The Glomerular Filtration Rate (GFR) measures how effectively the kidneys filter waste from the blood. Directly measuring GFR is complex, requiring the clearance of an injected substance, which is impractical for routine clinical use. Therefore, medical professionals rely on the estimated GFR (eGFR), a value calculated from a standard blood test. While convenient and widely accessible, the eGFR is fundamentally an estimate and can be inaccurate. A flawed eGFR can lead to misdiagnosis or a dangerous delay in treatment, making it important to understand the factors that compromise its reliability.
The Foundation of eGFR Calculation
The eGFR calculation relies primarily on measuring serum creatinine, a metabolic waste product. Creatinine is produced constantly from the breakdown of creatine in muscle tissue and is filtered almost entirely by the kidneys’ glomeruli. A rising level of creatinine in the blood thus suggests a decline in kidney filtration function.
The eGFR formula combines the creatinine value with demographic variables, typically age and sex, to standardize the creatinine level against expected muscle mass and production. Historically, formulas like the Modification of Diet in Renal Disease (MDRD) and the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) equations were used. Recent formulas, such as the CKD-EPI 2021 equation, have been updated to remove the race variable to ensure greater equity and accuracy across all populations.
Factors That Falsely Elevate or Lower Creatinine
The eGFR’s reliance on serum creatinine is its inherent weakness, as creatinine levels are easily influenced by factors unrelated to true kidney function. Variations in muscle mass significantly skew the result. High muscle bulk, such as in bodybuilders, produces more creatinine, making the eGFR appear falsely low.
Conversely, low muscle mass, common in individuals with amputations, severe malnutrition, or sarcopenia, produces less creatinine. This can cause the eGFR to be falsely high and potentially mask underlying kidney impairment. Dietary habits also impact the input value.
Consumption of cooked meat contains creatinine that can temporarily elevate serum levels for several hours. Similarly, creatine supplements directly increase blood creatinine, leading to a calculated eGFR that suggests worse kidney function than is actually present. Specific medications interfere with the test by blocking the kidney tubules from secreting creatinine (e.g., the antibiotic trimethoprim or the ulcer drug cimetidine). This blockage causes creatinine to build up in the blood, resulting in an artificially low eGFR despite stable kidney function.
Assay interference is another source of error, where circulating substances mimic creatinine in the laboratory test. In older testing methods, high levels of glucose or ketone bodies (often seen in uncontrolled diabetes) can falsely elevate the creatinine measurement. Other substances that interact with the chemical assay include bilirubin (elevated in certain liver conditions) or some antibiotics like cefoxitin, leading to inaccurate readings.
Clinical Scenarios Where eGFR Reliability Decreases
Certain clinical states violate the eGFR formula’s fundamental assumption that kidney function is stable. In Acute Kidney Injury (AKI), where function declines rapidly, the eGFR is unreliable because serum creatinine levels lag behind the actual change in filtration rate. The formula cannot accurately reflect this rapidly changing state, potentially delaying the recognition of severe kidney damage.
Patients with advanced liver disease, particularly cirrhosis, often see their eGFR significantly overestimate true kidney function. The impaired liver synthesizes creatine inefficiently, resulting in lower creatinine production and a lower serum creatinine level. This low input value suggests better function than the patient possesses. Muscle wasting common in advanced cirrhosis further contributes to low creatinine production, compounding the problem and masking serious renal impairment like hepatorenal syndrome.
The standard eGFR equation also loses accuracy at the extremes of the filtration rate, performing less reliably when the true GFR is above 60 mL/min/1.73 m². Since the formula was developed primarily to identify chronic kidney disease, its precision is highest in the range of moderate to severe impairment. For patients with near-normal or high-normal GFR, the estimate is less precise. Conditions involving significant fluid shifts, such as severe edema or ascites, can also dilute the concentration of creatinine in the blood, contributing to an inaccurate eGFR reading.
Confirmatory Testing for True GFR Measurement
When a patient’s eGFR is questionable due to conflicting clinical signs or known interfering factors, medical professionals use more accurate confirmatory tests. A primary alternative is the measurement of Cystatin C, a protein produced by all nucleated cells and filtered by the kidneys.
Unlike creatinine, Cystatin C levels are largely independent of muscle mass and diet, making it a more reliable marker for populations with extremes of body composition or malnutrition. Calculating eGFR using Cystatin C (eGFRcys), or combining it with creatinine (eGFRcr-cys), provides a more accurate estimate, especially when the creatinine-based eGFR is in the mildly impaired range (45–59 mL/min/1.73 m²).
If greater precision is required—for critical decisions like determining safe drug dosages or evaluating a kidney donor—a measured GFR (mGFR) study is performed. This gold standard involves injecting an exogenous filtration marker, such as iohexol or iothalamate, and then measuring its clearance from the blood over several hours. These direct clearance studies bypass estimation, offering the most definitive assessment of the kidney’s actual filtration capacity.