Introduction

The measurement of accurate renal function is vital for the routine care of patients.[1] Determining the renal function status can predict kidney disease progression and prevent toxic drug levels in the body.[2] 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 its clearance by the kidneys.[2] However, the use of inulin is invasive, time-consuming, and an expensive procedure. Alternatively, the biochemical marker creatinine found in serum and urine is commonly used in the estimation of GFR.[3] Creatinine clearance (CrCl) is the volume of blood plasma cleared of creatinine per unit time. It is a rapid and cost-effective method for the measurement of renal function. Both CrCl and GFR can be measured using the comparative values of creatinine in blood and urine.

Glomerular Filtration Rate

The GFR in 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 is dependent 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 the time of urine collection. This mass divided by the plasma concentration is equivalent to the volume of plasma from which the mass was originally filtered. Below is the equation used to determine GFR, typically recorded in volume per time (e.g., mL/min):

GFR = [UrineX (mg/mL)] * urine flow (mL/min)/ [PlasmaX (mg/mL)], where X is a substance that is completely excreted.

GFR approximation using Creatinine Clearance

Creatinine is a breakdown product of dietary meat and creatine phosphate found in skeletal muscle. Its production in the body is dependent on muscle mass.[6] The CrCl rate approximates the calculation of GFR since 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.

Cockcroft-Gault formula: Estimated creatinine clearance rate (eCCR)

Creatinine clearance can be estimated using serum creatinine levels. The Cockcroft-Gault (C-G) formula uses a patient’s weight (kg) and gender to predict CrCl (mg/dL).[7] The resulting CrCl is multiplied by 0.85 if the patient is female to correct for the lower CrCl in females.[7] The C-G formula is dependent on age as its main predictor for CrCl. Below is the formula:

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

Formulas used in the prediction of GFR

Formulas derived using variables that influence GFR can provide varying degrees of accuracy in estimating GFR. The widely used Modification of Diet in Renal Disease Study Group (MDRD) employs four variables, including serum creatinine, age, ethnicity, and albumin levels.[8] A further complex version of MDRD includes blood urea nitrogen and serum albumin in its formula. However, since MDRD formula does not adjust for body size, results of eGFR are given in units of ml^-1 min^-1 1.73m^-2, 1.73m^2 due to body surface area in an adult with a mass of 63kg and height of 1.7m.[9]

Other formulas used for GFR calculations and their employed variables to estimate GFR include Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) formulas.[10] The CKD-EPI formulas are in categories based on patients that are black females, black males, non-black females, and non-black males. The Mayo Quadratic formula was developed to better estimate GFR in patients that have preserved renal function.[11] Estimation of GFR in children uses the Schwartz formula, which employs serum creatinine (mg/dL) and the child’s height (cm).[1]

In current clinical practice, the use of creatinine derived from the KDIGO clinical practice guidelines recommend CKD-EPI formula for the estimation of GFR.[12]

Etiology and Epidemiology

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

Blood specimen

A blood sample of 1 mL (minimum 0.5 mL) in a labeled tube, preferably stored at refrigerated or frozen temperature.

Urine specimen

A 24-hour urine sample is collected from the patient to measure creatinine clearance.  A plastic collection container is used to collect urine. The collection starts with an empty bladder. At the start, the patient urinates into the toilet and flushes. The date and time get recorded at the start of the collection. For the next 24 hours, the patient will collect urine and store it in a container at room temperature. The total urine collected for 24 hours gets sent to the laboratory for analysis. The patient is required to drink at least 8 cups of liquid on the day of urine collection.

Specimen Requirements and Procedure

A physician may require a creatinine clearance test from patients when routine blood creatinine levels or the estimated GFR are not within normal ranges. Patients with signs and symptoms of deteriorating kidney function are candidates for the CrCl test.[13] Patients presenting with an obstruction within the kidney or dysfunction from another disease, such as congestive heart failure, may be required to perform a CrCl test.

Diagnostic Tests

Elevated serum creatinine levels and a decreased CrCl rate are usually indications of abnormal renal function. For these patients, it is recommended to perform a thorough history, physical exam, renal ultrasound, and urinalysis.[14] Relevant patient history includes medications, history of edema, gross hematuria, diabetes, and polyuria.[13] Physical examination for signs of vasculitis, lupus erythematous, endocarditis, and hypertension can help narrow the diagnosis — renal ultrasound assesses the kidney size, echogenicity, and possible hydronephrosis. Enlarged kidneys usually indicate diabetic nephropathy, focal segmental glomerulosclerosis, or multiple myeloma. A urinalysis positive for proteinuria or urinary sediment indicates the presence of glomerular disease.[13]

Testing Procedures

The normal range of CrCl is 110 to 150mL/min in males and 100 to 130mL/min in females.[15] Serum creatinine level for men with normal kidney function is approximately 0.6 to 1.2mg/dL and between 0.5 to 1.1 mg/dL for women.[15] Creatine levels above the normal range correlate with a reduction of GFR and indicate renal dysfunction.

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

Alteration of serum creatinine values can occur as its generation is subject to influence by muscle function, activity, diet, and health status of the patient.[16] Increased tubular secretion of creatinine in certain patients with dysfunctional kidneys could provide a false negative value.[17] 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.[16]

Interfering Factors

Results obtained from a 24-hour urine collection depend on accurate timing and completion. Improper urine sample collection leads to an underestimation of creatinine excretion; therefore, incorrect GFR. A significant limitation of CrCl measurement is an age-related increase in the tubular secretion of creatinine that results in an overestimation of GFR[18]

Creatinine clearance is affected by sex and race. Women have less muscle mass and a lower rate of creatinine production in comparison to men. Latinos produce lower clearance values, while blacks produce higher values, indicating greater muscle mass in blacks.[19] Patients with a unique dietary intake (e.g., vegetarian, creatine supplements) or have muscle wasting (e.g., malnutrition, amputation) can produce levels of creatinine that deviate from the general population. Drugs such as trimethoprim-sulfamethoxazole can increase serum creatinine levels by approximately 0.4 to 0.5 mg/dL[20]

Results, Reporting, and Critical Findings

It is essential to determine CrCl and serum creatine levels when there is suspicion of renal dysfunction. A common complication that results in increased serum creatine levels is acute kidney injury (AKI).[21] A sudden decrease in GFR and oliguria are signs of AKI. This type of injury is common in 20% of hospitalized patients and leads to volume overload, electrolyte imbalances, and drug toxicity.[21] Management for patients with AKI is to perverse kidney function and prevent further complications.

Persistently elevated levels of serum creatinine and severely reduced GFR are indicative of chronic kidney disease. CKD occurs through multiple pathologic mechanisms of injury and affects several compartments of the kidney.[22] The loss of microvasculature and increased fibrosis leads to hypoxia within the kidney, making patients more substile to acute kidney injuries with poor healing.  The continued loss of tubular cells becomes replaced with collagen scars and macrophage infiltration.[23] These chronic changes are associated with further loss of renal function and progression toward end-stage renal failure.[23]

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 especially vulnerable to 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] Staging of chronic kidney disease and nephropathies can be quantified using GFR. Drug dose adjustment may be necessary according to the patient's GFR and kidney functional status. The non-invasive technique to measure GFR via CrCl offers greater patient compliance.