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Risk factors for sodium valproate-induced renal tubular dysfunction

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Abstract

Objective

To explore the risk factors for the development of sodium valproate (VPA)-induced renal tubular dysfunction for early diagnosis and treatment.

Study design

The subjects were selected from patients who were diagnosed with epilepsy and administered VPA. Blood and spot urine samples were collected and measured the concentration of VPA, the level of serum phosphorus, serum uric acid, serum free carnitine, serum cystatin-c, and urine β2-microglobulin (BMG). Patients with urine BMG/creatinine levels above 219.2 were treated as renal proximal tubular dysfunction (RTD), with all others treated as non-RTD.

Results

Eighty-seven patients, 4–48 years, 53 men and 34 women, were studied. RTD group is 17 patients and non-RTD group is 70 patients. Univariate analyses revealed that the RTD patients were more likely to be bedridden, receiving enteral tube feeding, taking more anticonvulsants, and demonstrating significantly lower serum levels of free carnitine, uric acid, and phosphorus. Among them, bedridden, free serum carnitine, and phosphorus levels were associated with the development of RTD by multivariate analysis.

Conclusions

Bedridden patients receiving VPA are susceptible to hypocarnitinemia, which can cause RTD and may lead to FS. Therefore, urinary BMG should be measured regularly in all patients receiving VPA to assess renal tubular function. An additional measurement of serum free carnitine level should be considered in patients who developed RTD. Supplementation of carnitine for those patients to prevent such complication deserves for further study.

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Abbreviations

FS:

Fanconi syndrome

VPA:

Sodium valproate

BMG:

β2-microglobulin

Cr:

Creatinine

PTCs:

Proximal tubular cells

RTD:

Renal proximal tubular dysfunction

References

  1. Hall AM, Bass P, Unwin RJ. Drug-induced renal Fanconi syndrome. Q J Med. 2014;107:261–9.

    Article  CAS  Google Scholar 

  2. Izzedine H, Launay-Vacher V, Isnard-Bagnis C, Deray G. Drug-induced Fanconi’s syndrome. Am J Kidney Dis. 2003;41:292–309.

    Article  CAS  PubMed  Google Scholar 

  3. Dhillon N, Högler W. Fractures and Fanconi syndrome due to prolonged sodium valproate use. Neuropediatrics. 2011;42:119–21.

    Article  CAS  PubMed  Google Scholar 

  4. Patel SM, Graff-Radford J, Wieland ML. Valproate-induced Fanconi syndrome in a 27-year-old woman. J Gen Intern Med. 2011;26:1072–4.

    Article  PubMed  PubMed Central  Google Scholar 

  5. Inoue T, Tanaka Y, Otani R, Itabashi H, Murakami N, Nagai T, et al. Three cases of Fanconi syndrome associated with valproate sodium treatment. No To Hattatsu. 2011;43:233–7.

    PubMed  Google Scholar 

  6. Yoshikawa H, Yamazaki S, Abe T. Hypouricemia in severely disabled children: influence of elemental enteral nutrition on the serum uric acid levels. Brain Dev. 2004;26:43–6.

    Article  PubMed  Google Scholar 

  7. Takahashi M, Ueda S, Misaki H, Sugiyama N, Matsumoto K, Matsuo N, et al. Carnitine determination by an enzymatic cycling method with carnitine dehydrogenase. Clin Chem. 1994;40:817–21.

    CAS  PubMed  Google Scholar 

  8. Madsen MG, Nørregaard R, Palmfeldt J, Olsen LH, Frøkiær J, Jørgensen TM. Urinary NGAL, cystatin C, β2-microglobulin, and osteopontin significance in hydronephrotic children. Pediatr Nephrol. 2012;27:2099–106.

    Article  PubMed  Google Scholar 

  9. Takayanagi M. Abnormalities of carnitine metabolism in human diseases. J Anal Bio-Sci. 2012;35:281–92.

    CAS  Google Scholar 

  10. Lenoir GR, Perignon JL, Gubler MC, Broyer M. Valproic acid: a possible cause of proximal tubular renal syndrome. J Pediatr. 1981;98:503–4.

    Article  CAS  PubMed  Google Scholar 

  11. Yoshikawa H, Watanabe T, Abe T. Tubulo-interstitial nephritis caused by sodium valproate. Brain Dev. 2002;24:102–5.

    Article  PubMed  Google Scholar 

  12. Yoshikawa H, Watanabe T, Abe T. Fanconi syndrome caused by sodium valproate: report of three severely disabled children. Eur J Paediatr Neurol. 2002;6:165–7.

    Article  PubMed  Google Scholar 

  13. Zaki EL, Springate JE. Renal injury from valproic acid: case report and literature review. Pediatr Neurol. 2002;27:318–9.

    Article  PubMed  Google Scholar 

  14. Fukuda Y, Watanabe H, Ohtomo Y, Yabuta K. Immunologically mediated chronic tubulo-interstitial nephritis caused by valproate therapy. Nephron. 1996;72:328–9.

    Article  CAS  PubMed  Google Scholar 

  15. Keith KL, Koyelle P. Anticonvulsant-induced rickets and nephrocalcinosis. BMJ Case Rep. 2012;. doi:10.1136/bcr.12.2011.5359.

    Google Scholar 

  16. Shiari R, Bagherzade L, Alaei MR. Fanconi syndrome associated with valporic Acid: a case report. Iran Red Crescent Med J. 2011;13:844–5.

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Tanaka S, Suzukawa J, Araki A, Imai Y, Takaya J, Taniuchi S, et al. Hypouricemic acute renal failure in a patient with valproate-induced Fanconi syndrome. Jpn J Pediatr Nephrol. 2008;21:182–7.

    Google Scholar 

  18. Knights MJ, Finlay E. The effects of sodium valproate on the renal function of children with epilepsy. Pediatr Nephrol. 2010;29:1131–8.

    Article  Google Scholar 

  19. Endo A, Fujita Y, Fuchigami T, Takahashi S, Mugishima H. Fanconi syndrome caused by valproic acid. Pediatr Neurol. 2010;42:287–90.

    Article  PubMed  Google Scholar 

  20. Yamazaki S, Watanabe T, Sato S, Yoshikawa H. Outcomes of renal proximal tubular dysfunctions with Fanconi syndrome caused by sodium valproate. Pediatr Int. 2016;58:1023–6.

    Article  CAS  PubMed  Google Scholar 

  21. Watanabe T, Yoshikawa H, Yamazaki S, Abe Y, Abe T. Secondary renal Fanconi syndrome caused by valproate therapy. Pediatr Nephrol. 2005;20:814–7.

    Article  PubMed  Google Scholar 

  22. Hawkins E, Brewer E. Renal toxicity induced by valproic acid (Depakene). Pediatr Pathol. 1993;13:863–8.

    Article  CAS  PubMed  Google Scholar 

  23. Knorr M, Schaper J, Harjes M, Mayatepek E, Rosenbaum T. Fanconi syndrome caused by antiepileptic therapy with valproic Acid. Epilepsia. 2004;45:868–71.

    Article  PubMed  Google Scholar 

  24. Igarashi N, Sato T, Kyouya S. Secondary carnitine deficiency in handicapped patients receiving valproic acid and/or elemental diet. Acta Paediatr Jpn. 1990;32:139–45.

    Article  CAS  PubMed  Google Scholar 

  25. Bremer J. Carnitine-metabolism and functions. Phys Rev. 1983;63:1420–79.

    CAS  Google Scholar 

  26. Rebouche CJ. Carnitine function and requirements during the life cycle. FASEB J. 1992;6:3379–86.

    Article  CAS  PubMed  Google Scholar 

  27. Kato A. Carnitine deficiency with Valproate sodium therapy—the difference by normal diet and enteral nutrition. No To Hattatsu. 2013;45:17–20.

    PubMed  Google Scholar 

  28. Silva MF, Aires CC, Luis PB, Ruiter JP, IJlst L, et al. Valproic acid metabolism and its effects on mitochondrial fatty acid oxidation: a review. J Inherit Metab Dis. 2008;31:205–16.

    Article  CAS  PubMed  Google Scholar 

  29. Philippe ERL, Andrea P, Soheil Z, Mireille G. Science review: carnitine in the treatment of valproic acid-induced toxicity—what is the evidence? Crit Care. 2005;9:431–40.

    Article  Google Scholar 

  30. Nagata J. Basics of carnitine in health foods: analysis, biochemistry and physiological functions. Int J Anal Bio-Sci. 2012;35:275–80.

    CAS  Google Scholar 

  31. Lin CY, Chiang H. Sodium-valproate-induced interstitial nephritis. Nephron. 1988;48:43–6.

    Article  CAS  PubMed  Google Scholar 

  32. Raza M, Al-Bekairi AM, Ageel AM, Qureshi S. Biochemical basis of sodium valproate hepatotoxicity and renal tubular disorder: time dependence of peroxidative injury. Pharmacol Res. 1997;35:153–7.

    Article  CAS  PubMed  Google Scholar 

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Acknowledgements

We are grateful to the members of the Department of Pediatrics at Kansai Medical University for their important contributions to the experiments.

Author information

Authors and Affiliations

  1. Department of Pediatrics, Kansai Medical University, 2-5-1 Shin-machi, Hirakata-shi, Osaka, 573 1010, Japan

    Satoko Koga, Takahisa Kimata, Sohsaku Yamanouchi, Shoji Tsuji, Ken Yoshimura, Atsushi Araki & Kazunari Kaneko

Authors
  1. Satoko Koga
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  2. Takahisa Kimata
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  3. Sohsaku Yamanouchi
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  4. Shoji Tsuji
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  5. Ken Yoshimura
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  6. Atsushi Araki
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  7. Kazunari Kaneko
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Correspondence to Kazunari Kaneko.

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Conflict of interest

The authors have declared that no conflict of interest exists.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional and/or national research committee at which the studies were conducted (IRB approval number 26–30, H141172) and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards.

Informed consent

Informed consent was obtained from all individual participants included in the study.

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Koga, S., Kimata, T., Yamanouchi, S. et al. Risk factors for sodium valproate-induced renal tubular dysfunction. Clin Exp Nephrol 22, 420–425 (2018). https://doi.org/10.1007/s10157-017-1472-z

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  • DOI: https://doi.org/10.1007/s10157-017-1472-z

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