Advertisement

Clinical and Experimental Medicine

, Volume 18, Issue 2, pp 283–290 | Cite as

Xanthine oxidase and uric acid as independent predictors of albuminuria in patients with diabetes mellitus type 2

  • Aleksandra KlisicEmail author
  • Gordana Kocic
  • Nebojsa Kavaric
  • Milovan Jovanovic
  • Verica Stanisic
  • Ana Ninic
Original Article

Abstract

Xanthine oxidase (XO) is an important enzyme responsible for conversion of purine bases to uric acid and represents the major source of reactive oxygen species (ROS) production in circulation. Since pathophysiological mechanism of the relationship between XO activity and urinary albumin excretion (UAE) rate is not well elucidated, we aimed to investigate this association in patients with diabetes mellitus type 2 (DM2). In addition, we wanted to examine whether uric acid itself plays an independent role in albuminuria onset and progression, or it is only mediated through XO activity. A total of 83 patients with DM2 (of them 56.6% females) were included in this cross-sectional study. Anthropometric, biochemical parameters and blood pressure were obtained. Multivariate logistic regression analysis showed that uric acid and XO were the independent predictors for albuminuria onset in patients with DM2 [odds ratio (OR) 1.015, 95% CI (1.008–1.028), p = 0.026 and OR 1.015, 95% CI (1.006–1.026), p = 0.040, respectively]. Rise in uric acid for 1 µmol/L enhanced the probability for albuminuria by 1.5%. Also, elevation in XO activity for 1 U/L increased the probability for albuminuria for 1.5%. A total of 66.7% of variation in UAE could be explained with this Model. Both XO and uric acid are independently associated with albuminuria in diabetes. Better understanding of pathophysiological relationship between oxidative stress and albuminuria could lead to discoveries of best pharmacological treatment of XO- and/or uric acid-induced ROS, in order to prevent albuminuria onset and progression.

Keywords

Albuminuria Oxidative stress Type 2 diabetes Uric acid Xanthine oxidase 

Notes

Acknowledgement

This work was financially supported in part by a grant from the Ministry of Education, Science and Technological Development, Republic of Serbia (Project Number 175035).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

The study protocol was approved by the Ethical Committee of Primary Health Care Center in Podgorica, Montenegro, and the research was carried out in compliance with the Declaration of Helsinki.

Informed consent

All the participants included in this study provided written informed consent.

References

  1. 1.
    Miranda-Díaz AG, Pazarín-Villaseñor L, Yanowsky-Escatell FG, Andrade-Sierra J. Oxidative stress in diabetic nephropathy with early chronic kidney disease. J Diabetes Res. 2016;2016:7047238.  https://doi.org/10.1155/2016/7047238.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Papaetis GS, Papakyriakou P, Panagiotou TN. Central obesity, type 2 diabetes and insulin: exploring a pathway full of thorns. Arch Med Sci. 2015;11(3):463–82.  https://doi.org/10.5114/aoms.2015.52350.CrossRefPubMedPubMedCentralGoogle Scholar
  3. 3.
    Fakhruddin S, Alanazi W, Jackson KE. Diabetes-induced reactive oxygen species: mechanism of their generation and role in renal injury. J Diabetes Res. 2017;2017:8379327.  https://doi.org/10.1155/2017/8379327.CrossRefPubMedPubMedCentralGoogle Scholar
  4. 4.
    Bolignano D, Cernaro V, Gembillo G, Baggetta R, Buemi M, D’Arrigo G. Antioxidant agents for delaying diabetic kidney disease progression: a systematic review and meta-analysis. PLoS ONE. 2017;12(6):e0178699.  https://doi.org/10.1371/journal.pone.0178699.CrossRefPubMedPubMedCentralGoogle Scholar
  5. 5.
    George J, Struthers A. The role of urate and xanthine oxidase in vascular oxidative stress: future directions. Ther Clin Risk Manag. 2009;5:799–803.CrossRefPubMedPubMedCentralGoogle Scholar
  6. 6.
    Boban M, Kocic G, Radenkovic S, et al. Circulating purine compounds, uric acid, and xanthine oxidase/dehydrogenase relationship in essential hypertension and end stage renal disease. Ren Fail. 2014;36(4):613–8.  https://doi.org/10.3109/0886022X.2014.882240.CrossRefPubMedGoogle Scholar
  7. 7.
    Tam HK, Kelly AS, Metzig AM, Steinberger J, Johnson LA. Xanthine oxidase and cardiovascular risk in obese children. Child Obes. 2014;10(2):175–80.  https://doi.org/10.1089/chi.2013.0098.CrossRefPubMedPubMedCentralGoogle Scholar
  8. 8.
    Feoli AM, Macagnan FE, Piovesan CH, Bodanese LC, Siqueira IR. Xanthine oxidase activity is associated with risk factors for cardiovascular disease and inflammatory and oxidative status markers in metabolic syndrome: effects of a single exercise session. Oxidative Med Cell Longev. 2014;2014:587083.  https://doi.org/10.1155/2014/587083.CrossRefGoogle Scholar
  9. 9.
    Baskol G, Baskol M, Kocer D. Oxidative stress and antioxidant defenses in serum of patients with non-alcoholic steatohepatitis. Clin Biochem. 2007;40(11):776–80.  https://doi.org/10.1016/j.clinbiochem.2007.02.006.CrossRefPubMedGoogle Scholar
  10. 10.
    Raghuvanshi R, Kaul A, Bhakuni P, Mishra A, Misra MK. Xanthine oxidase as a marker of myocardial infarction. Indian J Clin Biochem. 2007;22(2):90–2.  https://doi.org/10.1007/BF02913321.CrossRefPubMedPubMedCentralGoogle Scholar
  11. 11.
    Kushiyama A, Nakatsu Y, Matsunaga Y, et al. Role of uric acid metabolism-related inflammation in the pathogenesis of metabolic syndrome components such as atherosclerosis and nonalcoholic steatohepatitis. Mediat Inflamm. 2016;2016:8603164.  https://doi.org/10.1155/2016/8603164.CrossRefGoogle Scholar
  12. 12.
    Miric DJ, Kisic BM, Filipovic-Danic S, et al. Xanthine oxidase activity in type 2 Diabetes mellitus patients with and without diabetic peripheral neuropathy. J Diabetes Res. 2016;2016:4370490.  https://doi.org/10.1155/2016/4370490.CrossRefPubMedPubMedCentralGoogle Scholar
  13. 13.
    Klisic A, Kavaric N, Jovanovic M, et al. Association between unfavorable lipid profile and glycemic control in patients with type 2 diabetes mellitus. J Res Med Sci. 2017;22:122.  https://doi.org/10.4103/jrms.JRMS_284_17.CrossRefPubMedPubMedCentralGoogle Scholar
  14. 14.
    Klisic A, Isakovic A, Kocic G, et al. Relationship between oxidative stress, inflammation and dyslipidemia with Fatty Liver Index in patients with type 2 diabetes mellitus. Exp Clin Endocrinol Diabetes. 2017;125:1–8.  https://doi.org/10.1055/s-0043-118667.CrossRefGoogle Scholar
  15. 15.
    Kavaric N, Klisic A, Ninic A. Are Visceral Adiposity Index and lipid accumulation product reliable indices for metabolic disturbances in patients with type 2 diabetes mellitus? J Clin Lab Anal. 2017.  https://doi.org/10.1002/jcla.22283.PubMedGoogle Scholar
  16. 16.
    Klisic A, Kavaric N, Jovanovic M, Soldatovic I, Gligorovic-Barhanovic N, Kotur-Stevuljevic J. Bioavailable testosterone is independently associated with Fatty Liver Index in postmenopausal women. Arch Med Sci. 2017;5(13):1188–96.  https://doi.org/10.5114/aoms.2017.68972.CrossRefGoogle Scholar
  17. 17.
    Hopkins WG. Estimating sample size for magnitude-based inferences. Sportscience. 2006;10:63–70.Google Scholar
  18. 18.
    Bland JM, Altman DG. Transformations, means and confidence intervals. BMJ. 1996;312:1079.CrossRefPubMedPubMedCentralGoogle Scholar
  19. 19.
    Swets JA. Measuring the accuracy of diagnostic systems. Science. 1988;240:1285–93.CrossRefPubMedGoogle Scholar
  20. 20.
    Liang CC, Lin PC, Lee MY, et al. Association of serum uric acid concentration with diabetic retinopathy and albuminuria in Taiwanese patients with type 2 diabetes mellitus. Int J Mol Sci. 2016;17(8):1248.  https://doi.org/10.3390/ijms17081248.CrossRefPubMedCentralGoogle Scholar
  21. 21.
    Yan D, Tu Y, Jiang F, et al. Uric acid is independently associated with diabetic kidney disease: a cross-sectional study in a Chinese population. PLoS ONE. 2015;10(6):e0129797.  https://doi.org/10.1371/journal.pone.0129797.CrossRefPubMedPubMedCentralGoogle Scholar
  22. 22.
    Nomura J, Busso N, Ives A, et al. Febuxostat, an inhibitor of xanthine oxidase, suppresses lipopolysaccharide-induced MCP-1 production via MAPK phosphatase-1-mediated inactivation of JNK. PLoS ONE. 2013;8(9):e75527.  https://doi.org/10.1371/journal.pone.0075527.CrossRefPubMedPubMedCentralGoogle Scholar
  23. 23.
    Battelli MG, Bolognesi A, Polito L. Pathophysiology of circulating xanthine oxidoreductase: new emerging roles for a multi-tasking enzyme. Biochim Biophys Acta. 2014;1842(9):1502–17.  https://doi.org/10.1016/j.bbadis.2014.05.022.CrossRefPubMedGoogle Scholar
  24. 24.
    Soletsky B, Feig DI. Uric acid reduction rectifies prehypertension in obese adolescents. Hypertension. 2012;60(5):1148–56.  https://doi.org/10.1161/HYPERTENSIONAHA.112.196980.CrossRefPubMedGoogle Scholar
  25. 25.
    Mazzali M, Kanellis J, Han L, et al. Hyperuricemia induces a primary renal arteriolopathy in rats by a blood pressure-independent mechanism. Am J Physiol Ren Physiol. 2002;282(6):F991–7.  https://doi.org/10.1152/ajprenal.00283.2001.CrossRefGoogle Scholar
  26. 26.
    Ahmad A, Manjrekar P, Yadav C, Agarwal A, Srikantiah RM, Hegde A. Evaluation of ischemia-modified albumin, malondialdehyde, and advanced oxidative protein products as markers of vascular injury in diabetic nephropathy. Biomark Insights. 2016;11:63–8.  https://doi.org/10.4137/BMI.S39053.CrossRefPubMedPubMedCentralGoogle Scholar
  27. 27.
    Piwowar A, Knapik-Kordecka M, Warwas M. Comparison of the usefulness of plasma levels of oxidatively modified forms of albumin in estimating kidney dysfunction in diabetic patients. Clin Investig Med. 2010;33(2):E109.CrossRefGoogle Scholar
  28. 28.
    Ruiz-Hurtado G, Condezo-Hoyos L, Pulido-Olmo H, et al. Development of albuminuria and enhancement of oxidative stress during chronic renin–angiotensin system suppression. J Hypertens. 2014;32(10):2082–91.  https://doi.org/10.1097/HJH.0000000000000292.CrossRefPubMedGoogle Scholar
  29. 29.
    Kachhawa K, Agrawal D, Rath B, Kumar S. Association of lipid abnormalities and oxidative stress with diabetic nephropathy. J Integr Nephrol Androl. 2017;4:3–9.  https://doi.org/10.4103/jina.jina_1_17.CrossRefGoogle Scholar

Copyright information

© Springer International Publishing AG, part of Springer Nature 2017

Authors and Affiliations

  1. 1.Center for Laboratory DiagnosticsPrimary Health Care CenterPodgoricaMontenegro
  2. 2.Department of Medical BiochemistryUniversity of Nis – School of MedicineNisSerbia
  3. 3.Clinical Center of MontenegroPodgoricaMontenegro
  4. 4.Department of Medical BiochemistryUniversity of Belgrade - Faculty of PharmacyBelgradeSerbia

Personalised recommendations