Introduction

The accurate measurement of renal function is crucial for the routine care of patients.[1] Determining renal function status can also predict kidney disease progression and prevent toxic drug levels in the body. The glomerular filtration rate (GFR) describes the flow rate of filtered fluid through the kidneys. The gold standard measurement of GFR involves the injection of inulin and the subsequent measurement of its clearance by the kidneys.[2] However, the use of inulin is invasive, time-consuming, and expensive. Alternatively, the biochemical marker creatinine found in serum and urine is commonly used to estimate GFR (eGFR).[3] Creatinine clearance (CrCl) is the volume of blood plasma cleared of creatinine per unit time and is a rapid and cost-effective method for assessing renal function. CrCl and GFR can be measured through urine creatinine, serum creatinine, and urine volume over a specified period.

Glomerular Filtration Rate

The GFR is the measurement of volume filtered through the glomerular capillaries and into the Bowman's capsule per unit of time.[4] The filtration in the kidney depends on the difference in high and low blood pressure created by the afferent (input) and efferent (output) arterioles, respectively.[5] The clearance rate for a given substance equals the GFR when it is neither secreted nor reabsorbed by the kidneys.[2] For such a given substance, the urine concentration multiplied by the urine flow equals the mass of the substance excreted during urine collection.

The characteristics of an ideal marker of GFR are as follows:

• It should appear endogenously in the plasma at a constant rate
• It should be freely filtered at the glomerulus
• It should be neither reabsorbed nor secreted by the renal tubule
• It should not undergo extrarenal elimination

As no such endogenous marker currently exists, exogenous markers of GFR are used. The reference method for measuring GFR involves inulin, a polysaccharide. This process involves the infusion of inulin and then measuring blood levels after a specified period to determine the rate of clearance of inulin. Other exogenous markers used are radioisotopes, such as chromium-51 ethylenediaminetetraacetic acid (51 Cr-EDTA) and technetium-99-labeled diethylenetriaminepentaacetic acid (99 Tc-DTPA). Currently, the most promising exogenous marker is the contrast agent iohexol, which is not radioactive, especially in children.

This mass divided by the plasma concentration is equivalent to the plasma volume per minute from which the mass was originally filtered. Below is the equation used to determine GFR, recorded in volume per time (mL/min):

GFR = [UrineS (mg/mL) × urine flow (mL/min)] / [PlasmaS (mg/mL)], where S is a substance that is freely filtered at the glomerulus, UrineS is the urine concentration and PlasmaS is the plasma concentration.

GFR Approximation Using Creatinine Clearance

Creatinine is a breakdown product of dietary meat and creatine phosphate found in skeletal muscle. The production of creatinine in the body is dependent on muscle mass.[6] Creatinine is not eliminated extra-renally, and under steady-state conditions, urinary excretion equals creatine production, regardless of the serum creatinine concentration.[7] The CrCl rate approximates the calculation of GFR as the glomerulus freely filters creatinine. However, it is also secreted by the peritubular capillaries, causing CrCl to overestimate the GFR by approximately 10% to 20%.[4] Despite the marginal error, it is an accepted method for measuring GFR due to the ease of measurement of CrCl.

Formulas Used in the Prediction of GFR

Formulas derived using variables that influence GFR can provide varying degrees of accuracy in estimating GFR. Of note, all of the following formulas are based on the assumption that creatinine levels are stable. If the creatinine is rapidly changing, it is challenging to estimate the GFR. If precise measurements are required, a calculated CrCl should be considered.

The Mayo Quadratic formula, an older method, was developed to more accurately estimate GFR in patients with preserved renal function using age, sex, and creatinine.[8]

The Cockcroft-Gault (C-G) formula uses a patient's weight (kg) and gender to predict CrCl (mL/min) previously in common use. The resulting CrCl is multiplied by 0.85 if the patient is female to correct for the lower CrCl in females.[9] The C-G formula is dependent on age as its main predictor for CrCl. Below is the formula:

CrCl = [(140 – Age) × Mass (kg) × 0.85 if female] / 72 × [Serum Creatinine (mg/dL)]

The previously widely used Modification of Diet in Renal Disease Study Group (MDRD) equation uses 4 variables, including serum creatinine, age, ethnicity, and albumin levels.[10] An advanced version of MDRD includes blood urea nitrogen and serum albumin in its formula. However, as the MDRD formula does not adjust for body size, results of eGFR are given in units of mL/min/1.73m² due to body surface area.[11] Both the MDRD and C-G formulas have mainly been replaced by the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) guidelines.

The CKD-EPI group has developed complex equations incorporating serum creatinine and cystatin C, using a population comprising healthy individuals and CKD patients. Due to their reduced bias, these equations are preferred when estimating GFRs in multi-ethnic populations.[12][13][14] A recent review by Inker et al presented new equations using cystatin C and creatinine without race that show an improved correlation between measured and calculated GFR. These complex equations can be found in this study and supplementary materials.[15]

Although some advocate for using race as a qualitative factor to estimate muscle mass, the majority of nephrology societies support removing race from GFR calculations. Many guidelines suggest using cystatin C as a marker instead of creatinine, as cystatin C is not dependent on muscle mass. In addition, further research is required to identify additional compounds consistent across age, sex, and race that can be used to estimate GFR.[16][17][18][19]

The CKD-EPI formulas have undergone several iterations.[20] Although some experts may prefer eGFR equations using cystatin or both cystatin and creatinine, in practice, cystatin is not widely measured. Therefore, the National Kidney Foundation (NKF) and the American Society of Nephrology (ASN) Task Force recommend using the 2021 CKD-EPI creatinine-based equation, which does not include race.[17] This formula has been adopted by most significant laboratories nationwide.

The estimation of GFR in children often uses the Chronic Kidney Disease in Children Study (CKiD or Schwartz bedside) equation, which uses serum creatinine (mg/dL) and the child's height (cm).[1] Another formula, the Schwartz-Lyon equation, has also been used for individuals younger than 18 and is believed to be more accurate compared to CKD-EPI when measured GFR is lower than 75 mL/min/1.72 m².[21][22] The CKD-EPI equation cannot be used in young children, and it is believed to overestimate GFR in young adults aged 18 to 39. Modifications to the CKD-EPI formula using sex-specific creatinine growth curves for children and adults aged 18 to 40 allow a well-validated improvement of eGFR; this formula is also referred to as CKD-EPI40.[1][21]

Etiology and Epidemiology

Serum and urine samples are required for CrCl. The serum sample must be collected within 24 hours of urine collection.

Blood Specimen

A blood sample of 1 mL (with a minimum of 0.5 mL) should be collected in a labeled tube and preferably stored at refrigerated or frozen temperatures.

Urine Specimen

A 24-hour urine sample is collected from the patient to measure CrCl. A plastic collection container is used to collect urine. The collection begins with patients completely emptying their bladders. Initially, the patient urinates into the toilet and flushes. The date and time are recorded at the beginning of the collection. For the next 24 hours, the patient collects urine and stores it in a container at room temperature. The urine collected for 24 hours is sent to the laboratory for analysis. The collection should end with the patient urinating the final sample exactly 24 hours after the collection starts. The patient should drink at least 8 cups of liquid on the day of urine collection.

Specimen Requirements and Procedure

Calculated CrCl is typically used when a more precise calculation of GFR is required compared to estimation formulas. This method is particularly useful when serum creatinine levels are higher or lower compared to what is expected for a given clinical context, such as in a healthy patient with elevated creatinine levels, or when creatinine levels are fluctuating rapidly.

Diagnostic Tests

Elevated serum creatinine levels and a decreased CrCl rate typically indicate abnormal renal function. In such cases, a comprehensive evaluation is recommended, including a detailed history, a thorough physical examination, renal ultrasound, and urinalysis.[23] Relevant patient history includes medications, history of edema, gross hematuria, and polyuria.[24] Physical examination for signs of vasculitis, systemic lupus erythematous, endocarditis, and hypertension can help narrow the diagnosis. A renal ultrasound may be performed to evaluate the kidney size, echogenicity, and possible hydronephrosis. Enlarged kidneys typically indicate diabetic nephropathy, focal segmental glomerulosclerosis, or multiple myeloma. A urinalysis positive for proteinuria or abnormal urinary sediment typically indicates the presence of glomerular disease.[24]

Testing Procedures

The normal range for CrCl is age-dependent, but for younger, healthy adults, it is about 100 to 120 mL/min in males and 90 to 110 mL/min in females.[25][26] Due to age-related decreases, a GFR of 68 mL/min could be normal in an otherwise healthy individual aged 65.[26] Serum creatinine level for men with normal kidney function is approximately 0.6 to 1.2 mg/dL and between 0.5 and 1.1 mg/dL for women.[25] Creatine levels above the normal range generally correlate with a reduction of GFR and indicate renal dysfunction.

The following are approximate numbers:

• Creatinine 1 mg/dL is the baseline for a given patient with normal GFR
• Creatinine 2 mg/dL is about a 50% reduction in GFR
• Creatinine 4 mg/dL is about a 70% to 85% reduction in GFR
• Creatinine 8 mg/dL is about a 90% to 95% reduction in GFR

Alteration of serum creatinine values can occur as its generation is influenced by muscle function, activity, diet, and health status of the patient.[27] Increased tubular secretion of creatinine in certain patients with dysfunctional kidneys could provide a false negative value.[28] Decreased serum creatinine levels are also present in patients with muscular dystrophy, paralysis, anemia, leukemia, and hyperthyroidism. Meanwhile, increased values are present in patients with glomerulonephritis, shock, congestive heart failure, polycystic kidney disease, acute tubular necrosis, and dehydration.[27]

Interfering Factors

Results from a 24-hour urine collection depend on accurate timing and thorough completion. Improper urine sample collection can lead to an underestimation of creatinine excretion, which results in incorrect GFR calculations. A significant limitation of CrCl measurement is an age-related increase in the tubular secretion of creatinine, resulting in an overestimation of GFR.[29]

Patients with a specific dietary intake, such as a vegetarian diet or creatine supplements, or decreased muscle mass, such as malnutrition or amputation, can have creatinine levels that differ from the general population.[30] Creatinine supplements, muscle-building compounds, and anabolic steroids, which are commonly used, can lead to higher serum creatinine levels that may not accurately reflect GFR. In such cases, measuring cystatin C for GFR calculation is often preferred.[31][32]

Drugs such as trimethoprim–sulfamethoxazole can also increase serum creatinine levels by approximately 15% to 22%. The trimethoprim component is believed to inhibit tubular secretion of creatinine, and the increase in creatinine levels typically reverses upon discontinuation of the drug.[33][34]

Results, Reporting, and Critical Findings

Determination of CrCl and serum creatine levels is essential when renal dysfunction is suspected. Acute kidney injury is a common complication that results in increased serum creatine levels.[35] A sudden decrease in GFR and oliguria are signs of acute kidney injury. This type of injury is common in 20% of hospitalized patients and can result in volume overload, electrolyte imbalances, and drug toxicity.[35] The primary treatment for patients with acute kidney injury is generally hemodynamic support.

Persistently elevated levels of serum creatinine and a significantly reduced GFR lasting for longer than 3 months are indicative of chronic kidney disease. CKD occurs through multiple pathological mechanisms and affects several compartments of the kidney.[36] The loss of microvasculature and increased fibrosis lead to hypoxia within the kidney, making patients more susceptible to acute kidney injuries with poor healing. The continued loss of tubular cells becomes replaced with collagen scars and macrophage infiltration. These chronic changes are associated with further loss of renal function and progression toward end-stage renal failure.[37]

Clinical Significance

Routine blood tests for serum creatinine levels, among other substances, can prevent future complications of renal disease. Patients with a chronic diagnosis of uncontrolled diabetes and hypertension are particularly at risk for kidney disease.

Quality Control and Lab Safety

The results of CrCl and its estimation of GFR allow for the assessment of the excretory function of the renal system. The CrCl test is used to monitor the progression of renal disease.[3] When available, CrCl can be correlated with other compounds used to measure GFR, such as inulin, cystatin, or iohexol.

Enhancing Healthcare Team Outcomes

A strategic approach to measuring CrCl is crucial, involving evidence-based strategies to optimize accurate measurement of GFR. Traditionally, creatinine has been used as a surrogate for the more difficult compounds to measure outside of a laboratory setting—namely inulin (the gold standard measurement), cystatin, and iohexol. Many different formulas have been proposed to estimate GFR using both creatinine and cystatin. Due to practical concerns, the most commonly used equation for eGFR is the 2021 CKD-EPI formula, which does not include race as a variable. Children younger than 18 and adults younger than 40 may also require adjustments to the CKD-EPI formula for more accurate GFR estimations.

Effective care coordination is pivotal in ensuring that CrCl is accurate, minimizing errors, and enhancing patient safety. Nursing staff and technicians are crucial for obtaining accurate timed urine collections by adhering to strict measurement standards. By embracing these principles of skill, strategy, ethics, responsibilities, interprofessional communication, and care coordination, healthcare professionals can deliver patient-centered care, ultimately improving patient outcomes and enhancing team performance when measuring CrCl.

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Disclosure: Hassan Shahbaz declares no relevant financial relationships with ineligible companies.

Disclosure: Preeti Rout declares no relevant financial relationships with ineligible companies.

Disclosure: Mohit Gupta declares no relevant financial relationships with ineligible companies.