Creatinine (C₄H₇N₃O), a cyclic amide of creatine, is the terminal product of the catabolism of creatine, a substance present above all in the muscular apparatus, where it participates, in phosphorylated form (phosphocreatine), in the storage of energy. During the reaction that allows the conversion of phosphocreatine to creatine, small amounts of creatine (1–2%), through a nonenzymatic process, are irreversibly transformed into creatinine, which passes from the muscle into the circulation, where it is finally removed through renal filtration due to its low MW, equal to 113.12 Da. In addition, a portion of creatinine (7–10%) is also eliminated through the mechanism of tubular secretion. Creatinine is a nontoxic substance, does not bind to proteins, is present in all biological fluids (sweat, bile, cerebrospinal fluid, etc.), and is physiologically inert. The amount of creatinine formed daily in the body is proportional to the amount of creatine, which in turn is a function of total muscle mass. Its production varies with age and sex, but in a healthy adult, the rate of formation is relatively constant and little affected by dehydration or other morbid conditions, such as sepsis, heart failure, etc. In a healthy adult, creatinine levels, obtained using a traceable enzymatic method, range from 64 to 104 μmol/L (0.72 1.18 mg/dL) in men and from 49 to 90 μmol/L (0.5–1 mg/ dL) in women. In newborns, plasma creatinine concentration is elevated, primarily because of the proportion derived from maternal blood; it is also higher in low-birth-weight infants and is inversely related to gestational age and postnatal age. During the first week of life, there is a significant decrease in creatininemia due to the progressive elimination of the maternal rate.

To convert a creatinine value from SI units (μmol/L) to traditional units (mg/dL), multiply the value by 0.0113; conversely, to obtain a value in SI units from a result expressed in milligrams per deciliter, multiply the value by 88.4.

In renal disease, the progressive increase in creatinine is less than the reduction in filtrate because the creatinine formed is metabolized or excreted extrarenally (at normal plasma concentrations, the amount of creatinine eliminated by the intestine is negligible, but in uremia, it becomes significant). In addition, when a major reduction in renal function appears, the creatinine clearance/inulin clearance ratio increases in relation to an increase in tubular creatinine secretion. In the clinical laboratory, the determination of plasma creatinine is the most widely used renal function test due to the simplicity of execution, the availability of commercial methods adaptable to automation, low costs, and the possibility of performing the test in emergency. Less common, because it has been replaced by eGFR, is the performance of creatinine clearance, which requires collection of a timed urine sample (usually 24 h) to determine urinary creatinine in addition to plasma creatinine and to calculate the clearance value (mL/min) through diuresis (volume). The absolute and reference methods for creatinine determination are, the isotope dilution gas chromatography-mass spectrometry (IDGC-MS) and the high-performance liquid chromatography (HPLC), respectively. However, the most popular assay for the routine determination of creatinine is the colorimetric one, developed and described about 100 years ago by Jaffe. This method is based on the reaction of creatinine with alkaline picrate, resulting in the formation of an orange- red- colored complex. Even today, although with different and sometimes substantial modifications, the alkaline picrate is the most widely used method in clinical laboratories, although up to 20% of the color that develops from the colorimetric reaction may derive from substances other than creatinine, such as glucose, uric acid, bilirubin, pyruvic acid, and drugs. However, the need to express eGFR by equations using plasma creatinine concentration has pro moted the acceleration of method standardization in order to minimize bias between methods and, in turn, between laboratories. Hence, the 2002 K/DOQI guidelines called for the urgent need to obtain traceable analytical methods, commercially available. Based on this requirement, a primary reference material (primary calibrator) was prepared, which allowed in vitro diagnostic (IVDs) companies to make available traceable methods for plasma creatinine. Clinical laboratories are, therefore, recommended to perform creatinine determination by traceable methods; moreover, the scientific community suggested a switch from colorimetric to enzymatic methods, based on the evidence of the lower analytical variability of the latter, in terms of imprecision, bias, and specificity. Unfortunately, even enzymatic methods are not completely free from analytical pitfalls: for example, high concentrations of ammonium significantly decrease the precision of enzymatic methods using creatinine deaminase, whereas high concentrations of catecholamines can give rise to important underestimates of the results.

Ultimately, although the spread of traceable methods has greatly improved the standardization of plasma creatinine measurement, critical issues remain regarding both the low number of laboratories using enzymatic methods and the differences between results obtained by colorimetric and enzymatic methods.

The validity of creatinine as a test of renal function is based on the observation that, in healthy subjects under steady-state conditions, the daily amount of creatinine released from the muscle mass is constant and is consistently removed from the kidneys. Despite the widespread use of plasma creatinine determinations, several critical pathophysiological issues make interpretation of the results problematic and limit the clinical significance of these tests. Creatinine concentration depends on extrarenal factors, the most important is muscle mass. Therefore, creatinine varies according to sex, age, ethnicity, and regular exercise (athletes). Other factors are diet, extrarenal creatinine elimination, and the mechanism of tubular secretion, which increases inversely with GFR and can be significantly affected by certain drugs, including cimetidine, cyclosporine, and trimethoprim. The tubular secretion of creatinine causes the overestimation of creatinine clearance, compared to the true value of GFR, by 10–40% in healthy subjects and by more than 40% in renal failure, and is the main cause of the poor sensitivity of the test (high number of false negatives); indeed, the GFR can decrease by up to 50% before the circulating concentration of creatinine significantly increases, just because the mechanism of tubular secretion counter balances the decrease in glomerular filtration. Depending on the clinical condition of the subject, further factors can induce the overestimation or underestimation of eGFR based on plasma creatinine, such as unstable metabolic status. This means that eGFR cannot be used in several unstable metabolic conditions, for example during pregnancy or in the early infancy. Finally, non-standardized water intake and incorrect or insufficient collection of timed urine samples (24-h, night urine, etc.) are additional causes of inaccurate creatinine clearance. In particular, the partial or inaccurate collection of the urine specimen during the 24-hours originates significant variations in clearance results. For these reasons, the K/DOQI guidelines advise against the determination of creatinine clearance and recommend the use of equations that employ plasma creatinine and other parameters in their calculation.

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مواضيع ذات صلة

Estimation of the Glomerular Filtration Rate by Equations

Urea test for Diagnosis of Kidney Diseases

Standard Urine Test for Diagnosis of Kidney Diseases

Diagnosis of Ventilator-Associated Pneumonia

protein C, protein S

prostate-specific antigen (PSA), prostate cancer gene 3 (PCA3), MI-prostate score (MiPS)

prolactin levels (PRLs)

Enzyme-Linked Immunosorbent Assay (ELISA)

Agglutination Reaction

Precipitation Reaction

Heparins and Fondaparinux

Activated Partial Thromboplastin Time (aPTT)