Legal Performance-enhancing Drugs Alter Course and Treatment of Rhabdomyolysis-induced Acute Kidney Injury.

Item request has been placed! ×
Item request cannot be made. ×
loading   Processing Request
Read Online Read More Add to Saved list
  • Additional Information
    • Source:
      Publisher: Oxford University Press Country of Publication: England NLM ID: 2984771R Publication Model: Print Cited Medium: Internet ISSN: 1930-613X (Electronic) Linking ISSN: 00264075 NLM ISO Abbreviation: Mil Med Subsets: MEDLINE
    • Publication Information:
      Publication: 2018- : Oxford : Oxford University Press
      Original Publication: Washington, D.C. : Association of Military Surgeons, United States, 1955-
    • Subject Terms:
      Performance-Enhancing Substances*/therapeutic use ; Acute Kidney Injury*/drug therapy ; Acute Kidney Injury*/etiology ; Rhabdomyolysis*/complications ; Rhabdomyolysis*/drug therapy; Humans ; Mice ; Animals ; Ibuprofen/pharmacology ; Ibuprofen/therapeutic use ; Caffeine/pharmacology ; Caffeine/therapeutic use ; Glycerol/therapeutic use ; Cilastatin/pharmacology ; Cilastatin/therapeutic use
    • Abstract:
      Introduction: Rhabdomyolysis-induced acute kidney injury (RIAKI) can interrupt physical training and increase mortality in injured warfighters. The legal performance-enhancing drugs caffeine and ibuprofen, which can cause renal injury, are widely used by service members. Whether caffeine or ibuprofen affects RIAKI is unknown. Cilastatin treatment was recently identified as an experimental treatment to prevent RIAKI at injury. To determine potential interacting factors in RIAKI treatment, we test the hypothesis that caffeine and ibuprofen worsen RIAKI and interfere with treatment.
      Materials and Methods: In mice, RIAKI was induced by glycerol intramuscular injection. Simultaneously, mice received caffeine (3 mg/kg), ibuprofen (10 mg/kg), or vehicle. A second cohort received volume resuscitation (PlasmaLyte, 20 mL/kg) in addition to caffeine or ibuprofen. In a third cohort, cilastatin (200 mg/kg) was administered concurrently with drug and glycerol administration. Glomerular filtration rate (GFR), blood urea nitrogen (BUN), urine output (UOP), renal pathology, and renal immunofluorescence for kidney injury molecule 1 were quantified after 24 hours.
      Results: Caffeine did not worsen RIAKI; although BUN was modestly increased by caffeine administration, 24-hour GFR, UOP, and renal histopathology were similar between vehicle-treated, caffeine-treated, and caffeine + PlasmaLyte-treated mice. Ibuprofen administration greatly worsened RIAKI (GFR 14.3 ± 19.5 vs. 577.4 ± 454.6 µL/min/100 g in control, UOP 0.5 ± 0.4 in ibuprofen-treated mice vs. 2.7 ± 1.7 mL/24 h in control, and BUN 264 ± 201 in ibuprofen-treated mice vs. 66 ± 21 mg/dL in control, P < .05 for all); PlasmaLyte treatment did not reverse this effect. Cilastatin with or without PlasmaLyte did not reverse the deleterious effect of ibuprofen in RIAKI.
      Conclusions: Caffeine does not worsen RIAKI. The widely used performance-enhancing drug ibuprofen greatly worsens RIAKI in mice. Standard or experimental treatment of RIAKI including the addition of cilastatin to standard resuscitation is ineffective in mice with RIAKI exacerbated by ibuprofen. These findings may have clinical implications for the current therapy of RIAKI and for translational studies of novel treatment.
      (Published by Oxford University Press on behalf of the Association of Military Surgeons of the United States 2023. This work is written by (a) US Government employee(s) and is in the public domain in the US.)
    • References:
      Kidney Int. 1993 Sep;44(3):643-53. (PMID: 8231040)
      Clin J Sport Med. 2018 Nov;28(6):e92-e94. (PMID: 28727638)
      Mil Med. 2019 Mar 1;184(3-4):81-83. (PMID: 30215751)
      Mil Med. 2015 Apr;180(4):391-401. (PMID: 25826344)
      Antioxidants (Basel). 2020 Sep 03;9(9):. (PMID: 32899204)
      Nephrol Dial Transplant. 2017 Oct 01;32(10):1645-1655. (PMID: 28340076)
      Int J Mol Sci. 2021 Nov 20;22(22):. (PMID: 34830406)
      J Clin Invest. 1966 May;45(5):724-35. (PMID: 5935360)
      J Sci Med Sport. 2019 Jul;22(7):758-762. (PMID: 30846355)
      Mil Med. 2017 Mar;182(3):e1709-e1712. (PMID: 28290947)
      Ann Epidemiol. 2012 May;22(5):318-30. (PMID: 22445519)
      Biochem Biophys Res Commun. 1985 Sep 16;131(2):974-9. (PMID: 3863619)
      J Am Soc Nephrol. 2017 Jun;28(6):1783-1791. (PMID: 28052987)
      Histol Histopathol. 2018 Nov;33(11):1227-1234. (PMID: 29901212)
      Eur J Intern Med. 2015 May;26(4):285-91. (PMID: 25862494)
      BMJ Case Rep. 2018 Apr 21;2018:. (PMID: 29680796)
      Cells. 2022 May 09;11(9):. (PMID: 35563891)
      Biomed Res Int. 2015;2015:704382. (PMID: 26504822)
      Eur J Intern Med. 2022 Jul;101:21-28. (PMID: 35534373)
      Phys Sportsmed. 2022 Dec;50(6):486-493. (PMID: 34278922)
      Crit Care Clin. 2004 Jan;20(1):171-92. (PMID: 14979336)
      J Spec Oper Med. 2015 Fall;15(3):108-113. (PMID: 26360365)
      J Trauma Acute Care Surg. 2015 May;78(5):988-93. (PMID: 25909420)
      Mil Med. 2013 Jun;178(6):659-64. (PMID: 23756073)
      Int J Mol Sci. 2021 Jan 27;22(3):. (PMID: 33513824)
      J Pharmacol Exp Ther. 2010 Aug;334(2):419-29. (PMID: 20435919)
      J Trauma Acute Care Surg. 2015 Oct;79(4 Suppl 2):S171-4. (PMID: 26131786)
      Kidney Int. 2012 Sep;82(6):652-63. (PMID: 22718191)
      Toxicol Rep. 2018 Nov 03;5:1140-1152. (PMID: 30505695)
      J Trauma Acute Care Surg. 2016 Mar;80(3):492-8. (PMID: 26670111)
      J Am Soc Nephrol. 2021 Oct;32(10):2579-2594. (PMID: 34341182)
    • Grant Information:
      TL1 TR002371 United States TR NCATS NIH HHS
    • Accession Number:
      WK2XYI10QM (Ibuprofen)
      0 (Performance-Enhancing Substances)
      3G6A5W338E (Caffeine)
      PDC6A3C0OX (Glycerol)
      141A6AMN38 (Cilastatin)
    • Publication Date:
      Date Created: 20231110 Date Completed: 20231113 Latest Revision: 20240210
    • Publication Date:
      20240210
    • Accession Number:
      PMC10637309
    • Accession Number:
      10.1093/milmed/usad142
    • Accession Number:
      37948276