There are a variety of differences among markers and clearance methods for GFR measurement compared with the classic method of inulin clearance. However, the bias appears relatively small, and imprecision can be reduced by adhering to standardized protocols, providing accuracy substantially greater than estimated GFR.
Based on advantages and disadvantages described above, plasma clearance of non-radioactive exogenous markers is likely the most simple to implement by clinical laboratories not already performing GFR measurements. However, one should consider the laboratory in which the exogenous marker will be assayed, as these methods are highly sensitive to error.
When to use confirmatory tests for eGFR from creatinine
The KDIGO [Kidney Disease: Improving Global Outcomes] 2012 update to the clinical practice guidelines for evaluation and management of chronic kidney disease included several recommendations for the evaluation of GFR.
The guidelines recommended using eGFRcr for initial assessment and eGFR cys or eGFRcr-cys or a measured GFR for confirmatory testing in specific circumstances when eGFRcr is less accurate (Table 2). The KDIGO guideline also recommends that for adults with eGFRcr 45-59 mL/min/1.73m2 without markers of kidney damage, clinicians should measure cystatin C if confirmation of CKD is required.
If eGFRcr-cys is also below 60 mL/min/1.73m2, the diagnosis of CKD is confirmed. If eGFRcr-cys is 60 ml/min/1.73m2 or above, the diagnosis of CKD is not confirmed. This recommendation is based on reclassification analyses based on data from the National Health and Nutrition Examination Survey (NHANES).15
The KDIGO guidelines do not make other specific recommendations as to other circumstances under which cystatin C based estimates should be used as the confirmatory test or when one should move directly to measured GFR.
It may appear obvious that eGFRcys or eGFRcr-cys would provide more accurate estimates in circumstances when creatinine is thought to be biased due to differences in non GFR determinants, such as chronic illness or muscle-wasting diseases, and conversely that eGFRcr would provide more accurate estimates in the presence of nonGFR determinants of cystatin. Supporting this perspective, as described above, eGFRcys is more accurate than eGFRcr at lower BMI, and eGFRcr is more accurate than eGFRcys at higher BMI.31
However, these data are from otherwise well individuals and may not be apply to the ill. Indeed, data from small studies in such populations are mixed32. Moreover, it is not possible for clinicians to know the magnitude of the non-GFR determinants of an individual patient.
The advantage of eGFRcr-cys equation is that each filtration marker provides approximately 50% of the information, and as such lessens the impact of the non-GFR determinants of each marker. As described above, data has shown that eGFRcr-cys provides more accurate estimates than either marker alone across a range of subgroups.
Use of the combined creatinine and cystatin C equation is likely to provide the best estimate in most circumstances. However, in circumstances of uncertainty, where there is large discordance between eGFRcr and eGFRcys, and particularly where accurate levels of GFR are required, measurement of GFR should be considered.
GFR estimation is essential to the assessment of kidney disease. GFR estimating equations provide more accurate estimates from serum markers than serum markers alone, and can be used in most clinical encounters, but have serious limitations in some circumstances.
Measured GFR and estimated GFR based on cystatin C in combination with creatinine are two confirmatory tests that can be used to enhance clinical decision making. New data on eGFRcr-cys suggests that it is more accurate than either eGFRcr or eGFRcys. Protocols for GFR measurement have been widely tested and are accurate and safe.
Nephrologists should provide leadership in changing the paradigm of a single test to assess GFR, to use of initial tests followed by confirmatory tests where applicable, and in collaboration with clinical laboratories or nuclear medicine departments, in the implementation of GFR measurement protocols in their local institutions.
Further research is necessary to determine specific circumstances when confirmatory tests should be implemented but in the meantime, the above suggestions are a start.
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