Side effects of long-term antiepileptic drugs on renal tubules of Indonesian children
Background Long-term treatment with antiepileptic drugs such as valproic acid (VPA) and carbamazepine (CBZ) may disrupt renal tubular function. Urinary N-acetyl-beta-D-glucosaminidase (NAG) may reflect tubular function and may be useful in detecting early-stage tubular injury. To date, no study has investigated the toxic effect of VPA and CBZ on renal tubules using urinary NAG in Indonesian children.
Objectives To determine the toxicity of long-term VPA and/or CBZ treatment on renal tubules in children with epilepsy by measuring urinary NAG index (iNAG).
Methods This cross-sectional study was conducted from January to March 2015 at Cipto Mangunkusumo Hospital and Anakku Clinic Pondok Pinang, Jakarta. We included children aged 3 to 16 years with epilepsy on VPA (n=36), CBZ (n=14), or VPA-CBZ combination (n=14) therapy. We measured urinary levels of creatinine and NAG. The urinary NAG reference value was obtained from age-matched healthy controls (n=30). To eliminate diurnal variations in NAG, iNAG was calculated by dividing urinary NAG by urinary creatinine. A urinary iNAG of more than two standard deviations above the mean for healthy children was considered elevated.
Results Mean urinary iNAG values for the control, VPA, CBZ, and combination groups were 3.01, 5.9, 4.07, and 6.9 U/g, respectively. All treated groups had higher mean urinary iNAG values compared to the control group. Urinary iNAG was increased in 11/36 children on VPA, 2/14 children on CBZ, and 9/14 children on combination therapy.
Conclusion Long-term VPA use may impair renal tubular function, as shown by the increased urinary iNAG. Combination therapy increases damage in the renal tubules.
Alatas H. Anatomi dan fisiologi ginjal. In: Alatas H, Tambunan T, Trihono PP, Pardede SO, editors. Buku Ajar Nefrologi Anak. 2nd ed. Jakarta: Ikatan Dokter Anak Indonesia, 2002. p.1-28. Indonesian.
Anaizi N. The drug monitor. [cited 2015 January 15]. Available from: http://126.96.36.199/Fisiologia/cardiovascular/Objetivo_11/diuretics.htm.
Nash K, Hafeez A, Hou S. Hospital-acquired renal insufficiency. Am J Kidney Dis. 2002;39:930-6.
Bellomo R. The epidemiology of acute renal failure: 1975 versus 2005. Curr Opin Crit Care. 2005;11:555-65.
Galley HF. Can acute renal failure be prevented? J R Coll Surg Edinb. 2000;45:44-50.
Naughton C. Drug-induced nephrotoxicity. Am Acad Fam Phys. 2008;78:743-50.
Wu I, Parikh CR. Screening for kidney disease: older measures versus novel biomarkers. Clin J Am Soc Nephrol. 2008;3:1895-901.
Waikar SS, Liu KD, Chertow GM. Diagnosis, epidemiology and outcomes of acute kidney injury. Clin Am Soc Nephrol. 2008;3:844-61.
Siew ED, Ware LB, Ikizler TA. Biological markers of acute kidney injury. Clin J Am Soc Nephrol. 2011;22:810-20.
Centers for Disease Control and Prevention. Targeting epilepsy. [cites 2015 February 4]. Available from: https://www.cdc.gov/epilepsy/index.html.
Cowan LD. The epidemiology of epilepsies in children. Ment Retard Dev Disabil Res Rev. 2002;8:171-81.
Korinthenberg R, Wehrle L, Zimmerhackl LB. Renal tubular dysfunction following treatment with anti-epileptic drugs. Eur J Pediatr. 1994;153:855-8.
Otsuka T, Sunaga Y, Hikima A. Urinary N-acetyl-b-glucosaminidase and guanidinoacetic acid levels in epileptic patients treated with anti-epileptic drugs. Brain Dev. 1994;16:437-40.
Yuksel A, Cengiz M, Seven M. N-acetyl-b-glucosaminidase and b-galactosidase activity in children receiving antiepileptic drugs. Pediatr Neurol. 1999;20:24-6.
Verotti R, Greco R, Pascarella V, Matera V, Morgese G, Chiarell F. Renal tubular function in patients receiving anticonvulsant therapy: a long-term study. Epilepsia. 2000;41:1432-5.
Csathy L, Olah AV, Clemens B, Gyorgy I, Varga J. Urinary N-acetyl-b-D-glucosaminidase in epileptic children treated in antiepileptic drugs. Arch Dis Child. 2000;83:420-2.
Unay B, Akin R, Sarici SU, Gok F, Kurt I, Gokcay E. Evaluation of renal tubular function in children taking anti-epileptic treatment. Nephrology. 2006;11:485-8.
Mazaheri M, Samaie A, Semnani V. Renal tubular dysfunction measured by N-acetyl-beta glucosaminidase/creatinine activity index in children receiving antiepileptic drugs: a randomized controlled trial. Ital J Pediatr. 2011;37:21.
Fricke-Galindon I, Jung-Cook H, Llerena A, Lopez-Lopez M. Pharmacogenetics of adverse reactions to antiepileptic drugs. Neurologia. 2018;33:165-76.
Verrotti A, Dâ€™Egidio C, Mohn A, Coppola G. Weight gain following treatment with valproic acid: pathogenic mechanism and clinical implications. Obese Rev. 2011;12:32-43.
Bae HM, Park YJ, Moon DE. Stevens-Johnson syndrome induced by carbamazepine in a patient who previously had carbamazepine induced pruritus. Korean J Pain. 2013;26:80-3.
Coleman A, Trappler B. Stevens-Johnson syndrome following treatment with carbamazepin for a mood disorder. Jeff J of Psych. 2012;13:1-5.
Devi K, George S, Criton S, Suja V, Sridevi PK. Carbamazepine-the commonest cause of toxic epidermal necrolysis and Steven-Johnson syndrome: a study of 7 years. Indian J Dermatol Venereol Leprol. 2005;71:325-8.
Gougoux A, Vinay P. Metabolic effects of valproate on dog renal cortical tubules. Can J PhysiolPharmacol. 1988;67:88-97.
Csathy L, Pocsy I. Urinary NAG determination in newborns and children: methods and diagnostic applications. Eur J Clin Chem Clin Biochem. 1995;33:575-87.
Skalova S, Chladek J. Urinary N-acetyl-b-D-glucosaminidase activity in healthy children. Nephrology. 2004;9:19-21.
Authors who publish with this journal agree to the following terms:
Authors retain copyright and grant the journal right of first publication with the work simultaneously licensed under a Creative Commons Attribution License that allows others to share the work with an acknowledgement of the work's authorship and initial publication in this journal.
Authors are able to enter into separate, additional contractual arrangements for the non-exclusive distribution of the journal's published version of the work (e.g., post it to an institutional repository or publish it in a book), with an acknowledgement of its initial publication in this journal.
This work is licensed under a Creative Commons Attribution-NonCommercial-ShareAlike 4.0 International License.