Pediatrics: Vesicoureteral Reflux

Epidemiology

• Age
  • The younger the child with UTI, the greater is the likelihood of discovering VUR
    • In children undergoing cystography for various indications, ≈30% for children with UTI and 17% without infection were found to have VUR
    • In contrast, VUR may be present in up to 70% of infants who present clinically with UTI
    • The majority of reflux detected later in life occurs in females; relatively uncommon in adult males
  • In asymptomatic infants followed for antenatal hydronephrosis, the prevalence of VUR ranges from 15% in infants with absent or mild hydronephrosis on postnatal US to 38% in neonates with various postnatal upper tract US anomalies, including hydronephrosis, renal cysts, or renal agenesis
• Gender
  • 76% of VUR infants are male
  • Antenatally detected reflux is usually high grade and bilateral in boys when compared with reflux in girls.
  • In later life, the likelihood of having VUR if presenting with a UTI is higher if patient is male than female
    • Uncircumcised male infants show a 12x greater risk for UTI than circumcised males, as well as a greater propensity for harboring periurethral uropathogenic flora
    • It is not known whether the incidence of VUR detection would rise in females if they were to be incidentally evaluated for reflux as often as infant males
• Race
  • The frequency of detected vesicoureteral reflux is lower in female children of African descent.

Embryology of the Ureterovesical Junction

• If the ureteric bud reaches the urogenital sinus too late (because of budding late), insufficient rotation occurs, resulting in an ectopic ureter
• A ureteral bud that is laterally (cranially) positioned from a normal takeoff at the trigone offers an embryologic explanation for primary reflux, whereas those inferiorly (caudally) positioned are often obstructed.

Functional Anatomy of the Antireflux Mechanism

• Normal physiologic factors that prevent reflux:
  1. Functional integrity of the ureter
     • Ureter represents a dynamic conduit
  2. Anatomic design of the UVJ
     • At the extravesical bladder hiatus, the 3 muscle layers of the ureter separate.
       • The outer ureteral muscle merges with the outer detrusor muscle to form the Waldeyer sheath, which contributes to formation of the deep trigone.
       • Intravesically, the inner muscle of the ureter merges with detrusor muscle to contribute to the superficial trigone. Some of these inner ureteral fibers pass medially to contribute to the intraureteric ridge (Mercier bar).
     • The intramural ureter remains passively compressed by the bladder wall during bladder filling, preventing urine from entering the ureter.
       • Adequate intramural length and fixation of the ureter between its extravesical and intravesical points is required to create this antirefluxing compression valve.
       • Ratio of tunnel length to ureteral diameter found in normal children without reflux is ≈5:1 compared with a 1.4:1 ratio in refluxing UVJs
  3. Functional dynamics of the bladder
  • It is likely that in addition to architectural deficiencies of tunnel length, abnormalities in uterovesical smooth muscle and extracellular matrix composition and neural function may contribute to reflux
• Opening of the UVJ is achieved by active contraction of the longitudinal muscles within the tunnel. Closure of the UVJ results both from compression of the intramural ureter and a return to its full tunnel length as the ureteral muscle relaxes.

Causes of VUR

• Classified: primary vs. secondary
• Primary reflux
  • Fundamental deficiency of the longitudinal muscle of the intravesical ureter resulting in an inadequate valvular mechanism while the remaining factors (bladder and ureter) remain normal or relatively noncontributory
    • VUR may be a normal variant in the population but becomes clinically relevant only in some because of a predisposition to UTI. This is supported by the observation that VUR without infection is of questionable clinical significance
  • Genetics
    • 66% rate of reflux in the offspring
      • Tendency for an autosomal dominant pattern of inheritance; probably many genes are involved
    • Prevalence of VUR in siblings to be ≈32%
      • Because the renal consequences of VUR are at issue, rather than reflux itself, siblings may be better served by non-invasively (ultrasound) screening for cortical abnormalities first, and screening for VUR if history of compounding factors such as UTI or bowel and bladder dysfunction are manifested.
        • By taking into account the imaging of the kidneys first, as well as the patient’s age and history of UTI, a rational top-down approach to sibling reflux screening emerges.
        • It cannot be assumed that all cortical abnormalities in siblings with VUR are acquired. The lack of prospective studies should temper the notion of mass screening of siblings
        • In any sibling, however, in whom reflux is diagnosed, the indications for treatment remain the same as for general reflux in the pediatric population.
• Secondary reflux
  • VUR caused by overwhelming the normal function of the UVJ
    • May be of an anatomic or functional origin in the UVJ, bladder, or bladder outlet
    • Reflux is also considered secondary if its absence was documented at some point before its detection.
    • Bladder dysfunction
      • Can be of a congenital, acquired, or behavioral nature
      • Often the cause of secondary VUR
    • Posterior urethral valve
      • Most common cause of bladder outlet obstruction in infants
        • In females, anatomic bladder obstruction is rare. The most common structural obstruction in females is from a ureterocele that prolapses into the bladder neck.
      • Reflux is present in 48-70% of patients with PUV patients
    • Neurogenic bladder
      • Spina bifida, in particular, is at risk for VUR
        • Special attention for the potential for occult spinal dysraphism is warranted during evaluation of any child with UTI
      • Urodynamic risk factors for VUR:
        1. Overactivity
           • Most common urodynamic abnormality associated with VUR in neurologically normal children
           • Overactive bladder frequently can be responsible for reflux
        2. Inadequate or obstructive voiding patterns
        3. Higher voiding pressures (may be due to inadequate sphincter relaxation)
    • Urinary Tract Infection
      • UTIs and their accompanying inflammation can also cause reflux by:
        1. Lessening compliance
        2. Elevating intravesical pressures
        3. Distorting and weakening the ureterovesical junction
    • Bladder and bowel dysfunction (BBD)
      • In older children, acquired abnormalities in bladder and bowel function commonly known as bladder and bowel dysfunction (BBD) have been associated with reflux

Grading VUR

• The International Classification System, devised in 1981 by the International Reflux Study, is the current standard for grading reflux on the basis of the appearance of contrast in the ureter and upper collecting system during voiding cystourethrography.
• Grade I: reflux limited to the ureter
• Grade II: reflux up to the renal pelvis
• Grade III: mild dilatation of ureter and pelvicalyceal system
• Grade IV:
  • Tortuous ureter with moderate dilatation
  • Blunting of fornices but preserved papillary impressions
• Grade V:
  • Tortuous ureter with severe dilatation of ureter and pelvicalyceal system
  • Loss of fornices and papillary impressions
  • Insert figure

• Accurate grading is impossible with coexistent ipsilateral obstruction.
• Grade of reflux positively correlated with risk of (2):
  1. Renal nuclear scan abnormalities
  2. Pyelonephritis

Pathophysiology of Acquired Scarring

• Reflux is not a general cause of UTI
• Reflux facilitates pyelonephritis
• In the context of normal voiding dynamics, nephropathy from primary VUR requires the colonization of urine with pathogenic bacteria in the face of normal voiding dynamics.
  • In the absence of infection, sterile urinary reflux is insufficient to cause renal damage
• Risk factors for scarring
  • Age
    • The greatest risk for post-infectious renal scarring occurs within the first year of life
      • The risk of post-pyelonephritic renal scarring is inversely proportional to age
  • Papillary Anatomy
    • Papillae with a concave architecture (compound papillae) present their ducts at right angles [and are at higher risk of postinfectious renal scarring], whereas more convex papillae possess ducts that end obliquely, producing a valvular effect that guards against backflow of urine into the medullary collecting ducts

Diagnosis and Evaluation

• UTI
  • Confirmation of UTI is paramount in the appropriate management of the patient with VUR
    • The method of urine collection and the presence of pyuria are of utmost importance in the diagnosis of UTI to avoid false-positive culture results
    • US of the kidneys and bladder can be considered a reasonable minimum evaluation in the infant or child after a UTI
      • Older children who present with asymptomatic bacteriuria or UTIs that manifest solely with lower tract symptoms can be screened initially with US alone, reserving cystography for those with abnormal upper tracts or recalcitrant infections.
        • The presence of structural renal anomalies or significant asymmetry would support proceeding with a cystogram.
• Assessment of the Lower Urinary Tract
  • Cystogram
    • VCUG and radionuclide cystogram (RNC) are the two common forms of direct cystography and constitute the present-day gold standard approaches to detect VUR
      • Both VCUG and RNC require catheterization
      • RNC
        • Advantages (2):
          1. Reduced radiation requirements
             • RNC has historically been described as a technique that requires a significantly lower dose of radiation than a regular VCUG, but the advances with modern digital techniques have significantly narrowed the difference between these two imaging modalities.
          2. Greater sensitivity for grade 2 to 5 VUR
        • Disadvantage:
          • Provides much less anatomic detail than does a VCUG
      • More recently, to eliminate the need for ionizing radiation, some studies have demonstrated a growing interest in US detection of VUR using either color Doppler imaging
    • Direct imaging of VUR is affected by several parameters which include:
      1. Bladder contraction during voiding
      2. Fluid volume instilled into the bladder
      3. Presence of infection and therefore inflammation of the UVJ mucosa.
      • Even during voiding, reflux may not be demonstrated on a single filling-voiding cycle. Several studies have demonstrated a roughly 12-20% greater detection rate for VUR if a cyclic study is performed
    • Passive reflux (VUR during filling of the bladder) is generally considered a poor prognostic sign for reflux resolution and suggests the presence of a fixed decompensation of the UVJ.
      • Filling assumes far lower intravesical pressure than that of voiding
      • Passive reflux is common finding in patients with acquired or neurogenic voiding dysfunction
    • Cystogram during active infection
      • The general consensus has been to delay the voiding study for at least a week or longer to allow for adequate recovery from the acute infection episode.
        • Evoking reflux during an active cystitis, by definition, will transmit bacteria to the upper urinary tract and renal pelvis and risks iatrogenic pyelonephritis.
      • Only if it is imperative to make the diagnosis of reflux in children with a history of recurrent pyelonephritis and repeatedly negative voiding studies in the intercurrent periods should cystography during UTI be considered.
        • Some UVJs maintain only borderline antireflux mechanisms, which are competent in a sterile milieu but become incompetent from edema and inflammation associated with mucosal inflammation during cystitis. Such patients may have VCUG studies negative for reflux in the absence of infection but suffer from repeated pyelonephritic episodes. Cystograms in such patients may demonstrate reflux if obtained during clinically active infection, whereas cystogram obtained in the presence of positive urine cultures alone may not.
    • VCUG Technique
      • Bladder contrast is instilled by gravity after urethral catheterization. Bladder capacity is recorded when contrast influx ceases. Static images record bladder contour, presence of diverticula or ureteroceles, grade of reflux, configuration and blunting of calyces, and intrarenal reflux. Passive or active reflux is demonstrated dynamically during fluoroscopy while filling and voiding, respectively. In addition, bladder neck anatomy, funneling or dilation, and urethral patency are parameters derived from the VCUG.
      • Delayed or postvoid films are crucial in documenting clearance of contrast from the upper tracts because retained contrast, particularly with dilated pelvicalyceal systems, could signify the presence of a concomitant UPJ obstruction (UPJO)
  • Diagnostic Controversies: Challenging the Assessment of VUR
    • Uroflowmetry
      • A valuable tool in the workup of a patient with vesicoureteral reflux
      • A minimal survey of bladder emptying characteristics can be obtained
        • Lack of smoothness of the flow-velocity curve suggest incomplete relaxation of the bladder outlet during voiding.
          • This implies the existence or development of relatively higher pressures during voiding, which could delay the natural history of VUR resolution or even perpetuate VUR.
        • Increased postvoid residual volume may be a risk factor for UTI.
          • In the setting of passive VUR, carrying infected postvoid residual urine also can lead to ascending infection and pyelonephritis.
    • Top-Down Approach
      • Only a dimercaptosuccinic acid (DMSA) renal scan is obtained after a febrile UTI, with cystography reserved only for patients with abnormal scintigraphy findings.
        • Children with a normal DMSA scan undergo no further evaluation unless they develop recurrent UTI, in which case a VCUG should be obtained.
        • Photopenic areas may result from postinfection renal scarring and some renal dysplasia.
        • Vesicoureteral reflux, particularly reflux of higher grades, may result in renal dysplasia, which often appears scintigraphically identical to postinfection pyelonephritic scars.
        • During an episode of active pyelonephritis, the renal scan may show an area of photopenia that later, if it persists, represents renal scarring secondary to the infection.
        • Neither renal scan nor ultrasonography can differentiate accurately between renal dysplasia and renal scarring
      • A critical assumption with this approach is that VUR in the absence of scintigraphic renal abnormality is unlikely to cause future renal damage
      • The top-down approach performs poorly at detecting high-grade VUR with a sensitivity and specificity of only 79% and 53%, respectively
  • American Academy of Pediatrics Guidelines for Febrile UTI Diagnosis and Management in Young Children
    • VCUG should be obtained after second febrile UTI
      • Previous recommendation was after the first febrile UTI
      • VCUG should be obtained after first febrile UTI if:
        1. US shows hydronephrosis, possible renal scarring or dysmorphism
        2. Other findings that suggest high-grade VUR
        3. Obstructive uropathy are present
        4. Any complex or clinically atypical scenario
  • Cystoscopy
    • Routine cystoscopy is contraindicated in reflux management
      • The assessment of appearance and configuration of the ureteric orifices and intramural tunnel length provide little correlation with either the diagnosis or grade of reflux
      • The cystoscopic position of the refluxing ureteric orifice is permanent lateral displacement
• Assessment of the Upper Urinary Tract
  • Rationale for Serial Assessment of Upper Tracts
    • Pyelonephritis propagated by VUR causes:
      1. Renal scarring
      2. Impedes attainment of full renal growth potential
      3. Increases risk for renovascular hypertension
    • Most parenchymal abnormalities are detected after the first episode of pyelonephritis
    • A fundamental goal in serial upper tract imaging with VUR is to ascertain whether abnormalities are due to ongoing or resolved reflux and differentiate them from intrinsic developmental disturbances, medical renal disease, or antegrade flow resistance.
    • Intensity of upper tract studies should be proportional to the propensity for renal damage
    • The challenge in imaging is to differentiate congenital reflux–associated renal dysmorphism from scarring acquired after infection
      • VUR, particularly of higher grades, may result in renal maldevelopment that often appears scintigraphically or sonographically identical to postinfection pyelonephritic scars
  • Renal US
    • The mainstay of renal imaging in VUR management
    • The appearance of the kidneys on ultrasound does not correlate with the absence or presence of reflux, or with its grade
    • Renal resistive index measurements are significantly increased in higher grades of reflux
  • Renal Scintigraphy
    • The gold standard for imaging functioning renal parenchyma is scintigraphy using 99mTc-labeled DMSA.
      • The radiotracer is taken up only by functioning proximal tubular tissue mass, where it binds for several hours.
        • Because pyelonephritis impairs tubular uptake of radiotracer, these areas will fail to radioemit photons and appear as unexposed or underexposed regions in the resultant renal cortical images
        • DMSA scanning provides 98% sensitivity and 92% specificity for scar detection
      • The uptake of DMSA provides a good proportional representation of glomerular filtration
      • No consensus exists on the precise use of DMSA scanning in reflux management.
  • DMSA and ultrasonography are often used complementarily, particularly when knowledge of relative renal function is desired since all DMSA defects are not necessarily scars.

Complications of Acquired Scarring

• Hypertension
  • Severity of reflux nephropathy in children is associated with progression to hypertension
    • Reflux nephropathy is the most common cause of severe hypertension in children and young adults
    • Remains unclear whether it is the nephropathy associated with postinfection scarring, congenital dysmorphism associated with reflux, or some combination of both that predisposes to hypertension
  • Successful correction of reflux alone is unlikely to ameliorate blood pressure
    • Removal of renal segments verified by selective renal vein sampling of arteriolar or segmental vessel renin levels has provided durable normalization of blood pressure in carefully selected patients
    • On occasion, complete removal of a small unilateral congenitally dysmorphic or globally scarred and shrunken kidney also may correct renovascular hypertension
• Renal Growth
  • Factors contributing to the effects of reflux on renal growth:
    1. Congenital dysmorphism often associated with, but not caused by, reflux
    2. Number and type of urinary infections and their resultant nephropathy
    3. Grade of reflux in the affected kidney
    4. Quality of the contralateral kidney and its implications for compensatory hypertrophy
       • Compensatory hypertrophy of the contralateral kidney will magnify the perceived impact of infection on renal growth because the contralateral developing kidney will assume the required renal function whenever the ipsilateral kidney is unable to contribute optimally to function.
• Renal Failure
  • The medical renal disease that accompanies renal scarring can include hyperfiltration, concentrating defects, proteinuria, microalbuminuria, renal tubular acidosis, and increased fractional excretion of sodium and magnesium.
• Somatic Growth
  • An accurate reflection of renal cortical integrity
    • Many children with VUR fall below the normal age-adjusted growth curve, particularly in patients with bilateral reflux and some degree of renal damage.
    • Successful suppression of pyelonephritis through either medical prevention of infection or surgical correction of reflux itself can result in catch-up growth, both for height and weight

Associated Anomalies and Conditions

• Ureteropelvic Junction Obstruction
  • VUR and UPJO are two of the most common pathologic conditions in pediatric urology
  • The incidence of VUR associated with UPJO ranges from 9-18%
  • Radiologic signs that suggest the existence of UPJO in the setting of reflux (3):
    1. Pelvis shows little or no filling while the ureter is dilated by contrast; this may indicate a point of kinking secondary to reflux or from a primary UPJO
    2. Poorly visualized contrast in the pelvis because of dilution in a large pelvic volume and exhibits a markedly reduced radiodensity compared with the ureter or bladder
    3. Large pelvis that fails to exhibit prompt drainage but retains contrast
  • Radiographic studies of UPJO associated with VUR may indicate true anatomic obstruction or simply dilation associated with pelvicureteral dilation from higher grades of reflux.
  • If scintigraphy (with catheter drainage) confirms obstruction, pyeloplasty should be performed.
    • If both the UPJ and UVJ meet criteria for operative repair of obstruction and reflux, respectively, the UPJ should be repaired first to avoid the incipient obstruction that may ensue if resistance is added to the UVJ when reflux is corrected.
    • With care, both processes may be repaired simultaneously when it is clear that they are independent significant problems
      • The simultaneous open correction of UPJO and reflux has always raised a concern over surgical manipulation of both the upper and lower ureter at the same time, as well as its potential negative impact on ureteral vascularity. However, the advent of endoscopic injection raises the possibility of correcting reflux at the time of pyeloplasty for secondary or primary UPJO.
• Ureteral Duplication
  • See Ectopic Ureter, Ureterocele, and Ureter Anomalies Notes
• Bladder Diverticula
  • Reflux associated with a paraureteral diverticulum
    • Mechanisms
      • More common: a paraureteral diverticulum, which shares an anatomic point of origin at or near the UVJ, compromises the anti-reflux configuration of the UVJ to cause reflux
      • Rarely: a large paraureteral diverticulum expands within the Waldeyer fascia to cause ureteral obstruction or project forward into the bladder to obstruct the bladder outlet, much as a ureterocele, and incite secondary reflux
    • Resolves at rates similar to primary reflux and should be managed according to the prevailing indications for the reflux itself, irrespective of the diverticulum
  • Reflux associated with a ureter entering a diverticulum
    • When a refluxing ureter enters a diverticulum, the diverticulum is no longer paraureteral
    • With no muscular support to the UVJ, reflux is not expected to resolve
    • Indications for repair requires the combined consideration of both the reflux and the diverticulum
• Renal Anomalies associated with VUR
  • Multicystic dysplastic kidney (MCDK)
  • Renal agenesis
    • Presence of either condition mandates a VCUG (CUA MCDK Guidelines do not mandate VCUG)
• Megacystis-Megaureter
  • Definiton of megacystis-megaureter: a non-obstructive condition by regurgitation from incompetent valves
  • The persistent large residual urine volume is a significant risk factor for recurrent UTI
  • Diagnosis and Evaluation
    • Normal posterior urethra on voiding studies
      • Posterior valves or prune-belly syndrome will demonstrate an open posterior urethra
  • Management
    • Surgical correction for the reflux is indicated given the propensity for VUR to exacerbate the effects of bacteriuria and the fact that UVJ dysfunction is the primary factor perpetuating the syndrome
    • Vesicostomy can temporize by eliminating the residual urine volume and establishing safe drainage of the upper tracts until ureteral reimplantation can be performed
    • A period of bladder rehabilitation by strict attention to emptying in the post-operative period usually will result in a return to normal bladder volume and contractile behavior
• Other Anomalies
  • Congenital conditions and syndromes associated with VUR:
    • VACTERL association (Vertebral, Anal, Cardiac, TracheoEsophageal, Renal, and Limb anomalies)
    • CHARGE syndrome (Coloboma, Heart disease, Atresia choanae, Retarded development, Genital hypoplasia, and Ear anomalies)
    • Imperforate anus
  • In cases in which VUR is anticipated, a VCUG is the initial study of choice to disclose both dysfunction at the UVJ and overall bladder and bladder outlet anatomy.

Natural History

• At birth, the probability of spontaneous resolution of primary VUR is inversely proportional to the initial grade
  • Most cases of low-grade reflux (grade 1 and 2) will resolve
  • Grade 3 reflux will resolve in ≈50% of cases
  • Very few cases of higher-grade reflux (grades 4 and 5, and bilateral grade 3) will resolve spontaneously
    • Attempting to discriminate true differences in resolution rates for grades 3 and higher reflux may not be particularly clinically relevant.
• At a later age, spontaneous resolution will depend on:
  1. Initial grade of reflux, if it is known
  2. Age at presentation (more important)
  • Resolution by Age
    • The age at which reflux begins or is first encountered will play a more potent role in the management of the patient with reflux than the grade itself
    • When reflux resolves, it often does so within the first few years of life
    • The traditional period of observation for resolution is 5 years

Management

• See AUA VUR Guideline Notes
• Essential tenets of reflux management:
  1. BBD is by far one of the most critical and modifiable variables that affect VUR management and attendant UTIs
     • Constipation must be recognized and eliminated as much as possible to establish optimal conditions for successful spontaneous or surgical resolution of reflux
     • BBD lowers VUR resolution rates.
  2. Parental perceptions of reflux management must be considered when treating a child with reflux
  3. Spontaneous resolution of reflux is very common
     • ≈80% of low-grade and ≈50% of grade 3 reflux will resolve spontaneously.
  4. High-grade reflux is less likely to resolve spontaneously
  5. Sterile reflux is benign
  6. "Extended use of prophylactic antibiotics is benign"
  7. Success of (open) surgical correction is very high
     • Ureteral reimplant is successful in correcting reflux in > 98% of cases
• Options:
  • Includes management of any bowel-bladder dysfunction
  • First-line (classic approach): watchful waiting with daily low-dose antibiotic prophylaxis
  • Second-line: intervention
    • Options:
      • Endoscopic
      • Open/laparoscopic ureteral reimplant
    • Failure to address voiding abnormalities can adversely affect outcome of anti-reflux surgery

• Watchful waiting with daily low-dose antibiotic prophylaxis
  • Underlying principle: every case of reflux should be offered time to resolve spontaneously, despite grade
  • Maintaining urine sterility (through both prophylactic antibiotics and strict attention to bladder and bowel management) is the cornerstone of watchful waiting medical management
  • Nighttime dosing allows for antibiotic concentration in the bladder urine over the longest period of expected physiologic retention, when infection is most likely to develop.
  • For children age < 2 months, the most commonly used medications are trimethoprim and amoxicillin.
  • In newborn patients, it is reasonable to wait until ≈5 years of age assuming no intercurrent breakthrough infections occur. Beyond this age, it is commonly believed that the kidneys become less prone to scarring after pyelonephritis. Thus, some withdraw prophylaxis as the child approaches the age of 5.
    • After this age, boys with asymptomatic reflux will require little or no formal follow-up as long as lifelong attention to good bladder habits is reinforced, and they are counseled to seek prompt medical attention if a pyelonephritis were to occur in the future, as well as reassessment of their reflux status.
      • Uncircumcised male children older than 1 year do not appear to be at higher risk for development of recurrent UTI after discontinuation of CAP.
    • Girls have traditionally undergone open surgical correction, even for asymptomatic reflux that fails to resolve by the age of 5, on the premise that it will reduce maternal and fetal morbidity during a future pregnancy
      • Women with a history of VUR have increased morbidity during pregnancy because of infection-related complications, whether the reflux has been corrected or not.
        • Addintional risk factors that may lead to increased morbidity in pregnant patients with VUR:
          1. Hypertension
          2. Renal insufficiency
             • Associated with increased risk for fetal demise and accelerated maternal renal disease
          3. Renal scarring
             • Associated with an increased incidence of hypertension, increased risk for preeclampsia, increased risk of developing acute pyelonephritis, and a higher rate of obstetric interventions
          4. History of prior infections
             • Associated with increased risk of bacteriuria during pregnancy
        • Persistent VUR is associated with increased risk of developing acute pyelonephritis
        • VUR with normal kidneys is associated with an increased risk for hypertension during the last trimester
        • Impaired renal function is
        • Most clinicians recommend surgical correction for females with reflux that persists beyond puberty to minimize maternal and fetal morbidity
  • In patients diagnosed after one or more episodes of pyelonephritis, the presence of scarring on renal scintigraphy may temper a decision for extended prophylaxis and observation, particularly if:
    • Scarring is extensive
    • Reflux is high grade
    • Renal function is already globally depressed
    • Congenital dysmorphism of one or both kidneys is present
  • Breakthrough febrile UTIs or pyelonephritis while on antibiotic prophylaxis are generally considered an indication for termination of watchful waiting and correcting the reflux. Anxiety related to ongoing reflux also warrants strong consideration for reflux correction
    • BBD is associated with higher breakthrough infection rates.
  • Adult patients who present with non-obstructive flank pain, febrile UTIs, or pyelonephritis and are found to have VUR have traditionally been offered antireflux surgery
  • Cystoscopy
    • Cystoscopy in the course of conservative management of VUR is indicated only to confirm or manage abnormalities found on other imaging modalities
  • Landmark Studies
    • International Reflux Study in Children
      • Population: 306 children aged < 11 years with high-grade reflux from North America and Europe
      • Randomized to watchful waiting with antibiotic prophylaxis vs. corrective open surgery
      • Primary end points: new renal scars and renal growth
      • Results:
        • No siginificant difference in risk of new renal scars
          • Antibiotic prophylaxis and surgery equally effective in reducing, but not eliminating, new scar formation
        • Surgery more effective than antibiotic prophylaxis in reducing, but not eliminating, the risk of pyelonephritis
        • Nosiginificant difference in risk of incident UTI (38%)
      • Jodal, Ulf, et al."Ten-year results of randomized treatment of children with severe vesicoureteral reflux. Final report of the International Reflux Study in Children." Pediatric Nephrology 21.6 (2006): 785.
    • RIVUR
      • Population: 607 children with dilated and non-dilated VUR that was diagnosed after a first or second febrile or symptomatic UTI
        • Population was overwhelmingly female (91%)
        • Half of the study participants were < 11 months of age
      • Randomized to trimethoprim-sulfamethoxazole prophylaxis vs. placebo
      • Primary outcome: recurrence of UTI
      • Results:
        • 45% significant decrease in UTI recurrence with antibiotic prophylaxis (RR: 0.55; 95% CI: 0.38-0.78)
          • When stratified into dilated and non-dilated groups, children with dilated VUR were more likely to have symptomatic recurrences than those with non-dilated VUR
          • Prophylaxis was particularly effective in children whose index infection was febrile and in those with baseline BBD.
        • No difference in the occurrence of renal scarring
        • Adverse reactions to antibiotics were reported in 2% of both the antibiotic prophylaxis and placebo groups.
      • Criticisms:
        • Population may not reflect typical patient in practice
          • Majority female and half under age 11 months
          • Trial does not address patients with VUR and no history of UTI
      • RIVUR Trial Investigators. Antimicrobial prophylaxis for children with vesicoureteral reflux. NEJM 2014; 370: 2367. https://www.nejm.org/doi/full/10.1056/NEJMoa1401811
  • Antibiotic Controversies and Potential New Approaches
    • There was a belief that the first febrile UTI, in the presence of reflux, will create the greater proportion of clinically significant post-infection scarring, This belief, in turn, spawned the now routine and widespread US follow-up of prenatal hydronephrosis for evidence of postnatal hydronephrosis, which, if present, then triggers the documentation of reflux by cystography to prevent the first febrile UTI by instituting immediate antibiotic prophylaxis if reflux is found.
    • Antibiotic prophylaxis is destined to fail without adequate teaching and periodic review of perineal hygiene techniques, timely bladder emptying habits, and anticonstipation measures
    • Prophylactic antibiotics are more likely to benefit patients with:
      • Higher grade reflux
      • Baseline bladder dysfunction
      • Bowel and bladder dysfunction
      • Febrile UTI
• Endoscopic
  • A reasonable alternative for children being considered for surgical correction
  • Success rates vary across centers and that outcomes may not be durable.
    • Higher success rates associated with:
      1. Volume of Dx/HA used
      2. Surgeon experience
      3. Volcano-shaped mound with no hydrodistention
      4. Utilization of the double hydrodistention-implantation technique
      5. Accurate needle entry point during endoscopic injection, as well as the needle placement
      • Negative intraoperative cystogram is not associated with endoscopic success rates
  • Untreated BBD is associated with decreased resolution rates of VUR at initial follow-up in children treated with endoscopic surgery
  • The learning curve for endoscopic injection is believed to be different from that of open surgical reimplantation, but studies have compared these two approaches
  • Indications for treatment are the same as that of open surgical reimplantation
  • Materials used for endoscopic correction of reflux
    • Characteristics of an ideal injectable biomaterial (4):
      1. Non-toxic and stable without migration to vital organs
      2. Cause minimal local inflammation, while at the same time be well encapsulated by normal fibrous tissue and fibrocytes
      3. Easy to inject through a long needle that passes easily through most standard endoscopic instruments
      4. Viscous enough to prevent leakage from the puncture site and maintain its injected volume and the mound shape after the normal process of exchange and excretion of any carrier molecules.
    • Classified as particulate vs. degradable and autologous vs. non-autologous
      • Disadvantage of particulate agents is risk of migration
      • Disadvantage of degradable agents is less durability
        • Deflux is biodegradable, the carrier gel is reabsorbed, and the dextranomer microspheres become capsulated by fibroblast migration and collagen ingrowth
        • DX/HA loses ≈23% of its volume beyond 3 months of follow-up
      • Autologous Materials
        • Fat, collagen, muscle, and chondrocytes have been evaluated as bulking agents
  • Follow-Up after Endoscopic Treatment
    • The child is maintained on antibiotics for 3 months.
    • US and VCUG are obtained at 3 months.
      • If reflux is persistent, a repeat injection can be considered 6 months after the initial injection
      • If there is still no resolution, open surgery is recommended.
        • Most reports to date have not indicated any additional difficulty with open surgery after endoscopic correction using Deflux
• Ureteral reimplant
  • The principles of ureteral reimiplant for reflux include the following:
    1. Exclusion of causes of secondary VUR
    2. Adequate mobilization of the distal ureter without tension or damage to its delicate blood supply
    3. Creation of a submucosal tunnel that is generous in caliber and satisfies the 5:1 ratio of length to width
    4. Attention to the entry point of the ureter into the bladder (hiatus), the direction of the submucosal tunnel, and the ureteromucosal anastomosis to prevent stenosis, angulation, or twisting of the ureter
    5. Attention to the muscular backing of the ureter to achieve an effective anti-reflux mechanism
    6. Gentle handling of the bladder to reduce postoperative hematuria and bladder spasms
    • Common to each type of open surgical repair for reflux is the creation of a valvular mechanism that enables ureteral compression with bladder filling and contraction, thus reenacting normal anatomy and function.
  • Ureteral duplication
    • Approximately 10% of children undergoing antireflux surgery have an element of ureteral duplication. The most common configuration is a complete duplication that results in two separate orifices. This is best managed by preserving a cuff of bladder mucosa that encompasses both orifices. Because the pair typically share blood supply along their adjoining wall, mobilization as one unit with a “common sheath” preserves vascularity and minimizes trauma.
  • Success rate for ureteroneocystostomy in patients with low-grade primary VUR approaches 100%
    • BBD does not alter surgical resolution rates in children treated with open surgery
    • BBD is associated with increased incidence of UTI after surgery.
  • Follow-Up after Ureteral Reimplant
    • An US is necessary at 6-12 weeks postoperatively
      • Ureteral obstruction can be clinically silent, and therefore, the absence of ureteral obstruction must be documented.
      • Minimal ureteral dilation and low-grade hydronephrosis on early post-operative ultrasonography is not unusual
        • Persistence of this dilation > 3 months or its progression should be further investigated
    • Postoperative VCUG can be avoided in patients with:
      1. Low-grade primary reflux initially
      2. Normal preoperative and post-operative US examinations
      • Recall that follow-up after endoscopic management includes post-operative antbiotics for 3 months and imaging with US and VCUG
    • Children with renal scarring should have their blood pressure measured at every visit with their family physician
  • Complications of Ureteral Reimplantation
    • Early Complications
      • Persistent Reflux
        • Early reflux after ureteroneocystostomy usually is not a significant clinical problem and commonly resolves by 1 year on repeat cystography
      • De novo contralateral Reflux
        • Prophylactic bilateral reimplantation for unilateral reflux, to avoid contralateral reflux, is not warranted on the basis of the high spontaneous resolution rates
      • Obstruction at the anastamosis
        • Early after surgery, various degrees of obstruction can be expected of the reimplanted ureter. Edema, subtrigonal bleeding, and bladder spasms all possibly contribute. Mucus plugs and blood clots are other causes.
        • Most postoperative obstructions are mild and asymptomatic and resolve spontaneously without requiring additional surgery. More significant obstructions are usually symptomatic.
          • Affected children typically present 1 to 2 weeks after surgery with acute abdominal pain, nausea, and vomiting
          • In the more significant cases, drainage of the system either by retrograde insertion of a double-J stent or a percutaneous nephrostomy tube may be necessary
        • Many of these cases resolve without requiring additional surgery
    • Late complications
      • Obstruction at the anastamosis
      • Recurrent or Persistent Reflux
        • Causes (4):
          1. High-grade reflux
          2. Inadequate ratio of tunnel length to ureteral diameter
             • Development of a short tunnel and failure to taper the excessively wide ureter are important factors
          3. Failure to recognize secondary reflux, especially associated with neurogenic bladders and PUV bladders.
          4. Bladder and bowel function preoperatively, as well as in all cases of persistent or recurrent reflux.
  • Laparoscopic approach
    • Should theoretically provide the success rate and durability of open surgery while avoiding its morbidity.
    • Procedures have been attempted laparoscopically (3)
      1. Extravesical reimplant
      2. Gil-Vernet procedure
      3. Cohen cross-trigonal reimplant.

Questions

1. What are radiographic signs that VUR coexists with UPJO?
2. What is the most common cause of bladder outlet obstruction in pediatric males? Females?
3. Which of the following is true?
   1. VUR associated with a paraureteral diverticulum is likely to resolve
   2. A screening VCUG is recommended in all siblings of a child with VUR
   3. VUR in the absence of infection is a risk factor for renal dysfunction
   4. The greatest risk of postinfectious renal scarring occurs within the first 2 years of life

Answers

1. What are radiographic signs that VUR coexists with UPJO?
2. What is the most common cause of bladder outlet obstruction in pediatric males? Females?
3. Which of the following is true?
   1. VUR associated with a paraureteral diverticulum is likely to resolve
   2. A screening VCUG is recommended in all siblings of a child with VUR
   3. VUR in the absence of infection is a risk factor for renal dysfunction
   4. The greatest risk of postinfectious renal scarring occurs within the first 2 years of life

References

• Wein AJ, Kavoussi LR, Partin AW, Peters CA (eds): CAMPBELL-WALSH UROLOGY, ed 11. Philadelphia, Elsevier, 2015, chap 137