Vesicoureteral reflux (VUR) is the intermittent reversal of normal antegrade flow of urine from the ureter into the bladder. In most affected patients, the important clinical consequence of VUR is the occurrence of recurrent infections that can lead to renal scarring. The major pathophysiological mechanism of scarring is thought to be passage of infected urine from the lower urinary tract into the pelvicaliceal system, with extension into the parenchyma by way of intrarenal reflux through the collecting tubules. When severe, renal scarring can lead to hypertension or renal failure. Severe VUR in the fetus or neonate can lead to renal damage or faulty kidney development. Primary VUR accounts for 15% to 20% of prenatally detected uropathies; this type of reflux occurs with a 5:1 male to female ratio.¹

VUR is the abnormal retrograde flow of urine from the bladder into the ureter. It is most often a primary developmental abnormality in which immaturity of the vesicoureteral junction or a short distal ureteric submucosal tunnel in the bladder wall results in a poorly functional valve mechanism. In some instances, there is a specific underlying anatomic abnormality, such as a periureteral diverticulum or ectopic ureteral insertion (Figure 48-1). VUR can also occur as a secondary phenomenon in patients with a bladder outlet obstruction, such as posterior urethral valves. Neuropathic bladder is accompanied by VUR in 15% to 60% of patients.^2–4 Dysfunctional voiding plays a role in some instances of primary reflux.⁵ About three-fourths of girls with reflux have evidence of inhibited bladder contractions.⁶

The valve mechanism at the ureterovesical junction includes both passive and active components. The anatomic characteristics of the ureter and bladder wall provide passive resistance to reflux. The portion of the distal ureter that passes through the bladder wall consists of intramural and submucosal segments. Fixation of the submucosal portion is by muscular segments that extend into the trigone and the bladder base. The intravesicular pressure of the bladder is transmitted to the roof of the submucosal tunnel. When the intravesicular pressure exceeds the intraureteral pressure, the submucosal segment collapses, thereby opposing the retrograde passage of urine from the bladder into the ureter. This anatomic arrangement results in progressive increase in the resistance to reflux with increase in the intravesicular pressure.

Several potential anatomic factors of the ureterovesical junction increase the propensity for reflux. These include an abnormal oblique course of the distal ureter as it courses through the bladder wall, an abnormally short length of the intramural segment (particularly the submucosal portion), and an inadequate ratio of the length to the diameter of the submucosal segment of the ureter. The normal submucosal segment of the ureter has a length-to-width ratio of approximately 4:1. An abnormally large and laterally situated ureteral orifice is also associated with a propensity for VUR; the orifices of the 2 ureters should be located approximately equidistant from the center of the trigone.

With normal growth and development of infants and young children, the submucosal segment of the ureter elongates and the ratio between the length of the submucosal tunnel and the diameter of the ureter increases; these factors combine to improve the efficacy of the ureterovesical valve mechanism and diminish the likelihood of reflux. This is the major factor accounting for the clinically observed inverse relationship between the prevalence of VUR and patient age. Resolution of VUR occurs spontaneously in most children.⁷

The prevalence of VUR in healthy children is less than 1%. The frequency of VUR in children who have had at least 1 urinary tract infection is up to 30%. VUR is reported to occur in 8% to 45% of siblings of children with reflux.⁸ The peak age at diagnosis of VUR is between 3 and 5 years.⁵ There is evidence of a strong genetic basis for primary VUR. The inheritance of a propensity for reflux may be linked to human leukocyte antigens. Segregation analysis suggests that there is a single dominant gene acting in combination with environmental factors.⁹

There is a propensity for VUR in patients with various urinary tract anomalies. The reported prevalence of ureteropelvic junction obstruction in patients with VUR ranges from 0.8% to 14%.^10,11 VUR is the most common abnormality associated with complete ureteral duplication; approximately 10% of children undergoing antireflux surgery have complete or incomplete duplication of the collecting system.¹² VUR is the cause of upper tract dilation in as many as 35% of children with hydronephrosis, although the collecting system prominence is usually mild in these patients.¹³

Categorization of the severity of VUR based on the imaging appearance is into 5 types: (1) grade I—reflux into the ureter only, without dilation; (2) grade II—reflux into the pelvicalyceal system, without dilation (the caliceal fornices are normal); (3) grade III—reflux associated with mild to moderate dilation or tortuosity of the ureter and/or mild to moderate dilation of the pelvicaliceal system, with no or minimal forniceal blunting; (4) grade IV—reflux with moderate dilation of the ureter and pelvicaliceal system, obliteration of the forniceal angles, and maintenance of the papillary impressions in most calyces; (5) grade V—reflux that causes marked dilation of the ureter and pelvicaliceal system, with loss of the papillary impressions in most calyces (Figure 48-2).¹⁴

Reflux nephropathy is a progressive disorder that involves fibrosis and focal segmental sclerosis within the kidney in association with VUR (Figure 48-3). The renal changes are primarily due to reflux of infected urine. Reflux nephropathy is estimated to cause 30% to 50% of cases of end-stage renal disease in children, and is responsible for approximately 20% of end-stage renal disease in adults. Up to 10% of children with substantial renal scarring due to reflux or pyelonephritis eventually develop end-stage renal disease and at least 20% develop hypertension. Somewhere between 4 and 7 years of age, VUR ceases to be a significant cause of scarring, in previously normal kidneys.^15–18

The pathogenesis of reflux nephropathy is multifactorial. The most important clinical variables include the severity of reflux, the number of infections, the age at diagnosis of reflux, timeliness in treatment of infections, and the organisms responsible for infections. VUR that is greater than grade I and detected after a urinary tract infection is associated with a threefold increased risk for renal scarring compared with children who have less severe reflux. Children with high-grade (grade III to V) VUR tend to develop larger scars after an episode of pyelonephritis than those with no or low-grade (grade I to II) VUR. Although the risk for reflux nephropathy increases with the severity of VUR, there are occasional patients who develop this complication despite having only low-grade reflux. Also, some children with substantial reflux never develop detectable scarring, even in the absence of medical therapy.^19,20

Genetic factors increase the susceptibility of some individuals (particularly females) to renal scarring as a consequence of reflux and urinary tract infections, for example, the DD genotype of the angiotensin-converting enzyme gene. End-stage renal disease due to reflux nephropathy is associated with various genetic markers, such as the human leukocyte antigens HLA-B12 in female patients, HLA-B8 in combination with HLA-A9 or HLA-Bw15 in male patients, and HLA-Bw15 in patients of both sexes. There is a dominant pattern of inheritance, with 25% to 50% of the siblings of index cases having VUR and a risk of approximately 65% for the offspring of an affected parent.^21–25

VUR is apparently important in the pathophysiology of some instances of congenital renal dysplasia, usually in males. This “congenital scarring” accounts for a disproportionate number of patients with end-stage renal disease. The parenchymal changes in these children often are similar to those of infection-related renal scarring despite lack of clinical evidence of prior infections. The cause and effect relationship between fetal reflux and renal dysplasia and congenital scarring is unclear. Fetal reflux could cause damage to the developing kidney even if spontaneous resolution of reflux occurs by the time of birth or shortly thereafter. Alternatively, reflux could occur as an associated, but noncausative, factor in patients with renal dysplasia due to abnormal metanephric development. Primary VUR accounts for 15% to 20% of prenatally detected uropathies; this type of reflux occurs with a 5:1 male to female ratio.¹