Índice neutrófilo-linfocitario como biomarcador inflamatorio y predictor potencial del riesgo de enfermedad cardiovascular aterosclerótica
Texto completo:
PDFResumen
Introducción: La aterosclerosis y los procesos inflamatorios asociados influyen directamente en la relación neutrófilos/linfocitos; esto es una herramienta auxiliar que contribuye a estratificar a los pacientes en las diferentes categorías de riesgo de desarrollar enfermedades cardiovasculares.
Objetivo: Analizar el papel del índice neutrófilo-linfocitario como biomarcador inflamatorio y predictor potencial del riesgo de enfermedad cardiovascular aterosclerótica.
Métodos: Se realizaron búsquedas bibliográficas en las bases de datos de Pubmed, SciELO, LILACS, CUMED y HINARI desde marzo hasta agosto de 2021. Las unidades de análisis fueron artículos originales, de revisión (revisiones sistemáticas y metaanálisis), publicados en los idiomas español e inglés. Se extrajeron los odds ratios o una razón de riesgo con un intervalo de confianza del 95 % para la mortalidad a corto o largo plazo y el riesgo de incidencia de eventos clínicos y complicaciones. Se utiliza un gráfico de embudo para mostrar la distribución simétrica y sin sesgo de la publicación.
Resultados: La evidencia señala que la respuesta inflamatoria desencadenada por la aterosclerosis se correlacionó positivamente con la elevación de los niveles basales del índice neutrófilo-linfocitario y un mayor riesgo de mortalidad por la enfermedad cardiovascular aterosclerótica. La proporción de neutrófilos-linfocitos es un biomarcador inflamatorio disponible que puede predecir eventos cardiovasculares fatales y no fatales en pacientes con la enfermedad arterial coronaria, la cerebrovascular, la renal crónica y la de las arterias de las extremidades inferiores.
Conclusiones: El índice neutrófilo-linfocitario es un biomarcador de inflamación y un potencial predictor del riesgo de la enfermedad cardiovascular aterosclerótica.
Palabras clave
Referencias
Ashry M, Hafez R, Atef EM. Predictive value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in decompensated heart failure. The Egypt J Intern Med. 2019 [acceso 03/03/2021];31(3):353–9. Disponible en: https://ejim.springeropen.com/track/pdf/10.4103/ejim.ejim_101_18.pdf
Selvaggio S, Abate A, Brugaletta G, Musso C, Di Guardo M, Di Guardo C, et al. Platelet to lymphocyte ratio, neutrophil to lymphocyte ratio and monocyte to HDL cholesterol ratio as markers of peripheral artery disease in elderly patients. Int J Mol Med. 2020;46(3):1210-6. DOI: https://doi.org/10.3892/ijmm.2020.4644
Haidegger M, Kneihsl M, Niederkorn K, Niederkorn K, Deutschmann H, Mangge H, et al. Blood biomarkers of progressive atherosclerosis and restenosis after stenting of symptomatic intracranial artery stenosis. Sci Rep. 2021 [acceso 05/03/2021];11(15599): [aprox. 10p]. Disponible en: https://www.nature.com/articles/s41598-021-95135-y
Rodríguez Blanco S, Leyva Quert AY, Aguilar Medina JM, Collazo PM, Hernández Valdés E, Pérez JC, et al. Valor del índice neutrófilo-linfocitario en la predicción de la severidad de enfermedad arterial coronaria. Rev Cuban Cardiol. 2020 [acceso 05/03/2021];26(1):[aprox. 12 p]. Disponible en: https://www.revcardiologia.sld.cu/index.php/revcardiologia/article/view/910
Rodríguez Blanco S, Obregón Santos AG, Leyva Quert AY, Gutiérrez Rojas AR. Índice neutrófilo-linfocitario: Una herramienta útil en la cardiología intervencionista. CorSalud. 2020 [acceso: 08/03/2021];12(2):209-13. Disponible en: https://www.revcorsalud.sld.cu/index.php/cors/article/view/655/1186
Oliveira Santos H, Moreira Izidoro LF. Neutrophil-Lymphocyte Ratio in Cardiovascular Disease Risk Assessment. Int J Cardiovasc Sci. 2018 [acceso 14/03/2021];31(5):532-7. Disponible en: https://www.scielo.br/j/ijcs/a/65QcFXFTMTdns5dSGygyWZL/?format=pdf〈=en
Gurbuz O, Kumtepe G, Ozkan H, Hasan Karal I, Velioglu Y, Ercan A, et al. Predictive Value of Neutrophil-Lymphocyte Ratio for Long-Term Cardiovascular Event Following Coronary Artery Bypass Grafting. Braz. J. Cardiovasc Surg. 2020 [acceso 12/03/2021];35 (3):[aprox. 9p].Disponible en: https://www.scielo.br/j/rbccv/a/QyCSRRrvK4sG5tfDfVgcH4F/?lang=en
Begg CB, Mazumdar M. Operating characteristics of a rank correlation test for publication bias. Biometrics. 1994 [acceso 12/03/2021]; 50(4):1088-101. Disponible en: https://www.jstor.org/stable/2533446
Stuck AE, Rubenstein LZ, Wieland D. Bias in meta-analysis detected by a simple, graphical test. Asymmetry detected in funnel plot was probably due to true heterogeneity. BMJ. 1998 [acceso 12/03/2021]; 316(7129): 469–71. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2665578/pdf/9492685.pdf
Duval S, Tweedie R. Trim and fill: a simple funnel-plot-based method of testing and adjusting for publication bias in meta-analysis. Biometrics. 2000 [acceso: 12/03/2021];56:455–63. Disponible en: https://www.gwern.net/docs/dual-n-back/2000-duval.pdf
Basbus L, Lapidus MI, Martingano I, Celeste Puga M, Pollán J. Índice neutrófilo-linfocito como factor pronóstico de covid-19. MEDICINA (Buenos Aires). 2020 [acceso 12/03/2021];80 (Supl. III): [aprox. 10 p]. Disponible en: https://www.medicinabuenosaires.com/revistas/vol80-20/s3/31.pdf
Zahorec R. Neutrophil-to-lymphocyte ratio, past, present and future perspectives. Bratisl Med J. 2021;122 (7):474–88. DOI: https://doi.org/10.4149/BLL_2021_078
Song M, Graubard B, Rabkin CS. Neutrophil-to-lymphocyte ratio and mortality in the United States general population. Sci Rep. 2021 [acceso 17/03/2021];11(464):[aprox. 9 p.]. Disponible en: https://www.nature.com/articles/s41598-020-79431-7#citeas
Yilmaz Y. Neutrophil-lymphocyte ratio and severity of atherosclerotic disease in stable coronary artery patients with chronic total occlusion. Ann Med Res. 2021 [acceso 16/03/2021];28(3):506-10. Disponible en: https://www.bibliomed.org/mnsfulltext/134/134-1584647517.pdf?1632313600
Gu LF, Gu J, Wang SB, Wang H, Wang YX, Xue Y, et al. Combination of D-dimer level and neutrophil to lymphocyte ratio predicts long-term clinical outcomes in acute coronary syndrome after percutaneous coronary intervention. Cardiology Journal. 2021 [acceso 14/03/2021]:1-22. Disponible en: https://journals.viamedica.pl/cardiology_journal/article/view/CJ.a2021.0097/63845
Zengin A, Karaca M, Aruğaslan E, Yıldırım E, Karataş MB, Çanga Y, et al. Performance of neutrophil to lymphocyte ratio for the prediction of long-term morbidity and mortality in coronary slow flow phenomenon patients presented with non-ST segment elevation acute coronary syndrome. J Cardiovasc Thorac Res. 2021 [acceso 12/03/2021];13(2): 125–30. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8302892/
Limijadi EKS, Setyadi A, Utami SB, Puruhito B, Sofia SN. The correlation between neutrophil lymphocyte ratio, c - reactive protein, and serum amyloid a with the degree of stenosis in acute coronary syndrome. Open Access Maced J Med Sci. 2020 [acceso 12/03/2021];8(B):1234-9. Disponible en: https://oamjms.eu/index.php/mjms/article/view/5232/5293
Zapponi KCS, Orsi FA, Cunha JLR, de Brito IR, Romano AVC, Bittar LF, et al. Neutrophil activation and circulating neutrophil extracellular traps are increased in venous thromboembolism patients for at least one year after the clinical event. J Thromb Thrombolysis. 2021[acceso 12/03/2021];53:30-42. Disponible en: https://link.springer.com/content/pdf/10.1007/s11239-021-02526-z.pdf
Dehghani T, Panitch A. Endothelial cells, neutrophils and platelets: getting to the bottom of an inflammatory triangle. Open Biol. 2020 [acceso 12/03/2021];10:1-15. Disponible en: https://royalsocietypublishing.org/doi/pdf/10.1098/rsob.200161
Kurup R, Patel S. Neutrophils in acute coronary síndrome. EMJ Cardiol. 2017 [acceso 12/03/2021];5[1]:79-87. Disponible en: https://emj.emg-health.com/wp-content/uploads/sites/2/2018/01/Neutrophils-in-Acute-Coronary-Syndrome.pdf
Charles E, Dumont BL, Bonneau S, Neagoe PE, Villeneuve L. Angiopoietin 1 release from human neutrophils is independent from neutrophil extracellular traps (NETs). BMC Immunol. 2021 [acceso 03/03/2021];22(51): [aprox. 9 p]. Disponible en: https://bmcimmunol.biomedcentral.com/articles/10.1186/s12865-021-00442-8#citeas
Thakur M, Evans B, Schindewolf M, Baumgartner I, Döring Y. Neutrophil extracellular traps affecting cardiovascular health in infectious and inflammatory diseases. Cells. 2021 [acceso 03/03/2021];10(1689):1-21. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8305819/
Döring Y, Libby P, Soehnlein O. Neutrophil extracellular traps participate in cardiovascular diseases: recent experimental and clinical insights. Circ Res. 2020 [acceso 17/03/2021];126(9):1228-41. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7185047/
Moschonas IC, Tselepis AD. The pathway of neutrophil extracellular traps towards atherosclerosis and thrombosis. Atherosclerosis. 2019 [acceso 17/03/2021];288:9-16. Disponible en: https://www.sciencedirect.com/science/article/abs/pii/S0021915019313917?via%3Dihub
Vorobjeva NV, Chernyak BV. NETosis: Molecular mechanisms, role in physiology and pathology. Biochemistry (Mosc). 2020 [acceso 17/03/2021];85(10):1178-90. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7590568/
Klopf J, Brostjan C, Eilenberg W, Neumayer C. Neutrophil extracellular traps and their implications in cardiovascular and inflammatory disease. Int. J. Mol. Sci. 2021 [acceso 17/03/2021]; 22(559):1-17. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7828090/
Soehnlein O, Libby P. Targeting inflammation in atherosclerosis — from experimental insights to the clinic. Nat Rev Drug Discov. 2021 [acceso 10/03/2021];20(8):589-610. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8112476/
Mutua V, Gershwin LJ. A review of neutrophil extracellular traps (NETs) in disease: potential anti-NETs therapeutics. Clinic Rev Allerg Immunol. 2021 [acceso 17/03/2021];61:194–211. Disponible en: https://link.springer.com/content/pdf/10.1007/s12016-020-08804-7.pdf
Langseth MS, Andersen GO, Husebye T, Arnesen H, Zucknick M, Solheim S, et al. Neutrophil extracellular trap components and myocardial recovery in post-ischemic acute heart failure. PLoS ONE 2020 [acceso 17/03/2021];15(10): [aprox. 10p]. Disponible en: https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0241333
Blasco A, Coronado M, Hernández-Terciado F. Assessment of neutrophil extracellular traps in coronary thrombus of a case series of patients with COVID-19 and myocardial infarction. JAMA Cardiol. 2021 [acceso 17/03/2021]; 6(4):469-74. Disponible en: https://jamanetwork.com/journals/jamacardiology/fullarticle/2774536
Bonaventura A, Vecchié A, Abbate A, Montecucco F. Neutrophil extracellular traps and cardiovascular diseases: an update. Cells. 2020 [acceso 17/03/2021]; 9(1): 231.Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7016588/
Sevencan NO, Ozkan AE. Associations between neutrophil/lymphocyte ratio, platelet/lymphocyte ratio, albuminuria and uric acid and the estimated glomerular filtration rate in hypertensive patients with chronic kidney disease stages 1–3. Arch Med Sci. 2019 [acceso 17/03/2021]; 15(5):1232–9. Disponible en: https://www.archivesofmedicalscience.com/Associations-between-neutrophil-lymphocyte-ratio-platelet-lymphocyte-ratio-albuminuria,91309,0,2.html
Yoon GS, Choi SH, Woo S, Baek YS, Park SD, ShinSH, et al. Neutrophil-to-lymphocyte ratio at emergency room predicts mechanical complications of ST-segment elevation myocardial infarction. J Korean Med Sci. 2021 [acceso 14/04/2021];36(19): 131. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8129614/
Chan KL, Feng X, Ip B, Huang S, Ho Ma S, Y Fan FS, et al. Elevated neutrophil to lymphocyte ratio associated with increased risk of recurrent vascular events in older minor stroke or TIA patients. Front. Aging Neurosci. 2021 [acceso 08/04/2021]; 13: [aprox. 10 p]. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8093519/
Sager HB, Koenig W. Immune cell-based cardiovascular risk assessment: spotlight on the neutrophil–lymphocyte ratio. European Heart Journal. 2021 [acceso 10/03/2021]; 42(Issue 9): 904–6.Disponible en: https://academic.oup.com/eurheartj/article/42/9/904/6075084?login=true
Angkananard T, Anothaisintawee T, McEvoy M, Attia J, Thakkinstian A. Neutrophil lymphocyte ratio and cardiovascular disease risk: a systematic review and meta-analysis. BioMed Research International. 2018 [acceso 08/04/2021]; 2018: [aprox. 10 p]. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6252240/
Martínez-Urbistondo D, Beltrán A, Beloqui O, Huerta A. El índice neutrófilo/linfocito como marcador de disfunción sistémica endotelial en sujetos asintomáticos. Nefrología. 2016 [acceso 08/04/2021];36(4): 397-403. Disponible en: https://scielo.isciii.es/scielo.php?script=sci_arttext&pid=S0211-69952016000400397
Yang Y, Xu Y, Wang J, Zhai X, Jiang H. Predictive efficacy of neutrophil-to-lymphocyte ratio for long-term prognosis in new onset acute coronary syndrome: a retrospective cohort study. BMC Cardiovasc Disord. 2020 [acceso 08/04/2021];20(1):500. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7706201/)
Shumilah AM, Othman AM, Al-Madhagi AK. Accuracy of neutrophil to lymphocyte and monocyte to lymphocyte ratios as new inflammatory markers in acute coronary syndrome. BMC Cardiovasc Disord. 2021 [acceso 14/04/2021]; 21(422):[aprox. 12 p]. Disponible en: https://bmccardiovascdisord.biomedcentral.com/articles/10.1186/s12872-021-02236-7#citeas)
Dong CH, Wang ZM, Chen SY. Neutrophil to lymphocyte ratio predict mortality and major adverse cardiac events in acute coronary syndrome: A systematic review and meta-analysis. Clinical Biochemistry. 2018 [acceso 14/04/2021];52: 131-6. Disponible en: https://www.sciencedirect.com/science/article/abs/pii/S0009912017309724?via%3Dihub
Wang R, Gu H, Ji C, Gao Y, Gao L, Qin S, et al. Relationship of Neutrophil–Lymphocyte Ratio with coronary artery disease and plaque composition of coronary artery. Research Square. 2021 [acceso 22/03/2021];1-19. Disponible en: https://assets.researchsquare.com/files/rs-826088/v1/9c95c637-1029-4de1-adfd-a17cc7cacd24.pdf?c=1632508536
Rodríguez Blanco S, Leyva Quert AY, Aguilar Medina JM, Barcelay Leyva FA, Tamargo Barbeito TO. Índice neutrófilo-linfocitario en el diagnóstico de infarto de miocardio tipo 4a. Revista Argentina de Cardioangiología Intervencionista. 2020 [acceso 04/03/2021];11(3):126-31. Disponible en: http://adm.meducatium.com.ar/contenido/articulos/24001260131_1787/pdf/24001260131.pdf
Lin G, Dai C, Xu K, Wu M. Predictive value of neutrophil to lymphocyte ratio and red cell distribution width on death for ST segment elevation myocardial infarction. Scientific Reports. 2021 [acceso 02/04/2021]; 11(11506): [aprox. 10 p.]. Disponible en: https://www.nature.com/articles/s41598-021-91082-w
Elamragy A, Hussein A, Kaddah A, Meshaal M. Neutrophil: Lymphocyte ratio predicts coronary artery disease severity in non-ST elevation myocardial infarction using syntax score. BMFJ. 2021 [acceso 03/04/2021];38 (2):465-73. Disponible en: https://bmfj.journals.ekb.eg/article_141705_61ae6a2ccb394619296c3db1fef0c531.pdf
Graca Santos L, Ruivo C, Montenegro Sa F, Ribeiro Carvalho R, Saraiva F, J Correia J, et al. Prognostic value of neutrophil-lymphocyte ratio in acute coronary syndrome patients. Eur Heart J. 2018 [acceso 03/04/2021];39(1): 2674. Disponible en: https://academic.oup.com/eurheartj/article/39/suppl_1/ehy565.P2674/5082600
Agarwal R, Aurora RG, Siswanto BB, Muliawan HS. The prognostic value of neutrophil-to-lymphocyte ratio across all stages of coronary artery disease. Coron Artery Dis. 2022 [acceso 03/04/2021];33(2):137-43. Disponible en: https://pubmed.ncbi.nlm.nih.gov/33826535/
Curran FM, Bhalraam U, Mohan M, Singh JS, Anker SD, Dickstein K, et al. Neutrophil-to-lymphocyte ratio and outcomes in patients with new-onset or worsening heart failure with reduced and preserved ejection fraction. ESC Heart Failure. 2021 [acceso 03/04/2021]; 8(Issue4): 3168-79. Disponible en: https://onlinelibrary.wiley.com/doi/epdf/10.1002/ehf2.13424
Cho JH, Cho HJ, Lee HY, Ki YJ, Jeon ES, Hwang KK, et al. Neutrophil-lymphocyte ratio in patients with acute heart failure predicts in-hospital and long-term mortality. J. Clin. Med. 2020 [acceso 03/04/2021];9(2): 557. Disponible en: https://www.mdpi.com/2077-0383/9/2/557/htm
Ashry M, Hafez R, Atef EM. Predictive value of neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio in decompensated heart failure. Egypt J Intern Med. 2019 [acceso 03/04/2021];31:353-9. Disponible en: https://ejim.springeropen.com/track/pdf/10.4103/ejim.ejim_101_18.pdf
Varastehravan H, Naghedi A, Naghedi A, Razavi-Ratki SK, Namiranian N, Nafisi Moghadam R, et al. Correlation between neutrophil to lymphocyte ratio and coronary calcium score in CT angiography. NLR and coronary calcification. Medicina Balear. 2020 [acceso 03/04/2021];35(2):41-6. Disponible en: https://dialnet-correlationBetweenneutrophilToLymphocyteRatioAndCo-7466285-1.pdf
Dávila-Collado R, Jarquín-Durán O, Solís-Vallejo A, Nguyen MA, Espinoza JL. Elevated monocyte to lymphocyte ratio and increased mortality among patients with chronic kidney disease hospitalized for covid-19. J Pers Med. 2021 [acceso: 11/04/2021];11(3):224. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8004261/
Zhang J, Lu X, Wang S, Li H. High neutrophil-to-lymphocyte ratio and platelet-to-lymphocyte ratio are associated with poor survival in patients with hemodialysis. Biomed Res Int. 2021[acceso 11/04/2021]: [aprox. 12 p]. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8159629/
Jaaban M, Billah Zetoune A, Hesenow S, Hessenow R. Neutrophil-lymphocyte ratio and platelet-lymphocyte ratio as novel risk markers for diabetic nephropathy in patients with type 2 diabetes. Heliyon. 2021 [acceso 11/04/2021]; 7(Issue 7): [aprox. 12p]. Disponible en: https://reader.elsevier.com/reader/sd/pii/S2405844021016674?token=808CB79057B381BE7DE8A6EEF277216B19606B6B41EEA85D88595090D9449E669180D1E7F7817D42DFFAF87C6134ABAB&originRegion=us-east-1&originCreation=20210922160814
Umeres-Francia G, Rojas-Fernández M, Herrera Añazco P, Benites-Zapata V. Neutrophil to lymphocyte ratio and platelet to lymphocyte ratio as a risk factor for mortality in peruvian adults with chronic kidney disease. Authorea. 2021 [acceso 04/03/2021]:[aprox. 12 p]. Disponible en: https://d197for5662m48.cloudfront.net/documents/publicationstatus/57197/preprint_pdf/8f857c7c6ea8c73221edbc13e5f614f0.pdf
Tonyali S, Ceylan, Yahsi S, Karakan MS. Does neutrophil to lymphocyte ratio demonstrate deterioration in renal function? Ren Fail. 2018 [acceso 25/03/2021]; 40(1); 209-12. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6014370/
Lu X, Wang S, Zhang G, Xiong R, Li H. High neutrophil-to-lymphocyte ratio is a significant predictor of cardiovascular and all-cause mortality in patients undergoing peritoneal dialysis. Kidney Blood Press Res.2018[acceso 25/03/2021];43(2):490-9. Disponible en: https://pubmed.ncbi.nlm.nih.gov/29627842/
Wang S, Dong L, Pei G, Jiang Z, Qin A, Tan J, et al. High neutrophil-to-lymphocyte ratio is an independent risk factor for end stage renal diseases in iga nephropathy. Front Immunol. 2021 [acceso18/03/2021];12:[aprox. 12 p]. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8387559/
Valga F, Monzón T, Henriquez F, Antón-Pérez G. Índices neutrófilo-linfocito y plaqueta-linfocito como marcadores biológicos de interés en la enfermedad renal. Nefrología. 2019 [acceso 14/03/2021];39(3):243-9. Disponible en: https://www.revistanefrologia.com/es-pdf-S0211699519300165
He P, He LJ, Huang C, Hu JP, Sun SR. Neutrophil-to-lymphocyte ratio and treatment failure in peritoneal dialysis-associated peritonitis. Front Med (Lausanne). 2021 [acceso 12/03/2021]; 26(8):[aprox. 14 p]. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8350030/
Bołtuć K, Bociek A, Dziugieł R, Bociek M, Zapolski T, Dąbrowski W, et al. Neutrophil-lymphocyte ratio (NLR) reflects myocardial inhomogeneities in hemodialyzed patients. Mediators Inflamm. 2020 [acceso 16/03/2021];[aprox. 6 p]. Disponible en: https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7486637/
Su MI, Liu CW. Neutrophil-to-lymphocyte ratio associated with an increased risk of mortality in patients with critical limb ischemia. PLoS ONE 2021 [acceso 17/03/2021];16(5):[aprox. 12 p]. Disponible en https://journals.plos.org/plosone/article?id=10.1371/journal.pone.0252030
Enlaces refback
- No hay ningún enlace refback.
Copyright (c) 2022 José Miguel Rodríguez Perón
Esta obra está bajo una licencia de Creative Commons Reconocimiento-NoComercial 4.0 Internacional.
