Creatinine

Creatinine (κρέας, "flesh") is a breakdown product of creatine phosphate in muscle, and is usually produced at a fairly constant rate by the body (depending on muscle mass).

Biological relevance
Serum creatinine (a blood measurement) is an important indicator of renal health because it is an easily measured byproduct of muscle metabolism that is excreted unchanged by the kidneys. Creatinine itself is produced via a biological system involving creatine, phosphocreatine (also known as creatine phosphate), and adenosine triphosphate (ATP, the body's immediate energy supply).

Creatine is synthesized primarily in the liver from the methylation of glycocyamine (guanidino acetate, synthesized in the kidney from the amino acids arginine and glycine) by S-adenosyl methionine. It is then transported through blood to the other organs, muscle, and brain, where, through phosphorylation, it becomes the high-energy compound phosphocreatine. During the reaction, creatine and phosphocreatine are catalyzed by creatine kinase, and a spontaneous conversion to creatinine may occur.

Creatinine is removed from the blood chiefly by the kidneys, primarily by glomerular filtration, but also by proximal tubular secretion. Little or no tubular reabsorption of creatinine occurs. If the filtration in the kidney is deficient, creatinine blood levels rise. Therefore, creatinine levels in blood and urine may be used to calculate the creatinine clearance (CrCl), which correlates with the glomerular filtration rate (GFR). Blood creatinine levels may also be used alone to calculate the estimated GFR (eGFR).

The GFR is clinically important because it is a measurement of renal function. However, in cases of severe renal dysfunction, the CrCl rate will overestimate the GFR because hypersecretion of creatinine by the proximal tubules will account for a larger fraction of the total creatinine cleared. Ketoacids, cimetidine, and trimethoprim reduce creatinine tubular secretion and, therefore, increase the accuracy of the GFR estimate, in particular in severe renal dysfunction. (In the absence of secretion, creatinine behaves like inulin.)

An alternate estimation of renal function can be made when interpreting the blood (plasma) concentration of creatinine along with that of urea. BUN-to-creatinine ratio (the ratio of blood urea nitrogen to creatinine) can indicate other problems besides those intrinsic to the kidney; for example, a urea level raised out of proportion to the creatinine may indicate a prerenal problem such as volume depletion.

Each day, 1-2% of muscle creatine is converted to creatinine. Men tend to have higher levels of creatinine than women because, in general, they have a greater mass of skeletal muscle. Increased dietary intake of creatine or eating a lot of meat can increase daily creatinine excretion.

Serum creatinine
Measuring serum creatinine is a simple test, and it is the most commonly used indicator of renal function.

A rise in blood creatinine level is observed only with marked damage to functioning nephrons. Therefore, this test is unsuitable for detecting early-stage kidney disease. A better estimation of kidney function is given by calculating the estimated glomerular filtration rate (eGFR). eGFR can be accurately calculated using serum creatinine concentration and some or all of the following variables: sex, age, weight, and race, as suggested by the American Diabetes Association without a 24-hour urine collection. Many laboratories will automatically calculate eGFR when a creatinine test is requested.

A concern as of late 2010 relates to the adoption of a new analytical methodology, and a possible impact this may have in clinical medicine. Most clinical laboratories now align their creatinine measurements against a new standardized isotope dilution mass spectrometry (IDMS) method to measure serum creatinine. IDMS appears to give lower values than older methods when the serum creatinine values are relatively low, for example 0.7 mg/dl. The IDMS method would result in a comparative overestimation of the corresponding calculated GFR in some patients with normal renal function. A few medicines are dosed even in normal renal function on that derived GFR. The dose, unless further modified, could now be higher than desired, potentially causing increased drug-related toxicity. To counter the effect of changing to IDMS, new FDA guidelines have suggested limiting doses to specified maxima with carboplatin, a chemotherapy drug.

In a recent Japanese study, a lower serum creatinine level was found to be associated with an increased risk for the development of type 2 diabetes in Japanese men.

Urine creatinine
Creatinine concentration is also checked during standard urine drug tests. Normal creatinine levels indicate the test sample is undiluted, whereas low amounts of creatinine in the urine indicate either a manipulated test or low individual baseline creatinine levels. Test samples considered manipulated due to low creatinine are not tested, and the test is sometimes considered failed.

Diluted samples may not always be due to a conscious effort of subversion, and diluted samples cannot be proved to be intentional, but are only assumed to be. Random urine creatinine levels have no standard reference ranges. They are usually used with other tests to reference levels of other substances measured in the urine. Diuretics, such as coffee and tea, cause more frequent urination, thus potently decreasing creatinine levels. A decrease in muscle mass will also cause a lower reading of creatinine, as will pregnancy.

Interpretation
In the United States, creatinine is typically reported in mg/dl, whereas in Canada, Australia, and a few European countries, μmol/litre may be used. One mg/dl of creatinine is 88.4 μmol/l.

The typical human reference ranges for serum creatinine are 0.5 to 1.0 mg/dl (about 45-90 μmol/l) for women and 0.7 to 1.2 mg/dl (60-110 μmol/l) for men. While a baseline serum creatinine of 2.0 mg/dl (150 μmol/l) may indicate normal kidney function in a male body builder, a serum creatinine of 1.2 mg/dl (110 μmol/l) can indicate significant renal disease in an elderly female.



The trend of serum creatinine levels over time is more important than absolute creatinine level.

Creatinine levels may increase when an ACE inhibitor (ACEI) or angiotensin II receptor antagonist (or angiotensin receptor blocker, ARB) is taken. Using both ACEI and ARB concomitantly will increase creatinine levels to a greater degree than either of the two drugs would individually. An increase of <30% is to be expected with ACEI or ARB use.

Chemistry
In chemical terms, creatinine is a spontaneously formed cyclic derivative of creatine. Several tautomers of creatinine exist; ordered by contribution, they are:
 * 2-Amino-1-methyl-1H-imidazol-4-ol (or 2-amino-1-methylimidazol-4-ol)
 * 2-Amino-1-methyl-4,5-dihydro-1H-imidazol-4-one
 * 2-Imino-1-methyl-2,3-dihydro-1H-imidazol-4-ol (or 2-imino-1-methyl-3H-imidazol-4-ol)
 * 2-Imino-1-methylimidazolidin-4-one
 * 2-Imino-1-methyl-2,5-dihydro-1H-imidazol-4-ol (or 2-imino-1-methyl-5H-imidazol-4-ol)

Creatinine starts to decompose around 300°C.