Creatinine: Difference between revisions

{{Short description|Breakdown product of creatine phosphate}}

{{Distinguish|creatine|Creatine kinase}}

| verifiedrevid = 460107980

| ImageFile = Creatinine-tautomerism-2D-skeletal.svg

| PIN = 2-Amino-1-methyl-5''H''-imidazol-4-one{{Citation needed|date=October 2011}}

| OtherNames = 2-Amino-1-methylimidazol-4-ol{{Citation needed| date=October 2011}}

|Section1={{Chembox Identifiers

| CASNo = 60-27-5

| CASNo_Ref = {{cascite|correct|CAS}}

| PubChem = 26009888

| PubChem1 = 588

| PubChem1_Comment = minor tautomer

| ChemSpiderID = 21640982

| ChemSpiderID_Ref = {{chemspidercite|correct|chemspider}}

| UNII = AYI8EX34EU

| UNII_Ref = {{fdacite|correct|FDA}}

| EINECS = 200-466-7

| UNNumber = 1789

| KEGG = D03600

| KEGG_Ref = {{keggcite|correct|kegg}}

| MeSHName = Creatinine

| ChEBI = 16737

| ChEBI_Ref = {{ebicite|changed|EBI}}

| ChEMBL = 65567

| ChEMBL_Ref = {{ebicite|changed|EBI}}

| Beilstein = 112061

| 3DMet = B00175

| DrugBank = DB11846

| SMILES = CN1CC(=O)N=C1N

| SMILES1 = CN1CC(=O)NC1=N

| StdInChI = 1S/C4H7N3O/c1-7-2-3(8)6-4(7)5/h2,8H,1H3,(H2,5,6)

| StdInChI_Ref = {{stdinchicite|correct|chemspider}}

| InChI = 1/C4H7N3O/c1-7-2-3(8)6-4(7)5/h2H2,1H3,(H2,5,6,8)

| StdInChIKey = BTXYOFGSUFEOLA-UHFFFAOYSA-N

| StdInChIKey_Ref = {{stdinchicite|correct|chemspider}}

| InChIKey = DDRJAANPRJIHGJ-UHFFFAOYAV

}}

|Section2={{Chembox Properties

| C=4 | H=7 | N=3 | O=1

| Appearance = White crystals

| Density = 1.09 g cm⁻³

| MeltingPtC = 300

| MeltingPt_notes = (decomposes)

| MeltingPt_ref = <ref name=Merck>''[[Merck Index]]'', 11th Edition, '''2571'''</ref>

| Solubility = 1 part per 12<ref name=Merck/>

90 mg/mL at 20°C<ref>{{cite web|url=https://www.scbt.com/scbt/product/creatinine-anhydrous-60-27-5|title=Creatinine, anhydrous - CAS 60-27-5|website=Scbt.com|access-date=2016-10-21|archive-date=2016-10-22|archive-url=https://web.archive.org/web/20161022022559/https://www.scbt.com/scbt/product/creatinine-anhydrous-60-27-5|url-status=live}}</ref>

| LogP = -1.76

| pKa = 12.309

| pKb = 1.688

| IsoelectricPt = 11.19

}}

|Section3={{Chembox Thermochemistry

| DeltaHf = −240.81–239.05 kJ mol⁻¹

| DeltaHc = −2.33539–2.33367 MJ mol⁻¹

| Entropy = 167.4 J K⁻¹ mol⁻¹

| HeatCapacity = 138.1 J K⁻¹ mol⁻¹ (at 23.4&nbsp;°C)

}}

|Section4={{Chembox Hazards

| NFPA-F = 1

| NFPA-H = 1

| NFPA-R = 0

| FlashPtC = 290

}}

'''Creatinine''' ({{IPAc-en|k|r|i|ˈ|æ|t|ɪ|n|ɪ|n|,_|-|ˌ|n|iː|n}}; {{etymology|grc|''{{wikt-lang|grc|κρέας}}'' ({{grc-transl|κρέας}})|flesh}}) is a breakdown product of [[phosphocreatine|creatine phosphate]] from [[muscle]] and protein metabolism. It is released at a constant rate by the body (depending on muscle mass).<ref>{{Cite web |title=Creatinine tests - Mayo Clinic|url=https://www.mayoclinic.org/tests-procedures/creatinine-test/about/pac-20384646|website=www.mayoclinic.org|archive-url=https://web.archive.org/web/20220605052251/https://www.mayoclinic.org/tests-procedures/creatinine-test/about/pac-20384646|archive-date=2022-06-05}}</ref><ref name="Lewis_2016">{{Cite book|title=Medical-surgical nursing : assessment and management of clinical problems| vauthors = Lewis SL, Bucher L, Heitkemper MM, Harding MM, Kwong J, Roberts D |date = September 2016 |isbn=978-0-323-37143-8 |edition=10th|location=St. Louis, Missouri | publisher = Elsevier Health Sciences |oclc=228373703 | page = 1025 }}</ref>

==Biological relevance==

[[Serum (blood)|Serum]] creatinine (a blood measurement) is an important indicator of [[kidney]] function, because it is an easily measured byproduct of muscle metabolism that is excreted unchanged by the kidneys. Creatinine itself is produced<ref>{{cite web|url=http://www.medicinenet.com/creatinine_blood_test/article.htm|title=What Is a Creatinine Blood Test? Low & High Ranges|website=Medicinenet.com|access-date=21 September 2018|archive-date=21 September 2018|archive-url=https://web.archive.org/web/20180921230201/https://www.medicinenet.com/creatinine_blood_test/article.htm|url-status=live}}</ref> 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 by methylation of [[glycocyamine]] (guanidino acetate, synthesized in the kidney from the [[amino acid]]s [[arginine]] and [[glycine]]) by [[S-adenosyl methionine]]. It is then transported in the blood to other organs, muscle and brain, where it is [[phosphorylation|phosphorylated]] to phosphocreatine, a high-energy compound .<ref name=ClinChem89 /> Creatine conversion to phosphocreatine is catalysed by [[creatine kinase]]; spontaneous formation of creatinine occurs during the reaction.<ref name="CreatineSupp">{{cite journal | vauthors = Allen PJ | title = Creatine metabolism and psychiatric disorders: Does creatine supplementation have therapeutic value? | journal = Neuroscience and Biobehavioral Reviews | volume = 36 | issue = 5 | pages = 1442–62 | date = May 2012 | pmid = 22465051 | pmc = 3340488 | doi = 10.1016/j.neubiorev.2012.03.005 }}</ref>

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 filtration in the kidney is deficient, blood creatinine concentrations rise. Therefore, creatinine concentrations in blood and urine may be used to calculate the [[Renal function#Creatinine Clearance CCr|creatinine clearance]] (CrCl), which correlates approximately with the [[glomerular filtration rate]] (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]]. However, in cases of severe kidney dysfunction the CrCl rate will overestimate the GFR, because hypersecretion of creatinine by the proximal renal tubules will account for a larger fraction of the total creatinine cleared.<ref>{{cite journal | vauthors = Shemesh O, Golbetz H, Kriss JP, Myers BD | title = Limitations of creatinine as a filtration marker in glomerulopathic patients | journal = Kidney International | volume = 28 | issue = 5 | pages = 830–8 | date = November 1985 | pmid = 2418254 | doi = 10.1038/ki.1985.205 | doi-access = free }}</ref> [[Ketoacid]]s, [[cimetidine]], and [[trimethoprim]] 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]]).<ref>{{Cite journal |last=Uemura |first=O |last2=Ishikura |first2=K |last3=Kamei |first3=K |last4=Hamada |first4=R |last5=Yamamoto |first5=M |last6=Gotoh |first6=Y |last7=Fujita |first7=N |last8=Sakai |first8=T |last9=Sano |first9=T |last10=Fushimi |first10=M |last11=Iijima |first11=K |date=2022 |title=Comparison of inulin clearance with 2-h creatinine clearance in Japanese pediatric patients with renal disease: open-label phase 3 study of inulin. |journal=Clin Exp Nephrol |volume=26 |issue=2 |pages=132-9 |via=PubMed}}</ref><ref>{{Cite journal |last=Toto |first=RD |date=1995 |title=Conventional measurement of renal function utilizing serum creatinine, creatinine clearance, inulin and para-aminohippuric acid clearance. |journal=Curr Opin Nephrol Hypertens |volume=4 |issue=6 |pages=505-9 |via=PubMed}}</ref>

An alternative estimation of kidney 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 concentration raised out of proportion to the creatinine may indicate a prerenal problem, such as volume depletion.

Counterintuitively, supporting the observation of higher creatinine production in women than in men, and putting into question the algorithms for GFR that do not distinguish for sex, women have higher muscle protein synthesis and higher muscle protein turnover across their life span.<ref>{{cite journal | vauthors = Henderson GC, Dhatariya K, Ford GC, Klaus KA, Basu R, Rizza RA, Jensen MD, Khosla S, O'Brien P, Nair KS | display-authors = 6 | title = Higher muscle protein synthesis in women than men across the lifespan, and failure of androgen administration to amend age-related decrements | journal = FASEB Journal | volume = 23 | issue = 2 | pages = 631–41 | date = February 2009 | pmid = 18827019 | pmc = 2630787 | doi = 10.1096/fj.08-117200 | doi-access = free }}</ref> As HDL supports muscle anabolism, higher muscle protein turnover links increased creatine to the generally higher serum HDL in women compared with serum HDL in men and the HDL associated benefits, such as reduced incidence of cardiovascular complications and reduced [[COVID-19]] severity.<ref name="pmid15976321">{{cite journal | vauthors = Lewis GF, Rader DJ | title = New insights into the regulation of HDL metabolism and reverse cholesterol transport | journal = Circulation Research | volume = 96 | issue = 12 | pages = 1221–32 | date = June 2005 | pmid = 15976321 | doi = 10.1161/01.RES.0000170946.56981.5c | s2cid = 2050414 }}</ref><ref name="pmid24170386">{{cite journal | vauthors = Lehti M, Donelan E, Abplanalp W, Al-Massadi O, Habegger KM, Weber J, Ress C, Mansfeld J, Somvanshi S, Trivedi C, Keuper M, Ograjsek T, Striese C, Cucuruz S, Pfluger PT, Krishna R, Gordon SM, Silva RA, Luquet S, Castel J, Martinez S, D'Alessio D, Davidson WS, Hofmann SM | display-authors = 6 | title = High-density lipoprotein maintains skeletal muscle function by modulating cellular respiration in mice | journal = Circulation | volume = 128 | issue = 22 | pages = 2364–71 | date = November 2013 | pmid = 24170386 | pmc = 3957345 | doi = 10.1161/CIRCULATIONAHA.113.001551 }}</ref><ref name="pmid33785815">{{cite journal | vauthors = Masana L, Correig E, Ibarretxe D, Anoro E, Arroyo JA, Jericó C, Guerrero C, Miret M, Näf S, Pardo A, Perea V, Pérez-Bernalte R, Plana N, Ramírez-Montesinos R, Royuela M, Soler C, Urquizu-Padilla M, Zamora A, Pedro-Botet J | display-authors = 6 | title = Low HDL and high triglycerides predict COVID-19 severity | journal = Scientific Reports | volume = 11 | issue = 1 | pages = 7217 | date = March 2021 | pmid = 33785815 | pmc = 8010012 | doi = 10.1038/s41598-021-86747-5 | bibcode = 2021NatSR..11.7217M }}</ref>

===Antibacterial and potential immunosuppressive properties===

Studies suggest that creatinine can be effective in killing bacteria of many species, both [[Gram positive]] and [[Gram negative]], as well as diverse [[Antimicrobial resistance|antibiotic-resistant]] bacterial strains.<ref>{{cite journal | vauthors = McDonald T, Drescher KM, Weber A, Tracy S | title = Creatinine inhibits bacterial replication | journal = The Journal of Antibiotics | volume = 65 | issue = 3 | pages = 153–156 | date = March 2012 | pmid = 22293916 | doi = 10.1038/ja.2011.131 | doi-access = free }}</ref> Creatinine appears not to affect the growth of fungi and yeasts; 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 currently known. Some reports also suggest that creatinine may have [[Immunosuppression|immunosuppressive]] properties.<ref>{{cite journal | vauthors = Smithee S, Tracy S, Drescher KM, Pitz LA, McDonald T | title = A novel, broadly applicable approach to isolation of fungi in diverse growth media | journal = Journal of Microbiological Methods | volume = 105 | pages = 155–61 | date = October 2014 | pmid = 25093757 | doi = 10.1016/j.mimet.2014.07.023 }}</ref><ref>{{cite journal | vauthors = Leland KM, McDonald TL, Drescher KM | title = Effect of creatine, creatinine, and creatine ethyl ester on TLR expression in macrophages | journal = International Immunopharmacology | volume = 11 | issue = 9 | pages = 1341–7 | date = September 2011 | pmid = 21575742 | pmc = 3157573 | doi = 10.1016/j.intimp.2011.04.018 }}</ref>

Serum creatinine is the most commonly used indicator (although not a direct measure) of [[renal function]]. A raised 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 reduced kidney function, to interference with the assay, or to reduced 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 actual kidney impairment, as in some cases associated with cholecystitis.{{Citation needed|date=December 2017}} Several medications and chromogens can interfere with the chemical assay. Creatinine secretion by the renal tubules can be blocked by some medications, again increasing measured creatinine.<ref name=pmid22745616>{{cite journal | vauthors = Samra M, Abcar AC | title = False estimates of elevated creatinine | journal = The Permanente Journal | volume = 16 | issue = 2 | pages = 51–2 | year = 2012 | pmid = 22745616 | pmc = 3383162 | doi = 10.7812/tpp/11-121 }}</ref>

=== Serum creatinine ===

Diagnostic serum creatinine studies are used to determine renal function.<ref name="Lewis_2016" /> The reference interval is 0.6–1.3&nbsp;mg/dL (53–115 μmol/L).<ref name="Lewis_2016" /> It is simple to measure serum creatinine, and it is the most commonly used indicator of renal function.<ref name=ClinChem89>{{cite book| vauthors = Taylor EH |title=Clinical Chemistry|year=1989|publisher=Wiley |isbn=0-471-85342-9 |oclc=19065010 |pages=4, 58–62}}</ref>

A rise in blood creatinine concentration is a late marker, observed only with marked damage to functioning [[nephron]]s. The test is therefore unsuitable for detecting early-stage [[kidney disease]]. A better estimate of kidney function is given by calculating the estimated glomerular filtration rate (eGFR). eGFR can be calculated without a 24-hour urine collection, using serum creatinine concentration and some or all of the following variables: sex, age, and weight, as suggested by the [[American Diabetes Association]].<ref>{{cite journal | vauthors = Gross JL, de Azevedo MJ, Silveiro SP, Canani LH, Caramori ML, Zelmanovitz T | title = Diabetic nephropathy: diagnosis, prevention, and treatment | journal = Diabetes Care | volume = 28 | issue = 1 | pages = 164–76 | date = January 2005 | pmid = 15616252 | doi = 10.2337/diacare.28.1.164 | doi-access = free }}</ref> 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#Estimated values|renal function]] article. Unfortunately, the MDRD Study equation was developed in people with chronic kidney disease, and its major limitations are imprecision and systematic underestimation of measured GFR (bias) at higher/normal values.<ref>{{cite journal | vauthors = Levey AS, Stevens LA, Schmid CH, Zhang YL, ((Castro AF 3rd)), Feldman HI, Kusek JW, Eggers P, Van Lente F, Greene T, Coresh J| title = A new equation to estimate glomerular filtration rate | journal = Ann Intern Med | date = 5 May 2009 | volume = 150 | issue = 9 | pages = 604–612 | pmid = 19414839 | pmc = 2763564 | doi = 10.7326/0003-4819-150-9-200905050-00006 | doi-access = free }}</ref>

A concern as of late 2010 relates to the adoption of a new analytical method, and the possible effect 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&nbsp;mg/dL. The IDMS method would result in comparative overestimation of the corresponding calculated GFR in some patients with normal renal function. A few medicines are dosed even in normal renal function using that derived value of GFR. The dose, unless further modified, could then 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 of carboplatin, a chemotherapy drug, to specified maxima.<ref>{{cite web|url=https://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm|archive-url=https://web.archive.org/web/20111119090611/https://www.fda.gov/AboutFDA/CentersOffices/CDER/ucm228974.htm|archive-date=2011-11-19|title=Carboplatin dosing|website=[[Food and Drug Administration]]|department=Center for Drug Evaluation and Research|url-status=dead}}</ref>

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.<ref>{{cite journal | vauthors = Harita N, Hayashi T, Sato KK, Nakamura Y, Yoneda T, Endo G, Kambe H | title = Lower serum creatinine is a new risk factor of type 2 diabetes: the Kansai healthcare study | journal = Diabetes Care | volume = 32 | issue = 3 | pages = 424–6 | date = March 2009 | pmid = 19074997 | pmc = 2646021 | doi = 10.2337/dc08-1265 }}</ref>

===Urine creatinine===

Males produce approximately 150&nbsp;μmol to 200&nbsp;μmol of creatinine per kilogram of body weight per 24&nbsp;h, while females produce approximately 100&nbsp;μmol/kg/24&nbsp;h to 150&nbsp;μmol/kg/24&nbsp;h. In normal circumstances, all the creatinine produced is excreted in the urine.

Creatinine concentration is checked during standard urine drug tests. An expected creatinine concentration indicates that 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.

In the United States and in most European countries creatinine is usually reported in [[Milli-|m]][[Gram|g]]/[[Deci-|d]][[Litre|L]], whereas in Canada, Australia,<ref>{{cite journal | vauthors = Faull R |title=Prescribing in renal disease |journal=Australian Prescriber |volume=30 |issue=1 |pages=17–20 |year=2007 |doi=10.18773/austprescr.2007.008|doi-access=free }}</ref> and a few European countries, such as the UK, [[Micro-|μ]][[Mole (unit)|mol]]/[[Litre|L]] is the usual unit. One&nbsp;mg/dL of creatinine equals 88.4&nbsp;μmol/L.

The typical human [[Reference ranges for blood tests|reference range]]s for serum creatinine are 0.5&nbsp;mg/dL to 1.0&nbsp;mg/dL (about 45&nbsp;μmol/L to 90&nbsp;μmol/L) for women and 0.7&nbsp;mg/dL to 1.2&nbsp;mg/dL (60&nbsp;μmol/L to 110&nbsp;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.<ref>{{Cite journal |last=Liu |first=C |last2=Levey |first2=AS |last3=Ballew |first3=SH |date=2024 |title=Serum creatinine and serum cystatin C as an index of muscle mass in adults |journal=Curr Opin Nephrol Hypertens |volume=33 |issue=6 |pages=557-65 |via=PubMed}}</ref>

[[File:Blood values sorted by mass and molar concentration.png|thumb|550px|center|[[Reference ranges for blood tests]], comparing blood content of creatinine (shown in [[Chartreuse (color)#Apple green|apple green]]) with other constituents]]

The trend of serum creatinine concentrations over time is more important than the absolute creatinine concentration.

Serum creatinine concentrations may increase when an [[ACE inhibitor]] (ACEI) is taken for [[heart failure]] and [[chronic kidney disease]]. ACE inhibitors provide survival benefits for patients with heart failure and slow disease progression in patients with chronic kidney disease. An increase not exceeding 30% is to be expected with use of an ACE inhibitor. Therefore, an ACE inhibitor should not be withdrawn when the serum creatinine increases, unless the increase exceeds 30% or [[hyperkalemia]] develops.<ref>{{cite journal | vauthors = Ahmed A | title = Use of angiotensin-converting enzyme inhibitors in patients with heart failure and renal insufficiency: how concerned should we be by the rise in serum creatinine? | journal = Journal of the American Geriatrics Society | volume = 50 | issue = 7 | pages = 1297–300 | date = July 2002 | pmid = 12133029 | doi = 10.1046/j.1532-5415.2002.50321.x | s2cid = 31459410 }}</ref>

==Chemistry==

In chemical terms, creatinine is a [[lactam]] and an [[imidazolidinone]], a spontaneously formed cyclic derivative of creatine.<ref>{{Cite web|url=https://pubchem.ncbi.nlm.nih.gov/compound/Creatinine|title=Creatinine|access-date=2022-04-09|archive-date=2022-04-09|archive-url=https://web.archive.org/web/20220409151433/https://pubchem.ncbi.nlm.nih.gov/compound/Creatinine|url-status=live}}</ref>

Several [[tautomer]]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 at around 300&nbsp;°C.

*[[Cystatin C]], a novel marker of kidney function

*[[Jaffe reaction]], an example of a method of assaying creatinine

*[[Rhabdomyolysis]], which may be diagnosed using serum creatinine concentrations

*[[Nephrotic syndrome]]

==External links==

*{{cite web | vauthors = Marshall W | date = 2012 | url = http://www.acb.org.uk/docs/default-source/committees/scientific/amalc/creatinine.pdf | archive-url = https://web.archive.org/web/20200614201806/http://www.acb.org.uk/docs/default-source/committees/scientific/amalc/creatinine.pdf | archive-date = 14 June 2020 | title = Creatinine: analyte monograph | publisher = The Association for Clinical Biochemistry and Laboratory Medicine}}

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[[Category:Nephrology]]