Journal http://jcn.sagepub.com/ of Child Neurology
Does Nephrotoxicity Exist in Pediatric Epileptic Patients on Valproate or Carbamazepine Therapy? Cengiz Havali, Kivilcim Gücüyener, Necla Buyan, Ünsal Yilmaz, Esra Gürkas, Özlem Gülbahar, Ercan Demir and Ayse Serdaroglu J Child Neurol published online 22 June 2014 DOI: 10.1177/0883073814538505 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/06/19/0883073814538505
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Jun 22, 2014 What is This?
Downloaded from jcn.sagepub.com at University of South Australia on August 11, 2014
Original Article
Does Nephrotoxicity Exist in Pediatric Epileptic Patients on Valproate or Carbamazepine Therapy?
Journal of Child Neurology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538505 jcn.sagepub.com
Cengiz Havali, MD1, Kıvılcım Gu¨cu¨yener, MD1, Necla Buyan, MD2, ¨ zlem Gu¨lbahar, MD4, ¨ nsal Yılmaz, MD3, Esra Gu¨rkas¸ , MD1, O U 1 Ercan Demir, MD , and Ays¸ e Serdarog˘lu, MD1
Abstract The aim of this study was to investigate the effects of valproate and carbamazepine, on renal glomerular and tubular functions. The patient group comprised 54 children with new-onset epilepsy treated with valproate (n ¼ 30) and carbamazepine (n ¼ 24). Twenty-six healthy children were in the control group. The serum creatinine and cystatin C levels and urinary excretion of N-acetyl-b-D-glucosaminidase (NAG) levels were measured and the glomerular filtration rate (GFR) was estimated. Serum creatinine and cystatin C concentrations were not different between patients and controls. The glomerular filtration rate of the patient groups were higher than those of the control group. Thus, both drugs probably lead to glomerular hyperfiltration and toxicity for glomerular functions. However, urinary N-acetyl-b-D-glucosaminidase/creatinine levels were significantly higher in patients receiving only valproate (6.1 + 5). The difference between carbamazepine and control groups was not significant for urinary N-acetyl-b-D-glucosaminidase/creatinine levels. Our data suggest that valproate has adverse effects on renal tubular functions. Keywords antiepileptic drugs, tubulopathy, glomerular toxicity Received March 10, 2014. Received revised April 15, 2014. Accepted for publication May 07, 2014.
Epilepsy is one the most prevalent chronic neurologic disorder, affecting 0.5% to 1.0% of children1,2; it requires continued medication for at least 2 years or more and occasionally lifelong management. It is well known that administration of antiepileptic drugs may have unwanted effects on many organs such as hepatic and thyroid functions; however, limited data exist for their influence on renal functions in children. Valproate and carbamazepine are effective and widely used antiepileptic drugs for the treatment of many types of epilepsy in children.3 A few studies have demonstrated their nephrotoxicity, particularly on renal tubular functions.4,5 Among many urinary enzymes studied in children either with epilepsy or other disorders, N-acetyl-b-D-glucosaminidase has been demonstrated as a sensitive and reliable measure for detecting renal tubulopathy.6-8 N-Acetyl-b-D-glucosaminidase is a hydrolytic enzyme located predominantly in the renal proximal tubules and is not normally filtered by the glomeruli. If tubular damage occurs, N-acetyl-b-D-glucosaminidase is delivered to urine at higher than normal levels,5 and this increased level of N-acetyl-b-D-glucosaminidase is accepted as a marker of tubular damage. Glomerular filtration rate (GFR) measurement is a reliable marker of glomerular function in children. Estimations with
24-hour creatinine clearance and practical formulas based on the serum creatinine level are widely used to determine the glomerular filtration rate. However, serum creatinine levels are influenced by several factors, such as age, gender, and muscle mass of the patients. In recent years, plasma cystatin C has been proposed as a better marker to show the variations in glomerular filtration rate than serum creatinine. Thus, practical formulas based on cystatin C for glomerular filtration rate measurements have also been developed.9-11
1
Department of Pediatric Neurology, Gazi University Faculty of Medicine, Ankara, Turkey 2 Department of Pediatric Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey 3 Department of Pediatric Neurology, Dr. Behc¸et Uz Children’s Hospital, Izmir, Turkey 4 Department of Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey Corresponding Author: Cengiz Havali, MD, Department of Pediatric Neurology, Faculty of Medicine, Gazi University, 10th Floor, 06500, Besevler/Ankara, Turkey. Email: [email protected]
Downloaded from jcn.sagepub.com at University of South Australia on August 11, 2014
2
Journal of Child Neurology
In this study, we evaluated the effect of valproate and carbamazepine on renal glomerular and tubular functions of children with epilepsy.
Table 1. GFR Estimation Formulas. Schwartz formula GFR (mL/min/1.73 m2)
k length (cm)/SCr (mg/dL) where k is a constant with values: 1-13 y old: 0.55 >13-y-old female: 0.57 >13-y-old male: 0.70
Cys Eq GFR (mL/min/1.73 m2)
75.94/[Cys C(1.17)]
Methods A total of 54 idiopathic epileptic children between the ages of 4 to 16 years were enrolled in the study. Twenty-six healthy age- and sexmatched (mean age 8.7 + 2.6 years) children without any history of neurologic, nephrologic, or other diseases such as diabetes mellitus that could affect renal functions were chosen as the control group. Duration of antiepileptic drug treatment of the patients was between 3 and 24 months, 30 of 54 patients (55.6%) were receiving valproate, and 24 of 54 (44.4%) were receiving carbamazepine monotherapy. Of the 54 patients, 26 (48%) had generalized seizure and generalized epileptic activity on electroencephalography (EEG); 28 (52%) had partial, complex partial seizure and focal epileptic activity on EEG. All patients were seizure free. Mean age was 10.4 + 3.5 years and 10.7 + 3.7 years in valproate and carbamazepine groups, respectively. Patients who had used any other antiepileptic drug previously; received any drug within the past 3 months that could affect renal function, such as aminoglycosides and steroids; any nephrologic disease, including glomerulonephritis, nephritic syndrome, or recurrent urinary tract infections; any chronic disease such as cardiovascular thyroid disease or diabetes mellitus; and those with refractory seizures were excluded from the study. The number of patients in both drug groups decreased at 6 months of the study. The valproate and carbamazepine groups had 24 and 18 patients, respectively. The study was approved by the local ethics committee, and written informed consent was obtained from the parents. Blood and urine samples from all patients were taken at the beginning of the study and after 6 months. They were taken for only once at the beginning of the study from the control group. Plasma concentrations of valproate and carbamazepine were measured in all patients taking these drugs. Blood levels of cystatin C and serum creatinine and urine creatinine (UCr) levels were measured on the same day with the nephelometric and Jaffe methods, respectively. Urine samples obtained for N-acetyl-b-D-glucosaminidase measurement were stored at 80 C until analysis. Urine dipstick analysis was also performed at the same time with N-acetyl-b-D-glucosaminidase measurement, and patients who were found to have proteinuria and/or hematuria were excluded from the study. Urine N-acetyl-b-Dglucosaminidase levels were measured with the calorimetric method. Three glomerular filtration rate calculation formulas based on creatinine, cystatin C, and combination of serum creatinine and cystatin C were used to determine the glomerular filtration rate (Table 1). According to the Schwartz et al equations,12 the glomerular filtration rate was calculated on the basis of serum creatinine levels. Glomerular filtration rate values were also calculated by 2 new Filler Formula that were introduced by Zapitelli et al.13 One of them uses cystatin C level for glomerular filtration rate calculations, and the other uses both cystatin C and serum creatinine levels. Reference values for glomerular filtration rate were derived from inulin clearance investigations in healthy children older than 2 years of age. The normal level of inulin clearance in the literature is 127 mL/s/1.73 m2 (range: 89-165).14,15 Our patients were divided into 2 different groups: patients having the drugs and the control groups. Data were also analyzed longitudinally between measurements at baseline and at month 6 in each drug group. The results of descriptive analyses were reported as a
Cys-Cr Eq GFR (mL/min/1.73 m2) (507.76 e0.003 x height) / Cys C(0.635) Scr(0.547) (Serum Cr: mmol/L, e ¼ 2.718) Abbreviations: Cys C, cystatin C; GFR, glomerular filtration rate; SCr, serum creatinine.
mean þ standard error for the group. Conformity for normal distribution of quantitative data was performed with the Shapiro-Wilks test. For statistical analysis, nonparametric tests were applied. For evaluations of categorical data, independent groups, and dependent groups, w2 test, Mann-Whitney U test, Kruskall-Wallis H test, and Wilcoxon test were used respectively. All tests were classified as significant if the P value was
Does Nephrotoxicity Exist in Pediatric Epileptic Patients on Valproate or Carbamazepine Therapy? Cengiz Havali, Kivilcim Gücüyener, Necla Buyan, Ünsal Yilmaz, Esra Gürkas, Özlem Gülbahar, Ercan Demir and Ayse Serdaroglu J Child Neurol published online 22 June 2014 DOI: 10.1177/0883073814538505 The online version of this article can be found at: http://jcn.sagepub.com/content/early/2014/06/19/0883073814538505
Published by: http://www.sagepublications.com
Additional services and information for Journal of Child Neurology can be found at: Email Alerts: http://jcn.sagepub.com/cgi/alerts Subscriptions: http://jcn.sagepub.com/subscriptions Reprints: http://www.sagepub.com/journalsReprints.nav Permissions: http://www.sagepub.com/journalsPermissions.nav
>> OnlineFirst Version of Record - Jun 22, 2014 What is This?
Downloaded from jcn.sagepub.com at University of South Australia on August 11, 2014
Original Article
Does Nephrotoxicity Exist in Pediatric Epileptic Patients on Valproate or Carbamazepine Therapy?
Journal of Child Neurology 1-6 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/0883073814538505 jcn.sagepub.com
Cengiz Havali, MD1, Kıvılcım Gu¨cu¨yener, MD1, Necla Buyan, MD2, ¨ zlem Gu¨lbahar, MD4, ¨ nsal Yılmaz, MD3, Esra Gu¨rkas¸ , MD1, O U 1 Ercan Demir, MD , and Ays¸ e Serdarog˘lu, MD1
Abstract The aim of this study was to investigate the effects of valproate and carbamazepine, on renal glomerular and tubular functions. The patient group comprised 54 children with new-onset epilepsy treated with valproate (n ¼ 30) and carbamazepine (n ¼ 24). Twenty-six healthy children were in the control group. The serum creatinine and cystatin C levels and urinary excretion of N-acetyl-b-D-glucosaminidase (NAG) levels were measured and the glomerular filtration rate (GFR) was estimated. Serum creatinine and cystatin C concentrations were not different between patients and controls. The glomerular filtration rate of the patient groups were higher than those of the control group. Thus, both drugs probably lead to glomerular hyperfiltration and toxicity for glomerular functions. However, urinary N-acetyl-b-D-glucosaminidase/creatinine levels were significantly higher in patients receiving only valproate (6.1 + 5). The difference between carbamazepine and control groups was not significant for urinary N-acetyl-b-D-glucosaminidase/creatinine levels. Our data suggest that valproate has adverse effects on renal tubular functions. Keywords antiepileptic drugs, tubulopathy, glomerular toxicity Received March 10, 2014. Received revised April 15, 2014. Accepted for publication May 07, 2014.
Epilepsy is one the most prevalent chronic neurologic disorder, affecting 0.5% to 1.0% of children1,2; it requires continued medication for at least 2 years or more and occasionally lifelong management. It is well known that administration of antiepileptic drugs may have unwanted effects on many organs such as hepatic and thyroid functions; however, limited data exist for their influence on renal functions in children. Valproate and carbamazepine are effective and widely used antiepileptic drugs for the treatment of many types of epilepsy in children.3 A few studies have demonstrated their nephrotoxicity, particularly on renal tubular functions.4,5 Among many urinary enzymes studied in children either with epilepsy or other disorders, N-acetyl-b-D-glucosaminidase has been demonstrated as a sensitive and reliable measure for detecting renal tubulopathy.6-8 N-Acetyl-b-D-glucosaminidase is a hydrolytic enzyme located predominantly in the renal proximal tubules and is not normally filtered by the glomeruli. If tubular damage occurs, N-acetyl-b-D-glucosaminidase is delivered to urine at higher than normal levels,5 and this increased level of N-acetyl-b-D-glucosaminidase is accepted as a marker of tubular damage. Glomerular filtration rate (GFR) measurement is a reliable marker of glomerular function in children. Estimations with
24-hour creatinine clearance and practical formulas based on the serum creatinine level are widely used to determine the glomerular filtration rate. However, serum creatinine levels are influenced by several factors, such as age, gender, and muscle mass of the patients. In recent years, plasma cystatin C has been proposed as a better marker to show the variations in glomerular filtration rate than serum creatinine. Thus, practical formulas based on cystatin C for glomerular filtration rate measurements have also been developed.9-11
1
Department of Pediatric Neurology, Gazi University Faculty of Medicine, Ankara, Turkey 2 Department of Pediatric Nephrology, Gazi University Faculty of Medicine, Ankara, Turkey 3 Department of Pediatric Neurology, Dr. Behc¸et Uz Children’s Hospital, Izmir, Turkey 4 Department of Biochemistry, Gazi University Faculty of Medicine, Ankara, Turkey Corresponding Author: Cengiz Havali, MD, Department of Pediatric Neurology, Faculty of Medicine, Gazi University, 10th Floor, 06500, Besevler/Ankara, Turkey. Email: [email protected]
Downloaded from jcn.sagepub.com at University of South Australia on August 11, 2014
2
Journal of Child Neurology
In this study, we evaluated the effect of valproate and carbamazepine on renal glomerular and tubular functions of children with epilepsy.
Table 1. GFR Estimation Formulas. Schwartz formula GFR (mL/min/1.73 m2)
k length (cm)/SCr (mg/dL) where k is a constant with values: 1-13 y old: 0.55 >13-y-old female: 0.57 >13-y-old male: 0.70
Cys Eq GFR (mL/min/1.73 m2)
75.94/[Cys C(1.17)]
Methods A total of 54 idiopathic epileptic children between the ages of 4 to 16 years were enrolled in the study. Twenty-six healthy age- and sexmatched (mean age 8.7 + 2.6 years) children without any history of neurologic, nephrologic, or other diseases such as diabetes mellitus that could affect renal functions were chosen as the control group. Duration of antiepileptic drug treatment of the patients was between 3 and 24 months, 30 of 54 patients (55.6%) were receiving valproate, and 24 of 54 (44.4%) were receiving carbamazepine monotherapy. Of the 54 patients, 26 (48%) had generalized seizure and generalized epileptic activity on electroencephalography (EEG); 28 (52%) had partial, complex partial seizure and focal epileptic activity on EEG. All patients were seizure free. Mean age was 10.4 + 3.5 years and 10.7 + 3.7 years in valproate and carbamazepine groups, respectively. Patients who had used any other antiepileptic drug previously; received any drug within the past 3 months that could affect renal function, such as aminoglycosides and steroids; any nephrologic disease, including glomerulonephritis, nephritic syndrome, or recurrent urinary tract infections; any chronic disease such as cardiovascular thyroid disease or diabetes mellitus; and those with refractory seizures were excluded from the study. The number of patients in both drug groups decreased at 6 months of the study. The valproate and carbamazepine groups had 24 and 18 patients, respectively. The study was approved by the local ethics committee, and written informed consent was obtained from the parents. Blood and urine samples from all patients were taken at the beginning of the study and after 6 months. They were taken for only once at the beginning of the study from the control group. Plasma concentrations of valproate and carbamazepine were measured in all patients taking these drugs. Blood levels of cystatin C and serum creatinine and urine creatinine (UCr) levels were measured on the same day with the nephelometric and Jaffe methods, respectively. Urine samples obtained for N-acetyl-b-D-glucosaminidase measurement were stored at 80 C until analysis. Urine dipstick analysis was also performed at the same time with N-acetyl-b-D-glucosaminidase measurement, and patients who were found to have proteinuria and/or hematuria were excluded from the study. Urine N-acetyl-b-Dglucosaminidase levels were measured with the calorimetric method. Three glomerular filtration rate calculation formulas based on creatinine, cystatin C, and combination of serum creatinine and cystatin C were used to determine the glomerular filtration rate (Table 1). According to the Schwartz et al equations,12 the glomerular filtration rate was calculated on the basis of serum creatinine levels. Glomerular filtration rate values were also calculated by 2 new Filler Formula that were introduced by Zapitelli et al.13 One of them uses cystatin C level for glomerular filtration rate calculations, and the other uses both cystatin C and serum creatinine levels. Reference values for glomerular filtration rate were derived from inulin clearance investigations in healthy children older than 2 years of age. The normal level of inulin clearance in the literature is 127 mL/s/1.73 m2 (range: 89-165).14,15 Our patients were divided into 2 different groups: patients having the drugs and the control groups. Data were also analyzed longitudinally between measurements at baseline and at month 6 in each drug group. The results of descriptive analyses were reported as a
Cys-Cr Eq GFR (mL/min/1.73 m2) (507.76 e0.003 x height) / Cys C(0.635) Scr(0.547) (Serum Cr: mmol/L, e ¼ 2.718) Abbreviations: Cys C, cystatin C; GFR, glomerular filtration rate; SCr, serum creatinine.
mean þ standard error for the group. Conformity for normal distribution of quantitative data was performed with the Shapiro-Wilks test. For statistical analysis, nonparametric tests were applied. For evaluations of categorical data, independent groups, and dependent groups, w2 test, Mann-Whitney U test, Kruskall-Wallis H test, and Wilcoxon test were used respectively. All tests were classified as significant if the P value was
