Vesicoureteral Reflux

Galen and Asclepiades described the valve action of the ureterovesical junction as early as the second century CE. In 1903, Sampson and Young described the functional flap-valve mechanism at the level of the ureterovesical junction, which is created by the oblique course of the ureter within the intramural portion of the bladder wall. In 1913, Legueu and Papin described a patient with hydronephrosis and hydroureter in whom urine was shown refluxing through a widely patent ureteral orifice.

In his report on cystography in 1914, Kretschmer demonstrated that 4 of the 11 children he studied had reflux. In 1929, Gruber noted that the incidence of VUR varied based on the length of the intravesical ureter and muscularity of the detrusor backing. Paquin reported that the tunnel length–to–ureteral diameter ratio should be approximately 5:1 to prevent reflux. In the mid-to-late 1950s, Hutch postulated the causal relationship between VUR and chronic pyelonephritis in a cohort of patients with spinal cord injury, and, in 1959, Hodson demonstrated that renal parenchymal scarring is more common in children with VUR and UTIs.

Ransley and Ridson confirmed the studies of Tanagho in 1975 by showing that reflux could be experimentally created in animals by modifying the ureterovesical junction; in subsequent studies, they were able to show the correlation between reflux, renal papilla anatomy, pyelonephritis, and renal injury. At the same time, Smellie and Normand performed long-term studies of patients with reflux; they documented the natural history of patients treated medically. ^[6]

At the same time, Paquin, Hutch, Lich and Gregoire, Daines and Hudson, Politano and Leadbetter, Glenn and Anderson, and Cohen developed and popularized various surgical techniques for treating VUR. The International Reflux Grading System was adopted in the early 1980s, and the International Reflux Study compared medical approaches with surgical approaches to reflux. Finally, endoscopic treatment for reflux was introduced in the late 1980s. In recent years, Noe and colleagues showed a genetic predisposition for reflux. In addition, the widespread use of antenatal ultrasonography has allowed identification of fetuses with urinary tract abnormalities, which can result in diagnosis of reflux prior to the development of UTIs.

The normal valve mechanism of the ureterovesical junction includes oblique insertion of the intramural ureter, adequate length of the intramural portion of the ureter, and strong detrusor support.

The ureter is composed of 3 muscle layers: inner longitudinal, middle circular, and outer longitudinal. The outer longitudinal layer is enveloped by ureteral adventitia. The inner longitudinal layer of smooth muscle passes through the ureteral hiatus, continues distally beyond the ureteral orifice into the trigone, and intertwines with the smooth muscle fibers of the contralateral ureter, forming the Bell muscle of the trigone and posterior urethra. The middle circular muscle fibers, outer longitudinal muscle fibers, and periureteral adventitia merge with the bladder wall in the upper part of the ureteral hiatus to form the Waldeyer sheath. This sheath attaches the extravesical portion of the ureter to the ureteral hiatus.

When the ureter inserts into the trigone, the distal end of the ureter courses through the intramural portion of the bladder wall at an oblique angle. The intramural tunnel length–to–ureteral diameter ratio is 5:1 for a healthy nonrefluxing ureter. As the bladder fills with urine and the bladder wall distends and thins, the intramural portion of the ureter also stretches, thins out, and becomes compressed against the detrusor backing. This process allows a continual antegrade flow of urine from the ureter into the bladder but prevents retrograde transmission of urine from the bladder back up to the kidney; thus, a healthy intramural tunnel, within the bladder wall, functions as a flap-valve mechanism for the intramural ureter and prevents urinary reflux.

An abnormal intramural tunnel (ie, short tunnel) results in a malfunctioning flap-valve mechanism and VUR. When the intramural tunnel length is short, urine tends to reflux up the ureter and into the collecting system. Pacquin reports that refluxing ureters have an intramural tunnel length–to–ureteral diameter ratio of 1.4:1. To prevent reflux during ureteral reimplantation, the physician must obtain a minimum tunnel length–to–ureteral diameter ratio of 3:1.

The human kidney contains two types of renal papillae: simple (convex) papilla and compound (concave) papilla. Compound papillae predominate at the polar regions of the kidney, whereas simple papillae are located at nonpolar regions. Approximately 66% of human papillae are convex and 33% are concave.

Intrarenal reflux or retrograde movement of urine from the renal pelvis into the renal parenchyma is a function of intrarenal papillary anatomy. Simple papillae possess oblique, slitlike, ductal orifices that close upon increased intrarenal pressure. Thus, simple papillae do not allow intrarenal reflux. However, compound papillae possess gaping orifices that are perpendicular to the papillary surface that remain open upon increased intrarenal pressure. These gaping orifices allow free intrarenal reflux.

Patients with uncorrected VUR may develop renal scarring and impaired renal growth. Renal scars are often present at initial diagnosis and usually develop during the first years of life. Persistent intrarenal reflux causes renal scarring and eventual reflux nephropathy. Reflux nephropathy leads to impaired renal function, hypertension, and proteinuria.

Two types of urine may enter the renal papillae: infected urine or sterile urine. Intrarenal reflux of infected urine appears to be primarily responsible for the renal damage. The presence of bacterial endotoxins (lipopolysaccharides) activates the host's immune response and a release of oxygen free radicals. The release of oxygen free radicals and proteolytic enzymes results in fibrosis and scarring of the affected renal parenchyma during the healing phase.

Initial scar formation at the infected polar region distorts local anatomy of the neighboring papillae and converts simple papillae into compound papillae. Compound papillae, in turn, perpetuate further intrarenal reflux and additional renal scarring. Thus, a potentially vicious cycle of events may occur after initial intrarenal introduction of infected urine. Compound papillae are most commonly found at the renal poles, where renal scarring is most commonly observed. Renal scan (DMSA) reveals these lesions focally. Diffuse lesions on renal scan are believed to be due to renal dysplasia, which results from abnormal kidney development. It is observed in patients who have higher grades of reflux (IV and V) and who have never had any evidence of UTI or pyelonephritis. As described by Yeung et al, these kidneys may have very low or no function in 5% of girls and 78% of boys. ^[7]

Intrarenal reflux of sterile urine (under normal intrapelvic pressures) has not been shown to produce clinically significant renal scars. Treatment with long-term low-dose antibiotic prophylaxis to maintain sterile urine appears seems to inhibit renal scarring in children with uncomplicated VUR. ^{[6, 8]} Thus, renal lesions appear to develop only in the setting of intrarenal reflux in combination with UTI. One exception to this may include intrarenal reflux of sterile urine in the setting of abnormally high detrusor pressures.

Hodson et al completely obstructed the urethra of Sinclair miniature piglets and created an artificially high intravesical pressure that was transmitted to the renal pelvis. Intrarenal reflux of sterile urine in this highly pressurized system led to the formation of renal lesions. Apparently (at least in animal model studies), sterile reflux may also produce scarring but only with high intravesical pressures (eg, infravesical outlet obstruction or poorly compliant neurogenic bladder).

Renal lesions are associated with higher grades of reflux. Pyelonephritic scarring may, over time, cause serious hypertension due to activation of the renin-angiotensin system. Scarring related to VUR is one of the most common causes of childhood hypertension. Wallace reports that hypertension develops in 10% of children with unilateral scars and in 18.5% with bilateral scars. Among adults with reflux nephropathy, 34% ultimately develop hypertension. Approximately 4% of children with VUR progress to end-stage renal failure. Renal units with low-grade reflux may grow normally, but high grades of reflux are associated with renal growth retardation.

Bladder outlet obstruction (functional or anatomical), learned voiding abnormalities (eg, nonneurogenic neurogenic bladder, or Hinman syndrome), and gastrointestinal dysfunction may cause VUR. Unphysiologically elevated intravesical pressures are common with all of these abnormalities. Children with overactive bladder (eg, detrusor hyperreflexia, detrusor instability) generate a high intravesical pressure, which can exacerbate pre-existing VUR or cause secondary VUR. These children empty their bladder relatively well, with minimal postvoid residual urine.

Acquired voiding dysfunction (eg, Hinman syndrome [nonneurogenic neurogenic bladder]) produces functional bladder outlet obstruction from voluntary contraction of the external sphincter during urination. These children generate high intravesical pressure, develop detrusor instability, and have high postvoid residual urine volumes. Encopresis and constipation are also common in this setting.

Primary causes of VUR include the following:

• Short or absent intravesical ureter
• Absence of adequate detrusor backing
• Lateral displacement of the ureteral orifice
• Paraureteral (Hutch) diverticulum

Secondary causes of VUR include the following:

• Cystitis or UTI
• Bladder outlet obstruction
• Neurogenic bladder
• Detrusor instability

The existence of a strong genetic component is indicated by the high rate of reflux in relatives of patients with reflux, but the mechanism of transmission is not clear. Some investigators have proposed a polygenic mode of inheritance, whereas others have suggested autosomal or sex-linked transmission.

VUR affects 1% to 2% of all children, and up to one-third of children with VUR will experience urinary tract infection (UTI). ^[2]  The incidence of VUR in children with febrile UTIs is estimated to be 30-40%. ^[3]

VUR is 10 times as common in white children as in black children, and children with red hair are recognizably at an increased risk. VUR is more prevalent in male newborns, but VUR seems to be 5-6 times more common in females older than one year than in males. The incidence decreases as patient age increases.

At present, the incidence of prenatally diagnosed hydronephrosis caused by VUR ranges from 17-37% in the pediatric population, and approximately 20-30% of children with VUR present with renal lesions. The incidence of VUR in children and young adults with end-stage renal failure (chronic renal insufficiency [CRI]) that necessitates therapy (dialysis or transplantation) is about 6%. VUR is the fifth-most-common cause of CRI in children. ^[9]

The success rate of ureteral reimplantation performed by experienced surgeons is higher than 95%. Following surgical repair, the incidence of pyelonephritis significantly decreases (in comparison to medical management with long-term antibiotic therapy); however, the incidence of cystitis or renal scarring is the same following both medical and surgical management of vesicoureteral reflux (VUR).

Endoscopic treatment carries a lower success rate than open surgical treatment but offers an alternative to either medical treatment or open surgical treatment. Unfortunately, to date, no long-term, multi-institutional study has been carried out to evaluate and compare the three management options. Outcome measures should consider not only resolution of reflux but also long-term renal health and rate of UTIs.