The serum creatinine concentration is widely interpreted as a measure of the glomerular filtration rate (GFR) and is used as an index of renal function in clinical practice. Glomerular filtration of creatinine, however, is only one of the variables that determines its concentration in serum. Alterations in renal handling and metabolism of creatinine and methodological interferences in its measurement may have a profound impact on the serum concentration of creatinine. We review the fundamental principles of physiology, metabolism, and analytical chemistry that are necessary to correctly interpret the serum creatinine concentration. These principles are then applied to important clinical circumstances, including aging, pregnancy, diabetes mellitus, drug administration, and acute and chronic renal failure. Despite numerous limitations, serum creatinine remains a useful clinical tool, but more accurate measures of renal function are frequently necessary.

Serum creatinine as an index of renal function: new insights into old concepts.

Background: Reliable serum creatinine measurements in glomerular filtration rate (GFR) estimation are critical to ongoing global public health efforts to increase the diagnosis and treatment of chronic kidney disease (CKD). We present an overview of the commonly used methods for the determination of serum creatinine, method limitations, and method performance in conjunction with the development of analytical performance criteria. Available resources for standardization of serum creatinine measurement are discussed, and recommendations for measurement improvement are given.

Methods: The National Kidney Disease Education Program (NKDEP) Laboratory Working Group reviewed problems related to serum creatinine measurement for estimating GFR and prepared recommendations to standardize and improve creatinine measurement.

Results: The NKDEP Laboratory Working Group, in collaboration with international professional organizations, has developed a plan that enables standardization and improved accuracy (trueness) of serum creatinine measurements in clinical laboratories worldwide that includes the use of the estimating equation for GFR based on serum creatinine concentration that was developed from the Modification of Diet in Renal Disease (MDRD) study.

Conclusions: The current variability in serum creatinine measurements renders all estimating equations for GFR, including the MDRD Study equation, less accurate in the normal and slightly increased range of serum creatinine concentrations [<133 μmol/L (1.5 mg/dL)], which is the relevant range for detecting CKD [<60 mL · min−1 · (1.73 m2)−1]. Many automated routine methods for serum creatinine measurement meet or exceed the required precision; therefore, reduction of analytical bias in creatinine assays is needed. Standardization of calibration does not correct for analytical interferences (nonspecificity bias). The bias and nonspecificity problems associated with some of the routine methods must be addressed.

/pdf/recommendations-for-improving-serum-creatinine-measurement-a-12te8ntjth.pdf

Recommendations for Improving Serum Creatinine Measurement: A Report from the Laboratory Working Group of the National Kidney Disease Education Program

PHYSIOLOGY Creatine is synthesised by the body in a two-step process (Fig. 1) involving the initial synthesis of guanidinoacetate, which takes place in the kidneys, small intestinal mucosa, pancreas, and probably the liver. The reaction between glycine and arginine is catalysed by a transamidase, which is subject to feedback inhibition by increased creatine levels. Guanidinoacetate is transported to the liver where it is methylated to creatine, which then enters the blood to be widely distributed, chiefly to muscle cells, in which it is converted to creatine phosphate-a source of high energy phosphate bonds for the immediate reformation of ATP during muscular contraction. Creatinine is formed by a spontaneous and irreversible conversion from creatine and creatine phosphate. Formation of creatinine is reasonably constant, and about 2% of whole body creatine is so transformed every 24 h. Consequently, creatinine formation also has a direct relationship to total muscle mass and roughly to the body weight. Creatinine production rate therefore remains approximately the same from day to day unless the muscle mass changes. It is not altered significantly by illness, sepsis, trauma or fever, nor by the state of hydration; however, increased protein intake can result in increases in creatinine production of the order of 10%.

https://journals.sagepub.com/doi/pdf/10.1177/000456328602300101

Analytical Reviews in Clinical Biochemistry: The Estimation of Creatinine:

Measurement of creatinine has many applications. We review the determination of urinary creatinine as a valid index of completeness of 24-h urine collection, the clinical utility of the determination of creatinine clearance ratios, and measurement of the ratio of the clearance of specific analytes, such as amylase, to the ratio of clearance of creatinine. The chemistry and variables that affect the Jaffe reaction are reviewed, and attempts at improvement of specificity are discussed. We also review and assess techniques other than the Jaffe reaction for measurement of creatinine.

Creatinine: a review.

We describe a new colorimetric method for measuring creatinine in serum and urine. Creatinine hydrolysis is catalyzed by creatinine amidohydrolase, and the creatine so produced is assayed in reactions catalyzed sequentially by creatine amidinohydrolase and sarcosine oxidase in a system that generates hydrogen peroxide. The hydrogen peroxide is measured at 510 nm in a reaction catalyzed by horseradish peroxidase, with 3,5-dichloro-2-hydroxybenzenesulfonic acid/4-aminophenazone as the chromogen. This series of reactions is complete in 30 min at room temperature. A blank sample measurement corrects for endogenous creatine. The standard curve is linear for creatinine concentrations as great as 2.21 mmol/L. Analytical recovery of creatinine in human sera and urine averaged 99.8%. Within-run and between-run precision studies gave CVs of less than or equal to 3.3 and less than or equal to 4.3% for a serum with a creatinine concentration of 69 mumol/L. Results by this method agree well (r greater than 0.99) with those by both the enzymic ultraviolet method of Wahlefeld and the fuller's earth/Jaffe method.

Enzymic creatinine assay: a new colorimetric method based on hydrogen peroxide measurement.

Towards a definitive assay of creatinine in serum and in urine: separation by high-performance liquid chromatography

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Towards a definitive assay of creatinine in serum and in urine: separation by high-performance liquid chromatography