Creatinine Ratio
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Creatinine (; ) is a breakdown product of
creatine phosphate Phosphocreatine, also known as creatine phosphate (CP) or PCr (Pcr), is a phosphorylated form of creatine that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle, myocardium and the brain to recycle adenosine trip ...
from
muscle Skeletal muscles (commonly referred to as muscles) are organs of the vertebrate muscular system and typically are attached by tendons to bones of a skeleton. The muscle cells of skeletal muscles are much longer than in the other types of muscl ...
and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).


Biological relevance

Serum creatinine (a blood measurement) is an important indicator of
kidney The kidneys are two reddish-brown bean-shaped organs found in vertebrates. They are located on the left and right in the retroperitoneal space, and in adult humans are about in length. They receive blood from the paired renal arteries; blood ...
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 Creatine ( or ) is an organic compound with the nominal formula (H2N)(HN)CN(CH3)CH2CO2H. It exists in various modifications (tautomers) in solution. Creatine is found in vertebrates where it facilitates recycling of adenosine triphosphate ( ...
,
phosphocreatine Phosphocreatine, also known as creatine phosphate (CP) or PCr (Pcr), is a phosphorylated form of creatine that serves as a rapidly mobilizable reserve of high-energy phosphates in skeletal muscle, myocardium and the brain to recycle adenosine tr ...
(also known as creatine phosphate), and
adenosine triphosphate Adenosine triphosphate (ATP) is an organic compound that provides energy to drive many processes in living cells, such as muscle contraction, nerve impulse propagation, condensate dissolution, and chemical synthesis. Found in all known forms of ...
(ATP, the body's immediate energy supply). Creatine is synthesized primarily in the liver from the methylation of
glycocyamine Glycocyamine (or guanidinoacetate) is a metabolite of glycine in which the amino group has been converted into a guanidine by guanylation (transfer of a guanidine group from arginine). In vertebrate organism it is then transformed into creatine b ...
(guanidino acetate, synthesized in the kidney from the
amino acid Amino acids are organic compounds that contain both amino and carboxylic acid functional groups. Although hundreds of amino acids exist in nature, by far the most important are the alpha-amino acids, which comprise proteins. Only 22 alpha am ...
s
arginine Arginine is the amino acid with the formula (H2N)(HN)CN(H)(CH2)3CH(NH2)CO2H. The molecule features a guanidino group appended to a standard amino acid framework. At physiological pH, the carboxylic acid is deprotonated (−CO2−) and both the am ...
and
glycine Glycine (symbol Gly or G; ) is an amino acid that has a single hydrogen atom as its side chain. It is the simplest stable amino acid (carbamic acid is unstable), with the chemical formula NH2‐ CH2‐ COOH. Glycine is one of the proteinogeni ...
) by
S-Adenosyl methionine ''S''-Adenosyl methionine (SAM), also known under the commercial names of SAMe, SAM-e, or AdoMet, is a common cosubstrate involved in methyl group transfers, transsulfuration, and aminopropylation. Although these anabolic reactions occur throug ...
. It is then transported through blood to the other organs, muscle, and brain, where, through
phosphorylation In chemistry, phosphorylation is the attachment of a phosphate group to a molecule or an ion. This process and its inverse, dephosphorylation, are common in biology and could be driven by natural selection. Text was copied from this source, wh ...
, it becomes the high-energy compound phosphocreatine. Creatine conversion to phosphocreatine is catalyzed by
creatine kinase Creatine kinase (CK), also known as creatine phosphokinase (CPK) or phosphocreatine kinase, is an enzyme () expressed by various tissues and cell types. CK catalyses the conversion of creatine and uses adenosine triphosphate (ATP) to create phosp ...
; spontaneous formation of creatinine occurs during the reaction. Creatinine is removed from the blood chiefly by the kidneys, primarily by
glomerular filtration Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood pre ...
, but also by proximal
tubular secretion Renal physiology (Latin language, Latin ''rēnēs'', "kidneys") is the study of the physiology of the kidney. This encompasses all functions of the kidney, including maintenance of acid-base balance; regulation of fluid balance; regulation of sod ...
. Little or no
tubular reabsorption In renal physiology, reabsorption or tubular reabsorption is the process by which the nephron removes water and solutes from the tubular fluid (pre-urine) and returns them to the circulating blood. It is called ''reabsorption'' (and not ''absorpt ...
of creatinine occurs. If the filtration in the kidney is deficient, blood creatinine concentrations rise. Therefore, creatinine concentrations in blood and urine may be used to calculate the
creatinine clearance Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's fluid ...
(CrCl), which correlates approximately with the
glomerular filtration rate Renal functions include maintaining an acid–base balance; regulating fluid balance; regulating sodium, potassium, and other electrolytes; clearing toxins; absorption of glucose, amino acids, and other small molecules; regulation of blood p ...
(GFR). Blood creatinine concentrations may also be used alone to calculate the estimated GFR (eGFR). The GFR is clinically important as a measurement of
kidney function Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's fluid ...
. However, in cases of severe kidney 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.
Ketoacid In organic chemistry, keto acids or ketoacids (also called oxo acids or oxoacids) are organic compounds that contain a carboxylic acid group () and a ketone group ().Franz Dietrich Klingler, Wolfgang Ebertz "Oxocarboxylic Acids" in Ullmann's En ...
s,
cimetidine Cimetidine, sold under the brand name Tagamet among others, is a histamine H2 receptor antagonist that inhibits stomach acid production. It is mainly used in the treatment of heartburn and peptic ulcers. The development of longer-acting H2 rec ...
, and
trimethoprim Trimethoprim (TMP) is an antibiotic used mainly in the treatment of bladder infections. Other uses include for middle ear infections and travelers' diarrhea. With sulfamethoxazole or dapsone it may be used for ''Pneumocystis'' pneumonia in peop ...
reduce creatinine tubular secretion and, therefore, increase the accuracy of the GFR estimate, in particular in severe kidney dysfunction. (In the absence of secretion, creatinine behaves like
inulin Inulins are a group of naturally occurring polysaccharides produced by many types of plants, industrially most often extracted from chicory. The inulins belong to a class of dietary fibers known as fructans. Inulin is used by some plants as a mea ...
.) An alternate estimation of kidney function can be made when interpreting the blood plasma concentration of creatinine along with that of
urea Urea, also known as carbamide, is an organic compound with chemical formula . This amide has two amino groups (–) joined by a carbonyl functional group (–C(=O)–). It is thus the simplest amide of carbamic acid. Urea serves an important r ...
.
BUN-to-creatinine ratio In medicine, the BUN-to-creatinine ratio is the ratio of two serum laboratory values, the blood urea nitrogen (BUN) (mg/dL) and serum creatinine (Cr) (mg/dL). Outside the United States, particularly in Canada and Europe, the term urea is often use ...
(the ratio of
blood urea nitrogen Blood urea nitrogen (BUN) is a medical test that measures the amount of urea nitrogen found in blood. The liver produces urea in the urea cycle as a waste product of the digestion of protein. Normal human adult blood should contain 6 to 20 mg/dL ...
to creatinine) can indicate other problems besides those intrinsic to the kidney; for example, a urea concentration raised out of proportion to the creatinine may indicate a prerenal problem such as volume depletion. Each day, 1% to 2% of muscle creatine is converted to creatinine. The conversion is nonenzymatic and irreversible. Men tend to have higher concentrations 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 protein (like meat) can increase daily creatinine excretion. Counterintuitively, supporting the observation of higher creatinine production in women compared to men, and putting into question the algorithms for GFR that do not distinguish for sex accordingly, women have higher muscle protein synthesis and higher muscle protein turnover across the life span. As HDL supports muscle anabolism, higher muscle protein turnover links increased creatine to the generally higher serum HDL in women as compared to serum HDL in man and the HDL associated benefits like reduced incidence of cardiovascular complications and reduced
COVID-19 Coronavirus disease 2019 (COVID-19) is a contagious disease caused by a virus, the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). The first known case was COVID-19 pandemic in Hubei, identified in Wuhan, China, in December ...
severity.


Antibacterial and potential immunosuppressive properties

Studies indicate creatinine can be effective at killing bacteria of many species in both the
Gram positive In bacteriology, gram-positive bacteria are bacteria that give a positive result in the Gram stain test, which is traditionally used to quickly classify bacteria into two broad categories according to their type of cell wall. Gram-positive bact ...
and
Gram negative The gram (originally gramme; SI unit symbol g) is a unit of mass in the International System of Units (SI) equal to one one thousandth of a kilogram. Originally defined as of 1795 as "the absolute weight of a volume of pure water equal to th ...
as well as diverse
antibiotic resistant Antimicrobial resistance (AMR) occurs when microbes evolve mechanisms that protect them from the effects of antimicrobials. All classes of microbes can evolve resistance. Fungi evolve antifungal resistance. Viruses evolve antiviral resistance. P ...
bacterial strains. Creatinine appears not to affect growth of fungi and yeast; this can be used to isolate slower growing fungi free from the normal bacterial populations found in most environmental samples. The mechanism by which creatinine kills bacteria is not presently known. A recent report also suggests that creatinine may have
immunosuppressive Immunosuppression is a reduction of the activation or efficacy of the immune system. Some portions of the immune system itself have immunosuppressive effects on other parts of the immune system, and immunosuppression may occur as an adverse reacti ...
properties.


Diagnostic use

Serum creatinine is the most commonly used indicator (but not direct measure) of
renal function Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's fluid ...
. Elevated creatinine is not always representative of a true reduction in GFR. A high reading may be due to increased production of creatinine not due to decreased kidney function, to interference with the assay, or to decreased tubular secretion of creatinine. An increase in serum creatinine can be due to increased ingestion of cooked meat (which contains creatinine converted from creatine by the heat from cooking) or excessive intake of protein and creatine supplements, taken to enhance athletic performance. Intense exercise can increase creatinine by increasing muscle breakdown. Dehydration secondary to an inflammatory process with fever may cause a false increase in creatinine concentrations not related to an actual kidney injury, as in some cases with cholecystitis. Several medications and chromogens can interfere with the assay. Creatinine secretion by the tubules can be blocked by some medications, again increasing measured creatinine.


Serum creatinine

Diagnostic serum creatinine studies are used to determine renal function. The reference interval is 0.6–1.3 mg/dL (53–115 μmol/L). Measuring serum creatinine is a simple test, and it is the most commonly used indicator of renal function. A rise in blood creatinine concentration is a late marker, observed only with marked damage to functioning
nephron The nephron is the minute or microscopic structural and functional unit of the kidney. It is composed of a renal corpuscle and a renal tubule. The renal corpuscle consists of a tuft of capillaries called a glomerulus and a cup-shaped structure ca ...
s. Therefore, this test is unsuitable for detecting early-stage
kidney disease Kidney disease, or renal disease, technically referred to as nephropathy, is damage to or disease of a kidney. Nephritis is an inflammatory kidney disease and has several types according to the location of the inflammation. Inflammation can ...
. A better estimation of kidney function is given by calculating the estimated glomerular filtration rate (eGFR). eGFR can be accurately calculated without a 24-hour urine collection using serum creatinine concentration and some or all of the following variables: sex, age, weight, and race, as suggested by the
American Diabetes Association The American Diabetes Association (ADA) is a United States-based nonprofit that seeks to educate the public about diabetes and to help those affected by it through funding research to manage, cure and prevent diabetes (including type 1 diabetes, ...
. Many laboratories will automatically calculate eGFR when a creatinine test is requested. Algorithms to estimate GFR from creatinine concentration and other parameters are discussed in the
renal function Assessment of kidney function occurs in different ways, using the presence of symptoms and signs, as well as measurements using urine tests, blood tests, and medical imaging. Functions of a healthy kidney include maintaining a person's fluid ...
article. 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 Isotope dilution analysis is a method of determining the quantity of chemical substances. In its most simple conception, the method of isotope dilution comprises the addition of known amounts of isotopically enriched substance to the analyzed samp ...
(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. A 2009 Japanese study found a lower serum creatinine concentration to be associated with an increased risk for the development of type 2 diabetes in Japanese men.


Urine creatinine

Males produce approximately 150 μmol to 200 μmol of creatinine per kilogram of body weight per 24 h while females produce approximately 100 μmol/kg/24 h to 150 μmol/kg/24 h. In normal circumstances, all this daily creatinine production is excreted in the urine. Creatinine concentration is checked during standard urine drug tests. An expected creatinine concentration indicates the test sample is undiluted, whereas low amounts of creatinine in the urine indicate either a manipulated test or low initial baseline creatinine concentrations. Test samples considered manipulated due to low creatinine are not tested, and the test is sometimes considered failed.


Interpretation

In the United States and in most European countries creatinine is usually reported in m g/ d L, whereas in Canada, Australia, and a few European countries, μ mol/ L is the usual unit. One mg/dL of creatinine is 88.4 μmol/L. The typical human
reference range In medicine and health-related fields, a reference range or reference interval is the range or the interval of values that is deemed normal for a physiological measurement in healthy persons (for example, the amount of creatinine in the blood, or ...
s for serum creatinine are 0.5 mg/dL to 1.0 mg/dL (about 45 μmol/L to 90 μmol/L) for women and 0.7 mg/dL to 1.2 mg/dL (60 μmol/L to 110 μmol/L) for men. The significance of a single creatinine value must be interpreted in light of the patient's muscle mass. Patients with greater muscle mass have higher creatinine concentrations. The trend of serum creatinine concentrations over time is more important than absolute creatinine concentration. Serum creatinine concentrations may increase when an
ACE inhibitor Angiotensin-converting-enzyme inhibitors (ACE inhibitors) are a class of medication used primarily for the treatment of hypertension, high blood pressure and heart failure. They work by causing relaxation of blood vessels as well as a decrease i ...
(ACEI) is taken for
heart failure Heart failure (HF), also known as congestive heart failure (CHF), is a syndrome, a group of signs and symptoms caused by an impairment of the heart's blood pumping function. Symptoms typically include shortness of breath, excessive fatigue, a ...
and
chronic kidney disease Chronic kidney disease (CKD) is a type of kidney disease in which a gradual loss of kidney function occurs over a period of months to years. Initially generally no symptoms are seen, but later symptoms may include leg swelling, feeling tired, vo ...
. ACE inhibitors provide survival benefits for patients with heart failure and slow the disease progression in patients with chronic kidney disease. An increase not exceeding 30% is to be expected with ACEI use. Therefore, usage of ACEI should not be stopped unless an increase of serum creatinine exceeded 30% or
hyperkalemia Hyperkalemia is an elevated level of potassium (K+) in the blood. Normal potassium levels are between 3.5 and 5.0mmol/L (3.5 and 5.0mEq/L) with levels above 5.5mmol/L defined as hyperkalemia. Typically hyperkalemia does not cause symptoms. Occasi ...
develops.


Chemistry

In chemical terms, creatinine is a
lactam A lactam is a cyclic amide, formally derived from an amino alkanoic acid. The term is a portmanteau of the words ''lactone'' + ''amide''. Nomenclature Greek prefixes in alphabetical order indicate ring size: * α-Lactam (3-atom rings) * β-Lacta ...
and an 
imidazolidinone Imidazolidinones or imidazolinones are a class of 5-membered ring heterocycles structurally related to imidazole. Imidazolidinones feature a saturated C3N2 nucleus, except for the presence of a urea or amide functional group in the 2 or 4 positi ...
, so a spontaneously formed cyclic derivative of creatine. Several
tautomer Tautomers () are structural isomers (constitutional isomers) of chemical compounds that readily interconvert. The chemical reaction interconverting the two is called tautomerization. This conversion commonly results from the relocation of a hydr ...
s of creatinine exist; ordered by contribution, they are: *2-Amino-1-methyl-1''H''-imidazol-4-ol (or 2-amino-1-methylimidazol-4-ol) *2-Amino-1-methyl-4,5-dihydro-1''H''-imidazol-4-one *2-Imino-1-methyl-2,3-dihydro-1''H''-imidazol-4-ol (or 2-imino-1-methyl-3''H''-imidazol-4-ol) *2-Imino-1-methylimidazolidin-4-one *2-Imino-1-methyl-2,5-dihydro-1''H''-imidazol-4-ol (or 2-imino-1-methyl-5''H''-imidazol-4-ol) Creatinine starts to decompose around 300 °C.


See also

*
Cystatin C Cystatin C or cystatin 3 (formerly gamma trace, post-gamma-globulin, or neuroendocrine basic polypeptide), a protein encoded by the CST3 gene, is mainly used as a biomarker of kidney function. Recently, it has been studied for its role in predictin ...
, novel marker of kidney function *
Jaffe reaction The Jaffe reaction is a colorimetric method used in clinical chemistry to determine creatinine levels in blood and urine. In 1886, Max Jaffe (1841–1911) wrote about its basic principles in the paper ''Über den Niederschlag, welchen Pikrinsäur ...
, an example of creatinine assay methodology *
Rhabdomyolysis Rhabdomyolysis (also called rhabdo) is a condition in which damaged skeletal muscle breaks down rapidly. Symptoms may include muscle pains, weakness, vomiting, and confusion. There may be tea-colored urine or an irregular heartbeat. Some of th ...
, may be diagnosed using creatinine levels *
Nephrotic syndrome Nephrotic syndrome is a collection of symptoms due to kidney damage. This includes protein in the urine, low blood albumin levels, high blood lipids, and significant swelling. Other symptoms may include weight gain, feeling tired, and foamy ...


References


External links

* * {{Authority control Guanidines Metabolism Nephrology Renal physiology Imidazolidines