Vesicoureteral reflux (VUR) is the retrograde urine flow from the urinary bladder to the upper urinary tract, usually during voiding. A short intramural ureter often causes this abnormal backward flow of urine. The clinical significance of VUR was not recognized until 1960, when the condition was associated with recurrent urinary tract infections (UTIs), renal cortical scarring, and permanent kidney damage, particularly in children. VUR is the most prevalent urological abnormality in neonates, occurring in approximately 1% of all newborns. However, this percentage rises significantly, up to 15%, in those diagnosed with prenatal hydronephrosis.
VUR is 3 times more prevalent in White than Black patients and twice as likely in women than men, except for cases identified with prenatal hydronephrosis, where VUR is more commonly found in boys. A systematic review of 34 studies indicated that approximately 16% of neonates with ultrasound evidence of hydronephrosis eventually have VUR. When tested, about 30% to 40% of children with a febrile UTI exhibit some degree of VUR, compared to 17% of patients without UTI evidence. In phenotypically male infants with dilated ureters, the odds for the presence of VUR are significantly higher, while in infants with UTI, the prevalence of VUR increases to over 66%.
A genetic predisposition for the disorder exists, as up to two-thirds of children born to women with primary VUR will also exhibit the condition. The incidence of primary VUR is very high in twins. Among siblings, the incidence of VUR is about 30%, although routine screening of asymptomatic siblings with normal renal ultrasound examinations is presently not recommended. VUR may also be associated with other congenital conditions such as posterior urethral valves, neurogenic bladder, spina bifida, urinary outlet obstruction, bladder overactivity, imperforate anus, ureterocele, and bladder exstrophy.
VUR can be asymptomatic, unilateral or bilateral, or associated with nephropathy, which can be severe. End-stage renal failure in children due to reflux nephropathy accounts for about 5% of all pediatric renal transplants. However, early diagnosis and timely treatment of VUR can prevent renal damage and recurrent UTIs and salvage the kidneys.
Bladder or bowel dysfunction includes lower urinary tract abnormalities in children, including detrusor overactivity, urinary urgency, urge incontinence, hypoactive bladder, postponement of urination, and other voiding disturbances. These conditions may be accompanied by gastrointestinal and bowel disorders such as encopresis and chronic constipation. Bladder or bowel dysfunction is more commonly found in females.
Patients with VUR with bladder or bowel dysfunction are at a higher risk of developing infections despite continuous prophylaxis and have a much lower rate of spontaneous resolution (31% compared to 61%) and reduced success rates after endoscopic VUR surgical procedures. Treatment for bladder or bowel dysfunction, including timed voiding, laxatives, pelvic floor therapy and exercises, behavioral modifications, and anticholinergic therapy, effectively reduces voiding symptoms, improves bladder function, and increases spontaneous resolution.
Approach to Diagnosis
The initial evaluation starts with a urinalysis (dipstick and microscopic), including an evaluation for proteinuria and bacteriuria and a urine culture and sensitivity, if indicated. In addition, obtaining a baseline creatinine level is advisable to establish baseline renal function, particularly in severe cases. Renal ultrasonography is recommended for both initial and follow-up examinations to evaluate renal anatomy, cortical thickness, the presence of hydronephrosis, and any structural abnormalities. Unfortunately, ultrasound lacks high sensitivity or specificity for detecting high-grade VUR.
Technetium-99m–labeled dimercaptosuccinic acid radionuclide renal imaging is recommended to assess kidney function and determine the extent of renal scarring. However, the gold standard for evaluating VUR is direct cystography with voiding cystourethrogram (VCUG). VCUG provides detailed anatomical visualization, detects bladder diverticula, identifies ureteral duplications, demonstrates the extent of bladder wall trabeculation, and facilitates VUR grading. Nevertheless, performing VCUG in infants and young children requires specialized expertise to minimize emotional and physical trauma and reduce radiation exposure (see Image. Fluoroscopic Spot Image Revealing Bilateral VUR on VCUG).
The initial imaging method for a child experiencing their first febrile UTI typically involves renal ultrasound, with VCUG being recommended if sonography reveals abnormalities, a second UTI occurs, or if the patient presents with other high-risk factors such as bowel or bladder dysfunction. However, neither ultrasound nor radionuclide scanning can replace the VCUG as the definitive imaging modality for VUR. Multiple VCUG imaging cycles (at least 2) are recommended to identify reflux that may only occur early or late in the voiding cycle. Notably, it is advised to use diluted contrast at body temperature, administered into the bladder through a small urethral catheter with only gravity pressure. Anesthesia should be avoided as it can impact the results, although limited sedation may be necessary for some patients.
Imaging is performed using the lowest reasonable radiation dose ("as low as reasonably achievable" or "ALARA") to ensure quality imaging, as accurate diagnosis and grading are crucial for selecting optimal therapy. Additionally, urethral spot images during voiding, and scout and post-void films, should be obtained. In addition, it is important to document the maximum contrast in the bladder and the volume at which reflux is initially observed. To ensure optimal VCUG imaging quality with minimal discomfort and risk to the patient, it is advisable to adhere to the 2016 protocol outlined by the American Academy of Pediatrics (AAP) Sections on Urology and Radiology.
The VCUG findings, along with the patient's age and clinical presentation, determine the VUR grading used to formulate the treatment plan. An International Grading System for VUR has been established to streamline clinical decision-making processes.
Grade I: Reflux solely into the non-dilated ureter.
Grade II: Reflux into both the ureter and renal pelvis without dilatation.
Grade III: Reflux with a mildly dilated ureter and pyelocalyceal system with only mild or minimal blunting of the calyces.
Grade IV: Reflux characterized by a somewhat tortuous, mildly to moderately dilated ureter, with blunting of the renal calyces while preserving the visual impression of the renal papilla.
Grade V: Reflux involving a very tortuous, severely dilated ureter, and significant pyelocalyceal dilatation, resulting in the loss of renal fornices and no visual papillary impression on imaging.
Grades III to V are considered dilating or high-grade VUR and are associated with an increased risk of UTIs and renal scarring, especially grades IV and V. Although grade III may be categorized as low, moderate, or intermediate in some grading systems, the consensus opinion typically positions it at the lower end of the high-grade category.
Grading VUR becomes challenging when there is a concurrent urinary tract obstruction, as ureteral dilatation and tortuosity may not solely result from VUR. The presence of obstruction is common and might lead to an overestimation of the VUR grade. Post-void delayed imaging should be obtained if urinary obstruction is suspected. Alternative diagnostic methods include radionuclide cystograms and contrast-enhanced voiding ultrasonography, which can be performed with simultaneous video urodynamics. These alternative techniques offer reduced radiation exposure at the expense of anatomical detail. They are particularly valuable for monitoring or tracking VUR, which was previously identified by VCUG. Radionuclide cystograms are especially useful in monitoring patients with high-grade (grade III-V) reflux.
Imaging the upper tracts is crucial, and initial ultrasound imaging can be conveniently conducted in various settings such as clinics, offices, or hospitals. Although a formal VCUG may not always be indicated, ultrasound gives immediate results and is painless, inexpensive, radiation-free, and readily available. Ultrasound imaging of the bladder can detect abnormal changes in bladder wall thickness, detect diverticula, highlight ureteroceles, and measure post-void residual urine volumes. Serial ultrasounds offer an efficient method to monitor renal growth and track changes in ureteral and renal pelvic diameters (RPDs), providing evidence of any hydronephrosis.
Radionuclide studies enable split differential kidney function assessments and offer superior visualization of non-functional (scarred) kidney segments compared to ultrasound. However, intravenous (IV) access is required, and sedation may be necessary for some children. Dimercaptosuccinic acid exhibits higher sensitivity but lower specificity than ultrasound for detecting VUR. In addition, it is recommended to conduct contrast-enhanced ultrasonography and radionuclide scanning before VCUG, allowing patients who test negative on both examinations to potentially avoid a VCUG study. Although a dimercaptosuccinic radionuclide scan can effectively rule out high-grade VUR, it often produces false positives. Neither dimercaptosuccinic radionuclide scan nor renal ultrasound alone, or in combination, have demonstrated reliability or accuracy in replacing VCUG for diagnosing VUR.
Baseline ultrasound imaging for siblings of patients with VUR is recommended, as their incidence of VUR is reported to be between 27% and 46%, particularly in those children aged 3 or younger. Further imaging, including VCUG, should be considered if renal abnormalities are detected or if they experience UTIs. Screening older, toilet-trained siblings without symptoms or UTI history is optional, and children of previously treated patients with VUR are addressed similarly.
The evaluation of prenatal hydronephrosis is primarily based on ultrasonography findings during the third trimester of pregnancy. However, the timing of postnatal follow-up studies varies based on prenatal sonography results and clinical presentation. The severity of hydronephrosis is typically determined by the anterior-posterior RPD observed on a third-trimester ultrasound. For most practical purposes, only those with an RPD of 10 mm or more are considered clinically significant.
Mild hydronephrosis: RPD <10 mm
Moderate hydronephrosis: RPD of 10 to 15 mm
Severe hydronephrosis: RPD >15 mm
Urgent cases that require ultrasonography within the first 48 hours after birth include neonates with significant bilateral hydronephrosis, particularly if accompanied by ureteral dilation or bladder distension, or a markedly hydronephrotic solitary kidney (RPD of 10 mm or more). These instances may demand immediate surgical intervention to safeguard renal function.
In most non-urgent cases, ultrasound is postponed at least 48 hours, as any hydronephrosis is likely to be underestimated due to significant postnatal extracellular fluid changes, which are normal. Mild cases, such as unilateral prenatal hydronephrosis with a normal contralateral kidney, can safely be postponed for 3 to 4 weeks to allow the neonate to become normovolemic. Otherwise, hydronephrosis might be missed due to fluid shifts and dehydration. While some advocate for this approach, others argue that there is little harm in obtaining an earlier ultrasound at 48 hours. This also verifies that the situation does not require more rapid intervention or has significantly deteriorated since the prenatal ultrasound. A follow-up ultrasound examination at 4 to 6 months is recommended in either scenario.
In general, patients with bilateral hydronephrosis and those who demonstrate postnatal hydronephrosis with either ureteral dilation or an anterior-posterior RPD greater than 15 mm should undergo VCUG for further evaluation. Given the significantly higher risk of UTIs in uncircumcised male infants, the decision regarding circumcision for a male child with VUR should be extensively discussed with the parents. Shared decision-making discussions should ensue, ensuring that both the risks and benefits of circumcision are thoroughly reviewed with the family. Families opting against circumcision for their child should receive comprehensive education on proper foreskin care and be thoroughly instructed on recognizing signs and symptoms of UTIs in this age group. Prompt identification and treatment of any new infections are crucial. Long-term follow-up examinations have revealed permanent renal damage in approximately 40% of children initially presenting with moderate or severe hydronephrosis.
Urodynamic and video urodynamic studies may be considered in older children with VUR who are toilet-trained but still have urinary dysfunction or fail prophylactic therapy. These patients may exhibit various forms of neurogenic bladder, such as uninhibited detrusor contractions or detrusor sphincter dyssynergia, which must be addressed and resolved before considering potential surgical intervention.
Approach to Treatment
Managing VUR varies depending on factors such as clinical presentation, patient age, VUR grade, kidney function, UTI frequency, and renal growth patterns. Antibiotic prophylaxis is not indicated in children with a normal urinary tract after a UTI. Accurately predicting which patients will outgrow their VUR without significant permanent renal damage can be challenging. Generally, spontaneous resolution is more likely in patients with lower VUR grades and younger age at diagnosis. Key predictors of additional renal damage and scarring include the severity of reflux, UTI frequency, and the presence of high-pressure bladder conditions. Negative predictive factors for spontaneous resolution of VUR include female gender, higher grade reflux (grades IV and V), other ureteral abnormalities, complete renal duplication, periureteral diverticula, bladder or bowel disorders, and renal pelvic filling without bladder contraction.
Abnormal bowel function significantly increases the risk of UTIs, particularly in patients with VUR and abnormal bladder function. About 75% (70% to 80%) of children with grade I and II VUR will spontaneously resolve their VUR by age 5. For grades III and IV, spontaneous resolution is most likely if the reflux is unilateral and discovered before age 2, whereas VUR will resolve in 60% to 70% over 5 years. However, in children over age 5 with bilateral VUR, the rate of spontaneous resolution drops to only 10% to 20% over 5 years. For patients with grade V disease, spontaneous resolution without surgical intervention is rare.
The optimal treatment approach for VUR in infants remains a topic of ongoing debate. Many infants with VUR, including those with high-grade reflux, often outgrow the condition spontaneously by age 5. Moreover, up to 30% of boys with VUR experience kidney problems, and infants typically have immature bladder function. Consequently, the focus of treatment has shifted from solely addressing the reflux to preventing UTIs and associated renal damage until the child naturally outgrows the condition. Recently, some experts have advocated for endoscopic surgery as an alternative to conservative approaches like continuous antibiotic prophylaxis. However, endoscopic treatment does not offer significant advantages over antibiotic prophylaxis in preventing new UTIs or renal scarring in most patients. Furthermore, endoscopic intervention carries risks such as anesthesia-related complications, reflux recurrence, bladder perforation, urethral trauma, hematuria, and ureteral obstruction.
Minimally invasive anti-reflux procedures are feasible in infants, but they should not be routinely used due to the high rates of spontaneous resolution of VUR and the immature bladder function in neonates, which reduces the necessity for surgery. Generally, the most effective approach to managing VUR in infants involves closely monitoring them for UTIs and kidney damage. Antibiotic prophylaxis or surgical intervention may be considered if a child experiences recurrent UTIs, shows progressive kidney damage, or exhibits inadequate kidney growth.
In children with high-grade VUR (grades III-V), antibiotic prophylaxis is typically administered to prevent UTIs. In a recent randomized, open-label trial involving over 290 young infants (approximately 75% uncircumcised males with a mean age of 3 months) with high-grade VUR and no prior UTIs, prophylaxis over a 2-year period significantly decreased the proportion of patients experiencing their first symptomatic UTI compared to those receiving a placebo. However, urine cultures from children on prophylaxis showed a higher incidence of antibiotic resistance. Similar findings were observed in the larger Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial. These findings and results from similar studies confirm the benefit of antibiotic prophylaxis in young infants with high-grade VUR and no prior UTIs. However, a closer analysis indicates that patients with grade IV or V reflux, as well as those with combined bladder or bowel dysfunction along with any grade of reflux, received the most benefit from continuous prophylaxis as they have the highest risk.
For those patients on prophylaxis, renal imaging (usually ultrasound) is recommended every 6 to 12 months to compare levels of renal scarring, monitor kidney growth, and check cortical thickness. Periodic VCUG or radionuclide cystography should be conducted every 1 to 2 years to assess reflux severity, along with regular blood pressure checks. In asymptomatic children, spontaneous reflux resolution on VCUG indicates cessation of routine imaging.
Continuous antibiotic prophylaxis, while historically the standard of care, is now being reevaluated due to several concerns. These include issues related to adherence patterns and long-term compliance, the necessity for ongoing surveillance, escalating bacterial antibiotic resistance, potential adverse effects on human metabolism, and alterations to the gut microbiome that could contribute to obesity. Additionally, research suggests that prophylaxis may be unnecessary for many children with mild VUR and healthy kidneys.
Certain children with low-grade VUR who are toilet-trained, exhibit normal bladder and bowel function, show no abnormalities on kidney imaging, have been free of UTIs for 1 year, and are asymptomatic. A proposed predictive computer model has shown promise in identifying approximately 60% of children with VUR who could safely undergo surveillance instead of receiving prophylaxis. However, this model has yet to be validated and is not currently available for clinical use.
The latest guidelines from the American Urological Association (AUA) Pediatric Vesicoureteral Reflux Guidelines Panel recommend continuous antibiotic prophylaxis for children aged 1 or younger with VUR who have a history of febrile UTI, high-grade reflux (grades III-V), or concurrent bladder or bowel dysfunction. Patients at higher risk, such as those with bladder or bowel dysfunction, uncircumcised males, chronic constipation or diarrhea, and grade IV or V reflux, received the most benefit from continuous antibiotic prophylaxis. Compliance with prophylactic treatment is crucial for success, particularly for high-risk patients. Those who strictly adhere to the treatment regimen are 2.5 times less likely to experience a UTI and subsequent renal scarring compared to those with poor compliance.
Continuous prophylaxis was once the standard treatment for VUR but is now considered optional for non-high-risk patients over the age of 1. Current recommendations emphasize individualized therapy following a comprehensive discussion of all treatment options with the family. Patients experiencing recurrent infections or showing signs of progressive kidney damage, scarring, or impaired renal growth should be placed on prophylaxis. They may consider a surgical VUR procedure if prophylaxis fails to safeguard the kidneys and prevent UTIs. In cases where patients on continuous prophylaxis develop a single breakthrough febrile UTI and have healthy, unscarred kidneys, changing the prophylactic agent is a reasonable alternative to surgery.
Recommended prophylactic oral antibiotics: The recommended prophylactic oral antibiotics are listed below.
Amoxicillin: 12.5 mg/kg daily (recommended for infants aged <3 months)
Cephalexin: 12.5 mg daily (alternative in neonates aged <2 months or for breakthrough infections as a second agent)
Nitrofurantoin: 1 mg/kg daily (not for infants aged <1 month or if glomerular filtration rate (GFR) is <40 mL/min)
Sulfamethoxazole or trimethoprim: 10 mg/kg of sulfamethoxazole and 2 mg/kg of trimethoprim daily (not recommended for infants aged <1 month)
Trimethoprim: 2 mg/kg daily (not for infants aged <2 months)
Amoxicillin, ampicillin, and cephalosporins are recommended for prophylaxis in neonates <2 months but are not otherwise recommended as primary antimicrobial agents due to their propensity to increase bacterial resistance patterns. They are used in neonates because nitrofurantoin, sulfonamides, and trimethoprim can cause hyperbilirubinemia and other possible adverse effects in these very young children. Prophylactic oral antibiotics are not without problems, such as developing resistant bacterial strains, fungal infections, and antibiotic-related complications, including allergic reactions and pseudomembranous colitis. This has prompted investigations into alternative prophylactic therapies that would help avoid oral medications in patients with VUR at risk for UTIs. Continuous antibiotic prophylaxis can generally be discontinued when the VUR spontaneously resolves or after surgical correction.
Intravesical prophylactic antimicrobial instillation has emerged as a viable alternative for managing recurrent bacterial and fungal UTIs in children with VUR. This approach offers several advantages—it avoids systemic complications, minimizes allergic responses, achieves high concentrations of antimicrobials directly in the bladder, allows for the use of nephrotoxic drugs that may not be safe for systemic administration, reduces the development of antibiotic resistance, and preserves the availability of standard antimicrobials for therapeutic intervention in case of infection.
Several studies have demonstrated the effectiveness and safety of intermittent intravesical antimicrobial therapy in both children and adults for UTI prophylaxis. Although most pediatric studies are small-scale, larger studies involving adults strongly support the use of intermittent intravesical antimicrobial instillation. Gentamicin solutions are the most commonly used, but tobramycin, povidone-iodine, neomycin-polymixin, and neosporin have also been utilized. Notably, systemic absorption of gentamicin has not been observed with intravesical use, and the development of gentamicin-resistant bacteria is exceedingly rare.
Prophylactic intravesical gentamicin solutions: The recommended prophylactic intravesical gentamicin solutions are listed below.
Gentamicin 8 mg/20 mL or 20 mg/50 mL of 0.9% saline daily for adults and children aged 1 year or older.
Gentamicin 480 mg/1 L of 0.9% saline should be instilled in 30 to 60 mL daily.
The use of continuous antibiotic prophylaxis is not without some controversy. The Emilia-Romagna Pediatric Urinary Tract Infections Study Group, comprising a panel of pediatric nephrologists, infectious disease specialists, and pediatric urologists, conducted a comprehensive review of the medical literature spanning 25 years. Based on this extensive analysis, their conclusion is that continuous antibiotic prophylaxis is generally not recommended for most children with VUR, irrespective of grade or infection history, except in cases of significant urinary obstruction where definitive surgery is pending. Their recommendation advocates for vigilant monitoring and prompt treatment of any emerging UTIs in these individuals. This is based on their finding that while the advantages of UTI prevention and reduction of renal scarring were relatively modest, the risk of promoting bacterial resistance was considerably high.
Although the issue remains controversial, in the United States, most practitioners adhere to the AUA Pediatric Vesicoureteral Reflux Guidelines and similar references. These guidelines suggest continuous antibiotic prophylaxis, especially for higher-risk individuals exhibiting bowel or bladder dysfunction, high-grade VUR, progressive renal scarring, recurrent UTIs, or in the case of uncircumcised males. To date, no alternative therapy, apart from surgery or continuous prophylactic antibiotics, has demonstrated consistent reliability and effectiveness in UTI prevention among children with VUR. Nonetheless, there is some encouraging evidence regarding the efficacy of cranberry-related products.
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