Role of Oxidative Stress in Lithium-Induced Nephropathy

  • Georgina P. Ossani
  • Ana M. Uceda
  • Juan M. Acosta
  • Néstor R. Lago
  • Marisa G. Repetto
  • Diego J. Martino
  • Jorge E. Toblli


Long-term lithium treatment was associated with chronic kidney disease and renal failure although the underlying pathogenic mechanisms are not certainty known. The aim of this study was to evaluate changes in oxidative stress measures as well as renal functional and structural alterations associated with chronic use of lithium in rats. Forty Wistar male rats were randomized into four groups: control groups fed ad libitum powered standard diet for 1 and 3 months and experimental groups fed ad libitum the same diet supplemented with 60 mmol/kg diet for 1 and 3 months. Histopathological changes, laboratory parameters, and oxidative stress measurements were assessed at months 1 and 3. The experimental animals showed alteration of the cortical tubules from the first month of lithium-treatment and a decrease in the glomerular filtration rate and in the glomerular area at the third month. There was an increase in thiobarbituric acid reactive substances and carbonyls, as well as an increase in reduced glutathione, in the kidney of rats exposed to lithium. These changes were evident from the first month of treatment and remained throughout the experiment. Our results suggest that, oxidative stress could be one of the pathogenic mechanisms involved in the structural and functional alterations of the kidney associated with prolonged use of lithium. The study of the pathogenic mechanisms involved in lithium-induced nephropathy is a critical issue for the development of new strategies for prevention and/or early detection.


Lithium Chronic kidney disease Renal function Oxidative stress 


Compliance with Ethical Standards

Conflict of Interest

The authors declare that they have no conflict of interest.

Ethical Approval

All procedures performed in studies involving animals were in accordance with the ethical standards of the institution or practice at which the studies were conducted (Animal Welfare Committee number 2366).


  1. 1.
    Yatham LN, Kennedy SH, Parikh SV, Schaffer A, Beaulieu S, Alda M, O’Donovan C, MacQueen G, McIntyre RS, Sharma V, Ravindran A, Young LT, Milev R, Bond DJ, Frey BN, Goldstein BI, Lafer B, Birmaher B, Ha K, Nolen WA, Berk M (2013) Canadian network for mood and anxiety treatments (CANMAT) and International Society for Bipolar Disorders (ISBD) collaborative update of CANMAT guidelines for the management of patients with bipolar disorder: update 2013. Bipolar Disord 15(1):1–44CrossRefGoogle Scholar
  2. 2.
    Ng F, Mammen OK, Wilting I, Sachs GS, Ferrier IN, Cassidy F, Beaulieu S, Yatham LN, Berk M, International Society for Bipolar Disorders (2009) International Society for Bipolar Disorders. The International Society for Bipolar Disorders (ISBD) consensus guidelines for the safety monitoring of bipolar disorder treatments. Bipolar Disord 11(6):559–595CrossRefGoogle Scholar
  3. 3.
    Bendz H, Aurell M, Lanke J (2001) A historical cohort study of kidney damage in long-term lithium patients: continued surveillance needed. Eur Psychiatry 16(4):199–206CrossRefGoogle Scholar
  4. 4.
    Bassilios N, Martel P, Godard V, Froissart M, Grünfeld JP, Stengel B, Néphropar R (2008) Monitoring of glomerular filtration rate in lithium-treated outpatients-an ambulatory laboratory database surveillance. Nephrol Dial Transplant 23(2):562–565CrossRefGoogle Scholar
  5. 5.
    Bocchetta A, Ardau R, Carta P, Ligas F, Sardu C, Pani A, del Zompo M (2013) Duration of lithium treatment is a risk factor for reduced glomerular function: a cross-sectional study. BMC Med 11(11):33. CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    McCann SM, Daly J, Kelly CB (2008) The impact of long-term lithium treatment on renal function in an outpatient population. Ulster Med J 77(2):102–105PubMedPubMedCentralGoogle Scholar
  7. 7.
    Tredget J, Kirov A, Kirov G (2010) Effects of chronic lithium treatment on renal function. J Affect Disord 126(3):436–440CrossRefGoogle Scholar
  8. 8.
    Close H, Reilly J, Mason JM et al (2014) Renal failure in lithium-treated bipolar disorder: a retrospective cohort study. PLoS One 9(3):e90169CrossRefGoogle Scholar
  9. 9.
    Hestbech J, Aurell M (1979) Lithium-induced uraemia. Lancet 1:212–213CrossRefGoogle Scholar
  10. 10.
    Markowitz GS, Radhakrishnan J, Kambham N, Am V, Hines WH, VD D’A (2000) Lithium nephrotoxicity: a progressive combined glomerular and tubulointerstitial nephropathy. J Am Soc Nephrol 11(8):1439–1448PubMedGoogle Scholar
  11. 11.
    Walker RJ, Leader JP, Bedford JJ, Gobe G, Davis G, Vos FE, deJong S, Schollum JBW (2013) Chronic interstitial fibrosis in the rat kidney induced by long-term (6-mo) exposure to lithium. Am J Physiol Renal Physiol 304(3):F300–F307CrossRefGoogle Scholar
  12. 12.
    Alsady M, Baumgarten R, Deen PM, de Groot T (2016) Lithium in the kidney: friend and foe? J Am Soc Nephrol 27(6):1587–1595CrossRefGoogle Scholar
  13. 13.
    Rej S, Pira S, Marshe V, Do A, Elie D, Looper KJ, Herrmann N, Müller DJ (2016) Molecular mechanisms in lithium-associated renal disease: a systematic review. Int Urol Nephrol 48(11):1843–1853CrossRefGoogle Scholar
  14. 14.
    Oktem F, Ozguner F, Sulak O, Olgar Ş, Akturk O, Yilmaz HR, Altuntas I (2005) Lithium-induced renal toxicity in rats: protection by a novel antioxidant caffeic acid phenethyl ester. Mol Cell Biochem 277(1–2):109–115CrossRefGoogle Scholar
  15. 15.
    Nciri R, Allagui MS, Bourogaa E, Saoudi M, Murat JC, Croute F, Elfeki A (2012) Lipid peroxidation, antioxidant activities and stress protein (HSP72/73, GRP94) expression in kidney and liver of rats under lithium treatment. J Physiol Biochem 68(1):11–18CrossRefGoogle Scholar
  16. 16.
    Toplan S, Ozdemir S, Tanriverdi G, Akyolcu MC, Ozcelik D, Darıyerli N (2016) The effects of lithium administration on oxidant/antioxidant status in rats: biochemical and histomorphological evaluations. Biol Trace Elem Res 169(2):279–284CrossRefGoogle Scholar
  17. 17.
    Ossani GP, Castiglia NI, Martino MF, Fariña SL, Uceda AM, Monserrat AJ (2009) Morphometry of the glomerular tuft during normal postnatal growth in female rats. Effects of age, location of glomeruli and methods of obtaining and processing the renal tissue SJLAS 36(3):265–269.Google Scholar
  18. 18.
    González Flecha B, Llesuy S, Boveris A (1991) Hydroperoxide-initiated chemiluminescence: an assay for oxidative stress in biopsies of heart, liver, and muscle. Free Radic Biol Med 10:93–100CrossRefGoogle Scholar
  19. 19.
    Repetto MG, Ossani G, Monserrat AJ, Boveris A (2010) Oxidative damage: the biochemical mechanism of cellular injury and necrosis in choline deficiency. Exp Mol Pathol 88:143–149CrossRefGoogle Scholar
  20. 20.
    Fraga C, Leibovitz B, Tappel AL (1988) Lipid peroxidation measured as thiobarbituric acid-reactive substances in tissue slices: characterization and comparison with homogenates and microsomes. Free Radic Biol Med 4:155–161CrossRefGoogle Scholar
  21. 21.
    Reznick A, Packer L (1994) Oxidative damage to proteins: spectrophotometric method for carbonyl assay. Meth Enzymol 233:357–363CrossRefGoogle Scholar
  22. 22.
    Maehly AC, Chance B (1954) The assay of catalases and peroxidases. Methods Biochem Anal 1:357–424PubMedGoogle Scholar
  23. 23.
    Akerboom TP, Sies H (1981) Assay of glutathione, glutathione disulfide, and glutathione mixed disulfides in biological samples. Methods Enzymol 77:373–382CrossRefGoogle Scholar
  24. 24.
    Loghin F, Olinic A, Popa D, Socaciu C, Leucuta S (1999) Effects of long-term administration of lithium and hydrochlorothiazlde in rats. Met Based Drugs 6(2):87–93CrossRefGoogle Scholar
  25. 25.
    Ahmad M, Elnakady Y, Farooq M, Wadaan M (2011) Lithium induced toxicity in rats: blood serum chemistry, antioxidative enzymes in red blood cells and histopathological studies. Biol Pharm Bull 34(2):272–277CrossRefGoogle Scholar
  26. 26.
    Nyengaard JR, Bendtsen TF (1992) Glomerular number and size in relation to age, kidney weight, and body surface in normal man. Anat Rec 232:194–201CrossRefGoogle Scholar
  27. 27.
    Severus E, Bauer M (2013) Managing the risk of lithium-induced nephropathy in the long-term treatment of patients with recurrent affective disorders. BMC Med 11(11):34. CrossRefPubMedPubMedCentralGoogle Scholar
  28. 28.
    Devarajan P (2010) The use of targeted biomarkers for chronic kidney disease. Adv Chronic Kidney Dis 17(6):469–479CrossRefGoogle Scholar
  29. 29.
    Musik I, Kiełczykowska M, Rajtar B, Świątek L, Polz-Dacewicz M, Kocot J (2017) Lithium as a prooxidant? A possible protective role of selenium – in vitro study. Annals Agr Environ Med 24(3):423–427CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Georgina P. Ossani
    • 1
    • 2
    • 3
  • Ana M. Uceda
    • 1
    • 2
  • Juan M. Acosta
    • 4
  • Néstor R. Lago
    • 1
  • Marisa G. Repetto
    • 4
    • 3
  • Diego J. Martino
    • 5
    • 3
  • Jorge E. Toblli
    • 6
    • 2
    • 3
  1. 1.School of Medicine, Department of Pathology, Centre of Experimental and Applied PathologyUniversity of Buenos AiresBuenos AiresArgentina
  2. 2.Laboratory of Experimental MedicineHospital AlemánBuenos AiresArgentina
  3. 3.National Council of Scientific and Technical Research (CONICET)Buenos AiresArgentina
  4. 4.School of Pharmacy and Biochemistry, Department of Analytical Chemistry and Physicochemistry, Cathedra of General and Inorganic ChemistryUniversity of Buenos AiresBuenos AiresArgentina
  5. 5.Institute of Cognitive and Translational Neuroscience (INCyT), INECO FoundationFavaloro UniversityBuenos AiresArgentina
  6. 6.School of MedicineUniversity of Buenos AiresBuenos AiresArgentina

Personalised recommendations