eMedicine Specialties > Pediatrics: Surgery > Urology

Vesicoureteral Reflux

Author: Caleb P Nelson, MD, MPH, Instructor in Surgery, Department of Urology, Harvard Medical School; Consulting Staff, Division of Pediatric Urology, Department of Urology, Children's Hospital Boston
Coauthor(s): Harry P Koo, MD, Chairman of Urology Division and Director of Pediatric Urology, Virginia Commonwealth University; Professor of Surgery, VCU School of Medicine, Medical College of Virginia; Director of Urology, Children's Hospital of Richmond
Contributor Information and Disclosures

Updated: Sep 9, 2008

Introduction

Background

Vesicoureteral reflux (VUR), or the retrograde flow of urine from the bladder into the ureter, is an anatomic and functional disorder with potentially serious consequences. Primary reflux is vesicoureteral reflux in an otherwise normally functioning lower urinary tract, whereas secondary reflux is vesicoureteral reflux that is associated with or caused by an obstructed or poorly functioning lower urinary tract, such as that observed with posterior urethral valves or a neurogenic bladder. In both conditions, the ureterovesical junction (UVJ) fails to function as a one-way valve, giving lower urinary tract bacteria access to the normally sterile upper tracts. Although vesicoureteral reflux has been recognized as an anatomic phenomenon for centuries, not until relatively recently were the substantial morbidity and mortality associated with the condition recognized.

Early studies demonstrated a correlation between reflux and chronic pyelonephritis in paraplegic individuals and a correlation among urinary tract infection (UTI), reflux, and chronic pyelonephritis in children, which suggested that prevention of vesicoureteral reflux may result in reduced prevalence of renal complications. The subsequent developments in the medical and surgical management of vesicoureteral reflux formed the basis of the evolving field of pediatric urology.

The objectives in the current treatment of vesicoureteral reflux are twofold. The first goal is the prevention of episodes of acute pyelonephritis with its associated morbidity and mortality. The second goal is to prevent the scarring of the kidney associated with vesicoureteral reflux (reflux nephropathy), which increases the risk of hypertension and renal failure in children and adults with vesicoureteral reflux. Controversy persists over the optimal management of vesicoureteral reflux, specifically with respect to the timing, technique, and benefits of surgical correction.

Pathophysiology

After entering the bladder through the muscular hiatus of the detrusor muscle, the normal distal ureter passes through a submucosal tunnel before opening into the bladder lumen via the ureteral orifice. If the length of the submucosal tunnel or its muscular backing is inadequate, the valve mechanism is incompetent, resulting in reflux. Careful anatomic measurements suggest that the ratio of tunnel length to ureteral diameter must be at least 5:1 to prevent reflux. This fundamental observation is the basis for almost all surgical procedures to correct the disorder.

Beyond the fetal stage, anatomic reflux alone rarely produces renal damage. Experiments in pigs have demonstrated renal scarring in sterile refluxing systems; although the kidneys may display scarring, dysplasia, or both in some patients with prenatally identified and presumably sterile reflux, the overwhelming majority of data implicate ascending infection and pyelonephritis as the essential causes of reflux nephropathy. Large studies have repeatedly demonstrated a close correlation between the frequency of UTI and severity of reflux nephropathy in patients with vesicoureteral reflux.^1,2,3

Scarring may result from a single episode of pyelonephritis, especially in very young patients. Ransley and Risdon named this occurrence the "big bang" effect.⁴ Most scarring tends to occur at the renal poles, where the anatomy of the renal papillae permits backflow of urine into the collecting ducts. This phenomenon is referred to as intrarenal reflux and gives pathogenic bacteria access to the renal tubules. The subsequent cascade of inflammation, with release of superoxide and other mediators, results in local tissue ischemia and fibrosis. Over time, when enough renal parenchyma is affected, hypertension, renal insufficiency, and renal failure can result. The reason kidneys of children are so susceptible to damage is unclear; this may be due to reduced levels of renal superoxide dismutase in children.

Frequency

United States

Overall prevalence of vesicoureteral reflux is unknown because many children are asymptomatic and the invasive testing required for diagnosis is performed only when clinically indicated. Several older reports of imaging studies performed on healthy children prior to oversight by institutional review boards demonstrated rates of 1-2%, but most of these studies were small and failed to clearly characterize their subject populations. The evidence is clear that the prevalence of vesicoureteral reflux is higher among children with UTIs (15-70%, depending on age). Among infants prenatally identified with hydronephrosis on ultrasonography, approximately one third were postnatally found to have vesicoureteral reflux.

The incidence of reflux clearly is influenced by genetic factors, although specific modes of inheritance have yet to be identified. Siblings of children with vesicoureteral reflux have a 25-33% risk of also having vesicoureteral reflux, whereas offspring of parents with reflux have a 66% incidence (higher in female offspring than male offspring). Even when asymptomatic, these siblings and offspring can have high-grade reflux and often have renal scarring at evaluation.

Screening of asymptomatic siblings and offspring continues to be an area of controversy. Advocates point out that early identification of children with reflux may prevent episodes of UTI and renal scarring, but other authorities feel that screening asymptomatic individuals is likely to result in significant overtreatment of clinically insignificant vesicoureteral reflux, with associated morbidity. As a middle ground, some pediatric urologists screen newborn siblings of children with vesicoureteral reflux but not their older, asymptomatic siblings.

International

Many large studies have been performed in Europe, where prevalence is estimated to be similar to that in the United States. Disease frequency in other parts of the world is not well described but has been shown to be lower in people of West African descent.

Mortality/Morbidity

With modern antibiotics and supportive care, mortality from acute pyelonephritis in children with vesicoureteral reflux is very rare. However, morbidity associated with vesicoureteral reflux is substantial, both from acute infection and from the sequelae of reflux nephropathy.

• Changes in renal function: Decreases in urine-concentrating ability (proportional to the degree of reflux) and in glomerular filtration rate (proportional to the degree of renal scarring) have been measured in children with vesicoureteral reflux.
• Decreased renal and somatic growth: Although renal growth assessment in children is difficult because of imaging variability, several studies have documented smaller kidneys in children with reflux and recurrent infections. Surgery may improve growth rates, but small, scarred kidneys are unlikely to grow. Although early studies suggested that somatic growth is negatively affected in children with reflux, more recent data have shown that carefully monitored, properly treated children with vesicoureteral reflux have growth rates within normal ranges. In contrast, children with significant renal insufficiency or end-stage renal disease clearly have decreased growth rates.
• Hypertension and renal failure
  • Reflux nephropathy may be the most common cause of childhood hypertension. Presence of hypertension correlates well with the degree of renal scarring, especially when scarring is bilateral. The mechanism is thought to be elevated renin levels produced by damaged renal tissues.
  • Although not all scarred kidneys in children with hypertension produce excess renin, resection of renal units in cases where unilateral renal vein renin levels are elevated substantially (ratio >1.5) can result in resolution of hypertension.
  • Improvements in management may result in decreased rates of hypertension among adults who had childhood reflux.
  • The most devastating outcome of reflux nephropathy is renal failure. The true incidence of chronic renal insufficiency among refluxing children is uncertain. Older studies consistently attributed 15-30% of renal failure in children and young adults to chronic pyelonephritis and reflux nephropathy. However, one transplant series attributed just 2.2% of cases to chronic pyelonephritis. Most authorities now agree that, although renal failure is a devastating complication of vesicoureteral reflux, it actually affects only a small minority of children with reflux.

Race

Reflux is more common in white children than in those of other races. This disparity extends to children with antenatal hydronephrosis. The editor of this article reviewed his prenatal registry of 1019 patients with prenatal hydronephrosis and found a 15% incidence of vesicoureteral reflux in African American patients enrolled in the registry. Although vesicoureteral reflux is less common in black children, screening is still recommended after a single UTI in this population. Because little is known about the specific genetic linkage of vesicoureteral reflux and because of the wide variation of genes with intermarriage, excluding any group from evaluation is difficult.

Although vesicoureteral reflux is much less common in other ethnic groups, the range of severity and rate of spontaneous resolution (grade for grade) are similar between the races.

Sex

UTIs are more common in females, as one might expect given the anatomic differences. This leads to greater screening and, therefore, diagnosis of vesicoureteral reflux in females. However, among all children with UTI, boys are more likely to have vesicoureteral reflux than girls (29% of males vs 14% of females). Boys also tend to have higher grades of vesicoureteral reflux diagnosed at younger ages, but their vesicoureteral reflux is more likely to resolve.

Age

Vesicoureteral reflux is more common among infants and progressively resolves in a substantial proportion of children; thus, prevalence decreases as children age. One study of patients who presented with UTI demonstrated prevalence rates of 70% in patients younger than 1 year, 25% in patients aged 4 years, 15% in those aged 12 years, and 5.2% in adult patients.²

Clinical

History

Most children with vesicoureteral reflux (VUR) present in 2 distinct groups.

• The first group presents with hydronephrosis, often prenatally identified using ultrasonography. These children typically progress through evaluation and treatment in the absence of clinical illness.
• The second group presents with clinical urinary tract infection (UTI). Even for experienced pediatricians, the diagnosis of UTI in children can be difficult.
  • Children often present with nonspecific signs and symptoms. Infection in infants can manifest as failure to thrive, with or without fever. Other features include vomiting, diarrhea, anorexia, and lethargy.
  • Older children may report voiding symptoms or abdominal pain.
  • Pyelonephritis in young children is more likely to manifest with vague abdominal discomfort rather than with the classic flank pain and tenderness observed in adults. The presence of fever, while highly suggestive of pyelonephritis, is not reliable enough to lead to the diagnosis.
  • Even today, children occasionally present with advanced reflux nephropathy, manifesting as headaches or congestive heart failure from untreated hypertension, or with uremic symptoms from renal failure.
  • A small group of children without evidence of UTI present with symptoms of sterile reflux, which can include flank or abdominal pain before or during voiding, as well as double voiding or incomplete emptying resulting from delayed drainage of urine out of the upper tracts.

Physical

As with the history, few findings on physical examination suggest vesicoureteral reflux or UTI.

• Fever, flank or abdominal tenderness, or an enlarged palpable kidney may be present;
• In the absence of reliable historical or physical findings, diagnosis depends on laboratory testing and imaging, as well as family history.

Causes

The cause of the defect in primary reflux is unknown.

• 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 favor a polygenic mode of inheritance, whereas others have suggested autosomal or sex-linked transmission with variable penetrance.
• The possibility that UTI may cause reflux has also been investigated. Indeed, a subset of patients has been identified in whom reflux was detectable only during an episode of cystitis. However, most authorities think that UTI and reflux are independent variables and that rates of vesicoureteral reflux are higher in children with UTI because these children are actively screened for reflux. The cause-and-effect picture is even less clear in children with secondary reflux.
• Rates of reflux are likely increased in the setting of congenital bladder outlet obstruction and neurogenic bladder. More than 50% of boys with posterior urethral valves have vesicoureteral reflux. Similar results were seen in a series of children undergoing urodynamic studies for neurogenic bladder.
• Dysfunctional voiding, with its inherent increase in intravesical pressure, likely also results in reflux, even in otherwise healthy children. Uninhibited bladder contractions, often associated with contraction of the voluntarily controlled external urinary sphincter to prevent wetting, increase intravesical pressure. The combination of high-pressure voiding and vesicoureteral reflux increases the risk of pyelonephritis beyond that of the child with low-pressure reflux.
• Confounding all of these data is the fact that urodynamic studies on children are difficult to perform and evaluate; this is true especially with infants, in whom normal reference data are sparse. Whether vesicoureteral reflux observed in association with voiding dysfunction and obstruction is a direct result of that dysfunction or simply a component of a grossly abnormal urinary tract is not known.
• A unique and complex group of children presents with dysfunctional elimination, which consists of a symptom complex heralded by infection, severe constipation, and daytime wetting. Despite the primary urinary tract presentation, the primary focus should be in the management of constipation and bowel habits. A subset of these children have infrequent voiding and incomplete bladder emptying, which further increases the likelihood of UTI.

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