring. Knowing which patient with chronic kidney disease is at risk for end-stage kidney disease or death could tell us who needs intensive monitoring or intervention. The glomerular filtration rate (GFR), the classic measure of kidney function, describes the amount of plasma that is cleared of an endogenous or exogenous marker filtered by the glomeruli per unit of time. Direct measurement of endogenous clearance is difficult, since it requires the timed collection of urine specimens and concomitant blood tests in which an endogenous marker, such as creatinine, is measured. In the measurement of the clearance of an exogenous substance that is infused intravenously, it is necessary to measure the substance in blood and urine samples after a steady-state level is reached, to calculate a disappearance curve from serial blood samples after the substance is injected, or to measure blood and infusate levels. Thus, direct measurement of the GFR is timeconsuming, labor-intensive, and costly. As an alternative, various methods for estimating the GFR have been developed.2-5 The National Kidney Disease Education Program has recommended the use of the estimated GFR (eGFR) rather than measurement of serum creatinine alone. Until recently, estimating methods were based on serum creatinine as a marker of kidney function. However, because creatinine is also affected by diet, muscle mass or breakdown, and tubular secretion, it is not ideal, and a variety of estimating equations have been used. Recently, cystatin C, a nonglycosylated protein consisting of 120 amino acid residues encoded by CST3, has gained traction as an alternative marker.6 Cystatin C is synthesized and secreted at a nearly constant rate by virtually all nucleated cells. Given its 13-kDa size, cystatin C is freely filtered by the glomeruli. In contrast to creatinine, cystatin C is not excreted in the urine but, rather, is metabolized by the proximal tubule, so timed urine collections are not needed. Cystatin C is particularly useful for estimating kidney function when creatinine production is variable or unpredictable. In some patients (e.g., those with muscle-wasting or chronic disease, elderly persons, women, or vegetarians), the serum creatinine level may be low, yet the true GFR is impaired. In contrast, in other patients, the serum creatinine level may be high, but the true GFR is normal (e.g., in patients with African ancestry, a muscular body habitus, or a highprotein diet). Two key advances have improved the understanding of cystatin C as a biomarker in kidney disease.7 First, international laboratory reference standards for cystatin C now exist, which is important when multiple laboratories are performing tests. Second, the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) has developed accurate GFR-estimating equations, specifically the 2012 CKD-EPI cystatin C equation and the 2012 CKD-EPI creatinine–cystatin C equation. The development of these equations represents an advance over the 2009 CKD-EPI creatinine equation, which itself is more precise than the equation used in the Modification of Diet in Renal Disease study, especially at increased GFRs. With such equations, it is now possible to compare the classification and utility of equations by each method of calculating the eGFR. In this issue of the Journal, Shlipak et al.8 describe a meta-analysis of individual-patient data