Human albumin and its modifications in emergency medicine

Relevance. Human albumin (HA) accounts for 60% of all plasma proteins and is an important component of extracellular fluids, including lymph, interstitial and cerebrospinal fluid. This protein has multifunctional properties — it supports oncotic blood pressure, regulates the immune system, stabilizes the endothelium and affects key pathophysiological mechanisms. The aim of the review is to determine the features of the structure, properties and use of HA in acute medicine with a primary focus on brain damage of hypoxic-traumatic origin. Literature was searched in the databases PubMed, Google Academic, Web of Science, RSCI by keywords: human albumin, critical conditions, brain hypoxia, reactive oxygen species and nitrogen, search depth of 10 years. An analysis of data on the structure and modifications of HA in hypoxia/ischemia under conditions of increased formation of reactive oxygen species (ROS) and nitrogen (RNS) is presented. The informative value of HA modifications (“ischemia–modified albumin” — IMA and albumin oxidized by RNS from tyrosine — 3-nitrotyrosine — 3-HT residues) in the diagnosis and prognosis of various diseases is considered. One of the limitations of the use of HA in critical condition medicine is the lack of knowledge of the mechanisms of action of HA and modifications of endogenous and exogenous (injected) HA during infusion therapy. In the reduced state, HA has antioxidant activity and can neutralize the action of ROS and RNS formed during hypoxia. However, under conditions of hypoxia/ischemia and oxidative/nitrosative stress, HA is susceptible to oxidation and modification, which leads to the loss of its protective properties.

Contribution:
Sorokina E.G., Reutov V.P. — the concept and design of the study;
Sorokina E.G., Karaseva O.V., Semenova Zh.B. — collection of literature data;
Sorokina E.G., Reutov V.P. — writing the text;
Smirnov I.E. — editing the text.
All co-authors — approval of the final version of the article, responsibility for the integrity of all parts of the article.

Acknowledgment. The study had no sponsorship.

Conflict of interest. The authors declare no conflict of interest.

Received: December 20, 2024
Accepted: March 18, 2025
Published: April 29, 2025

1. Ahn S.M., Simpson R.J. Body fluid proteomics: Prospects for biomarker discovery. Proteomics Clin. Appl. 2007; 1(9): 1004–15. https://doi:10.1002/prca.200700217

2. Rabbani G., Ahn S.N. Structure, enzymatic activities, glycation and therapeutic potential of human serum albumin: A natural cargo. Int. J. Biol. Macromol. 2019; 123: 979–90. https://doi.org/10.1016/R.j.ijbiomac.2018.11.053

3. Mishra V., Heath R.J. Structural and biochemical features of human serum albumin essential for eukaryotic cell culture. Int. J. Mol. Sci. 2021; 22(16): 8411. https://doi.org/10.3390/ijms22168411

4. De Simone G., di Masi A., Ascenzi P. Serum albumin: a multifaced enzyme. Int. J. Mol. Sci. 2021; 22(18): 10086. https://doi.org/10.3390/ijms221810086

5. Chen C.B., Hammo B., Barry J., Radhakrishnan K. Overview of albumin physiology and its role in pediatric diseases. Curr. Gastroenterol. Rep. 2021; 23(8): 11. https://doi.org/10.1007/s11894-021-00813-6

6. Wu N., Liu T., Tian M., Liu C., Ma S., Cao H., et al. Albumin, an interesting and functionally diverse protein, varies from ‘native’ to ‘effective’ (Review). Mol. Med. Rep. 2024; 29(2): 24. https://doi.org/10.3892/mmr.2023.13147

7. Belayev L., Liu Y., Zhao W., Busto R., Ginsberg M.D. Human albumin therapy of acute ischemic stroke: marked neuroprotective efficacy at moderate doses and with a broad therapeutic window. Stroke. 2001; 32(2): 553–60. https://doi.org/10.1161/01.str.32.2.553

8. Smith J.D., Wilson S., Schneider H.G. Misclassification of calcium status based on albumin-adjusted calcium: studies in a tertiary hospital setting. Clin. Chem. 2018; 64(12): 1713–22. https://doi.org/10.1373/clinchem.2018.291377

9. Maher P., van Leyen K., Dey P.N., Honrath B., Dolga A., Methner A. The role of Ca2+ in cell death caused by oxidative glutamate toxicity and ferroptosis. Cell Calcium. 2018; 70: 47–55. https://doi.org/10.1016/j.ceca.2017.05.007

10. Al-Harthi S., Lachowicz J.I., Nowakowski M.E., Jaremko M., Jaremko Ł. Towards the functional high-resolution coordination chemistry of blood plasma human serum albumin. J. Inorg. Biochem. 2019; 198: 110716. https://doi.org/10.1016/j.jinorgbio.2019.110716

11. Soeters P.B., Wolfe R.R., Shenkin A. Hypoalbuminemia: pathogenesis and clinical significance. JPEN. J. Parenter. Enteral Nutr. 2019; 43(2): 181–93. https://doi.org/10.1002/jpen.1451

12. Brock F., Bettinelli L.A., Dobner T., Stobbe J.C., Pomatti G., Telles C.T. Prevalence of hypoalbuminemia and nutritional issues in hospitalized elders. Rev. Lat. Am. Enfermagem. 2016; 24: e2736. https://doi:10.1590/1518-8345.0260.2736

13. Yin M., Si L., Qin W., Li C., Zhang J., Yang H., et al. Predictive value of serum albumin level for the prognosis of severe sepsis without exogenous human albumin administration: a prospective cohort study. J. Intensive Care Med. 2018; 33(12): 687–94. https://doi.org/10.1177/0885066616685300

14. Vincent J.L., Russell J.A., Jacob M., Martin G., Guidet B., Wernerman J., et al. Albumin administration in the acutely ill: what is new and where next. Crit. Care. 2014; 18(4): 231. https://doi.org/10.1186/cc13991

15. Myburgh J., Cooper D. J., Finfer S., Bellomo R., Norton R., Bishop N., et al. Saline or albumin for fluid resuscitation in patients with traumatic brain injury. N. Engl. J. Med. 2007; 357(9): 874–84. https://doi.org/10.1056/NEJMoa067514

16. Gillen C.M., Lee R., Mack G.W., Tomaselli C.M., Nishiyasu T., Nadel E.R. Plasma volume expansion in humans after a single intense exercise protocol. J. Appl. Physiol. (1985). 1991; 71(5): 1914–20. https://doi.org/10.1152/jappl.1991.71.5.1914

17. Finfer S., Bellomo R., Boyce N., French J., Myburgh J., Norton R., et al. A comparison of albumin and saline for fluid resuscitation in the intensive care unit. N. Engl. J. Med. 2004; 350(22): 2247–56. https://doi.org/10.1056/NEJMoa040232

18. Quinlan, G.J., Mumby S., Martin G.S., Bernard G.R., Gutteridge J.M., Evans T.W. Albumin influences total plasma antioxidant capacity favorably in patients with acute lung injury. Crit. Care Med. 2004; 32(3): 755–9. https://doi.org/10.1097/01.ccm.0000114574.18641.5d

19. Rustogi D., Yusuf K. Use of Albumin in the NICU: an evidence-based review. NeoReviews. 2022; 23(9): e625–34. https://doi.org/10.1542/neo.23-9-e625

20. Yu Y., Liu J., Hu B., Wang R., Yang X., Shang X., et al. Expert consensus on the use of human serum albumin in critically ill patients. Chin. Med. J. (Engl.) 2021; 134(14): 1639–54. https://doi.org/10.1097/CM9.0000000000001661

21. Udeh C.I., You J., Wanek M.R., Dalton J., Udeh B.L., Demirjian S., et al. Acute kidney injury in postoperative shock: is hyperoncotic albumin administration an unrecognized resuscitation risk factor? Perioper. Med. (Lond.). 2018; 7: 29. https://doi.org/10.1186/s13741-018-0110-y

22. Bratton S.L., Chestnut R.M., Ghajar J., McConnell Hammond F.F., Harris O.A., Hartl R., et al. Guidelines for the management of severe traumatic brain injury. I. Blood pressure and oxygenation. J. Neurotrauma. 2007; 24(Suppl. 1): S7–13. https://doi.org/10.1089/neu.2007.9995

23. Asgeirsson B., Grände P.O., Nordström C.H. A new therapy of post-trauma brain oedema based on haemodynamic principles for brain volume regulation. Intensive Care Med. 1994; 20(4): 260–7. https://doi.org/10.1007/BF01708961

24. Cooper D.J., Myburgh J., Heritier S., Finfer S., Bellomo R., Billot L., et al. Albumin resuscitation for traumatic brain injury: is intracranial hypertension the cause of increased mortality? J. Neurotrauma. 2013; 30(7): 512–8. https://doi.org/10.1089/neu.2012.2573

25. Gergelé L., Manet R. Postural regulation of intracranial pressure: a critical review of the literature. Acta Neurochir. Suppl. 2021; 131: 339–42. https://doi.org/10.1007/978-3-030-59436-7_65

26. Schirmer-Mikalsen K., Moen K.G., Skandsen T., Vik A., Klepstad P. Intensive care and traumatic brain injury after the introduction of a treatment protocol: a prospective study. Acta Anaesthesiol. Scand. 2013; 57(1): 46–55. https://doi.org/10.1111/j.1399-6576.2012.02785.x

27. Palesch Y.Y., Hill M.D., Ryckborst K.J., Tamariz D., Ginsberg M.D. The ALIAS pilot trial: a dose-escalation and safety study of albumin therapy for acute ischemic stroke – II: neurologic outcome and efficacy analysis. Stroke. 2006; 37(8): 2107–14. https://doi.org/10.1161/01.str.0000231389.34701.b5

28. Martin R.H., Yeatts S.D., Hill M.D., Moy C.S., Ginsberg M.D., Palesch Y.Y. ALIAS (Albumin in Acute Ischemic Stroke) trials: analysis of the combined data from parts 1 and 2. Stroke. 2016; 47(9): 2355–9. https://doi.org/10.1161/strokeaha.116.012825

29. Kuwabara K., Fushimi K., Matsuda S., Ishikawa K.B., Horiguchi H., Fujimori K. Association of early post-procedure hemodynamic management with the outcomes of subarachnoid hemorrhage patients. J. Neurol. 2013; 260(3): 820–31. https://doi.org/10.1007/s00415-012-6710-4

30. Huang Z., Dong W., Yan Y., Xiao Q., Man Y. Effects of intravenous human albumin and furosemide on EEG recordings in patients with intracerebral hemorrhage. Clin. Neurophysiol. 2002; 113(3): 454–8. https://doi.org/10.1016/s1388-2457(02)00015-9

31. Di Napoli M., Behrouz R., Topel C.H., Misra V., Pomero F., Giraudo A., et al. Hypoalbuminemia, systemic inflammatory response syndrome, and functional outcome in intracerebral hemorrhage. J. Crit. Care. 2017; 41: 247–53. https://doi.org/10.1016/j.jcrc.2017.06.002

32. Xie Y., Guo H., Wang L., Xu L., Zhang X., Yu L., et al. Human albumin attenuates excessive innate immunity via inhibition of microglial Mincle/Syk signaling in subarachnoid hemorrhage. Brain Behav. Immun. 2017; 60: 346–60. https://doi.org/10.1016/j.bbi.2016.11.004

33. Sorokina E.G., Reutov V.P., Pinelis V.G., Vinskaya N.P., Vergun O.V., Khodorov B.I. The mechanism of potentiation of the glutamate-induced neurotoxicity by serum albumin. A possible role of nitric oxide. Biologicheskie membrany. 2000; 13(3): 389–96. (in Russian)

34. Plantier J.L., Duretz V., Devos V., Urbain R., Jorieux S. Comparison of antioxidant properties of different therapeutic albumin preparations. Biologicals. 2012; 44(4): 226–33. https://doi.org/10.1016/j.biologicals.2016.04.002

35. Watanabe H., Imafuku T., Otagiri M., Maruyama T. Clinical implications associated with the posttranslational modification-induced functional impairment of albumin in oxidative stress-related diseases. J. Pharm. Sci. 2017; 106(9): 2195–203. https://doi.org/10.1016/j.xphs.2017.03.002

36. Reutov V.P., Sorokina E.G. NO-synthase and nitrite-reductase components of nitric oxide cycle. Biokhimiya. 1998; 63(7): 874–84. https://elibrary.ru/lfdtdn

37. Tsikas D. Extra-platelet low-molecular-mass thiols mediate the inhibitory action of S-nitrosoalbumin on human platelet aggregation via S-transnitrosylation of the platelet surface. Amino Acids. 2021; 53(4): 563–73. https://doi.org/10.1007/s00726-021-02950-8

38. Sorokina E.G., Reutov V.P., Karaseva O.V., Semenova Zh.B., Pinelis V.G., Smirnov I.E., et al. The effect of NO-generating compounds on the lymphocytes’ ATP content and the relationship with the levels of autoantibodies to glutamate receptors in children who have suffered a traumatic brain injury. Rossiyskiy pediatricheskiy zhurnal. 2024; 27(3): 161–7. https://doi.org/10.46563/1560-9561-2024-27-3-161-167 https://elibrary.ru/vjvlht (in Russian)

39. Ramos-Fernández E., Tajes M., Palomer E., Ill-Raga G., Bosch-Morató M., Guivernau B., et al. Posttranslational nitro-glycative modifications of albumin in Alzheimer’s disease: implications in cytotoxicity and amyloid-β peptide aggregation. J. Alzheimer’s Dis. 2014; 40(3): 643–57. https://doi.org/10.3233/JAD-130914

40. Menon B., Ramalingam K., Krishna V. Study of ischemia modified albumin as a biomarker in acute ischaemic stroke. Ann. Neurosci. 2018; 25(4): 187–90. https://doi.org/10.1159/000488188

41. Wayenberg J.L., Ransy V., Vermeylen D., Damis E., Bottari S.P. Nitrated plasma albumin as a marker of nitrative stress and neonatal encephalopathy in perinatal asphyxia. Free Radic. Biol. Med. 2009; 47(7): 975–82. https://doi.org/10.1016/j.freeradbiomed.2009.07.003

42. Reutov V.P., Azhipa Ia.I., Kaiushin L.P. Electron paramagnetic resonance study of the products of the reaction between nitrogen oxides and several organic compounds. Byulleten’ eksperimental’noy biologii i meditsiny. 1978; 86(9): 299–301. (in Russian)

43. Bar-Or D., Lau E., Winkler J.V. A novel assay for cobalt-albumin binding and its potential as a marker for myocardial ischemia-a preliminary report. J. Emerg. Med. 2000; 19(4): 311–5. https://doi.org/10.1016/s0736-4679(00)00255-9

44. Christenson R.H., Duh S.H., Sanhai W.R., Wu A.H., Holtman V., Painter P., et al. Characteristics of an Albumin Cobalt Binding Test for assessment of acute coronary syndrome patients: a multicenter study. Clin. Chem. 2001; 47(3): 464–70.

45. Berenshtein E., Mayer B., Goldberg C., Kitrossky N., Chevion M. Patterns of mobilization of copper and iron following myocardial ischemia: possible predictive criteria for tissue injury. J. Mol. Cell. Cardiol. 1997; 29(11): 3025–34. https://doi.org/10.1006/jmcc.1997.0535

46. Cengiz H., Dagdeviren H., Kanawati A., Suzen Çaypinar S., Yesil A., Ekin M., et al. Ischemia-modified albumin as an oxidative stress biomarker in early pregnancy loss. J. Matern. Fetal Neonatal Med. 2016; 29(11): 1754–7. https://doi.org/10.3109/14767058.2015.1061494

47. Kahveci H., Tayman C., Laoğlu F., Celik H.T., Kavas N., Kılıç Ö., et al. Serum ischemia-modified albumin in preterm babies with respiratory distress syndrome. Indian J. Clin. Biochem. 2016; 31(1): 38–42. https://doi.org/10.1007/s12291-015-0494-0

48. Talat M.A., Saleh R.M., Shehab M.M., Khalifa N.A., Sakr M.M.H., Elmesalamy W.M. Evaluation of the role of ischemia modified albumin in neonatal hypoxic-ischemic encephalopathy. Clin. Exp. Pediatr. 2020; 63(8): 329–34. https://doi.org/10.3345/cep.2019.01410

49. Cho D.K., Choi J.O., Kim S.H., Choi J., Rhee I., Ki C.S., et al. Ischemia-modified albumin is a highly sensitive serum marker of transient myocardial ischemia induced by coronary vasospasm. Coron. Artery Dis. 2007; 18(2): 83–7. https://doi.org/10.1097/MCA.0b013e328010a49f

50. Ellidag H.Y., Eren E., Yılmaz N., Cekin Y. Oxidative stress and ischemia-modified albumin in chronic ischemic heart failure. Redox Rep. 2014; 19(3): 118–23. https://doi.org/10.1179/1351000213Y.0000000083

51. Sbarouni E., Georgiadou P., Koutelou M., Sklavainas I., Panagiotakos D., Voudris V. Ischaemia-modified albumin in dilated cardiomyopathy. Ann. Clin. Biochem. 2009; 46(Pt. 3): 241–3. https://doi.org/10.1258/acb.2009.009022

52. Turedi S., Gunduz A., Mentese A., Karahan S. C., Yilmaz S. E., Eroglu O., et al. Value of ischemia-modified albumin in the diagnosis of pulmonary embolism. Am. J. Emerg. Med. 2007; 25(7): 770–3. https://doi.org/10.1016/j.ajem.2006.12.013

53. Gunduz A., Turedi S., Mentese A., Karahan S.C., Hos G., Tatli O., et al. Ischemia-modified albumin in the diagnosis of acute mesenteric ischemia: a preliminary study. Am. J. Emerg. Med. 2008; 26(2): 202–5. https://doi.org/10.1016/j.ajem.2007.04.030

54. Turedi S., Cinar O., Kaldirim U., Mentese A., Tatli O., Cevik E., et al. Ischemia-modified albumin levels in carbon monoxide poisoning. Am. J. Emerg. Med. 2011; 29(6): 675–81. https://doi.org/10.1016/j.ajem.2010.02.006

55. Jena I., Nayak S.R., Behera S., Singh B., Ray S., Jena D., et al. Evaluation of ischemia-modified albumin, oxidative stress, and antioxidant status in acute ischemic stroke patients. J. Nat. Sci. Biol. Med. 2017; 8(1): 110–3. https://doi.org/10.4103/0976-9668.198346

56. Demirci B., Karakılıç M.E., Coşkun A., Yel C., Uyanık S.A., Ünal K., et al. The brain ischemic volume correlation with the ischemic modified albumin level. Bagcilar Med. Bull. 2021; 6(1): 26–31. https://doi.org/10.4274/BMB.galenos.2020.10.068

57. Costa M., Horrillo R., Ortiz A.M., Pérez A., Mestre A., Ruiz A., et al. Increased albumin oxidation in cerebrospinal fluid and plasma from Alzheimer’s disease patients. J. Alzheimer’s Dis. 2018; 63(4): 1395–404. https://doi.org/10.3233/JAD-180243

58. Radwan T.A.M., Fahmy R.S., El Emady M.F.M., Khedr A.S.E.D.M., Osman S. H., ElSonbaty M.I., et al. Ischemia-modified albumin as a biomarker for prediction of poor outcome in patients with traumatic brain injury: an observational cohort study. J. Neurosurg. Anesthesiol. 2021; 33(3): 254–7. https://doi.org/10.1097/ANA.0000000000000647

59. Tan H., Yang W., Wu C., Liu B., Lu H., Wang H., et al. Assessment of the role of intracranial hypertension and stress on hippocampal cell apoptosis and hypothalamic-pituitary dysfunction after TBI. Sci. Rep. 2017; 7(1): 3805. https://doi.org/10.1038/s41598-017-04008-w

60. Zou X., Wu Z., Huang J., Liu P., Qin X., Chen L., et al. The role of matrix metalloproteinase-3 in the doxycycline attenuation of intracranial venous hypertension-induced angiogenesis. Neurosurgery. 2018; 83(6): 1317–27. https://doi.org/10.1093/neuros/nyx633

61. Chen T., Zhu J., Wang Y.H., Hang C.H. ROS-mediated mitochondrial dysfunction and ER stress contribute to compression-induced neuronal injury. Neuroscience. 2019; 416: 268–80. https://doi.org/10.1016/j.neuroscience.2019.08.007

62. Xu Z., Weng X., Cao L., Liang D., Zeng F., Chen S., et al. Correlation analysis of serum 3-NT, NPASDP-4, and S100β protein levels with cognitive function in patients diagnosed with cerebral infarction. Altern. Ther. Health Med. 2024; 30(4): 54–9.

63. Sorokina E.G., Semenova Z.B., Reutov V.P., Arsenieva E.N., Karaseva O.V., Fisenko A.P., et al. Brain biomarkers in children after mild and severe traumatic brain injury. Acta Neurochir. Suppl. 2021; 13: 103–7. https://doi.org/10.1007/978-3-030-59436-7_22