The estimated glomerular filtration rate as a test for chronic kidney disease: Problems and solutions

BEYOND CREATININE?

As Simon and colleagues point out,⁵ although serum creatinine is a flawed surrogate for GFR, there are many problems with determining GFR by other means.

Direct GFR measurement relies on the use of an exogenous marker such as inulin or iothalamate that is infused or injected, followed by timed urine and plasma measurements to calculate GFR by the urinary clearance method (UV/P, where U is the concentration of the marker in the urine, V is the urine volume, and P is the concentration of the marker in the plasma). Alternatively, timed plasma measurements of the marker alone can be used to determine GFR by the plasma clearance method. The problem is that direct GFR measurement is costly, invasive, imprecise, time-consuming, and impractical in most clinical settings.

Exogenous markers for determining GFR are chosen because they are metabolically inert, are cleared by glomerular filtration without tubular secretion or reabsorption, and have no extrarenal clearance via the liver or intestines. Endogenous markers such as serum creatinine do not fulfill all of these ideal criteria.

Simon and colleagues highlight the problem of using the estimated GFR to screen for CKD in populations of ostensibly healthy persons.⁵ The MDRD and CKD-EPI equations contain demographic variables to approximate the creatinine generation rate. The primary source of creatinine generation is muscle, and the coefficients in these equations reflect the higher muscle mass of younger individuals, males, and African Americans. However, any creatinine-based equation is fundamentally flawed because overall health also affects muscle mass: healthy people have greater muscle mass than people with chronic illness, including those with CKD. Therefore, at the same serum creatinine level, a healthy person has a higher GFR than a patient with CKD.^1,7 This problem leads to circular reasoning, since you need to know whether the patient has CKD or is healthy in order to accurately estimate GFR, but estimated GFR is being used to determine whether the patient is healthy or has CKD.

Therefore, other endogenous markers that are also eliminated via glomerular filtration, such as cystatin C, have been used to construct equations that estimate GFR. Unfortunately, factors other than GFR, such as inflammation, can also influence blood cystatin C levels. This in turn impairs the accuracy of equations that use cystatin C to estimate GFR in the general population.⁸ No known endogenous marker of GFR can be used in all patients without any confounding factors.

To rectify this problem, recent studies have investigated the use of a confirmatory test to determine which patients with a creatinine-based estimated GFR less than 60 mL/min/1.73 m² actually have kidney disease or have a false-positive result due to higher-than-average creatinine generation. Both albuminuria and elevated serum cystatin C are examples of useful confirmatory tests that substantially decrease the misdiagnosis of CKD in healthy adults with an estimated GFR less than 60 mL/min/1.73 m².^9,10

Imagine if we identified and staged systemic lupus erythematosus on the basis of antinuclear antibody levels alone: this would parallel the current approach that largely uses serum creatinine alone to classify CKD. Confirmatory tests and considering patient-specific risk factors could avoid potential harm to healthy individuals and yet retain gains that have been made to improve the interpretation of serum creatinine levels in CKD patients.