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Creatinine, Serum

Measurement of serum creatinine is the most widely used measure of renal function. The diagnostic usefulness of serum creatinine as an indicator of glomerular filtration rate (GFR) is based upon its constant production from muscle creatine and its relatively constant renal excretion rate. About 1 to 2% of the creatine in muscle is converted to creatinine daily (15 to 30 mg creatinine per kg body weight). The amount of creatinine formed is proportional to muscle mass. Creatinine is removed from plasma by glomerular filtration and then excreted in the urine without significant tubular reabsorption.

Serum creatinine is a crude indicator of renal disease. Moderate changes in GFR may not be detected by serum creatinine levels. A change in serum creatinine from 0.6 to1.2 mg/dL reflects a 50% decline in GFR, even though creatinine is still within the normal range. If a previous baseline creatinine is not available for comparison, a serum creatinine level of 1.2 mg/dL might be considered clinically insignificant.

Serum creatinine is decreased in individuals with small stature, cachexia, amputations, or muscle disease. Advanced liver disease causes low serum creatinine because of decreased hepatic conversion of creatine to creatinine, decreased dietary protein intake, muscle wasting, and increased renal tubular secretion of creatinine. Patients with liver disease may have a normal serum creatinine even though creatinine clearance is less than 60 mL/min. Elderly patients have decreased muscle mass and decreased creatinine production. Creatinine levels are reduced during pregnancy because of increased GFR.

Acute renal failure (ARF) is a sudden loss of renal function occurring over several hours to days. An increased serum creatinine concentration, accumulation of nitrogenous wastes and a decline in urinary output are the hallmarks of ARF. An increase of serum creatinine level by more than 0.5 mg/dL, a 50% increase of serum creatinine over a baseline level, or a >25% decline in creatinine clearance are accepted indicators of ARF.

Serum creatinine is increased when GFR is decreased. Causes of high creatinine levels include intrinsic renal disease, urinary tract obstruction, and reduced renal blood flow from congestive heart failure, shock or dehydration. In acute renal failure, serum creatinine will rise 1 to 2 mg/dL per day. If the rate of rise is less, residual renal function exists. If the rate of rise exceeds 3 mg/dL per day, skeletal muscle or increased catabolism is also present. Rhabdomyolysis can cause a sudden increase in serum creatinine. In patients with reduced renal blood, creatinine rises more slowly than BUN.

Creatinine clearance can be estimated from the serum creatinine using the following formulas (weight is expressed in kg, age in years, and serum creatinine in mg/dL):

Creatinine clearance (male) = weight x (140 - age)/72 x serum creatinine

Creatinine clearance (female) = weight x (140 - age) x 0.85/72 x serum creatinine

The ratio of BUN to creatinine can be used to determine the etiology of acute renal failure. Normally, the ratio is 10 to 1. The ratio usually exceeds 20 in prerenal failure due to decreased renal perfusion, such as occurs with hypertension, hemorrhage, or dehydration. Postrenal diseases, such as urinary tract obstruction, also increase the ratio between 10 and 20. It is normal (10 to12) in intrinsic renal disease because BUN and creatinine rise proportionately. The clinical usefulness of this ratio is limited by nonrenal factors that increase BUN such as; GI bleed, parenteral nutrition, and glucocorticoid therapy. GI bleed increases BUN more than creatinine because of increased amino acid absorption from digested blood and hypovolemia.

In 2008, the National Kidney Disease Education Program (NKDEP), in collaboration with the International Federation of Clinical Chemistry and Laboratory Medicine (IFCC) and the European Communities Confederation of Clinical Chemistry (EC4), launched the Creatinine Standardization Program to reduce inter-laboratory variation in creatinine assay calibration and provide more accurate estimates of glomerular filtration rate (eGFR).

Previous laboratory methods for serum creatinine had a small, but somewhat variable, positive bias due to interfering substances in normal serum. Consequently, better inter-laboratory standardization of serum creatinine was necessary to promote standardization of eGFR and its use in clinical guidelines for kidney disease.

To support this initiative, all manufacturers of instruments and reagents for measurement of serum or plasma creatinine began supplying reagents that have been re-calibrated to an isotope dilution mass spectrometry (IDMS) reference method in 2008. With the Beckman Coulter reagents, this change caused creatinine results less than 4.0 to decrease by 0.1–0.2 mg/dL, while creatinine results higher than 4.0 increased by 0.2-0.4 mg/dL. Creatinine clearance calculated from serum and urine measurements were not significantly affected by the recalibration of creatinine.

As a result of this change, the lower end of the reference range for serum creatinine performed on a Beckman Coulter Dxc 600 instrument became slightly lower.

Gender

Old Range

New Range

Male

0.9 – 1.3

0.6 – 1.3

Female

0.6 – 1.1

0.4 – 1.1

The original equation to estimate GFR was developed from the Modification of Diet in Renal Disease (MDRD) Study using the older creatinine methods with a slight positive bias. The new version of the MDRD equation has incorporated different coefficients for the IDMS calibrated serum creatinine method.

For most patients, an eGFR using the MDRD Study equation is more accurate than a creatinine clearance calculated from serum and urine measurements. Therefore, NKDEP recommends not performing a measured creatinine clearance procedure for adults except when the patient's basal creatinine production is very abnormal. This may be the case with patients of extreme body size or muscle mass (e.g., obese, severely malnourished, amputees, paraplegics or other muscle-wasting diseases) or with unusual dietary intake (e.g., vegetarian, creatinine supplements). Creatinine measurements at the low values usually observed in pediatric patients have greater variability than for values seen in adults. Estimates of kidney function based on these values will exhibit greater variability than seen in adults.

Reference range for urine creatinine is:

Male 0.8 – 2.0 g/24 hour

Female 0.6 – 1.8 g/24 hour

Specimen requirement is one SST tube of blood.

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