Creatinine Clearance

The accurate measurement of renal function is crucial for the routine care of patients. 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. 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). 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. The GFR is the measurement of volume filtered through the glomerular capillaries and into the Bowman's capsule per unit of time. 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. The clearance rate for a given substance equals the GFR when it is neither secreted nor reabsorbed by the kidneys. 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 aschromium-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. 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. Creatinine is not eliminated extra-renally, and under steady-state conditions, urinary excretion equals creatine production, regardless of the serum creatinine concentration. 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%. Despite the marginal error, it is an accepted method for measuring GFR due to the ease of measurement of CrCl. 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. 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. 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. 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/1.73m due to body surface area. 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. 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. 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. The CKD-EPI formulas have undergone several iterations. 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. 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). 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 m. 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.