A 3 year old female presents with fever, nausea, vomiting, left flank and abdominal pain, as well as dysuria. Her history is negative for previous urinary tract infection (UTI) or bladder/bowel dysfunction. A CBC shows a WBC of 20,000 per uL with a left shift. Urinalysis shows 50 to 100 WBCs per high power field. Intravenous fluids and IV ceftriaxone are administered with clinical improvement. A renal and bladder ultrasound shows left mild hydronephrosis. She is discharged home on a full course of oral cephalexin for 2 weeks. Urine culture later grows out E. coli with a concentration of greater than 100,000 colonies forming units per mL (cfu/mL) sensitive to cephalosporins.
An outpatient voiding cystourethrogram (VCUG) is performed and shows left Grade II vesicoureteral reflux. A decision is made to follow the child with regular observation; however, over the course of the following year, the child develops two additional episodes of febrile UTIs. She is started on daily antibiotic prophylaxis with trimethoprim/sulfamethoxazole. A nuclear cystogram at 4 years of age shows persistence of the reflux. A subsequent nuclear cystogram one year later (at 5 years of age) shows spontaneous resolution of the reflux. Antibiotic prophylaxis is discontinued, and the patient has no further problems with febrile UTIs or pyelonephritis.
Vesicoureteral reflux (VUR) refers to the pathologic retrograde flow of urine from the bladder into the upper urinary tract. VUR is congenital and often familial, occurring at a rate of 1 to 2 per 1000 children in the general population (1). Up to 30% of children with an affected older sibling and 66% of those with an affected parent also develop reflux, suggesting an autosomal dominant inheritance pattern (2). Reflux is typically discovered in 15% of infants with antenatal hydronephrosis and 30% of children diagnosed with a UTI (2). While there is a strong male predominance for neonatal reflux, females make up the majority of VUR cases and are typically diagnosed after presenting with a UTI in the first 3 years of life (1,2).
Primary vesicoureteral reflux is a consequence of abnormal ureteral development. Normally, the ureter attaches to the bladder at an oblique angle, creating a one-way flap valve that prevents the retrograde flow of urine. Primary VUR may occur because the ureteral bud arises ectopically, leading to a laterally placed ureteral orifice and a short, perpendicular submucosal bladder tunnel, which allows for reflux. Functional and anatomic bladder outlet obstruction abnormalities, such as neurogenic bladder and posterior urethral valves can also lead to the backflow of urine in the upper urinary tract, resulting in secondary reflux (1,2). Primary or secondary vesicoureteral reflux predisposes an individual to pyelonephritis by facilitating the transport of bacteria from the bladder to the upper urinary tract. The immunologic and inflammatory reaction caused by a pyelonephritic infection may result in renal injury or scarring. Extensive renal scarring causes reduced renal function and may result in permanent renal damage, pediatric renal failure, and potentially increasing the risk of renal failure in adulthood, especially with other adult comorbidities such as diabetes and/or hypertension. Historically, reflux nephropathy accounted for 15% to 20% of end-stage renal disease in the pediatric population (1).
Children with vesicoureteral reflux may present with clinical pyelonephritis, fever, abdominal/flank pain, malaise, nausea, vomiting, cystitis with dysuria, frequency, urgency, and urge incontinence.
Cystography is the gold standard imaging modality for the detection of urinary reflex. There are two types of cystograms: a voiding cystourethrogram (VCUG) and a radionuclide cystogram (RNC). Both procedures involve injecting a contrast agent into the bladder via a urinary catheter to analyze the structure and function of the urinary tract. A VCUG provides more anatomic detail than the RNC, but involves higher radiation exposure. VCUG is preferred for the initial study and grading of VUR. Follow-up cystography is usually done using radionuclide cystography (2). Due to a concern for radiation exposure and sedation in children, the initial evaluation of a febrile UTI should involve ultrasonography rather than cystography. In this population, a VCUG is only indicated if there are abnormalities observed on renal/bladder ultrasound. Cystography also becomes necessary in children with recurrent febrile UTIs (3).
Reflux grade is determined by VCUG and has important implications for disease prognosis. A higher reflux grade is associated with increased rates of renal injury, lower rates of spontaneous resolution, and less successful treatment (2). The grading of vesicoureteral reflux is as follows: Grade I describes urine reflux into the distal ureter only. Grade II reflux results in urine backflow into the ureter and the renal pelvis, with no ureteral dilation and no distension of the renal pelvis (i.e., normal calyces). Grade III results when urine refluxes into the ureter and the renal pelvis, causing mild hydronephrosis (pelvic and calyceal dilation) and mild hydroureter (dilated ureter). Grade IV results in moderate hydronephrosis and hydroureter. Grade V results in severe hydronephrosis and severe hydroureter (2). See Figure 1.
Figure 1. Grading of vesicoureteral reflux (VUR)
The main goals of management in children with VUR are to prevent recurrent UTIs and renal injury, and to minimize the burden of treatment and follow-up (4). In the past, all reflux patients were treated uniformly with continuous antibiotic prophylaxis (CAP). Recently, however, the efficacy of CAP has been called into question. While large randomized trials, such as the RIVUR trial support CAP, a 2019 Cochrane review concluded that the use of long-term antibiotics makes little or no difference in the prevention of recurrent UTIs in children with VUR (5,6). Current recommendations favor a more conservative, individualized approach to the management of children with VUR. For example, the American Urological Association recommends that children with VUR less than one year of age receive CAP only if they have a positive history of febrile UTI or grade III to V reflux. Antibiotic prophylaxis in children older than one year of age is recommended in those with bladder/bowel dysfunction and may be an option for those with recurrent UTIs (4).
Follow-up imaging and labs are indicated for the management of VUR, regardless of whether a child receives continuous antibiotic prophylaxis. Many clinicians treating children with reflux obtain urine specimens annually for a urinalysis and/or culture. Ultrasonography is also performed every 12 months to monitor for changes to the kidney parenchyma. Follow-up cystography (radionuclide cystogram) is conducted less frequently (every 12 to 24 months). A DMSA renal scan may also be considered when the renal ultrasound is abnormal and the physician is concerned about renal scarring (e.g., from a breakthrough urinary tract infection) (4). Medical management is considered successful if the child remains free of infection, develops no new renal scarring, and the reflux resolves spontaneously. Failure of medical management is indicated by breakthrough UTIs, the development of new renal scars, or the failure of the reflux to resolve (7).
Most cases of vesicoureteral reflux tend to resolve spontaneously over time as the bladder grows and matures and the intravesical segment of the ureter elongates. Higher rates of spontaneous resolution generally occur in those with the lowest grades (I and II) of reflux, with a mean age of 6 years at VUR resolution (1). High-grade VUR, renal abnormalities, prenatal hydronephrosis, and older age at diagnosis are all associated with a lower likelihood of spontaneous resolution (3).
Surgical repair of the refluxing ureter is indicated when medical management fails. The gold standard for operative intervention is ureteral reimplantation, which involves modifying the abnormal ureterovesical attachment to create a more substantial intravesical ureteral component. The outcome of surgical reimplantation varies with disease severity, with successful correction occurring in 98% of cases of grade I to IV reflux and 80% of patients with grade V reflux (1,3). Endoscopic injection is another less-invasive option for surgical correction of uncomplicated VUR. A bulking agent is injected beneath the ureteral orifice, creating an effective one-way flap valve. Success rates for endoscopic injection range from 50% to 88%, depending on the severity of reflux (7).
Vesicoureteral reflux remains an important cause of urinary tract infection and renal injury in the pediatric population. Over the past 20 years, there has been a shift towards more conservative and individualized follow-up and treatment. While the use of traditional imaging (i.e., a VCUG) and continuous antibiotic prophylaxis remain important in the management of VUR, there is no longer one single-best approach.
Ectopic Ureter and Duplex Collecting Systems
An ectopic ureter is one that drains into any location other than the bladder trigone. It occurs 3 to 5 times more often in females compared to males (8,9). Embryologically, ectopic ureters are thought to arise from the failed separation of the ureteric bud and mesonephric duct, leading to a more caudal ureteral insertion (8). In some instances, the ureter may not even incorporate itself into the bladder but may enter other genitourinary structures. In males, the abnormal insertion always occurs above the external sphincter (i.e., the bladder, prostatic urethra, epididymis, seminal vesicles, vas deferens, or ejaculatory ducts) and thus does not cause urinary incontinence, presenting instead as a UTI or epididymitis (9). This is in contrast to female patients, where the ureter typically implants below the external sphincter and results in continuous urinary incontinence. Common sites of abnormal ureteral implantation in females include the urethra, introitus, vagina, uterus, and fallopian tube (8,9).
Although ectopic ureters may occur in isolation, most cases (80%) are associated with duplex collecting systems (8). Duplication of the collecting system results from early splitting of the ureteric bud, which creates two pyelocaliceal systems (10). It is the most common congenital ureteral abnormality, with an estimated prevalence of 8 per 1000 individuals (8). Duplex collecting systems can be further classified as complete or incomplete. Complete systems have two distinct whole-length ureters, while the ureters of incomplete systems fuse before the ureterovesical junction (8). In a complete duplex collecting system, it is the ureter of the upper pole that implants ectopically (10). While most cases of duplex collecting systems are asymptomatic, the presence of an ectopic ureter may also result in renal dysplasia, hydronephrosis, and vesicoureteral reflux.
The evaluation of an ectopic ureter and duplex collecting system includes US, VCUG, and renal scans. Duplex collecting systems are often detected on prenatal or postnatal ultrasound. Ultrasound findings suggestive of a duplicated collecting system include unequal renal lengths, asymmetric pelvicalyceal dilatation between the upper and lower poles, and the presence of parenchymal tissue dividing the renal pelvis (10). Ultrasonography is less useful in the assessment of an ectopic ureter, as it does not rule out the condition. As a result, the use of CT and MR urography has been gaining in popularity for the evaluation of urinary tract anomalies, even in children (10). A VCUG may be helpful if the ectopic ureter inserts into the bladder or urethra and in the presence of reflux (8). MAG3 (mercaptoacetyltriglycine) or DMSA (dimercaptosuccinic acid, also known as succimer) renal scans are also indicated to assess kidney function and guide treatment decisions (10).
Ectopic ureters are treated surgically based upon whether the patient presents with single or duplex systems, how well each kidney pole functions, and whether there is ipsilateral lower pole reflux. Partial nephrectomy and ureterectomy are indicated for upper poles that are nonfunctioning or poorly functioning. In those with upper pole function and no evidence of lower pole reflux, ureteropyelostomy or high ureteroureterostomy are reasonable approaches. Ureteral reimplantation (ureteroneocystostomy) is a good option for patients with upper pole function and lower pole reflux (9).
A ureterocele refers to a dilation of the distal ureter at the level of the ureteral orifice (intravesical ureter). It results from a failure of normal ureteral development, possibly due to the persistence of an embryologic membrane around the distal ureter (8). Ureteroceles can be categorized as orthotopic (occurring at the vesicoureteral junction) or ectopic (occurring inferiorly and medially to the expected vesicoureteral junction). In the pediatric population, ectopic ureteroceles are much more common, while orthotopic ureteroceles are almost always seen in adults. Ureteroceles are four to six times more common in females than males. In children, 80% of ureteroceles are associated with a duplex system and arise from the upper pole of the kidney (8). These upper pole segments usually demonstrate varying degrees of renal dysplasia secondary to ureterocele-induced obstruction (9).
Ureteroceles may be picked up initially with prenatal ultrasound and appear as intravesical cysts that are continuous with the distal ureter (8). In older children, ureteroceles are usually discovered during the workup for UTIs, incontinence, hematuria, failure to thrive, and non-specific abdominal or pelvic pain. In females, ureteroceles may even present as a palpable abdominal mass or cystic intralabial mass (the result of a large ureterocele that has prolapsed through the urethral lumen). A VCUG will show a filling defect in the bladder with possible reflux into the lower pole collecting system (9).
The management of ureteroceles is similar to ectopic ureteral management in that the approach taken is dependent upon the presence of single or duplex systems, ipsilateral or contralateral reflux, obstruction, and degree of renal function. Treatment goals for ureteroceles are the same as for any other congenital renal or urinary tract anomaly; to preserve renal function, correct obstruction and reflux, prevent urinary stasis and UTIs, and preserve urinary continence with minimal impact on morbidity and mortality (11). Management options specific to ureteroceles range from observation and transurethral ureterocele punctures to more complex surgical reconstruction of the urinary system (e.g., upper pole nephrectomy with partial ureterectomy, ureteroneocystostomy, high ureteroureterostomy, or transvesical ureterocele repair) (9,11).
Posterior Urethral Valves
Posterior urethral valves (PUV) describe the presence of valve-like leaflets in the posterior urethra which result in varying degrees of obstruction to the outflow of urine (sometimes severe). It is the most common congenital cause of lower urinary tract obstruction, occurring in as many as 1 in 5000 boys (9,12). The obstruction created by the posterior urethral valves may have serious deleterious effects on renal and fetal development. Severe cases of obstruction are associated with high rates of fetal and neonatal mortality (30%), a consequence of oligohydramnios and the resulting pulmonary hypoplasia (12). Of the male infants who survive into childhood and adulthood, about one-third go on to develop end-stage renal failure (12,13).
Posterior urethral valves are typically discovered on prenatal ultrasound, which may show hydroureteronephrosis, bladder thickening, and oligohydramnios if severe (9). Characteristic findings alluding to the presence of posterior urethra valves can also be picked up on the newborn physical exam, including a distended bladder, a palpable prostate, poor urinary stream, and signs and symptoms of renal and pulmonary insufficiency. Children diagnosed at an older age typically have a less severe obstruction and may present with daytime incontinence, infrequent voiding, poor urinary stream, chronic severe urinary frequency, and complicated enuresis (9).
The presence of a bladder outlet obstruction is readily established on VCUG. Posterior urethral valves show a characteristic appearance of a prominent bladder neck, dilated posterior urethra, and a bulging membrane at the junction of the membranous and prostatic urethra (the verumontanum). In addition, the bladder is usually thickened, with trabeculation and diverticula. There is associated reflux in 50% of patients (9).
Posterior urethral valves should ideally be treated in the neonatal period. Treatment is centered on securing adequate drainage of the urinary tract, initially with the placement of a urinary catheter and later by primary cystoscopic ablation of the valves, vesicostomy, or upper urinary tract diversion. Standard practice also includes circumcision and antimicrobial prophylaxis to reduce the risk of UTI (9,12). The long-term outcome is dependent upon the degree of renal dysplasia present with 30% of children eventually requiring renal transplantation. Up to 80% of vesicoureteral reflux cases should resolve after valve ablation (12). Persistent bladder dysfunction is common despite adequate treatment (55% of patients) and should be treated with anticholinergics, alpha-blockers, and clean intermittent catheterization, as indicated (13).
In certain circumstances, intrauterine intervention may be an option to minimize the deleterious effects of lower urinary tract obstruction on the developing fetus and kidneys. Antenatal intervention should be considered only if persistent or progressive oligohydramnios develops in a fetus with a normal karyotype, there are no other life-threatening anomalies, and fetal immaturity precludes delivery (14). The main goal of fetal intervention is to restore the amniotic fluid volume necessary to maintain normal lung development. This is typically achieved by insertion of a vesicoamniotic shunt (VAS), which requires normal renal function and allows urinary drainage of the bladder into the amniotic sac. Studies suggest 40% to 50% survival after shunt placement, but the procedure is associated with high rates of complication. Other interventions include fetoscopic ablation of posterior urethral valves and serial amnioinfusions to maintain adequate amniotic fluid volume (14).
Prune-belly syndrome, also known as Eagle-Barrett or triad syndrome, is a rare disorder of mesodermal development resulting in abnormalities of the genitourinary system and abdominal musculature. The three characteristic features of the syndrome include aplasia of abdominal muscles (a flabby abdomen), bilateral cryptorchidism, and urinary tract malformations. The incidence is 1 per 40,000 live births, with 95% of the cases occurring in boys. Genitourinary anomalies that most commonly occur are renal dysplasia or agenesis, vesicoureteral reflux, and a large capacity poorly contractile bladder. Cardiac, pulmonary, and orthopedic anomalies are also common in these patients (9).
Prune-belly syndrome treatment primarily involves optimization of urinary tract drainage, management of renal insufficiency, and antibiotic prophylaxis. Surgical repair of reflux, orchiopexy, and abdominal wall reconstruction is performed later in childhood. Prognosis typically depends on the degree of pulmonary hypoplasia and renal dysplasia, with high rates of neonatal mortality (30%) and end-stage renal disease (30%) (9).
1. What is the cause of primary vesicoureteral reflux?
2. How does antibiotic prophylaxis for the management of vesicoureteral reflux prevent renal scarring?
3. What are the indications for surgical treatment of primary vesicoureteral reflux?
4. What is a ureterocele and how is it treated?
5. What further studies should be obtained for a 2-day-old male with US findings of bilateral hydroureteronephrosis, and a thick-walled bladder? What diagnosis is suspected and what is the appropriate treatment?
1. Elder JS. Vesicoureteral Reflux. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp. 2796-2800.
2. Khoury AE, Wehbi E. Management Strategies for Vesicoureteral Reflux. In: Partin AW, Dmochowski RR, Kavoussi LR, Peters CA (eds). Campbell-Walsh-Wein Urology, 12th ed. 2021, Elsevier, Philadelphia, PA. pp:489-517.
3. Läckgren G, Cooper CS, Neveus T, Kirsch AJ. Management of Vesicoureteral Reflux: What Have We Learned Over the Last 20 Years? Front Pediatr. 2021;9:650326. doi:10.3389/fped.2021.650326
4. Management and Screening of Primary Vesicoureteral Reflux in Children. American Urological Association. https://www.auanet.org/guidelines/guidelines/vesicoureteral-reflux-guideline#x3321. Published 2010, Amended 2017. Accessed May 20, 2022.
5. Lee T, Park JM. Vesicoureteral reflux and continuous prophylactic antibiotics. Investig Clin Urol. 2017;58(Suppl 1):S32-S37. doi:10.4111/icu.2017.58.S1.S32
6. Williams G, Hodson EM, Craig JC. Interventions for Primary Vesicoureteric Reflux. Cochrane Database of Systematic Reviews. 2019;20(2): CD001532. doi:10.1002/14651858.cd001532.pub5
7. Coco C, Jacobs M. Surgical indications for operative management of vesicoureteral reflux in children. Curr Opin Pediatr. 2021;33(2):243-246. doi:10.1097/MOP.0000000000001000
8. Houat AP, Guimarães CTS, Takahashi MS, et al. Congenital Anomalies of the Upper Urinary Tract: A Comprehensive Review. Radiographics. 2021;41(2):462-486. doi:10.1148/rg.2021200078
9. Elder, JS. Obstruction of the Urinary Tract. In: Kliegman RM, St. Geme JW, Blum NJ, et al (eds). Nelson Textbook of Pediatrics, 21st edition. 2020, Elsevier, Philadelphia, PA. pp. 2800-2810.
10. Didier RA, Chow JS, Kwatra NS, Retik AB, Lebowitz RL. The duplicated collecting system of the urinary tract: embryology, imaging appearances and clinical considerations. Pediatr Radiol. 2017;47(11):1526-1538. doi:10.1007/s00247-017-3904-z
11. Le HK, Chiang G. Long-term Management of Ureterocele in Duplex Collecting Systems: Reconstruction Implications. Curr Urol Rep. 2018;19(2):14. doi:10.1007/s11934-018-0758-3
12. Diamond DA, Chan IHY, Holland AJA, et al. Advances in paediatric urology. Lancet. 2017;390(10099):1061-1071. doi:10.1016/S0140-6736(17)32282-1
13. Deshpande AV. Current strategies to predict and manage sequelae of posterior urethral valves in children. Pediatr Nephrol. 2018;33(10):1651-1661. doi:10.1007/s00467-017-3815-0
14. Safdar A, Singh K, Sun RC, Nassr AA. Evaluation and fetal intervention in severe fetal hydronephrosis. Curr Opin Pediatr. 2021;33(2):220-226. doi:10.1097/MOP.0000000000001001
Answers to questions
1. The ectopic insertion of the ureter into the bladder wall laterally results in a short intravesical ureter (a short submucosal bladder tunnel), which acts as an incompetent valve during urination, allowing urine to reflux back up into the ureter.
2. Antibiotic prophylaxis sterilizes the urine, preventing bacteria from ascending the refluxing ureters and causing pyelonephritis and renal scarring/damage. This allows time for normal growth and development of the ureter and bladder to occur. With growth, lengthening of the submucosal bladder tunnel/intravesical ureter results in the resolution of reflux over time, particularly in those with lower grades of reflux. Observation includes annual urinalysis, renal ultrasound, and serial cystograms (usually nuclear scintigraphy) every 12 to 24 months.
3. The failure of medical management (and thus the need for ureteral reimplantation or ureteroneocystostomy) is indicated by breakthrough UTIs, the development of new renal scars, or the failure of reflux to resolve over time. Noncompliance or allergic reactions to the prescribed antibiotics may also lead to the failure of medical management.
4. A ureterocele is a dilation of the distal ureter at the level of the ureteral orifice. The management of ureteroceles is dependent upon the presence of single or duplex systems, ipsilateral or contralateral reflux, obstruction, and degree of renal function. Treatment options include observation, transurethral incision, upper pole nephrectomy with partial ureterectomy, ureteroneocystostomy with ureterocele excision, high ureteroureterostomy, and transvesical ureterocele repair.
5. A VCUG should be obtained to evaluate for posterior urethral valves. If PUV are present, the VCUG will show a prominent bladder neck, a dilated posterior urethra, with a bulging membrane at the distal aspect of the verumontanum. The bladder may be thickened. Reflux may be present. The treatment is centered on securing adequate drainage of the urinary tract; initially with the placement of a urinary catheter, and later by transurethral ablation of the valves. A vesicostomy (surgical formation of a cutaneous bladder stoma) may be done as a temporary measure if the infant cannot undergo transurethral ablation of the valves.