December 2011: Volume 37, Number 12
Glomerular Filtration Rate
The Importance of Standardized Serum Creatinine in Detecting Kidney Disease
By W. Greg Miller, PhD
The Centers for Disease Control and Prevention estimates that more than 20 million Americans age 20 and older may have chronic kidney disease (CKD), a type of kidney disease most commonly caused by diabetes and high blood pressure (1). Despite its high prevalence, many people go undiagnosed because the disease has no symptoms. Furthermore, healthcare providers often fail to identify CKD because patients’ serum or plasma creatinine concentrations appear normal even when they have lost significant kidney function. One of the most important indicators of early disease is glomerular filtration rate (GFR), an indicator of how well the kidneys filter waste products from blood. Early detection is important because effective treatments exist that can delay or even avoid the costly progression of the disease to kidney failure.
An equation developed 13 years ago to estimate GFR from the Modification of Diet in Renal Disease (MDRD) Study provided a simple clinical tool to better identify and monitor people with CKD (2) (Table 1). The equation relates creatinine concentration to filtration rate by the kidneys. Because measuring serum or plasma creatinine is a standard component of the basic metabolic profile performed during many routine healthcare visits, the hope was that routine reporting of eGFR would raise awareness of CKD among patients and providers and improve early intervention efforts.
However, the prevalence of the disease continued to soar and place a substantial burden on the healthcare system. In 2000, the National Institute of Diabetes and Digestive and Kidney Diseases established the National Kidney Disease Education Program (NKDEP) to educate providers and the public about CKD. The goal of the program was to improve identification of people with CKD and to promote evidence-based interventions. The NKDEP formed a Laboratory Working Group (LWG) in 2002 to promote routine reporting of eGFR by laboratories and to standardize creatinine measurements. The goal of this group was to reduce variability among the different measurement procedures used by laboratories and therefore reduce the variability in eGFR results.
AACC, the College of American Pathologists (CAP), and other laboratory and nephrology organizations around the world endorsed reporting eGFR (3), although some individuals expressed opposing opinions (4,5). Based on a May 2011 CAP survey of predominantly North American laboratories, 84% of participants now report eGFR, and of those, 82% report eGFR whenever they provide serum creatinine results.
Measuring creatinine and reporting eGFR are critical to promoting early detection and management of CKD. This article will describe the steps laboratories should take to ensure that they are reporting eGFRs according to the most current NKDEP recommendations.
How Sensitive is Creatinine?
One obstacle to using eGRF as an indicator of early kidney disease is that some medical professionals are not convinced that creatinine is a sensitive biomarker for the disease. The National Health and Nutrition Examination Survey (NHANES) data from 1999–2000 showed that 80% of adults with an eGFR <60 mL/min/1.73m2 were not identified as having CKD (6). Physicians likely failed to recognize patients’ creatinine concentration as an indicator of early kidney disease because the value fell within the so called “normal range.” Creatinine reference intervals are based on the central 95% of results for a presumably healthy group of people. This group is likely to include some that have non-symptomatic CKD, as well as a wide range of muscle masses. Consequently, eGFR at the upper limit of a given reference interval is consistent with loss of approximately half of the normal kidney function for many individuals.
Researchers have shown that creatinine, as well as cystatin C and beta-trace protein, are sensitive biomarkers for GFR and that changes in their concentrations have equivalent abilities to reflect deteriorating kidney function and to predict risk for progression of CKD (7,8). The NKDEP recommends that laboratories report eGFR along with creatinine concentrations to provide a better assessment of kidney function. The equations used to calculate the eGFR include age, gender, and race factors that partially compensate for changes in muscle mass and therefore the rate of creatinine production. In comparison to creatinine concentrations, physicians more easily recognize eGFR as a continuous variable that reflects kidney function.
Limitations in Estimating GFR from Creatinine
Although eGFR is valuable in detecting early kidney disease, creatinine concentration in blood is influenced by factors other than the GFR. In particular, muscle mass, diet, and differences in the rate of kidney tubular secretion all can affect creatinine concentration.
It is important to recognize that eGFR is not the patient’s actual GFR. Rather, eGFR is an estimate based on an equation that captures the average GFR for a large number of persons. An individual’s eGFR can be different from their actual GFR based on differences between that individual’s age, gender, race, or weight and the average for the persons used to generate the equation. In addition, the relationship between creatinine and GFR only is reliable for patients in a stable metabolic state. In other words, eGFR is less useful in pregnant women, hospitalized patients, and in individuals with acute or prolonged illnesses.
Furthermore, any condition that affects muscle mass or muscle metabolism will decrease the reliability of creatinine to assess kidney function. For example, frail elderly, critically ill, obese, and cancer patients will be affected, as well as people who have had an amputation, are immobile, or participate in strenuous exercise or bodybuilding. Creatinine also is a less useful biomarker in individuals with vegan diets or who take creatinine supplements. In addition, creatinine concentration increases following consumption of meat. Finally, creatinine is poorly correlated with GFR in conditions associated with increased tubular secretion or extra-renal elimination of creatinine, such as severe CKD.
New Equations for eGFR
Five years ago, the NKDEP LWG published recommendations for laboratories reporting eGFR and for standardizing creatinine measurements (9). All large, global in vitro diagnostic companies have now recalibrated their routine creatinine measurement procedures to be traceable to an isotope dilution mass spectrometry (IDMS) reference measurement procedure. Most whole-blood measurement systems also have been calibrated to IDMS. With this standardization, the need for new equations for calculating eGFR became clear for reasons described below, and the LWG has recently focused on this area for both adult and pediatric populations.
Adult equations. The authors of the original MDRD Study equation for adults age 18 or older developed it using a routine creatinine measurement procedure that had a positive bias compared to the IDMS reference measurement procedure. In fact, at the time, all routine creatinine measurement procedures had positive biases of varying magnitudes compared to the IDMS procedure. Not unexpectedly, this variability in bias produced variability in patients’ eGFRs. When the NKDEP LWG standardized creatinine measurement procedures, the results were typically 5–30% lower (10), causing a positive bias in eGFR calculated using the original MDRD Study equation or any other older equation. Following publication of the LWG’s recommendations, researchers re-expressed the four-variable MDRD Study equation for eGFR using serum creatinine standardized to the reference measurement procedure (11) (Table 1).
Equations Used to Calculate Glomular Filtration Rate Using Standardized Creatinine Results
Modification of Diet in Renal Disease (MDRD) Study Equation (for adults ≥18 years) eGFR (mL/min/1.73 m2) = 175 x (Creatinine)–1.154 x (Age)–0.203 x (0.742 if Female) x (1.212 if African American)
This equation is for creatinine in mg/dL. Numeric values should not be reported above 60 mL/min/1.73 m2 because they are excessively biased to lower values.
Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) Study Equation* eGFR is in mL/min/1.73 m2
|Non-African American Female creatinine ≤0.7 mg/dL
||eGFR = 144 x (Scr/0.7)–0.329 x (0.993)Age|
|Non-African American Female creatinine >0.7 mg/dL
||eGFR = 144 x (Scr/0.7)–1.209 x (0.993)Age|
|African American Female creatinine ≤0.7 mg/dL
||eGFR = 166 x (Scr/0.7)–0.329 x (0.993)Age|
|African American Female creatinine >0.7 mg/dL
||eGFR = 166 x (Scr/0.7)–1.209 x (0.993)Age|
|Non-African American Male creatinine ≤0.9 mg/dL
||eGFR = 141 x (Scr/0.9)–0.411 x (0.993)Age|
|Non-African American Male creatinine >0.9 mg/dL
||eGFR = 141 x (Scr/0.9)–1.209 x (0.993)Age|
|African American Male creatinine ≤0.9 mg/dL
||eGFR = 163 x (Scr/0.9)–0.411 x (0.993)Age|
|African American Male creatinine >0.9 mg/dL
||eGFR = 163 x (Scr/0.9)–1.209 x (0.993)Age|
*for adults ≥18 years
Modified Schwartz Equation+ eGFR (mL/min/1.73m2) = 0.41 x (height / serum creatinine)
Height is in cm and creatinine is in mg/dL. eGFR is applicable from 15–80 mL/min/1.73m2.
+ for children <18 years
Of note, the NKDEP recommends against laboratories reporting MDRD equation values >60 mL/min/1.73m2, because these values are negatively biased and have increased variability. This variability is related to the proportionally larger influence of small calibration biases and the poorer precision of creatinine methods at lower concentrations, as well as to greater imprecision in the measured GFRs in the population used to develop the equation.
The Chronic Kidney Disease Epidemiology (CKD-EPI) Collaboration has published a new equation to estimate GFR in adults using standardized creatinine measurements and the other variables in the four-parameter MDRD equation (12) (Table 1). The CKD-EPI equation was developed from a much larger cohort of patients, including healthy and CKD individuals, but still relatively few elderly people. eGFRs calculated from the CKD-EPI equation show consistent performance across studies and subgroups defined by age, gender, race, diabetes, transplant status, and body mass index. The equation also has improved accuracy, particularly for GFRs >60 mL/min/1.73m2, making it suitable for reporting numeric values in this higher GFR range. The variability of results at higher eGFR values is slightly better for the CKD-EPI equation than for the MDRD equations, but it remains a factor when interpreting results. It is not clear if an upper limit for numeric values should be used for the CKD-EPI equation. However, the influence of imprecision at lower creatinine concentrations corresponding to more normal GFRs will contribute to increased imprecision in the eGFR value and needs further investigation. Additional information on both equations is available on the NKDEP website under the Laboratory Professionals section.
Pediatric equations. Investigators from the Chronic Kidney Disease in Children (CKiD) group developed a revised Schwartz equation (13) for use with standardized creatinine results (Table 1). As with the adult equations, all older pediatric equations for estimating GFR give erroneously high values and should not be used with standardized creatinine results. The CKiD investigators also are developing other equations that will likely use creatinine and cystatin C values; however, the NKDEP LWP cannot recommend laboratories use these equations until cystatin C calibration standardization has been accomplished. (See section on Cystatin C: An Alternative to Creatinine).
Using eGFR to Estimate Drug Dose
eGFR values also are important for dosing medications that are excreted by the kidneys, especially in patients with impaired kidney function. Labeling guidelines from the Food and Drug Administration (FDA) provide adjustments of drug dosages for these patients. Current FDA labeling recommends either creatinine, measured GFR, or estimated creatinine clearance (eCrCl) calculated from the Cockcroft and Gault (C-G) equation for most dosages of these drugs. However, the creatinine measurement procedures used by pharmaceutical companies to develop recommendations for drug dosing were likely calibrated differently than the one used to develop the C-G equation in 1976. Furthermore, the C-G equation estimates creatinine clearance, not GFR, and researchers have shown that the MDRD Study equation gives results that are closer to a measured GFR than does the C-G equation (2).
Clearly, FDA’s labeling recommendations for dosing these medications need to be updated to take into account standardized creatinine measurements. Resolution of this discrepancy is still ongoing. The basic issue is that standardized creatinine results today are typically 5–30% lower than older methods. The recommendations included in drug product labeling are based on older equations and non-standardized creatinine measurement procedures that had a positive calibration bias, as well as variability in the bias itself among different measurement procedures. Consequently, the NKDEP LWG recommends not using an equation to back calculate a value that could be used in the C-G or other older estimating equations.
A recent report simulated dose determinations for 15 drugs using both the re-expressed four-variable MDRD and the C-G equations to estimate eGFR and eCrCl, respectively (14). In the study, the researchers compared dosages of the drugs based on standardized creatinine results to those calculated from measured GFRs in 5,504 adult patients. For most patients and drugs examined, there was little difference in the drug dose that patients would receive using either equation to estimate kidney function; however, the discordance rates increased for drugs with dose adjustments based on narrower intervals of kidney function. Based on these results, as well as the difficulty establishing the calibration condition of creatinine measurement procedures used to develop the labeling for drug-dose recommendations, the NKDEP recommends that either equation may be used to determine drug dosing in patients with impaired kidney function unless the drug has a narrow index for kidney toxicity or the patient’s condition is such that creatinine is not a reliable measure of kidney function (Table 2). More details are available on the NKDEP website.
NKDEP Recommendations for Dosing Medications
The following recommendations are for adults and are based on standardized creatinine measurements.
- Use eGFR or eCrCl for drug dosing.
- If using eGFR in very large or very small patients, multiply the reported eGFR by the estimated body surface area (BSA) in order to obtain eGFR in units of mL/min:
eGFR (mL/min/1.73m2) x estimated BSA = eGFR (mL/min) for drug dosing
Note: BSA can be obtained from a standard nomogram or can be calculated using equations such as:
IMPORTANT CAUTION: Physicians should assess kidney function using alternative methods, such as measured CrCl or measured GFR when prescribing drugs with narrow therapeutic or toxic indices, when eGFR and eCrCl provide different estimates of kidney function, or for individuals in whom any estimates based on creatinine are likely to be inaccurate. (See section on Limitations in Estimating GFR from Creatinine).
Of particular note, however, is an FDA advisory on the chemotherapeutic agent carboplatin. The FDA in October 2010 notified the oncology community of a potential safety issue related to the dosing of this drug, which is used to treat advanced ovarian and other cancers and has a narrow index for kidney toxicity (15). The most common method for calculating dosage for this drug is the Calvert equation (Table 3), in which the drug dose is based on the area under the desired concentration of drug versus time curve (AUC). In its advisory, FDA warned oncologists that GFR estimated from a standardized creatinine result should not exceed 125 mL/min, irrespective of the equation used to calculate the value. This eGFR limit is intended to prevent excessive doses of the drug, and consequently kidney damage, for people with relatively normal kidney function.
Total Drug Dose (mg) = Target AUC × GFR (mL/min) + 25
This is the most common method for calculating dosage of the chemotherapeutic agent, carboplatin. The total drug dose is based on the area under the desired concentration versus time curve (AUC) for the drug. The value for GFR should not exceed 125 mL/min irrespective of the equation used for its estimation.
Specificity of Creatinine Measurement Procedures
While standardization of serum creatinine measurement procedures has improved the quality of eGFR calculations, it does not address limitations of a measurement procedure caused by interfering substances. To gain a better understanding of the influence of interfering substances on creatinine measurement, the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) Working Group on Glomerular Filtration Rate Assessment and the NKDEP LWG investigated potentially interfering substances in a panel of 365 individual clinical samples, representing 19 different disease categories and a healthy control group. The study also included sera supplemented with acetoacetate, acetone, ascorbate, and pyruvate. Investigators measured serum creatinine by four enzymatic and three Jaffe procedures, as well as an IDMS measurement procedure that was used to determine biases for each method. The results showed differences in both magnitude and direction of bias among measurement procedures, whether enzymatic or Jaffe. Furthermore, although the influence of interfering substances was less frequent with the enzymatic procedures, no procedure was unaffected (16).
Cystatin C: An Alternative to Creatinine
Another excellent biomarker for kidney disease is cystatin C, which also is a risk factor for cardiovascular disease, one of the major complications of CKD (17). Nucleated cells throughout the body produce the protein; however, it is unaffected by muscle mass and age >1 year. The primary limitation to using cystatin C in clinical practice has been lack of standardized measurement procedures (18,19). Consequently, equations that have been developed to estimate GFR from cystatin C are only suitable for that specific measurement procedure and a population similar to that used to develop the equation.
The IFCC Working Group on Standardization of Cystatin C has developed a reference material that is now available from the Institute for Reference Materials and Measurements in Belgium (20). This serum-based reference material is in the process of being characterized for commutability among commercial measurement procedures with the goal of enabling manufacturers to standardize calibration traceability to this reference material. The working group also is developing a new, more universal equation using a large and diverse population to estimate GFR from standardized cystatin C results.
When these standardization activities are complete, cystatin C will be a valuable addition to the tests available to monitor kidney disease. It will be particularly useful for pediatric and elderly patients and those in whom the relationship between creatinine and kidney function is compromised.
Strides in CKD Detection
The economic burden of CKD on the healthcare system will continue to grow, especially from the increasing prevalence of diabetes in the U.S. population. The improvements resulting from standardization of creatinine have made the equations used to calculate eGFR better clinical tools. While there are still imperfections in these tools, the laboratory has an essential role in improving detection of early kidney disease in at risk patients.
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W. Greg Miller, PhD, is a professor of pathology and director of the Clinical Chemistry Laboratory and Pathology Information Systems at Virginia Commonwealth University Medical Center, Richmond, Va. Email: firstname.lastname@example.org. He is chair of the Laboratory Working Group of NKDEP and President-Elect of AACC.