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Clinical assessment of kidney function is central to the practice of medicine. Glomerular filtration rate (GFR) is widely accepted as the best index of kidney function in health and disease and accurate values are required for optimal decision making in many clinical settings, including detection of kidney disease, understanding its severity, and for making decisions about diagnosis, prognosis and treatment1.


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Estimated GFR based on serum creatinine (eGFRcr) is now widely reported by clinical laboratories and is available in most clinical encounters as a “first line” test of kidney function. In other fields of medicine, first-line tests are followed by more accurate confirmatory tests when required.

Classically, the confirmatory tests available for clinicians are measured GFR using urinary or plasma clearance of exogenous filtration markers at specialized centers, or measured creatinine clearance from timed urine collections.

However, timed urine collections are difficult to obtain and fraught with error. More recently, there are data that the use of estimated GFR creatinine in combination with cystatin C can also serve as a confirmatory test.

This review suggests that confirmation of eGFRcr should be performed in select circumstances using, where appropriate, either measured GFR or cystatin C. In this review, I will describe indications for use of a confirmatory test and then briefly review the strengths and limitations of each.

Current methods to estimate GFR

GFR is most commonly estimated from serum creatinine using the Modification of Diet in Renal Disease  (MDRD) Study equation or the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation.2,3

Indeed, it is estimated that serum creatinine is ordered to estimate the GFR more than 281 million times annually in the U.S., and recent reports show that more than 80% of U.S. clinical laboratories now report estimated GFR (eGFR) whenever serum creatinine is ordered.45

An increasing number of laboratories are now beginning to use the CKD-EPI 2009 creatinine equation6,7 (personal communication Olivier Allaire and Tazeen Jafar).

The CKD-EPI creatinine equation was published in 2009 and was shown in the original publication, as well as several publications since then, to be more accurate than the MDRD Study equation, particularly at higher levels of GFR.3,8,9

In addition, several publications, including a large meta-analysis, have demonstrated that the CKD-EPI equation better predicts future risk for adverse outcomes than the MDRD Study equation.10 As such, in most stable outpatients without major co-morbid conditions, the CKD-EPI equation provides GFR estimates that are sufficiently accurate for clinical decision making.

However, large differences between measured and estimated GFR may be observed in some populations and clinical settings. Recognition of the strengths and limitations of any estimating equation and particular clinical settings when creatinine-based GFR estimates are likely to be inaccurate enable identification of patients in whom a kidney function confirmatory test should be considered.

Creatinine and all serum levels of endogenous filtration markers are determined by generation, renal excretion (filtration, secretion, and reabsorption), and extra-renal elimination. Estimating equations use easily measured clinical variables as surrogates for these unmeasured physiologic processes and provide more accurate estimates than the serum level alone.11

However, equations can only capture the average relationship of the surrogates to some of these physiologic processes, leading to error in some individuals (Table 1).

Click here to enlarge Table 1

Creatinine-based estimating equations include age, sex, race, or weight as surrogates for differences in creatinine generation from muscle mass.11

The individuals most likely to have large differences between measured and estimated GFR are those who are at the extremes of muscle mass and diet, who are malnourished or have a reduction in muscle mass from illness or amputation, who are of different races or ethnicities from individuals included in studies used to develop the equations, or who have changes in the non-GFR determinants over time.11-13

Use of a confirmatory test may be helpful in such patients or in clinical circumstances in which decisions based on inaccurate estimates may have adverse consequences. Below is a description of clinical situations in general medicine and nephrology where use of cystatin or measurement of GFR should be considered (Table 2).

Click here to enlarge Table 2

Reliance on eGFRcr could lead to medical errors in these populations, such as toxicity from excess medication doses and inappropriate use of imaging tests, or inappropriate decisions regarding dialysis initiation or kidney donation.