Background

Vesicoureteral reflux (VUR) is the most common congenital urinary tract in children associated with the abnormal development of the UVJ. VUR is a critical risk factor for developing urinary tract infections in the paediatric population [1]. It is observed in ~ 30% of children presenting with urinary tract infections and about ~ 1% of the general population [2,3,4].

Untreated VUR leads to parenchymal injury and fibrotic scarring of the kidney, known as reflux nephropathy (RN), which is a significant cause of end-stage renal disease (ESRD) [5]. Chronic renal failure in these patients requires long-term dialysis and renal transplantation [6, 7].

Micturating cystourethrogram (MCUG) is the method of choice to diagnose VUR in children, which involves urinary catheterization and administration of a contrast agent into the bladder [8]. The risk of exposure to ionizing radiation is involved. Moreover, MCUG has a low detection rate to diagnose early and mild (low-grade) VUR. On that account, noninvasive, contrast free and radiation-free methods are required to diagnose VUR.

Only a few studies have demonstrated the utility of ureteric jet angle (UJA) and its significance in diagnosing VUR [9]. In this study, we attempt to correlate the UJA with grades (severity) of VUR and evaluate its role as an indicator to diagnose VUR in children. Early diagnosis/screening of children with this parameter can provide prophylactic antibiotic coverage to prevent secondary urinary tract infection (UTI), reducing morbidity and mortality in these patients.

Methods

In this hospital-based, cross-sectional study, we evaluated 34 children (total 68 renal units) of age group 8 months–12 years with urinary symptoms referred to the Department of Radiodiagnosis, GMC, Bhopal, for VCUG from January to June 2020 following the approval from institutional ethical committee. The patients were divided into VUR positive (cases) and VUR negative (controls) groups according to the presence of VUR in VCUG, and individual grades of VUR were noted according to the international grading system of VUR.

VCUG is the standard gold method to confirm the presence of VUR in infants and children. It also provides a detailed anatomy of the bladder and urethra. For performing VCUG, first informed written consent was obtained from parents, and the procedure was explained. All patients came with a urinary catheter in place from referring clinical departments. The empty bladder was gradually distended with a mixture of normal saline (20%) and radio-opaque contrast media Omnipaque (Iohexol 350 mg I/ml, 80%) under fluoroscopic guidance. After achieving optimal distension (observer-dependent), full bladder, micturating, and empty bladder, spot films were taken. Interpretations were made, and documentation was done.

For UJA measurements, all patients, irrespective of the presence of VUR on VCUG, were evaluated by the 2D (Figs. 1, 2, 34 and 5) and colour Doppler sonography (Fig. 6). Patients were examined in the supine position for about 10–15 min with BPL E-CUBE B, 2D, and a colour Doppler machine following the adjustments of appropriate USG parameters. Though the ultrasound parameters varied for each patient, the frequency was 6.0 on 2D and 6.5 on colour flow images in most patients (age group 8 months–3 years). The other parameters were as follows-

Fig. 1
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Distended Urinary bladder in transverse axis

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Fig. 2
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Depiction of the horizontal floor of the distended urinary bladder

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Fig. 3
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Visualization of the right ureteric orifice

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Fig. 4
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Visualization of left ureteric orifice

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Fig. 5
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Grey scale depiction of ureteric jet angles as moving echoes

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Fig. 6
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Schematic diagram to visualize and calculate ureteric jet angle on colour Doppler ultrasonography

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For 2D-Frq = 6.5, P = 100%, Gn = 49, DR = 77, FR = 15, D = 7.0 and colour flow (CF)—Frq = 6.0, p = 100%, Gn = 50, WF = 4, with 0.9 kHz. Due to difficulty localizing bilateral ureteric jets in a single transverse plane, each side was examined as one after another. Angles on both sides were recorded. The ureteric jet was identified as fast-moving echoes from the ureteric orifice with linear colour coding on each side (Figs. 5 and 6). Images were frozen, and the auto-calculated angle with three points between the longitudinal axis of this linear colour coding and the horizontal floor of the optimally distended urinary bladder (Fig. 2) was measured on a transverse scan with a high-frequency linear probe (5–7.5 MHZ). Most infants and younger children were examined during sleep. No sedation was given.

Statistical analysis

We analysed the data using the updated version of SPSS. Quantitative variables were described as median values. For the assessment of categorical variables, the Pearson chi-square test was utilized. The correlation coefficient (r) was calculated, and for the signification of any correlations between variables, the p value was derived with a significance level of less than 0.05. The confidence interval was 95%. The cut-off angle of 58° was calculated from Youden’s J index. The diagnostic efficacy of UJA 58 °C or more in detecting VUR grade was calculated, including sensitivity, specificity, PPV, NPV, and likelihood ratios using standard formulas (using the number of true positives, true negatives, false positives and false negatives).In addition, AUC was calculated to assess the diagnostic efficacy of (UJA 58° or more) to detect VUR.

Results

A total of 34 children (Total of 68 renal units), including 20 males (M) and 14 females (F), were examined. The overall incidence of VUR was 0.61 in VCUG. Age ranges from 8 months (0.66 years) to 12 years. The mean age was 4.96 ± 2.87 years for the total population, including 4.60 ± 2.02 years for boys and 5.47 ± 2.75 years for girls. The total population angle ranges from 27 to 84° with a median angle of 54.5°. Out of 34 children, 21 (61.74%) patients showed evidence of VUR, including 11 (55.00%) males and 10 (71.42%) females (Table 1). 13 children showed normal findings on VCUG (Table 1). Significant overlapping of UJA was seen when groups were compared between VUR positive and VUR negative populations; however, statistically, significantly higher angles were seen in the VUR positive population (p < 0.005).

Table 1 Age-wise distribution of angle range and median angle
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In the VCUG-positive population (for VUR), the angle ranges from 40 to 84° with a median angle of 62.13°. On the other hand, the negative population angle ranges from 27 to 60°with a median angle of 42.03°.

Under the age group 8 months–3 years, 14 (41.71%) patients were examined, including nine males and five females. Under this age group, the VUR positive population angle ranges from 40 to 84° with a median angle of 64°, and VUR negative population angle ranges from 40 to 60°with a median angle of 48°. Under the age group 4–6 years, ten patients (29.41%), including seven males and three females, were evaluated. In VUR-positive cases, the angle varies from 45 to 84° with a median angle 62°. In VUR negative cases, the angle ranges from 23 to 46° with a median angle 33.8. In the age group 8 months–3 years, mean ureteric jet angles were higher with increased refluxing units. A total of 16 cases showed bilateral refluxing units. Under the age group of 7–9 years (all female children), the VUR-positive population (total of four patients) showed an angle range from 46–76° with a median angle of 63° (11.76%).In VUR negative population under this age group angle ranges from 27 to 49°with a median angle of 39°. Under the age group of 10–12 years, 6 (17.64%) children showed VUR in VCUG with UJA ranging from 44–45°, with a median angle was 44.5°. In VUR negative population under this age, the group angle ranges from 27 to 45° with a median angle of 39° (Table 1).

In male children, 11 (32.35%) males show VUR in MCUG with an angle range of 44–84° and a median angle of 65.59°. On the other hand, VUR hostile male population shows a rise ranging from 23 to 60°and a median angle of 44.27°. Ten (29.41%) female children show some evidence of VUR on MCUG with an angle range of 42–79° and a median angle of 58.5°. On the other hand, the negative female population offers an angle range from 27 to 53° with a median gradient of 37°. 

Overall median angles were higher in the male population than in the female population. The median angle was also higher in VUR positive male population compared to VUR negative male population.

In VUR positive male population, the median angle was large (69.11°), and the VUR grade was high when similar findings were compared to the female population. Positive female children show a median angle of 62.66° with a milder VUR grade (I). Male children with bilateral refluxing units also showed significantly high VUR grades (Tables 2 and 3).

Table 2 Laterality wise distribution of VUR
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Table 3 Gender-wise distribution of angle range and grades in refluxing and nonrefluxing units
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The male population shows high incidences of VUR with higher grades (median grade III, seen in 5 male children) with a median angle of 69.84°. On the contrary, the female child population show low grades (most frequently grade I). In refluxing units, higher rates were seen in only two female children, with a mean angle of 54.35°. 

A total of 8 children show High grade (III–V) VUR and a median angle of 76.31°. Thirteen children show low-grade VUR (I–II) with a median angle of 54.23°.

Widespread occurrence and grade of VUR were higher in bilateral ureters, i.e., 15 (71.42% {9 M + 6F}, eight patients from the age of 8 months–6 years showing high grade (III-IV) VUR, five children under the age of 8 mon-3 years showed the equal number of cases. Isolated right (3) and left side VUR (3), and both sides were showing female predominance (2 females out of 3). The average angle in bilateral refluxing units was 68.2 on the right (R) and 64.8 on the left (L), which were higher on the right side. Grade I VUR was seen most frequently in bilateral refluxing units. Grade I VUR was also seen most frequently in children aged 1–10 years (total of 4). No sex predilection was seen in isolated right-sided VUR. In right-sided, isolated refluxing units, the angle ranges from 45 to 65° with a median angle of 48°. In left-sided isolated refluxing units, the grade ranges from 44 to 63 with a median angle of 63° (Tables 3 and 4).

Table 4 Gender-wise distribution of refluxing units with mean age and grades
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Nine male children, with a mean age of 2.91 year, showed sonographic features of urinary tract infection/cystitis in contradictory to only one 9 year, old female.

A positive linear correlation between UJA and grades of VUR is seen with a significant p value (p < 0.05) for grades of VUR (Table 5).

Table 5 Values of correlation coefficient and p value in refluxing units with grades of VUR and median angles
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Cut off the angle of 58° or less was calculated from Youden’s J index. The overall sensitivity of curve 58°or more to detect VUR was 0.66, which means the probability of getting VUR in children with urinary complaints is low. Therefore, it has a low potential for recognizing children with VUR. On the other hand, the overall specificity of an angle 58° or more to detect VUR is 0.92, which means the probability of getting negative VUR in healthy children is high. However, sensitivity and specificity vary greatly depending on the spectrum of VUR in the studied population (Table 6).

Table 6 Diagnostic accuracy of angle 58° of more for detecting VUR grades
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The positive and negative predictive values for this parameter (UJA) to diagnose high-grade VUR were 0.93 and 0.63, respectively. The probability of having the VUR in VUR-positive children is high (PPV = 0.93). However, the likelihood of not having VUR in VUR-negative children is low (NPV = 0.63). The likelihood ratio for diagnosing negative cases was 0.36 and for positive patients was 8.25. The high positive likelihood ratio suggests angle > 58° is more indicative of VUR. These ratios explain how much more likely positive test results occur in children with VUR than those without VUR. The negative likelihood ratio (LR-) for angle 58° to detect VUR is 0.36 for this study, which suggests this parameter may prove to be of value for ruling out the diagnosis (Table 6).

The area under the curve (AUC) was 0.7, which suggests the acceptability of this parameter as a screening tool to detect high-grade VUR.

Discussion

Hiroshi et al. [9] were the first (in 2016) to evaluate the role of UJA in detecting VUR in children. In their study, they evaluated children with urinary tract infections or hydronephrosis. They concluded that mean ureteric jet angles were significantly higher in refluxing units (67.9°) than in non-refluxing units (47.8°). Similar findings of higher angles in refluxing units (60.47°) and lower in non-refluxing units (42.59°) were reported by Nedra et al. [10]. Both studies have also suggested a greater angle for each reflux grade. In our research, we have evaluated symptomatic children with urinary complaints irrespective of the presence of urinary tract infection, hydronephrosis, or other detectable urinary abnormalities with a higher median angle in refluxing units (62.13°) and lower angles in non-refluxing units (42.03°) similar to above two studies with positive linear correlation (r = 0.81) between UJA and reflux grade suggesting high grade for higher angles.

There were many refluxing units in the age group 8 months–3 years compared to the age group 10–12 years 1. This difference suggests that the incidence of VUR is higher in infants and younger children than the older children. These results support previous literature, offering increased incidences of VUR in infants more than in younger children [3]. Longitudinal studies have demonstrated that ~ 50 to 65% of cases of non-syndromic primary VUR undergo spontaneous resolution with age [11, 12]. The mechanism leading to this resolution is not studied; however, the elongation of the intra-vesical ureter (0.5 cm at birth vs 1.5–2.5 cm in adults) due to somatic growth has been suggested as an explanation for the improved function of the VUJ in older children [13]. Alternatively, morphological changes in the bladder and ureter’s smooth muscle layer and its supporting extracellular microenvironment could be why most VUR resolves over time [14, 15]. High-grade VUR was also reported in children younger children < 1 year, and low-grade VUR were mostly seen in older children between ages 3–5 year by Lipana et al. [16]. Still, no statistical difference was noted in their study’s proportion of patients having VUR by age group.

In addition, high-grade VUR causes repeated urinary tract infections leading to significant renal damage in infants [16]. Studies have shown that in children under the age of 1 year with a urinary tract infection, 70% will have VUR. This number decreases to 15% by the age of 12. The younger the patient and the lower the grade at a presentation, the higher the chance of spontaneous resolution. Approximately 85% of stage I & II VUR cases will resolve spontaneously. About 50% of grade III VUR and a lower percentage of higher grades will also resolve spontaneously.

In this study, the overall incidence of VUR was higher (71.42%) in the female population, however, low-grade, compared to the male children [17, 18]. Some studies showed that VUR is more common in males antenatally; however, there is a definite female preponderance in later life, with 85% of cases being female. Hiraoka et al. [12] found no gender difference in the incidence of VUR detected in the prospective study of babies from mothers with a positive family history of VUR. Most of the VUR identified in family studies were classified as low grades without dilation of the renal pelvis or ureter [19, 20].

In this study, the male population showed higher grade VUR (7 males with 63.63%) in contradiction to the female population (10%, 8 months old female infants). This finding supports other studies showing that most VUR in male infants is of higher grades, whereas VUR in female infants is equally distributed between low and high grades [9]. Lipana et al. [16] reported similar results, with more males having higher VUR grades in both the right and left kidneys than females. Still, there was no statistical difference in the proportion of patients with VUR according to sex. The primary reason is frequent voiding dysfunction/ high urethral resistance found in male babies, which enhances intra-vesicle pressure and causes higher VUR incidences in male infants [13, 14]. However, this finding also allows for earlier detection of VUR by ultrasound in male infants (by causing repeated urinary symptoms).

Average angles were higher (63°) on the left side when compared to right refluxing units (48.33°), which is in support of previous studies which showed high angles on the left side [11].

Additionally, Asanuma et al. [9] evaluated the diagnostic accuracy of cut-off UJA 70° or more to detect grade IV/V VUR with a sensitivity of 0.81 and specificity of 0.82, which were higher than our study. However, results similar to our research (diagnostic efficacy of cut-off angle 58° with relatively lower sensitivity 0.66 and higher specificity 0.92) have also been reported by Zadeh et al. [10], who has evaluated the diagnostic efficacy of cut-off angle 50° with sensitivity and specificity of 0.70 and 0.79, respectively.

In our study, the value for the area under the curve was 0.7, less than the diagnostic efficacy reported by Hiroshi et al. [1] but similar to the effectiveness written by Lipana et al. [16].

Lipana et al. [16] also stated low sensitivity and negative predictive value of angle 52 to detect high-grade VUR with AUC < 0.7. They evaluated the sensitivity and specificity of curve 52° to detect VUR, which were 0.60 and 0.58, with poor correlation between ureteral jet angle and VUR owing to functional abnormalities such as voiding dysfunction in examined population [12]. Though not promising, this value suggests the acceptability of this parameter (UJA) as an alternative tool to diagnose high-grade VUR in children.

The significant difference between the diagnostic efficacy of this parameter (UJA) from other studies can be due to the small sample size of the population in the present study.

Mohanan et al. [21] have reported that higher grade VUR (IV/V) is related to moderate to severe renal scarring. However, the prevalence of this renal dysfunction was found to be lower in children with high-grade VUR without the occurrence of urinary tract infections (UTI). This suggests early detection by screening (by measuring UJA in these children) can prevent urinary tract infections (by administering prophylactic antibiotics) and could avoid ESRD.

Therefore, early diagnosis in children is crucial as studies have shown that the children with VUR who present with a UTI and associated acute pyelonephritis are more likely to develop permanent renal cortical scarring than those without VUR, with an odds ratio of 2.8. Thus VUR increases the frequency of UTIs and the risk of damage to upper urinary structures and end-stage renal disease [6].

The limitation of the study

Low sensitivity of UJA equal or > 58° to detect VUR in this study may be attributed to the smaller sample size and widely varying spectrum of VUR in the studied population. Furthermore, the interpretations and values may not be precise. Therefore, these results cannot be generalized in an entire paediatric population, and firm conclusions about the positive outcomes cannot be made.

Conclusions

Measuring ureteric jet angle on colour Doppler is a simple, easy, and acceptable technique for detecting VUR in children. Furthermore, this parameter is noninvasive and does not involve any contrast administration. So this novel parameter can be used as an alternative to VCUG to diagnose high-grade VUR; however, more research with a larger sample size is suggested.