Clinical Measurements & eGFR Accuracy
Obtaining measured glomerular filtration rate (mGFR) is a complex and labor-intensive process that can be imprecise and is rarely done outside of the research setting. Instead, health care professionals rely on laboratory-measured filtration markers—creatinine, cystatin C, or both—along with body surface area (BSA) adjustment and demographic variables to estimate glomerular filtration rate (eGFR) in patients.
Creatinine
Serum creatinine is currently the most widely used filtration marker to assess kidney function. However, creatinine measurement alone to determine eGFR may provide an inaccurate or incomplete picture of kidney function. Creatinine levels can be affected by muscle mass and often are ineffective in detecting mild or moderate kidney injury.
Adjusting for variables that potentially affect serum creatinine levels—such as age and sex—may allow health care professionals to observe if chronic kidney disease (CKD) is present.
Physiological Limitations of Creatinine
All creatinine-based estimation equations suffer from physiologic limitations of creatinine as a filtration marker.1,2 The terms for age and sex—without or with race—only capture some of the non-GFR determinants of creatinine concentration in the blood, and the coefficients represent average effects observed in the population used to develop the equations.
Patients with Unstable Renal Function
Creatinine-based estimates of kidney function are most useful when kidney function is stable, and may not perform reliably in patients
- with unstable creatinine concentrations, including pregnant women, patients with serious comorbid conditions, and hospitalized patients, particularly those with acute kidney injury
- with extremes in body size, muscle mass, or diet, including—but not limited to—individuals who have an amputation, those with paraplegia, bodybuilders, and frail older adults
- who are critically ill
- with cancer
- with a muscle-wasting disease or a neuromuscular disorder
- experiencing malnutrition or who eat a vegetarian or low-meat diet
The use of creatine-based estimating equations with these patient groups may lead to errors in estimating GFR.2 eGFR can be used for patients who are in the hospital; however, eGFR has poorer agreement with mGFR for ill hospitalized patients than for community-dwelling patients.
Creatinine Measurement Error and eGFR
Errors in creatinine measurement impact the accuracy of the eGFR and may result in misclassification of patients and improper treatment. Creatinine measurement can be influenced by endogenous substances and by exogenous substances such as drugs. Enzymatic creatinine is less influenced by drugs and endogenous substances, with elevated bilirubin and hemolysis being the more important potential interferences. Alkaline picrate (Jaffe) methods are influenced by protein, glucose, ketone bodies, and many drugs.3
Total Protein Interference in Serum Creatinine Measurement
While enzymatic creatinine methods are not influenced by total protein concentrations, alkaline picrate (Jaffe) methods are subject to interference from proteins. Many routine alkaline picrate (Jaffe) methods use an approximate correction for the nonspecific contribution of total protein to a serum or plasma creatinine value by subtracting an "average" bias from all measured results. This average correction approach, sometimes called compensation, can be useful for adult blood samples with physiological concentrations of total proteins. However, for infants and children with lower serum total protein concentrations than adults, the correction may subtract too much from the measured creatinine concentration, causing an overcorrection with an erroneously low creatinine result and an erroneously high eGFR.
Some alkaline picrate (Jaffe) methods use other approaches to minimize the influence of protein interference on creatinine results. However, the difference in total protein between young children and adults may affect any alkaline picrate (Jaffe) method. Further investigation is needed to better understand the influence of protein on commonly used methods for creatinine.
The combined effect of isotope dilution mass spectrometry (IDMS)-traceable calibration and an erroneous correction for serum proteins can cause a relatively large error in the eGFR that is more pronounced in children under the age of 2.
Glucose and Ketone Bodies Interference in Serum Creatinine Measurement
Elevated glucose and ketone bodies found in diabetic patients cause falsely elevated creatinine using alkaline picrate (Jaffe) methods. Enzymatic methods are not affected by glucose or ketone bodies.
Bilirubin and Hemolysis Interference in Serum Creatinine Measurement
Caution should be used when the blood sample is hemolyzed or has elevated bilirubin. These interferences generally cause lower serum creatinine, but the magnitude varies depending on the specific enzymatic or alkaline picrate (Jaffe) method.
Measurement Error in Children
Children naturally have a lower serum creatinine concentration and lower serum total protein concentration than adults. As such, a measurement error using alkaline picrate (Jaffe) methods has a proportionally larger effect in a child’s sample than it would in an adult’s sample and may result in greater error in eGFR calculations in children.
Alternatives to Serum Creatinine Measurement
In cases where estimating GFR using serum creatinine alone may be problematic, a measured creatinine clearance or exogenously measured GFR may be indicated. Alternatively, serum/plasma cystatin C concentration may be used to estimate GFR.
Cystatin C
Cystatin C is a more recently established filtration marker that has been found to accurately assess kidney function. However, measurement of cystatin C may not be widely available in hospital laboratories in the United States due to higher cost and limited reimbursement ICD10 codes. Cystatin C is generally available from referral laboratories with longer turnaround times. . As use of the preferred 2021 Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) creatinine-cystatin C equation4 increases, the availability of and capacity for cystatin C measurement is expected to increase.
Cystatin C Measurement Error and eGFR
Similar to creatinine, using standardized cystatin C measurement procedures is crucial. Cystatin C appears to be generally less influenced by non-GFR determinants compared to creatinine. However, it is essential to acknowledge that certain non-GFR factors can still impact blood cystatin C levels, potentially affecting the precision of cystatin C-based eGFR measures. Factors such as steroid use, thyroid dysfunction, adiposity, and inflammation have been identified as contributors to elevations in cystatin C levels.5 Notably, these factors differ from those associated with creatinine non-GFR determinants. This distinction underscores one of the rationales behind combining cystatin C and creatinine for a more accurate eGFR calculation, as each biomarker complements some of the limitations of the other when used independently. However, a single parameter equation may be preferred when important non-GFR determinants are present for either creatinine or cystatin C.
Body Surface Area (BSA)
eGFR equations do not require a weight variable because the results are reported normalized to an accepted average adult BSA of 1.73 m². However, there are instances when a BSA adjustment may be necessary to compare a patient's kidney function to normal values, to the levels defining the stages of CKD, or for drug dose adjustments. For some, serum creatinine may be higher or lower due to changes in muscle mass rather than changes in kidney function.
As kidney size and function tends to be proportional to BSA, an adjustment may be needed for patients who differ from the population average used to develop the estimating equation. For people who have an amputation, those with paraplegia, frail older adults, bodybuilders, and those who have obesity, failing to make a BSA adjustment could lead to reduced accuracy in the patient’s eGFR, which could in turn influence care decisions and drug dosing.