Vesicoureteral reflux
Vesicoureteral reflux (VUR), also known as vesicoureteric reflux, is a common urologic condition in which urine abnormally flows backward from the bladder into the ureters and sometimes up to the kidneys, rather than being expelled during urination.[1][2] This retrograde flow disrupts the normal one-way valve mechanism at the ureterovesical junction, potentially leading to recurrent urinary tract infections (UTIs) and kidney damage if untreated.[3] VUR is classified into five grades based on severity, from grade 1 (mild, involving only the ureter) to grade 5 (severe, with ureter dilation, tortuosity, and kidney blunting).[1] It primarily affects infants and young children, with an estimated prevalence of 1% to 2% in the general pediatric population, though up to one-third of children with febrile UTIs are found to have VUR.[1][3] The condition arises from two main forms: primary VUR, which is congenital and results from an immature or defective ureteral valve that fails to prevent backflow, often resolving spontaneously as the child grows and the ureters lengthen; and secondary VUR, caused by acquired factors such as bladder outlet obstruction, neurogenic bladder dysfunction (e.g., from spina bifida), or high bladder pressure from conditions like posterior urethral valves in boys.[2][1] Risk factors include a family history (affecting more than one in four siblings or one in three offspring of affected parents), female sex (particularly after infancy), and age under 2 years.[1][3] Many cases are asymptomatic and detected incidentally via prenatal ultrasound showing hydronephrosis or during evaluation for UTIs, but symptoms when present may include fever, painful urination, frequent or urgent urination, abdominal pain, bed-wetting beyond typical age, and poor weight gain in infants.[2][3] Diagnosis typically involves renal and bladder ultrasound to assess for dilation or scarring, followed by a voiding cystourethrogram (VCUG) to visualize reflux during urination and assign a grade, along with urinalysis and culture to rule out infection.[1][3] Management focuses on preventing complications like renal scarring, which can lead to hypertension or chronic kidney disease; low-grade VUR (grades 1–3) often resolves without intervention within 5 years in up to 80% of cases, while higher grades may require continuous low-dose antibiotics to prevent UTIs, endoscopic injections of bulking agents to strengthen the valve, or surgical ureteral reimplantation for persistent severe reflux.[2][3] Early detection and treatment are crucial, as untreated VUR increases the risk of pyelonephritis and long-term renal impairment.[1]Overview
Definition
Vesicoureteral reflux (VUR) is defined as the abnormal retrograde flow of urine from the bladder into the ureters and potentially the kidneys, resulting from incompetence at the vesicoureteral junction.[4] This condition disrupts the normal unidirectional flow of urine during voiding, allowing backflow that can lead to stasis in the upper urinary tract.[5] The ureterovesical junction (UVJ) serves as the primary anti-reflux mechanism in the urinary system, featuring an oblique insertion of the ureter into the bladder wall, a sufficient length of the intravesical submucosal tunnel, and muscular support from the detrusor muscle that compresses the ureter during bladder contraction.[4] Incompetence here, often due to a shortened or absent tunnel, impairs the passive flap-valve action that prevents reflux under normal intravesical pressures.[5] VUR can manifest as unilateral, affecting a single ureter, or bilateral, involving both ureters, with the latter more commonly associated with certain underlying anomalies.[1] As a prevalent congenital anomaly, VUR affects approximately 1-2% of children, particularly in pediatric populations, and is a significant risk factor for recurrent urinary tract infections (UTIs) due to bacterial ascension into the kidneys.[1] Untreated, it can contribute to renal scarring and long-term damage, including hypertension and chronic kidney disease, underscoring its importance in early detection and management.[6]Pathophysiology
Vesicoureteral reflux (VUR) occurs when the normal antireflux mechanism at the ureterovesical junction (UVJ) fails, allowing retrograde flow of urine from the bladder into the ureters and potentially the kidneys during voiding or increased intravesical pressure.[4] In primary cases, this incompetence stems from an abnormally short intramural ureteral segment, which reduces the length-to-diameter ratio (typically less than 5:1) and impairs the flap-valve mechanism that compresses the ureter against the bladder wall.[5] Additionally, aperistaltic distal ureteral segments contribute by failing to generate adequate peristaltic waves to propel urine unidirectionally, further compromising UVJ function. The hydrodynamic basis of VUR involves transmission of elevated intravesical pressure—often exceeding 35 mm Hg during voiding—to the upper urinary tract, overcoming residual UVJ resistance and driving urine retrograde.[4] This reflux promotes urine stasis in the ureters and renal pelvis, creating an environment conducive to bacterial proliferation and ascension, which heightens the risk of pyelonephritis.[7] In secondary VUR, associated bladder dysfunctions such as detrusor-sphincter dyssynergia generate abnormally high voiding pressures, exacerbating pressure transmission and reflux without inherent UVJ anomalies.[4] At the renal level, severe reflux enables intrarenal reflux, where urine enters the collecting ducts through compound (flat or concave) papillae, which are more permeable than simple papillae.[5] This can lead to papillary damage from direct bacterial invasion and inflammatory mediators, with high pressures potentially causing forniceal rupture and perirenal urine extravasation. The resulting inflammatory response triggers fibrosis through release of oxygen free radicals and proteolytic enzymes, initiating scarring in the renal parenchyma.[5]Etiology
Primary Vesicoureteral Reflux
Primary vesicoureteral reflux (VUR) originates from congenital developmental anomalies at the ureterovesical junction (UVJ), where the ureter fails to insert properly into the bladder during embryogenesis. The ureteric bud, which forms the ureter, arises from the Wolffian duct around the fifth week of gestation and must migrate cranially for correct positioning. Abnormal budding too caudal along the Wolffian duct results in an ectopic ureteral orifice, typically lateral and superior to the normal site, leading to a shortened intramural ureteral tunnel that inadequately supports the antireflux mechanism.[8][4] This anatomical defect manifests as a reduced tunnel length-to-ureter diameter ratio, normally approximately 5:1, which correlates directly with VUR severity grading; milder grades (I-II) feature relatively longer tunnels that may improve with somatic growth, while higher grades (IV-V) have more pronounced shortening and incompetence.[4] Unlike secondary VUR, primary forms involve no underlying bladder dysfunction or obstruction, relying solely on these intrinsic UVJ variants for reflux occurrence. The short tunnel contributes to retrograde urine flow during bladder contraction, as explored in the pathophysiology section.[8] Genetic influences play a key role in primary VUR pathogenesis, with familial clustering evident in 27-51% of siblings of affected children, indicating a 30-50% recurrence risk. Mutations in genes like ROBO2, which regulates ureteric bud outgrowth and guidance, are identified in 3-5% of familial cases and disrupt normal UVJ formation. Additionally, primary VUR associates with syndromes such as VACTERL, occurring in up to 40% of patients due to related congenital anomalies.[9][10] In neonates, primary VUR affects about 1% overall but up to 15-16% of those with prenatal hydronephrosis detected via third-trimester ultrasound, often prompting postnatal evaluation. Low-grade cases (I-II) exhibit high spontaneous resolution rates of 70-80% by age 5 and up to 80% by adolescence, attributed to progressive ureteral elongation and tunnel maturation without intervention.[4][11]Secondary Vesicoureteral Reflux
Secondary vesicoureteral reflux (VUR) is an acquired condition characterized by the retrograde flow of urine from the bladder into the ureters and kidneys, resulting from elevated intravesical pressures due to underlying urinary tract obstructions or bladder dysfunctions, rather than inherent defects in the ureterovesical junction.[4][2] This contrasts with primary VUR, which stems from congenital anomalies, as secondary VUR often arises from treatable or reversible factors that overwhelm the normal antireflux mechanism at the ureterovesical junction.[1] Anatomical causes of secondary VUR primarily involve obstructions that generate high bladder pressures, such as posterior urethral valves (PUV) in boys, which are obstructive membranes in the urethra leading to bladder outlet obstruction and bilateral reflux.[4][1] Ureteroceles, cystic dilatations of the distal ureter, can also obstruct urine flow and contribute to reflux, while extrinsic compression from tumors or other masses may similarly elevate pressures within the urinary tract.[2] These anatomical issues disrupt normal voiding dynamics, forcing urine backward during bladder contraction.[4] Functional causes include neurogenic bladder, often associated with conditions like spina bifida or spinal dysraphism, where impaired neural control leads to detrusor overactivity and incomplete bladder emptying, increasing outlet resistance and promoting reflux.[4][2] Dysfunctional voiding, characterized by abnormal coordination of bladder and sphincter muscles, and iatrogenic factors such as post-surgical complications (e.g., after bladder or urethral procedures), can similarly result in high-pressure voiding and secondary VUR.[4] In these scenarios, the underlying bladder dysfunction drives persistent high pressures that exceed the protective capacity of the ureterovesical junction.[1] Secondary VUR typically presents later in childhood or adulthood, often triggered by the progression of the underlying pathology, unlike the congenital onset of primary VUR.[2] It has lower rates of spontaneous resolution—approximately 31% in cases with associated bladder or bowel dysfunction compared to 61% without—necessitating interventions targeted at the root cause, such as relieving obstructions or managing neurogenic issues, to mitigate ongoing reflux.[4] Associated conditions like prune belly syndrome, involving abdominal wall deficiency and urinary tract dilation, further exemplify how underlying pathologies drive secondary VUR through chronic high bladder pressures and impaired drainage.[4] In spinal dysraphism, the neural tube defects lead to neurogenic bladder dysfunction, emphasizing the role of the primary condition in perpetuating reflux.[1]Clinical Features
Signs and Symptoms
Vesicoureteral reflux (VUR) is frequently asymptomatic, particularly in cases of low-grade reflux, where it may remain undetected until incidentally identified through imaging studies performed for other reasons, such as evaluation of urinary tract infections (UTIs) or prenatal ultrasound findings revealing hydronephrosis.[1][2][4] When symptoms occur, they are typically secondary to associated UTIs resulting from urine stasis, and may include recurrent febrile UTIs, dysuria, abdominal or flank pain, foul-smelling or cloudy urine, and voiding dysfunction such as urgency or incontinence.[1][2][4] In infants, additional features can involve failure to thrive, poor feeding, fussiness, or vomiting, while older children might experience enuresis or daytime wetting after toilet training.[1][2] Age-specific manifestations vary, with neonatal cases often presenting as prenatal hydronephrosis without overt symptoms postnatally.[4] In infants under 2 years, febrile UTIs are common, particularly in uncircumcised males, and may lead to poor growth or weight gain issues.[1][4] School-age children, especially girls, are prone to breakthrough UTIs despite prophylaxis, alongside symptoms like constipation or bowel control problems that exacerbate voiding issues.[2][4] VUR is rare in adults unless secondary to other conditions, typically presenting with similar UTI-related symptoms.[1] Screening for VUR is often prompted by a family history, as siblings of affected children have approximately a 27% risk and children of affected parents about a 33% risk, leading to targeted evaluation even in asymptomatic individuals.[1][4] There are no unique physical examination findings specific to VUR; presentation relies on history of recurrent infections or related symptoms.[4]Complications
Vesicoureteral reflux (VUR) predisposes individuals, particularly children, to recurrent urinary tract infections (UTIs), including pyelonephritis, which can escalate to acute kidney injury if untreated.[4] High-grade VUR combined with recurrent pyelonephritis significantly heightens the risk of renal scarring, with studies identifying delayed antibiotic treatment as a key exacerbating factor.[12] In children, the presence of VUR during a UTI increases the risk of pyelonephritis due to bacterial ascent into the kidneys.[6] The primary renal complication of VUR is reflux nephropathy, characterized by cortical scarring from repeated episodes of pyelonephritis, leading to focal segmental glomerulosclerosis (FSGS) through glomerular hypertrophy and interstitial nephritis.[13] This scarring can progress to chronic kidney disease (CKD) and, in severe cases, end-stage renal disease (ESRD), particularly with bilateral involvement or high-grade reflux.[4] Untreated VUR is associated with an increased risk of CKD, as evidenced by longitudinal studies linking early renal parenchymal damage to long-term functional decline.[14] Systemic effects of VUR-related renal damage include hypertension, often driven by activation of the renin-angiotensin system in scarred kidneys, and proteinuria resulting from glomerular injury.[15] In adults with reflux nephropathy, hypertension prevalence ranges from 38% to 60%, contributing to further cardiovascular and renal morbidity.[15] Bilateral renal involvement heightens the risk of complete renal failure, while proteinuria serves as a poor prognostic indicator in affected patients.[16] Long-term risks in children with VUR include growth impairment linked to renal scarring and recurrent infections, with studies showing significant associations between scarred kidneys and delayed somatic development.[17] In females with scarred kidneys from VUR, overall pregnancy complications occur in approximately 39% of cases, with preeclampsia reported in about 10%, underscoring the need for preconception renal evaluation.[6]Diagnosis
Diagnostic Methods
Diagnosis of vesicoureteral reflux (VUR) typically begins with laboratory evaluation to identify associated urinary tract infections (UTIs) and assess renal function, followed by imaging studies to detect structural abnormalities and confirm reflux. Urinalysis and urine culture are essential for detecting bacteriuria and confirming concurrent UTIs, which often prompt further investigation in children.[18][4] Baseline serum creatinine is recommended to estimate glomerular filtration rate and monitor for renal impairment, though no specific biomarkers exist for VUR itself.[18][19] Renal and bladder ultrasound serves as the initial non-invasive imaging modality, screening for hydronephrosis, ureteral dilatation, and renal scarring, particularly in infants and young children. It is recommended within 24 hours of a febrile UTI in infants or for follow-up of prenatal hydronephrosis, with postnatal imaging delayed until after the first week to avoid transient findings.[20][19] While ultrasound identifies upper tract abnormalities in about 15% of cases, its sensitivity for high-grade VUR is limited at approximately 59%, making it unsuitable as a standalone diagnostic tool.[19][4] A technetium-99m-labeled dimercaptosuccinic acid (DMSA) scan is used to evaluate renal parenchymal scarring and cortical defects, often performed 6 months after a febrile UTI to assess for pyelonephritis-related damage. It is indicated when ultrasound shows abnormalities, in cases of breakthrough UTIs, or for grades III-V VUR, with a sensitivity of 75% for detecting reflux-related changes but lower specificity at 48%.[18][19] Due to radiation exposure, its use has decreased in recent guidelines, prioritizing it for high-risk scenarios.[19] The voiding cystourethrogram (VCUG) remains the gold standard for confirming VUR, visualizing reflux into the ureters and renal pelvis during bladder filling and voiding under fluoroscopy, while also allowing grading of severity. Performed with diluted contrast at body temperature and low-pressure filling, it is indicated after a first febrile UTI if ultrasound reveals hydronephrosis, scarring, or other anomalies, or routinely after a second UTI in children aged 2-24 months. Contrast-enhanced voiding urosonography (ceVUS) offers a radiation-free alternative using ultrasound contrast agents, providing comparable sensitivity and specificity for VUR detection and grading, particularly recommended in European guidelines for initial evaluation or follow-up to minimize radiation exposure.[20][4][21] Radionuclide cystography offers an alternative with substantially lower radiation (about 10% of VCUG), suitable for follow-up screening in high-grade cases, though it provides less anatomical detail.[18][4] Indications for diagnostic evaluation include febrile UTIs in children under 2 years, familial screening in siblings with a history of VUR or renal abnormalities, and follow-up of prenatal hydronephrosis. Guidelines from the 2010s and 2020s, such as those from the American Academy of Pediatrics (reaffirmed 2016) and American Urological Association (2017), emphasize a risk-based approach to reduce unnecessary VCUGs, limiting routine imaging after an initial UTI unless abnormalities are present.[20][18] The European Association of Urology's paediatric urology guidelines similarly advocate selective use based on clinical factors like recurrent infections or congenital anomalies.[19]Severity Grading
Vesicoureteral reflux (VUR) is classified using the International Reflux Study grading system, a standardized radiographic scale developed to assess severity based on voiding cystourethrogram (VCUG) findings. This system categorizes VUR into five grades, from I (mild) to V (severe), focusing on the extent of reflux, ureteral dilation, and calyceal involvement. The grading provides visual and anatomical criteria to ensure consistency in evaluation across clinical settings.[22] The grades are defined as follows:| Grade | Description |
|---|---|
| I | Reflux limited to the distal ureter without involving the renal pelvis or calyces. No dilation or tortuosity. |
| II | Reflux extends to the renal pelvis and calyces, but without dilation, blunting, or tortuosity of the ureter or collecting system. |
| III | Reflux into the renal pelvis and calyces with mild to moderate dilation and tortuosity of the ureter, and mild to moderate dilation of the pelvis and calyces, but no or slight blunting of the fornices. |
| IV | Reflux into the renal pelvis and calyces with moderate to gross dilation and tortuosity of the ureter, moderate dilation of the pelvis and calyces, and complete blunting of the fornices. |
| V | Reflux into the renal pelvis and calyces with gross dilation and tortuosity of the ureter, marked dilation of the pelvis and calyces, and tortuosity of the papillae with intrarenal reflux. |