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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 4  |  Page : 731-736
Urinary endothellin-1 level in children with pyelonephritis and hydronephrosis

Pediatric Infections Research Center (PIRC), Shahid Beheshti University of Medical Sciences, Tehran, IR Iran

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Date of Web Publication24-Jun-2013


Hydronephrosis is a common finding in patients with urinary tract infection (UTI). Endothellin-1 (ET-1) is a potent vasoactive peptide that has vasoconstrictive effects. It has been shown that urinary ET-1 increases in urinary obstructions. In this study, we measured the urinary ET-1 level in patients with UTI and hydronephrosis of various causes. In this case-control study, we evaluated the urinary ET-1 level in 45 patients who had UTI and hydronephrosis, serving as a case group, and 45 patients who had UTI without hydronephrosis, serving as a control group. Urinary ET-1 was quantified using enzyme-linked immunosorbent assay and urinary creatinine (Cr) by Jaffe method. To rule out the effect of urinary flow rate, the urinary ET-1 to Cr correlation was considered for analysis of the results. The mean age of the patients in the case and control groups was 36.5 ± 27.2 and 26.2 ± 15.5 months, respectively (P >0.01). The mean urinary ET-1 was 89.6 ± 41.7 pg/dL in the case group and 29.3 ± 26 pg/dL in the control group, P <0.001. The mean urinary ET-1 was 121 ± 55.4 pg/dL in patients who had grade 4 hydronephrosis. We conclude that urinary ET-1 was significantly higher in the obstructed than in non-obstructed cases. Urinary ET-1 could be a useful marker that can be utilized in young children for diagnosis of hydronephrosis, especially obstructive cases.

How to cite this article:
Sharifian M, Ahmadi M, Karimi A, Zand RE, Moghadar R, Ahmadi R, Chimeh MD. Urinary endothellin-1 level in children with pyelonephritis and hydronephrosis. Saudi J Kidney Dis Transpl 2013;24:731-6

How to cite this URL:
Sharifian M, Ahmadi M, Karimi A, Zand RE, Moghadar R, Ahmadi R, Chimeh MD. Urinary endothellin-1 level in children with pyelonephritis and hydronephrosis. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2021 May 8];24:731-6. Available from: https://www.sjkdt.org/text.asp?2013/24/4/731/113865

   Introduction Top

Urinary tract infection (UTI) is one of the common diseases in childhood. It has been estimated that the prevalence of this disease is 3-5% in girls and 1% in boys. [1] In spite of a low mortality rate, UTI is considered as an important risk factor for developing hypertension and renal insufficiency and has a high morbidity. [2] It has been estimated that in 40% of the patients with pyelonephritis, we can find some degrees of renal scars, which can result in renal insufficiency or hypertension. [3]

Urinary tract obstruction and hydronephrosis are pathologic disorders with a known relationship with UTI. The effects of obstruction relate to the level of obstruction, the extent of involvement, the age of initiation and the chronicity of the cases. In childhood, most of the obstructive lesions are congenital and the patient may be without any signs or have manifestations such as abdominal mass, abdominal pain, flank pain, urinary tract infection and pyelonephritis. [4],[5],[6],[7],[8] Regarding the low sensitivity of using ultrasonography and voiding cystourethrography (VCUG), and intravenous pyelography (IVP) to rule out obstruction, radioisotope methods are considered as a gold standard for this purpose. [9],[10] However, this latter method has some limitations, such as requiring equipment and radioisotope materials and significant burden of radiation. For this reason, investigators try to find novel diagnostic methods that are more favorable regarding safety, equipment, simplicity and expense.

Endothelin-1 (ET-1) is a strong vasoconstrictor that has a proven role in developing stenosis in the pre-glomerular arterioles. [11] Studies on animal models show that using ET-1 receptor antagonists in the urinary obstruction in animal models may improve the circulation in the obstructive hydronephrotic kidney and decrease apoptosis. Animal-based studies support this hypothesis that ET-1 is a mediator of vascular and cellular damage in the course of urinary system obstruction. [12],[13],[14],[15],[16],[17]

We aimed in this study to measure the urinary ET-1 levels in patients with hydronephrosis due to urinary tract obstruction and to examine the relations between urinary ET-1 level and degrees of hydronephrosis.

   Materials and Methods Top

This case-control study was performed in the Mofid Children Hospital, Tehran, in 2008. We included in the study children suffering from urinary infection with hydronephrosis (case group) and urinary infection without hydronephrosis (control group).

We included in the study patients with age older than one month to 12 years, clinical documentations for UTI and hydronephrosis (for the case group) and UTI and lack of hydronephrosis (for the control group). Children with hypertension or heart failure were excluded from the study. The sample size for each group was calculated as 45 subjects in each group (considering error type 1(α) equal to 5%, sensitivity of test equal to 70% and accuracy equal to 0.12). Demographic data including age and gender were collected from the case and control groups. Severity of hydronephrosis and underlying disease, which resulted in hydronephrosis in the case group, were determined.

Urine samples were obtained from patients before performing any therapeutic intervention. The urinary ET-1 concentrations were measured by using an enzyme-linked immunosorbent assay (ELISA) assay. The dilution of ELISA kits used in this study was equal to 1.5 ng/mL. At the same time, the urine creatinine (Cr) was also measured. To omit the effect of urinary flow rate, urinary ET-1 and Cr were considered for analysis of the results.

   Statistical Analysis Top

The analysis was performed using SPSS software. The Kolmogorov - Smirnoff test was used for normal distribution, T test and ANOVA for comparing the means and χ 2 test for comparing rates. Differences were considered statistically significant in case of P <0.05.

   Results Top

The mean age of the patients in the case and the control groups was 36.5 ± 27.2 and 26.2 ± 15.5 months, respectively, P = 0.129. There were 22 (48.9%) females and 23 (51.1%) males in the case group and 37 (82.2%) females and eight (17.8%) males in the control group (P = 0.001).

The mean of the ET-1 levels in the case and control groups was 89.6 ±41.7 and 29.3 ± 26.1 pg/dL, respectively, (P = 0.001). The mean urinary creatinine in the case and the control groups was 90 ± 86 and 103 ± 101 mg/dL, respectively, P = 0.497.

The mean of the ET-1 levels according to underlying diseases in the case group is shown in [Table 1]. A significant statistical difference was demonstrated using the ANOVA test (P = 0.005).
Table 1: Mean urinary endotheline-1 (ET-1) in the various diseases in the case group.

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The mean of the ET-1 levels in various grades of hydronephrosis in the case group is shown in [Table 2]. Using the ANOVA test, a significant difference of ET-1 levels in various grades of hydronephrosis (P = 0.005) was disclosed.
Table 2: Mean of urinary endotheline-1 in the various grades of hydronephrosis in the case group.

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Evaluating the correlation between urine creatinine and urinary ET-1 levels in the case group shows a 0.534 coefficient correlation between these two variables, P = 0.015. The coefficient correlation of ET-1 after treatment was 0.361 (P = 0.015) [Figure 1]. In addition, there was a significant correlation between the age and ET-1 levels [Figure 2].
Figure 1: Correlation between urine creatinine and urinary ET-1 in the case group.

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Figure 2: Correlation between urinary ET-1 and age of patients in the case group.

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Considering a cutoff point equal to or above 50 pg/dL for diagnosis of hydronephrosis, the sensitivity and specificity of this test would be 88.9% and 75.5%, respectively, and the positive and negative predictive values would be 78.4% and 87.2%, respectively [Table 3].
Table 3: Comparison of the ET-1 test with a cutoff point equal 50 pg/dL for differentiating the case and control groups

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   Discussion Top

ET-1 has been considered as a urinary biochemical marker during recent years, although there are not many investigations regarding its diagnostic value. Most of these studies are in animal models or other organs and tissues other than the kidneys. [18],[19],[20],[21],[22],[23] Most of these studies have intrigued investigators in using ET-1 for evaluating inflammatory disorders in living humans.

The role of urinary biomarkers in the diagnosis of congenital upper urinary tract obstruction was searched by Shokeir from Egypt; he reviewed 23 experimental and 33 prospective controlled clinical studies. [24] The most important biomarkers included transforming growth factor-β 1 (TGFβ 1 ), epidermal growth factor (EGF), endothelin-1 (ET-1), urinary tubular enzymes [N-acetyl-β-D-glucosaminidase (NAG), γ-glutamyl transferase (GGT) and alkaline phosphatase (ALP)] and microproteins [β 2 -microglobulin (β 2 M), microalbumin (M. alb) and micrototal protein (M. TP)]. These biomarkers showed sensitivity of 74.3-100%, specificity of 80-90% and overall accuracy of 81.5-94% in the diagnosis of congenital obstructive uropathy in the pediatric population. As is noted in this study, these biomarkers had different success rates, but among the most valuable markers was ET-1.

In a study by Taha et al, the role of urinary ET-1 in the diagnosis of uretro-pelvis junction obstruction in children was investigated. [25] They concluded that urinary ET-1 was useful in the diagnosis of uretro-pelvis junction obstruction in children.

In our study, we tried to evaluate the role of ET-1 in the diagnosis of hydronephrosis in patients with UTI. Our findings show that urinary ET-1 levels in the group with hydronephrosis was significantly higher than those in the control group, and correlated with the severity of hydronephrosis. In addition, in patients with obstruction in the ureter-pelvis junction and urinary stones, higher concentrations of ET-1 levels were found. The control group also had UTI but not as much elevated ET-1 levels, which raises hydronephrosis as the main factor for this elevation, and not UTI. [25]

Our study also showed that there was no significant association between gender of the patients and urinary ET-1 levels. However, with increasing age, the urinary ET-1 concentrations increased. This finding shows that for using ET-1, its level must be adjusted based on patients' age. Furthermore, the levels of ET-1 should be adjusted according to urine creatinine.

Our study also disclosed that if we consider the ET-1 cutoff point equal to 50 pg/dL, the sensitivity of this test for the diagnosis of hydronephrosis would be about 90% and the specificity would be around 75%. These figures show that the ability of ET-1 for finding patients with hydronephrosis is acceptable; however, its ability for ruling out hydronephrosis and detecting healthy individuals is not much acceptable. Because the aim of using ET-1 is detecting patients with hydronephrosis, applying this test for this purpose is significantly valuable.

We conclude that the results of our study, which is performed on a pediatric population, support the hypothesis that ET-1 levels can be used for the diagnosis of hydronephrosis; however, further studies are required with a higher number of patients for achieving more definitive results.

   Acknowledgement Top

We thank all staff in Pediatric Infections Research Center (PIRC), and Nephrology ward at Mofid Children's hospital for their kind cooperation.

This study was funded by Pediatric Infections Research Center (PIRC), Shahid Beheshti University of Medical Sciences.

   References Top

1.Elder JS, Urologic Disorders in Infants and Children in: Kliegman RM, Behrman RE, Jenson HD, Stanton. Nelson Textbook of Pediatrics, 18 th ed. Philadelphia: Elsevier; 2007.  Back to cited text no. 1
2.Downs SM. Technical report: Urinary tract infections in febrile infants and young children. The Urinary Tract Subcommittee of American Improvement. Pediatrics 1999;103:e54.  Back to cited text no. 2
3.Girardet P, Frutiger P, Lang R. Urinary tract infection in pediatric practice. A comparative study of three diagnostic tools: Dip-slides, bacterioscopy, and leukocyturia. Pediatrician 1980;9:322-37.  Back to cited text no. 3
4.Goldsmith BM, Campos JM. Comparison of urine dipstick, microscopy, and culture for detection of bacteriuria in children. Clin Pediatr (Phila) 1990;29:214-8.  Back to cited text no. 4
5.Anderson JD, Chambers GK, Johnson HW. Application of leukocyte and nitrite urine test strip to the management of children with neurogenic bladder. Diagn Microbiol Infect Dis 1993; 17:29-33.  Back to cited text no. 5
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10.Practice parameter: The diagnosis, treatment, and evaluation of initial UTI in febrile infants and young children. American Academy of Pediatrics. Committee on quality Improvement. Subcommittee on Urinary Tract Infection. Pediatrics 1999;103:843-52.  Back to cited text no. 10
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12.Alon US, Ganapathy S. Should renal ultra-sonography be done routinely in children with first urinary tract infection? Clin Pediatr (Phila) 1999;38:21-5.  Back to cited text no. 12
13.Yanagisawa M, Kurihara H, Kimura S, et al. A novel potent vasoconstrictor peptide produced by vascular endothelial cells. Nature 1998; 332:411-5.  Back to cited text no. 13
14.Masaki T, Yanagisawa M. Endothelials. Essays Biochem 1992;27:79-89.  Back to cited text no. 14
15.Naylor WG. Endothelin: Isoforms, binding sites and possible implications in pathology. Trends Pharmacol Sci 1990;11:96-9.  Back to cited text no. 15
16.Remuzzi G, Perico N, Benigni A. New therapeutics that antagonize endothelin: Promises and frustrations. Nat Rev Drug Discov 2002;1:989-1001.  Back to cited text no. 16
17.Maxey M, Maddipati KR. Interference in enzyme immunoassays. J Clin Immunoassay 1992;15:116-20.  Back to cited text no. 17
18.Hegarty NJ, Young LS, O'Neill AJ, Watson RW, Fitzpatrick JM. Endothelin in unilateral Ureteral obstruction: Vascular and cellular effects. J Am Urol 2003;169:740-4.  Back to cited text no. 18
19.Knerr I, Nyul Z, Miller J, et al. Increased endothelin -1 and decreased adrenomedullin gene expression in the stenotic tissue of congenital pelviuretic junction obstruction in children. B J Urol 2001;87:667-71.  Back to cited text no. 19
20.Fagan KA, McMurtry IF, Rodman DM. Role of endothelin-1 in lung disease. Respir Res 2001;2:90-101.  Back to cited text no. 20
21.Kohan DE. Biology of endothelin receptors in the collecting duct. Kidney Int 2009;76:481-6.  Back to cited text no. 21
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23.Mencarelli M, Pecorelli A, Carbotti P, Valacchi G, Grasso G, Muscettola M. Endothelin receptor a expression in human inflammatory cells. Regul Pept 2009;158:1-5.  Back to cited text no. 23
24.Shokeir AA. Role of urinary biomarkers in the diagnosis of congenital upper urinary tract obstruction. Indian J Urol 2008;24:313-9.  Back to cited text no. 24
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25.Taha MA, Shokeir AA, Osman HG, Abd el-Aziz Ael-A, Farahat SE. Diagnosis of uretropelvis junction obstruction in children: Role of endothelin -1 in voided urine. Pediatric urology 2007;69:560-4.  Back to cited text no. 25

Correspondence Address:
Mostafa Sharifian
Mofid Hospital, Shariati Street, Tehran
IR Iran
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DOI: 10.4103/1319-2442.113865

PMID: 23816722

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  [Figure 1], [Figure 2]

  [Table 1], [Table 2], [Table 3]

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