Clinicians usually measure renal function by using surrogate markers because directly measuring glomerular filtration rate (GFR) is not routinely feasible in a clinical setting.1,2 Creatinine (Cr) and cystatin C (CysC) are the 2 main surrogate molecules used to estimate GFR.3
Creatine is a molecule nonenzymatically converted into Cr, weighing only 113 Da in skeletal muscles.4 It is then filtered at the glomeruli and secreted at the proximal tubules of the kidneys. However, serum Cr (sCr) levels are affected by several factors, including age, biological sex, liver function, diet, and muscle mass.5 Historically, sCr levels also are affected by race.5 In an early study of factors affecting accurate GFR, researchers reported that self-identified African American patients had a 16% higher GFR than those who did not when using Cr.6 Despite this, the inclusion of Cr on a basic metabolic panel has allowed automatic reporting of an estimated GFR using sCr (eGFRCr) to be readily available.7
In comparison to Cr, CysC is an endogenous protein weighing 13 kDa produced by all nucleated cells.8,9 CysC is filtered by the kidney at the glomeruli and completely reabsorbed and catabolized by epithelial cells at the proximal tubule.9 Since production is not dependent on skeletal muscle, there are fewer physiological impacts on serum concentration of CysC. Levels of CysC may be elevated by factors shown in the Table.
Estimating Glomerular Filtration Rates
Multiple equations were developed to mitigate the impact of extraneous factors on the accuracy of an eGFRCr. The first widely used equation that included a variable adjustment for race was the Modification of Diet in Renal Disease study, presented in 2006.10 The equation increased the accuracy of eGFRCr further by adjusting for sex and age. It was followed by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equation in 2009, which was more accurate at higher GFR levels.11
CysC was simultaneously studied as an alternative to Cr with multiple equation iterations shown to be viable in various populations as early as 2003.12-15 However, it was not until 2012 that an equation for the use of CysC was offered for widespread use as an alternative to Cr alongside further refinement of the CKD-EPI equation for Cr.16 A new formula was presented in 2021 to use both sCr and serum CysC levels to obtain a more accurate estimation of GFR.17 Research continues its effort to accurately estimate GFR for diagnosing kidney disease and assessing comorbidities relating to decreased kidney function.3
All historical equations attempted to mitigate the potential impact of race on sCr level when calculating eGFRCr by assigning a separate variable for African American patients. As an unintended adverse effect, these equations may have led to discrimination by having a different equation for African American patients.18 Moreover, these Cr-based equations remain less accurate in patients with varied muscle mass, such as older patients, bodybuilders, athletes, and individuals with varied extremes of daily protein intake.1,8,9,19 Several medications can also directly affect Cr clearance, reducing its ability to act as a surrogate for kidney function.1 In this case report, we discuss an African American patient with high muscle mass and protein intake who was initially diagnosed with kidney disease based on an elevated Cr and found to be misdiagnosed based on the use of CysC for a more accurate GFR estimation.