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Saudi Journal of Kidney Diseases and Transplantation
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Year : 2013  |  Volume : 24  |  Issue : 1  |  Page : 54-59
Risk factors for renal scarring in children with primary vesicoureteral reflux disease

1 Department of Pediatric Nephrology, Faculty of Medicine, Ege University, Izmir, Turkey
2 Department of Pediatric Nephrology, Faculty of Medicine, Celal Bayar University, Manisa, Turkey
3 Department of Pediatric Nephrology, Faculty of Medicine, Trakya University, Edirne, Turkey

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Date of Web Publication22-Jan-2013


To determine the incidence of renal scarring among patients with primary vesicoureteral reflux (VUR) and the possible risk factor(s), we studied 90 children (60 girls and 30 boys) with VUR followed in the Pediatric Nephrology Unit at the Ege University Hospital from 1998 to 2003. All the patients were assessed for VUR grade by voiding cystoureterography and for presence of renal scarring by (99 m) technetium dimercapto-succinic acid scintigraphy. All infants with VUR were given low-dose prophylactic antibiotics and followed-up until resolution of the reflux. Grade of reflux and number of urinary tract infection (UTI) episodes (≥3) were found to be statistically significant risk factors for renal scarring (P <0.05). However, gender, familial history and laterality of the disease were not found to be statistically significant risk factors (P >0.05). Similarly, there was no statistically significant difference of frequency of renal scarring among the different age groups (P >0.05). We conclude that recurrences of UTI and VUR severity are significant risk factors for renal scarring in children with VUR. Therefore, identification of VUR at an early age may offer the opportunity to prevent episodes of UTI and possible formation of renal scars that may result in end-stage renal failure.

How to cite this article:
Mir S, Ertan P, Ozkayin N. Risk factors for renal scarring in children with primary vesicoureteral reflux disease. Saudi J Kidney Dis Transpl 2013;24:54-9

How to cite this URL:
Mir S, Ertan P, Ozkayin N. Risk factors for renal scarring in children with primary vesicoureteral reflux disease. Saudi J Kidney Dis Transpl [serial online] 2013 [cited 2022 Jun 25];24:54-9. Available from: https://www.sjkdt.org/text.asp?2013/24/1/54/106241

   Introduction Top

The incidence of vesicoureteral reflux (VUR) is estimated as 1% in asymptomatic and 25-40% in symptomatic children, and is present with urinary tract infection (UTI). [1] UTI is the most common factor associated with VUR, and it is a pre-requisite for formation of further renal parenchymal lesions and scars that may cause later problems, such as hypertension, chronic renal failure and, in most cases, end-stage renal disease. [2],[3],[4],[5] At the time of diagnosis, 30-49% of children with VUR were reported to have renal parenchymal scarring. [6] UTI, along with other etiologic factors including VUR, is important in the pathogenesis of scarring. [7],[8],[9] The risk factors in the development of renal scars include growing kidney, delay in treatment of UTI, recurrence of UTI and higher grade of VUR. [7],[8],[9] The aim of this study was to determine the risk factors for development of renal scarring in patients with primary VUR.

   Materials and Methods Top

Ninety children with VUR (60 girls, 30 boys), followed-up in the Pediatric Nephrology Unit at the Ege University Hospital, between 1998 and 2003, were enrolled in the study. Children included in the study were enrolled into three groups according to their age. Group 1 included children ≤1 year old, group 2 included children aged between one and five years and group 3 included children aged between five and 15 years. Exclusion criteria included urinary tract malformations and clinical signs/ symptoms of dysfunctional voiding, such as history of nocturnal and/or diurnal incontinence and urgency incontinence, and elevated voiding frequency associated with recurrent urinary infections and constipation and soiling. Ultrasonographic findings of dysfunctional voiding were defined as vesical thickness greater than 3 mm with a full bladder, vesical capacity above two standard deviations from the norm for their age and post-voiding residue greater than 5% of the total vesical volume. [10] The initial evaluation of all patients included a detailed history of voiding patterns and physical examination. Moreover, detailed family history for presence of VUR and renal scarring was questioned. The neurological examination included anal tone and voluntary control of the anal sphincter, the bulbocavernous reflex, lower limb reflexes and perineal sensitivity, besides lumbosacral examination for occult neurospinal dysraphism. Complete urological investigations included urinalysis, urine culture, renal ultrasonography, voiding cystourethrogram (VCUG) and dimercaptosuccinic acid (DMSA) scintigraphy. For all children, the VUR investigation was performed after the diagnosis of UTI. VCUG was performed routinely in children who had UTI in the first five years of life, in boys of any age and in girls older than five years and in those children who had recurrent UTI, dilation of the urinary system on renal ultrasonography or had no findings of bladder instability. VCUG was performed to search for possible VUR two weeks after antibiotic therapy for UTI was completed, and the VCUG results were evaluated by two independent radiologists. VUR grade was labeled on the basis of radiological findings using the International Reflux Study Committee grading system (IRSCGS), [11] (Grades from I to V), and grades three to five corresponded to high-grade VUR with dilation of the urinary tract. Renal scarring was assessed by DMSA performed minimally six months after the treatment of UTI. All scintigrams were assessed by two experienced radiologists according to the standard criteria described by Goldraich. [7] Renal scarring was diagnosed if areas of reduced capture were present in the renal parenchyma. Renal scarring was evaluated for patients and for individual kidneys if only presence or absence of renal scarring was considered. [12],[13] Renal scarring was classified as type 1: no more than two scarred areas, type 2: affecting more than two areas, but with remaining normal parenchyma, type 3: generalized parenchymal damage and type 4: shrunken end-stage kidney according to the modified scale of Goldraich et al. [7] All patients with UTI received antibiotics, depending on appropriate bacterial-susceptibility tests for seven to ten days. Initially, antibiotics were administered parenterally for at least three days. The total duration of antibiotic therapy depended on the results of bacteriological tests, patients' response to antibiotics, regression of the signs of inflammation and the results of radiological investigations. Nightly doses of prophylactic antibiotic therapy were prescribed either as powder or in a capsule form according to the child's preference until the VUR resolved.

   Statistical Analysis Top

The mean values of numeric variables were compared with the Mann-Whitney U test and the Student t test, and analysis of interrelation of categorical variables was done with the chi-square test. Odds ratio was determined for analysis of risk factors for renal scarring with 95% confidence interval. Renal scarring risk factors were evaluated by multiple logistic regression analysis with significant factors in one-way analysis.

   Results Top

The mean age of the study patients was 98.8 ± 2.76 months, the mean age at the diagnosis of VUR was 45.2 ± 4.46 months (range 1-180 months), and the mean follow-up period was 45.4 ± 4.20 months. Renal scarring was not detected among the two girls and three boys with Grade I VUR. On the other hand, seven of the 24 (29%) girls and five of the 15 (33%) boys with Grade II VUR and 13 of the 22 (59%) girls and 13 of the 30 (43%) boys with Grade III VUR had renal scarring. Moreover, four of the eight (50%) girls and 12 of the 15 (80%) boys with Grade IV VUR had renal scarring. All (100%) four girls and six boys with Grade V VUR had renal scarring. Gender did not have a statistically significant influence on renal scarring (P >0.05). The mean value of UTI frequency in the study was 2.86 ± 0.67. Renal scarring was detected in 25 of the 41 (61%) children who had more than or equal to three UTI attacks. UTI had a statistically significant influence on the development of renal scarring (P = 0.05, odds: 2.250, 95% CI: 0.963-5.257) [Table 1]. Unilateral VUR was observed in 51 (56.6%) and bilateral in 39 (43.3%) children. Grade I, II, III, IV, V was found in four (3%), 28 (20.7%), 35 (25.9%), 16 (11.9%) and seven (5.2%) children, respectively. Renal scarring was not significantly different between the different reflux sites (P >0.05). Renal scarring was detected in 44 (48.9%) patients. Considering 129 renal units of VUR, renal scarring were observed in none of the five units in Grade I, 12 of 39 (30.7%) units in Grade II, 26 of 52 (50%) in Grade III, 16 of 23 (69.5%) in Grade IV and all of 10 units (%100) in Grade V. Renal scarring was observed in a significantly greater proportion of units with dilated VUR compared with those with non-dilated VUR (P = 0.001, odds ratio: 4.909, 95% CI: 1.88-12.82) [Table 1]. [Table 2] shows the increased prevalence of scaring with the higher grades of VUR. Surgery was performed on 18 of the 35 (51%) patients with third degree VUR, on eight of the 16 (50%) patients with fourth degree VUR and on five of the seven (71%) patients with fifth degree VUR. When family history of the children enrolled in the study was obtained for the presence of VUR, positive history of VUR was found in four sisters and three brothers of the study patients. Among the relatives, VUR disease was graded as I and II. However, Grade III-V refluxes were present in five siblings, and one of them had bilateral VUR. Renal scarring did not significantly differ according to family history of VUR [Table 1]. When frequency of renal scarring was examined in the different age groups, it was not significantly different among the different age groups [Table 1]. Evaluation of the risk factors for renal scarring in children revealed that grade of reflux and number of UTI episodes (≥3) were statistically significant factors for the development of renal scarring (P <0.05). However, gender, age, familial history and laterality of the disease did not affect the development of renal scarring significantly [Table 1].
Table 1: Evaluation of different characteristics in children with and without renal scarring.

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Table 2: Distribution of scarring types in kidneys with VUR according to DMSA findings.

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   Discussion Top

VUR, which is common among children with UTI, may result in renal scarring and nephropathy due to reflux of the infected urine to the upper tract. Unless treated promptly, 30-60% of the patients with VUR would have a radiographic evidence of renal scarring. [7],[14] Development of reflux nephropathy and renal scarring is a multifactorial process. Degree of reflux, infection frequency, age at diagnosis, delay in infection treatment and properties of infectious agents are the most important risk factors for renal scarring. [8],[15],[16],[17] Twenty percent and 40% of the children with renal transplantations or on hemodialysis, respectively, have reflux nephropathy. [18] Frequency of renal scarring in this study was similar to the values reported previously, which was between 30% and 70%. [19],[20] This huge variability in the incidence may be partly attributed to the method for diagnosis of renal scarring. In previous studies in which renal scarring was detected by intravenous pyelography, the incidence of renal scarring was reported to be between 34% and 49%. [20] Renal DMSA scintigraphy used in this study is considered to be the most sensitive test for the diagnosis of renal scarring. There are controversial results in previous research about the role of gender in the development of renal scarring; some reported no influence and others reported a male predominance. [10],[21],[22] In this study, gender was not found to be a significant risk factor for the development of renal scarring. There are several studies that have reported a higher risk of renal scarring in children younger than 1 year of age. [23],[24] Moreover, it has been reported that the incidence of renal scarring was higher in children younger than two years when assessed with intravenous pyelography or DMSA. [25] In this study, the incidence of renal scarring was greater among children older than five years, and this could be attributed, probably, to a late diagnosis of UTI. As proposed by previous studies, the severity of the inflammatory process and the volume of kidney involved are the major contributing factors for renal scar formation, independent of age. [26] In other words, both the host immunological defense and the microbiological virulence factors are critical co-factors for renal scarring. [27] UTI is the most common factor that may result in VUR. [28] There are contradictory reports about the role of VUR in the development of renal scarring, because some studies have reported a high incidence of renal scarring in post-UTI patients without VUR. [28] There is evidence that infection of the parenchyma is the pre-requisite for formation of renal scars instead of VUR, [28] but scars are more common in children with VUR of grade three or more. [28],[29],[30] This finding was consistent with our results that demonstrated significantly increased risk of renal scarring associated with more than or equal to three episodes of UTI. Familial tendency or trait in etiology of VUR has been reported, but the specific manner of inheritance is still unclear. This familial tendency was first described by Stephens in 1955 in twins. [31] Moreover, the presence of history of VUR in as many as 66% of mothers of children with VUR supported this concept. [32] Additionally, Puri et al reported the VUR incidence of 13.6% in siblings of children with VUR; these children also had more severe VUR and reflux nephropathy. [33] In our study, the rate of familial tendency for VUR was found in 7.7%, and it was 42.8% in children with renal scarring. In conclusion, we found that frequency of recurrences of UTI and severity of reflux were associated with a higher risk of renal scarring. Considering that the higher rate of renal scarring may be attributed to delayed diagnosis of VUR and ineffective treatment of previous UTI episodes, presence of scars, once detected, should alert the physician for prevention of UTI recurrences to avoid progressive injury to renal parenchyma and deterioration of function.

   References Top

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31.Stephens FD, Joske RA, Simmons RT. Megaureter with vesicoureteric reflux in twins. Aust N Z J Surg 1955;24:195.  Back to cited text no. 31
32.Noe HN, Wyatt RJ, Peeden JN, Rivas ML. The transmisson of vesicoureteral reflux from parent to child. J Urol 1992;148:1869-71.  Back to cited text no. 32
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Correspondence Address:
Pelin Ertan
Department of Pediatric Nephrology, Faculty of Medicine, Celal Bayar University, Manisa
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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/1319-2442.106241

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