GFR as the "Gold Standard": Estimated, Measured, and True.

Glomerular filtration rate (GFR) has long been considered the best overall index of kidney function in health and disease. The rationale is that GFR is a property of the kidney, has a large range, and is affected by physiologic, pharmacologic, and pathologic conditions. Furthermore, GFR decline is associated with many physiologic and clinical consequences and is correlated with decline in other excretory functions, such as tubular reabsorption and secretion, as well as endocrine and metabolic functions. Decreased GFR is one criterion in the definition and staging of acute and chronic kidney diseases, and GFR estimating equations are recommended for routine use for kidney function assessment in clinical practice. For a number of reasons, some have questioned the appropriateness of GFR as the “gold standard” for defining kidney disease and assessing kidney function. While it can be important to question accepted concepts, to date, no alternative measure has been proposed to replace GFR as an index of kidney function or decreased GFR as a criterion for defining kidney disease. Glomerular filtration cannot be measured directly in humans; thus “true” GFR cannot be known with certainty. However, GFR can be assessed from clearance measurements (measured GFR [mGFR]) or serum levels of endogenous filtration markers (estimated GFR [eGFR]). Urinary inulin clearance, the classic method for measuring GFR described by Smith, is too difficult for clinical practice and research purposes; consequently, alternative filtration markers and clearance methods are used to measure GFR (Table 1). In particular, 2 methods that have been used in recent studies are of importance in developing and validating GFR estimating equations. Urinary iothalamate clearance is the basis for the CKD-EPI (Chronic Kidney Disease Epidemiology Collaboration) equations using creatinine and cystatin C that are recommended by current guidelines. Meanwhile, plasma clearance of iohexol is now being used more widely in research studies, including those to assess the CKD-EPI equations and develop other equations. In this issue of AJKD, Seegmiller and colleagues describe observed differences between the urinary clearances of iothalamate and iohexol. The goals of this editorial are to provide explanations for these observed differences and explore the implications of these differences on the utility of GFR as a gold standard.