State of the Art Pediatrics: Vesicoureteral Reflux: Back to Basics

Column Author: Gino Vricella, MD | Assistant Professor of Surgery, University of Missouri-Kansas City School of Medicine

Column Editor: Amita R. Amonker, MD, FAAP | Assistant Professor of Pediatrics, University of Missouri-Kansas City School of Medicine; Clinical Assistant Professor of Pediatrics, University of Kansas School of Medicine

While vesicoureteral reflux (VUR), in and of itself, is not harmful to the kidney, its presence predisposes patients to acute pyelonephritis by transporting bacteria from the bladder to the kidney, which can lead to renal scarring, hypertension, and, ultimately, chronic kidney disease (CKD). Reflux nephropathy (RN) is estimated to be responsible for up to 20% of all children with chronic renal failure.¹ Reflux nephropathy is also the second leading cause of chronic tubulointerstitial disease and the fourth most common cause of end-stage renal disease (ESRD) in children behind focal segmental glomerulosclerosis (FSGS), renal aplasia, dysplasia and obstructive uropathy.^2,3 RN is responsible for ESRD in 7% to 17% of children worldwide; thus, it is important for all pediatric practitioners to understand its etiology, diagnosis and management strategies.

Based upon its pathogenesis, VUR is of two kinds: primary and secondary. In primary VUR, the most common form, reflux is due to inadequate intravesical tunnel length. Normally, reflux is prevented during bladder contraction by detrusor musculature compressing the intravesical ureter and creating an anti-reflux valve mechanism. When intravesical tunnel length is short, as it is in primary VUR, the anti-reflux mechanism is faulty and allows for retrograde flow of urine up the collecting system. This mechanism explains why we see spontaneous resolution of primary VUR over time. As the patient grows, so does the bladder and, consequently, the intravesical tunnel length, which improves the anti-reflux mechanism. In contrast, secondary VUR is related more to the pressure dynamics of the bladder and its effects on the ureterovesical junction (UVJ). Often associated with anatomic (e.g., posterior urethral valves) or functional (e.g., neurogenic bladder) obstruction of the bladder outlet, abnormally high voiding pressures are transmitted to the UVJ and results in failure of its closure during bladder filling and voiding. Both the severity and chronicity of the obstruction will impact the grade of reflux.

Regardless of its etiology, diagnosis of reflux has long been established with a contrast voiding cystourethrogram (VCUG). Alternative imaging modalities to diagnose VUR exist. We will be reviewing a few of these and comparing them to the gold standard VCUG.

Radionuclide cystography (RNC) is the most common, routinely performed alternative that uses a radiopharmaceutical agent (e.g., technetium-99m [Tc-99m] sodium pertechnetate, Tc-99m sulfur colloid, or Tc-99m diethylenetriamine penta-acetic acid [DTPA]) to image the ureters and bladder. RNC is performed exactly like a VCUG, through retrograde instillation of the radiopharmaceutical directly into the bladder via a catheter. Images are acquired through the detection of photons emitted from the radiopharmaceutical with a gamma camera.

When comparing the two studies (i.e., VCUG versus RNC), the VCUG will expose the patient to more radiation. Although recent improvements introducing low-dose fluoroscopy techniques like “as low as reasonably achievable” (ALARA) and pulse fluoroscopy with the aid of digital enhancing modalities have decreased the radiation dose to the patients dramatically,⁴ a VCUG exposes the patient to almost 10 times the radiation of an RNC. A special concern is the gonadal radiation dose, particularly with multiple studies of fluoroscopic monitoring.⁵ Despite the increased radiation exposure associated with VCUG, the anatomic detail that traditional VCUG provides is currently unmatched. Specifically, RNC does not reliably demonstrate bladder wall appearance, grade 1 reflux, ureteral duplication anomalies, ureteroceles, ureteral ectopia, and, perhaps most importantly in males, cannot delineate urethral anatomy. Consequently, in many centers (including or own), RNC is not used as the initial study, but may be used to monitor for persistent reflux in follow-up evaluation.

Contrast-enhanced voiding urosonography (CeVUS) is a relatively new technique (first introduced in the 1990s) employing an ultrasonographic contrast agent to image the collecting system and detect VUR.⁶ Although urethral catheterization is still required, this technique avoids ionizing radiation altogether. Additionally, since the images are not pulsed and performed in real time, coupled with the fact that even single microbubbles can be visualized with this ultrasound method, echo-enhanced ultrasonography is more sensitive in detecting low-grade reflux and can also image the male urethra (although still not depicting it with the level of detail in a typical VCUG). In a systematic review and meta-analysis from 2022 that culled data from 36 articles (2768 children), researchers found an AUC, sensitivity and specificity of CeVUS in the diagnosis of VUR of 0.97 (95% CI: 0.95, 0.98), 0.92 (95% CI: 0.86, 0.96) and 0.94 (95% CI: 0.95, 0.98), respectively.⁷ Despite the purported benefits of CeVUS and the excellent testing parameters just described, the inter-observer variability is high and a specially trained examiner is obligatory. This diagnostic modality also has a 3% false negative rate.⁷ Although a relatively low and acceptable number, questions remain about whether the amount of radiation exposure the patient receives in other diagnostic methods is harmful enough to outweigh the higher false negative rate of CeVUS. Finally, the diagnostic value of CeVUS for VUR may be influenced by children’s age due to developmental variations during childhood. In one study, the sensitivity and specificity of CeVUS in diagnosis of reflux in all the age groups were 0.86 and 0.95, respectively. Sensitivity and specificity then changed to 0.92 and 0.93 when the analyses were limited to children under 24 months of age.⁸

Ultimately, in the diagnosis of VUR, we should stop and return to basics. First, we need to ask ourselves why we are ordering this test and what critical information we can glean that will aid in the management of the patient? What are the parental concerns regarding radiation exposure or the invasiveness of the testing. Is this the first study that this patient has ever had or is this a follow-up exam? Is the diagnostic visualization of anatomic details paramount or do we just need to know whether VUR exists? What studies does our institution offer and how routinely are these studies performed? It is only after we answer these and other specific questions that we can participate effectively in shared decision-making to help parents decide what the best course of action is for their child.

References:

1. Deleau J, Andre JL, Briancon S, Musse JP. Chronic renal failure in children: an epidemiological survey in Lorraine (France) 1975-1990. Pediatr Nephrol.1994;8(4):472-476.
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8. Nakamura M, Shinozaki T, Taniguchi N, Koibuchi H, Momoi M, Itoh K. Simultaneous voiding cystourethrography and voiding urosonography reveals utility of sonographic diagnosis of vesicoureteral reflux in children. Acta Paediatr. 2003;92:1422-1426.