Does Nephrotoxicity Exist in Pediatric Epileptic Patients on Valproate or Carbamazepine Therapy?

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 = 30) and carbamazepine (n = 24). Twenty-six healthy children were in the control group. The serum creatinine and cystatin C levels and urinary excretion of N-acetyl-β-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-β-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-β-d-glucosaminidase/creatinine levels. Our data suggest that valproate has adverse effects on renal tubular functions.

Keywords

antiepileptic drugs tubulopathy glomerular toxicity

Epilepsy is one the most prevalent chronic neurologic disorder, affecting 0.5% to 1.0% of children^1,2; 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-β-d-glucosaminidase has been demonstrated as a sensitive and reliable measure for detecting renal tubulopathy.^6
–8 N-Acetyl-β-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-β-d-glucosaminidase is delivered to urine at higher than normal levels,⁵ and this increased level of N-acetyl-β-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

In this study, we evaluated the effect of valproate and carbamazepine on renal glomerular and tubular functions of children with epilepsy.

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 sex-matched (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-β-d-glucosaminidase measurement were stored at −80°C until analysis. Urine dipstick analysis was also performed at the same time with N-acetyl-β-d-glucosaminidase measurement, and patients who were found to have proteinuria and/or hematuria were excluded from the study. Urine N-acetyl-β-d-glucosaminidase 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).

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)]
Cys-Cr Eq GFR (mL/min/1.73 m²)	(507.76 × e^{0.003 x height}) /Cys C^(0.635) × Scr^(0.547) (Serum Cr: µmol/L, e = 2.718)

Abbreviations: Cys C, cystatin C; GFR, glomerular filtration rate; SCr, serum creatinine.

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 mean + 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, χ² 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 <.05. The Statistical Package for the Social Sciences (version 16.0, SPSS Inc, Chicago, Illinois) was used for all statistical analysis.

Results

The clinical characteristics of the patient and control groups were similar in regard to male-to-female ratio, mean age, body weight, height, and duration of treatment (Table 2). The concentrations of serum creatinine, serum cystatin C, and glomerular filtration rate values that were calculated by the 3 formulas at the beginning and at the sixth month of the study were denoted (Table 3). They were all normal according to the range of the laboratory. Mean serum creatinine and serum cystatin C concentrations were all similar in the patient and control group. Glomerular filtration rate cystatin C, glomerular filtration rate cystatin C–creatinine, Schwartz, and urine N-acetyl-β-d-glucosaminidase/creatinine values were higher in the valproate group when compared to the values of the control group. Glomerular filtration rate cystatin C–creatinine and Schwartz values were also higher but glomerular filtration rate cystatin C and urine N-acetyl-β-d-glucosaminidase/creatinine values were statistically insignificant in the carbamazepine group when compared to those of controls.

Table 2.

Baseline Characteristics of Study Groups.

Variables	VPA group (n = 30)	CBZ group (n = 24)	Control group (n = 26)	P value
Age (y), mean ± SD	10.4 ± 3.5	10.7 ± 3.7	8.7 ± 2.6	.059
Male (%)	15 (50)	15 (62.5)	12 (46.15)	.479
Female (%)	15 (50)	9 (37.5)	14 (53.85)
BW (kg), mean ± SD	35.57 ± 14.54	37.81 ± 14.65	31.27 ± 12.25	.275
Length (cm), mean ± SD	136.3 ± 20.4	139.3 ± 19	132 ± 15.1	.288
Duration of treatment (mo), mean ± SD	12.7 ± 7.4	11.2 ± 8.3	–	.354
Drug dose (mg/kg), mean ± SD	21.7 ± 6.5	16.2 ± 5.1	–	–

Abbreviations: BW, body weight; CBZ, carbamazepine; SD, standard deviation; VPA, valproate.

Table 3.

Baseline Serum Cr, Cys C, GFR, Drug, UNAG/Cr Levels in Patients and Controls.^a

Variables	VPA group (n = 30)	Control group (n = 26)	P value	CBZ group (n = 24)	Control group (n = 26)	P value
Cys C (mg/L)	0.64 ± 0.08 (0.49-0.82)	0.68 ± 0.06 (0.58-0.84)	.033	0.66 ± 0.08 (0.45-0.80)	0.68 ± 0.06 (0.58-0.84)	.316
Serum Cr (mg/dL)	0.56 ± 0.09 (0.41-0.86)	0.59 ± 0.07 (0.49-0.79)	.076	0.57 ± 0.08 (0.4-0.76)	0.59 ± 0.07 (0.49-0.79)	.334
GFR Cys C (mL/s/1.73 m²)	130 ± 19.8 (95-176)	119.3 ± 11.9 (93-143)	.034	125.5 ± 20.8 (98-187)	119.3 ± 11.9 (93-143)	.316
GFR Cys C–Cr (mL/s/1.73 m²)	121.9 ± 13 (103-152)	113 ± 8.2 (101-131)	.010	119.4 ± 10.9 (100-150)	113 ± 8.2 (101-131)	.036
Schwartz (mL/s/1.73 m²)	138.6 ± 19.2 (97-180)	122 ± 9.7 (93-140)	<.001	142.2 ± 20 (117-197)	122 ± 9.7 (93-140)	<.001
Drug level (μg/mL)	75 ± 22 (40-131)			7 ± 2.46 (2.6-10.5)
UNAG/Cr (U/gr)	6.1 ± 5 (0.3-23)	2.65 ± 1.39 (0.7-7.20)	<.001	3.13 ± 1.97 (0.3-11)	2.65 ± 1.39 (0.7-7.20)	.163

Abbreviations: CBZ, carbamazepine; Cr, creatinine; Cys C, cystatin C; GFR, glomerular filtration rate; SD, standard deviation; UNAG, urine N-acetyl-β-d-glucosaminidase; VPA, valproate.

^aValues are mean ± SD (range).

In longitudinal analyses, average serum cystatin C and creatinine concentrations, and glomerular filtration rate cystatin C, glomerular filtration rate cystatin C–creatinine, Schwartz, and urine N-acetyl-β-d-glucosaminidase/creatinine values in the valproate group did not change significantly at month 6 when compared to the baseline values (Table 4). In the carbamazepine group, however, average serum creatinine concentrations were increased, and the glomerular filtration rate cystatin C–creatinine and Schwartz values were decreased significantly at month 6 when compared to the baseline values, but these parameters were all within the normal laboratory reference values (Table 5). Mean drug doses and blood levels were shown in Tables 3 to 5. There were not any significant relations between time of the drug usage, dose, blood levels, and the concentrations of serum creatinine, serum cystatin C, estimated glomerular filtration rate, and urine N-acetyl-β-d-glucosaminidase/creatinine values.

Table 4.

Serum Cr, Cys C, GFR, drug, UNAG/Cr Levels at Baseline and at Month 6 in Patients Receiving Valproate.^a

Variables	Baseline	Month 6	P value
Cys C (mg/L), n = 23	0.65 ± 0.08 (0.49-0.82)	0.66 ± 0.08 (0.52-0.84)	.210
Serum Cr (mg/dL), n = 24	0.56 ± 0.09 (0.41-0.86)	0.57 ± 0.09 (0.41-0.83)	.434
GFR Cys C (mL/s/1.73 m²), n = 23	128 ± 19.3 (95-175)	124 ± 17.1 (93-163)	.205
GFR Cys C–Cr (mL/s/1.73 m²), n = 23	120.5 ± 13 (103-152)	118.1 ± 12.1 (102-148)	.223
Schwartz (mL/s/1.73 m²), n = 24	138.5 ± 20.6 (97-180)	136.0 ± 17.08 (101-177)	.428
Drug level (μg/mL)	75 ± 22 (40-131)	71.4 ± 28 (9-126)
UNAG/Cr (U/gr), n = 17	5.81 ± 5.96 (0.3-23)	4.37 ± 2.73 (0.3-10)	.887

Abbreviations: Cr, creatinine; Cys C, cystatin C; GFR, glomerular filtration rate; SD, standard deviation; UNAG, urine N-acetyl-β-d-glucosaminidase.

^aValues are mean ± SD (range).

Table 5.

Serum Cr, Cys C, GFR, drug, UNAG/Cr Levels at Baseline and at Month 6 in Patients Receiving Carbamazepine.^a

Variables	Baseline	Month 6	P value
Cys C (mg/L), n = 18	0.66 ± 0.09 (0.45-0.80)	0.68 ± 0.11 (0.44-0.84)	.96
Serum Cr (mg/dL), n = 18	0.56 ± 0.08 (0.4-0.68)	0.60 ± 0.10 (0.45-0.80)	.027
GFR Cys C (mL/s/1.73 m²), n = 18	125.5 ± 23.7 (98-187)	122.2 ± 25.6 (93-192)	.163
GFR Cys C–Cr (mL/s/1.73 m²), n = 18	120.7 ± 12.2 (100-150)	115.6 ± 14.6 (94-149)	.040
Schwartz (mL/s/1.73 m²), n = 18	147.7 ± 20 (124-197)	139.7 ± 20 (112-186)	.020
Drug level (μg/mL)	7 ± 2.46 2.6-10.5	6.7 ± 1.6 4.3-9.8
UNAG/Cr (U/gr), n = 14	3.07 ± 2.47 (0.3-11)	4.80 ± 3.89 (1.7-14.7)	.152

Abbreviations: Cr, creatinine; Cys C, cystatin C; GFR, glomerular filtration rate; SD, standard deviation; UNAG, urine N-acetyl-β-d-glucosaminidase.

^aValues are mean ± SD (range).

Discussion

Consistent with previous studies, the present prospective study showed an increased excretion of tubular N-acetyl-β-d-glucosaminidase enzyme in children receiving valproate and carbamazepine monotherapy.^4,6,8,16 In a former investigation, an increased urinary excretion of N-acetyl-β-d-glucosaminidase has been demonstrated in patients treated with valproate and carbamazepine and this increased levels were found higher in patients receiving valproate than those patients treated with carbamazepine.¹⁷ In this study, N-acetyl-β-d-glucosaminidase values in receiving carbamazepine patients were found to be increased, which was not statistically insignificant.

In our study, there was no correlation between the urinary N-acetyl-β-d-glucosaminidase elevations and the medication doses, blood levels of drug, duration of treatment, serum creatinine or cystatin C concentrations, and the glomerular filtration rate. Csáthy et al⁸ and Unay et al⁴ have reported that levels of urinary excretion of N-acetyl-β-d-glucosaminidase were found to be significantly higher in patients who have received valproate, carbamazepine, and a combined antiepileptic drug for longer than 10 years when compared to patients taking antiepileptic drug therapy shorter than 10 years. Additionally, Unay et al⁴ had also shown a significant correlation between the serum concentrations of valproate and carbamazepine and N-acetyl-β-d-glucosaminidase levels.

In another study, Verrotti et al¹⁷ showed an increased level of N-acetyl-β-d-glucosaminidase at the sixth month of antiepileptic drug treatment of children diagnosed with epilepsy, and this increased level had sustained until the end of 2 years of treatment. Similarly, in our study, children receiving valproate therapy for a period between 3 months and 2 years had increased levels of urinary excretion of N-acetyl-β-d-glucosaminidase. The levels of N-acetyl-β-d-glucosaminidase in children receiving carbamazepine were also higher than those of the levels of the control group, which was statistically insignificant. Moreover, the levels of urinary excretion of N-acetyl-β-d-glucosaminidase were similar in patients receiving either valproate or carbamazepine during a 6-month period of therapy.

All studies in the literature have emphasized an increased risk of tubular functional impairment in patients receiving valproate and carbamazepine therapies, and they all have suggested screening of tubular functions in these patients even if the renal function tests were normal.

One of our goals in this study was also to see the effect of antiepileptic drugs on the glomerular filtration rate of the patients. Inulin clearance and iohexol clearance are both considered as gold standards for glomerular filtration rate measuring.¹⁸ The most practical common marker used to estimate glomerular filtration rate is serum creatinine concentration. However, tubular creatinine secretion, muscle mass, age, gender, regular diet, and hepatic function of the patients all affect serum creatinine concentration. Creatinine clearance is a much more sensitive method for the detection of renal dysfunction, but it requires very precise urine collection for 24 hours. Therefore, a recent research has been directed toward the identification of a more specific, reliable, and practical serum marker of glomerular filtration rate.¹⁹ Serum cystatin C has been proposed as a new endogenous marker of glomerular filtration rate.²⁰ Several studies have shown that cystatin C correlated better with inulin or chromium ethylenediaminetetraacetic acid clearance than serum creatinine in patients with mild to moderately impaired renal function.^21–23

In our study, we evaluated both cystatin C and serum creatinine levels. Moreover glomerular filtration rate was estimated by using recent formula with cystatin C, serum creatinine, and cystatin C + serum creatinine . The values of the glomerular filtration rate calculated with all 3 formulas were within the normal reference values.^14,15 Although the glomerular filtration rate values calculated with all 3 different formulas of valproate and carbamazepine groups were within the normal reference ranges, they were significantly higher than the values of the control group. (However, the patients’ glomerular filtration rate values calculated using cystatin C levels in the carbamazepine group were higher than the values of the control group, though statistically insignificant. Because the glomerular filtration rate, cystatin C–creatinine formula was more predictive than the glomerular filtration rate cystatin C formula, this discrepancy is not considered important). Because the patients and control groups were similar in terms of age, height, body mass index, and body weight, this high value may suggest subclinical hyperfiltration of early glomerular toxicity, which is also seen in some other chronic disorders such as diabetes mellitus and sickle cell anemia.^24
–26 Studies in experimental animals indicate that dilatation of the afferent (precapillary) glomerular arteriole plays an important role in the hyperfiltration response, by raising both the intraglomerular pressure and renal blood flow.²⁴ Why these hemodynamic changes occur is not well understood in diabetes mellitus, but factors that may contribute to afferent arteriole dilation include insulin-like growth factor I, atrial natriuretic peptide, sex hormones, intracellular sorbitol, early glycation products, and enhanced tubular sodium reabsorption in the proximal tubule.^27

–32 Otherwise, glomerular ischemia appears to promote increased renal blood flow and glomerular filtration rate in sickle cell anemia. Studies in mice suggest that increased glomerular nitric oxide synthesis also could contribute to the glomerular hyperfiltration.^33,34 It could be speculated that antiepileptic drugs and their metabolites can cause glomerular arteriolar dilation and increased blood flow and glomerular hyperfiltration. When the antiepileptic drug usage is continued for a longer period of time as stated above, the glomerular filtration rate may be reduced in time because of the effect of the antiepileptic drugs rather than the disease itself. Patients who use these drugs for a certain amount of time should be reevaluated for glomerular filtration rate. Csáthy et al⁸ and Unay et al⁴ found normal urea and creatinine concentrations in patients receiving antiepileptic therapy. In addition, Altunbaşak et al³⁵ did not find impaired creatinine clearance in children receiving valproate. Because there is no other study in the literature using cystatin C level and serum creatinine for the estimation of glomerular filtration rate in the patients having antiepileptic drug, our results can be used as reference values.

The major limitations of this study can be stated as follows: we have no values of N-acetyl-β-d-glucosaminidase, cystatin C, serum creatinine, and glomerular filtration rate before drug initiation; the number of patients was low; and the period of follow-up was short. If we had the chance of measuring blood cystatin C levels before treatment, after 2 or more years of time or at the end of the antiepileptic drug usage, we could have prepared a longitudinal profile of the change of cystatin C levels in these patients. Thus, further studies with longer follow-up periods are needed to demonstrate the long-term effects of antiepileptic drugs on renal function.

In conclusion, our data suggest that valproate and carbamazepine have varying degrees of adverse effects on renal tubular functions in children with epilepsy. Whether these drugs affect glomerular function and what is the mechanism involved is not clearly known and has not been widely investigated. Therefore, renal tubular and glomerular function in children receiving carbamazepine and valproate should be kept in mind.

Footnotes

Acknowledgment

This study was conducted at the Gazi University Faculty of Medicine, Ankara, Turkey.

Author Contributions

CH, KG, and NB designed the study. UY, EG, OG, ED, and AS collected and analyzed patient data and drafted this article. All authors have contributed and agreed to the content of the manuscript.

Declaration of Conflicting Interests

The authors declared no potential conflicts of interest with respect to the research, authorship, and/or publication of this article.

Funding

The authors received no financial support for the research, authorship, and/or publication of this article.

Ethical Approval

The study received ethical approval from the Ministry of Health of Turkey General Directorate of Pharmaceuticals and Pharmacy Ethics Committee. Ethics Committee approval number: 45484.

References

Shinnar

Pellock

. Update on the epidemiology and prognosis of pediatric epilepsy. J Child Neurol. 2002;17 (suppl 1):S4–S17.

Serdaroğlu

Ozkan

Aydin

. Prevalence of epilepsy in Turkish children between the ages of 0 and 16 years. J Child Neurol. 2004;19:271–274.

Marson

Williamson

Hutton

. Carbamazepine versus valproate monotherapy for epilepsy. Cochrane Database Syst Rev. 2000;(3):CD001030.

Unay

Akin

Sarici

. Evaluation of renal tubular function in children taking antiepileptic treatment. Nephrology (Carlton). 2006,11:485–488.

Skálová

. The diagnostic role of urinary N-acetyl-beta-d-glucosaminidase (NAG) activity in the detection of renal tubular impairment. Acta Medica. (Hradec Kralove) 2005;48:75–80

Novo

MLP

Izumi

Yokota

Fukuyama

. Urinary excretion of N-acetyl β-glucosaminidase and β-galactosidase by patients with epilepsy. Brain Dev. 1993;15:157–160.

Watanabe

Kojima

Fukuda

. Reliability of urinary N-acetyl-β-d-glucosaminidase as an indicator of renal tubular damage in neonates. Biol Neonate. 1987;52:16–21.

Csathy

Olah

Clemens

. Urinary N-acetyl-β-d-glucosaminidase in epileptic children treated with antiepileptic drugs. Arch Dis Child. 2000;83:420–422.

Biomarkers for the early detection of acute kidney injury. Pediatric Nephrology Educational Feature Nephrology and Hypertension, MLC 7022, Cincinnati Children’s Hospital Medical Center.

10.

Cordeiro

Pinheiro

Silva

Jr . Comparative study of cystatin C and serum creatinine in the estimative of glomerular filtration rate in children. Clinica Chimica Acta. 2008;391:46–50.

11.

Rosenthal

Bökenkamp

Hofmann

. How to estimate GFR-serum creatinine, serum cystatin C or equations? Clin Biochem. 2007;40:153–161.

12.

Schwartz

Brion

Spitzer

. The use of plasma creatinine for estimating glomerular filtration rate in infants, children and adolescents. Pediatr Clin N Am. 1987;34:571–590.

13.

Zappitelli

Parvex

Joseph

. Derivation and validation of cystatin C based prediction equations for GFR in children. Am J Kidney Dis. 2006;48:221–230.

14.

Holliday

Barratt

Avner

. Glomerular filtration rate, inulin clearance. In Pediatric Nephrology. 3rd ed. Baltimore, MD: Williams & Wilkins; 1994:1306.

15.

Heilbron

Holliday

Al-Dahwi

Kogan

. Expressing glomerular filtration rate in children. Pediatr Nephrol. 1991;5:5–11.

16.

Yuksel

Cengiz

Seven

. N-Acetyl-P-glucosaminidase and P-galactosidase activity in children receiving antiepileptic drugs. Pediatr Neurol. 1999;20:24–26.

17.

Verrotti

Greco

Pascarella

. Renal tubular function in patients receiving anticonvulsant therapy: a long-term study. Epilepsia. 2000;41:1432–1435.

18.

Linblad

Berg

. Comparative evaluation of iohexol and inulin clearance for glomerular filtration rate determinations. Acta Paediatr. 1994;83;418–422.

19.

Swan

. The search continues: an ideal marker of glomerular filtration rate. Clin Chem. 1997; 43:913–914.

20.

Deinum

Derkx

FHM

. Cystatin C for estimation of glomerular filtration rate? Lancet. 2000;356:1624.

21.

Kyhse-Andersen

Schmidt

Nordin

. Serum cystatin C, determined by rapid, automated, particle enhanced turbidimetric method, is a better marker than serum creatinine for glomerular filtration rate. Clin Chem. 1994;40:1921–1926.

22.

Keevil

Kilpatric

Nichols

. Biological variation of cystatin C. Implications for the assessment of glomerular filtration rate. Clin Chem. 1998;44;1535–1539.

23.

Filler

Yasin

Medeiros

. Methods of assessing renal function. Pediatr Nephrol. 2014;29:183–192.

24.

Bank

. Mechanisms of diabetic hyperfiltration. Kidney Int. 1991;40:792.

25.

Vora

Dolben

Dean

. Renal hemodynamics in newly presenting non-insulin dependent diabetes mellitus. Kidney Int. 1992;41:829.

26.

Paula

Nascimento

Sousa

. Glomerular filtration rate is altered in children with sickle cell disease: a comparison between Hb SS and Hb SC. Rev Bras Hematol Hemoter. 2013;35:349–351.

27.

Serri

Beauregard

Brazeau

. Somatostatin analogue, octreotide, reduces increased glomerular filtration rate and kidney size in insulin-dependent diabetes. JAMA. 1991;265:888.

28.

Hirschberg

Brunori

Kopple

Guler

. Effects of insulin-like growth factor I on renal function in normal men. Kidney Int. 1993;43:387.

29.

Hirschberg

Kopple

. The growth hormone-insulin-like growth factor I axis and renal glomerular function. J Am Soc Nephrol. 1992;2:1417.

30.

Anderson

Vora

. Current concepts of renal hemodynamics in diabetes. J Diabetes Complications. 1995;9:304–307.

31.

Vervoort

Veldman

Berden

. Glomerular hyperfiltration in type 1 diabetes mellitus results from primary changes in proximal tubular sodium handling without changes in volume expansion. Eur J Clin Invest. 2005;35:330.

32.

Cherney

Sochett

Miller

. Gender differences in renal responses to hyperglycemia and angiotensin-converting enzyme inhibition in diabetes. Kidney Int. 2005;68:1722.

33.

Pham

Wilkinson

Lew

. Renal abnormalities in sickle cell disease. Kidney Int. 2000;57:1.

34.

Bank

Aynedjian

Qiu

. Renal nitric oxide synthases in transgenic sickle cell mice. Kidney Int. 1996;50:184.

35.

Altunbaşak

Yıldızdaş

Anarat

Burgut

. Renal tubular dysfunction in epileptic children on valproic acid therapy. Pediatr Nephrol. 2001;16:256–259.