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Abstract

Review Article

An update in the utilization of N-acetyl cysteine & vitamin c for tackling the oxidative stress in acute kidney injury secondary to robust sepsis - A systematic review

Kulvinder Kochar Kaur*, Gautam Allahbadia and Mandeep Singh

Published: 01 February, 2022 | Volume 6 - Issue 1 | Pages: 001-018

The commonest etiology of acute kidney injury (AKI) is Sepsis that results in an escalation of morbidity and mortality in the hospital intensive care units. Existentially, the therapy of septic AKI rather than being definitive or curative is just supportive, without tackling the pathophysiology. Usually, Sepsis gets correlated with systemic inflammation, along with the escalated generation of Reactive oxygen species (ROS), in particular superoxide. Simultaneously liberation of nitric oxide (NO) subsequently reacts with the superoxide, thus, resulting in the generation of reactive nitrogen species (RNS), that is mostly peroxynitrite. This sepsis stimulated generation of ROS in addition to RNS might cause a reduction in the bioavailability of NO that modulates microcirculation aberrations, localized tissue hypoxia as well as mitochondrial impairment, thus starting a vicious cycle of cellular damage which results in AKI. Here we conducted a systematic review utilizing search engine PubMed, Google scholar; Web of science; Embase; Cochrane review library utilizing the MeSH terms like septic AKI; ROS; inducible nitric oxide synthase (iNOS); nicotinamide adenine nucleotide phosphate(NADPH)oxidase complex; Oxidative stress; Renal medullary hypoxia; Hypoxia inducible factor1; hypoxia responsive enhancer A; mitochondrial impairment; Intrarenal oxygenation; urinary oxygenation; erythropoietin gene; RRT; NAC; Vitamin C from 1950 to 2021 till date. We found a total of 6500 articles out of which we selected 110 articles for this review. No meta-analysis was done. Thus here we detail the different sources of ROS, at the tie of sepsis, besides their pathophysiological crosstalk with the immune system, microcirculation as well as mitochondria that can result in the generation of AKI. Furthermore, we detail the therapeutic utility of N-acetylcysteine (NAC), besides the reasons for its success in ovine as well as porcine models of AKI. Moreover, we discuss preclinical along with clinical for evaluation of Vitamin C’s antioxidant effects as well as pleiotropic effects as a stress hormone that might aid in abrogation of septic AKI.

Read Full Article HTML DOI: 10.29328/journal.jcn.1001084 Cite this Article Read Full Article PDF

Keywords:

Sepsis; Acute kidney injury; Oxidative stress; Renal medullary hypoxia; NAC; Vitamin C

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  98. Zhou G, Kamenos G, Pendem D, Wilson JX, Wu F. Ascorbate protects against vascular leakage in cecal ligation and puncture induced septic peritonitis. Am J Physiol Integr Comp Physiol. 2012; 302: R409- R416. PubMed: https://pubmed.ncbi.nlm.nih.gov/22116513/
  99. Tym lK, Li F, Wilson JX. Septic impairment of capillary blood flow requires nicotinamide adenine nucleotide phosphate oxidase but not nitric oxide synthase and is rapidly reversed by Ascorbate through an endothelial nitric oxide synthase dependent mechanism. Crit Care Med. 2008; 36: 2355-2362. PubMed: https://pubmed.ncbi.nlm.nih.gov/18596627/
  100. Wu F, Wilson JX, Tyml K. Ascorbate protects against impaired arterioral constriction in sepsis byinhibiting induciblenitric oxide synthase Free Radical Biol Med. 2004; 37: 1282-1289. PubMed: https://pubmed.ncbi.nlm.nih.gov/15451067/
  101. Fowler AA, Syed A, Knowlson S, Sculthorpe R, Farhin D, et al. Phase I safety trial of intravenous ascorbic acid in patients with severe sepsis. J Transl Med. 2014; 12: 32. PubMed: https://pubmed.ncbi.nlm.nih.gov/24484547/
  102. Zabet MH, Mohammedi M, Ramezani M, Khalili H. Effect of high dose ascorbic acid on vasopressor requirements in septic shock. J Respharm Pract. 2016; 5: 94-100. PubMed: https://pubmed.ncbi.nlm.nih.gov/27162802/
  103. Marik PE, Khangoora V, Rivera R, Hooper MH, Catravas J. Hydrocortisone, Vitamin C, and Thiamine for the Treatment of Severe Sepsis and Septic Shock: A Retrospective Before-After Study. Chest. 2017; 151: 1229-1238. PubMed: https://pubmed.ncbi.nlm.nih.gov/27940189/
  104. Fuji T, Luethi N, Young PJ, Frei DR, Eastwood GM, et al. Effect of Vitamin C, Hydrocortisone, and thiamine vs Hydrocortisone alone on time alive and free of vasopressor support among patients with septic shock: VITAMINS randomized Clinical trial. JAMA. 2020; 323: 423-431. PubMed: https://pubmed.ncbi.nlm.nih.gov/31950979/
  105. Moscowitz A, Huang DT, Hou FC, Gong J, Doshi B, et al. Effects of ascorbic acid, corticosteroids and thiamine on organ injury in septic shock. The ACTS randomized Clinical trial. JAMA. 2020; 324: 642-650. PubMed: https://pubmed.ncbi.nlm.nih.gov/32809003/
  106. Hwang SY, Ryoo SM, Park JE, Jo YH, Jang DH, et al. Combination treatment of Vitamin C and thiamine for septic shock; a multicentre, double blinded randomized controlled study. Intensive Care Med. 2020; 46: 2015-2025. PubMed: https://pubmed.ncbi.nlm.nih.gov/32780166/
  107. Fowler AA. Truwit JD, Hie RD, Morris PE, de Wilde C, et al. Effect of Vitamin C organ failure and biomarkers of inflammation and Vascular injury in patients with sepsis and severe acute respiratory failure: the CITRIS ALI randomized Clinical trial. JAMA. 2019; 322: 1261-1270. PubMed: https://pubmed.ncbi.nlm.nih.gov/31573637/
  108. Subramanium VS, Sabui S, Moradi H, Marchant JS, Said HM. Tumor necrosis factor alpha reduces intestinal Vitamin C uptake; arole for NFκB mediated signaling. Am J Physiol Gastroenterol Liver Physiol. 2018; 315: G241-G248. PubMed: https://pubmed.ncbi.nlm.nih.gov/29631379/
  109. Yahase F, Fujii, Naorungroj T, Belletti A. Luethi N, et al. Harm of IV high dose Vitamin C the ray in adult patients: a scoping review. Crit Care Med. 2021; 48: e620- e628. PubMed: https://pubmed.ncbi.nlm.nih.gov/32404636/
  110. Lankadeva YR, Peiris RM, Okazaki N, BirchallI E, Trask-Marino A, et al. Reversal of the pathophysiological responses to gram negative sepsis by mega dose Vitamin C. Crit Care Med. 2021; 49: e179-e190. PubMed: https://pubmed.ncbi.nlm.nih.gov/33239507/
  111. Kaur KK, Allahbadi GN, Singh M. Have we done justice to Linus Pauling’s discovery in 1970s with Regards to utilization of Vitamin C for prevention of acute respiratory illnesses, besides role of Vitamin C in current COVID19 Epidemic - A Comprehenive review. Acta Sci Nutr Health. 2002; 6: 1-14.

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