Treating severe vesicoureteral reflux involved complicated, expensive surgery. Now an injectable agent that forms a valve can lead to normal urination.
Vesicoureteral reflux (VUR) is probably not at the top of the list of concerns for most managed care executives, but it is of great importance to the parents of toddlers with this dangerous disorder. It is also a good example of how the biotech industry has focused on a strategy that targets uncommon disorders with unique and innovative solutions.
Urine normally flows from the kidneys through the ureters to the bladder. A complex process coordinates the act of urination in which the urethra relaxes and the bladder contracts. A valve controls urination in normal anatomy. VUR is the abnormal flow of urine from the bladder back into the ureter, and ultimately into the kidney. This occurs because the valve-like mechanism is distorted at the ureter-bladder junction, because of abnormal anatomy, and it can lead to serious consequences. If urine from the bladder flows backwards, bacteria present in the bladder can reach the kidney, resulting in a potentially fatal infection of that organ. The severity of the condition is graded from I through IV, with IV being the most severe.
The standard course of therapy involved prophylactic use of antibiotics, bladder control training, watchful waiting for mild cases, and surgical repair for severe cases.
In 1997, a panel from the American Urologic Association established clinical guidelines for treating the condition. Since the mid-1970s, continuous prophylactic antibiotic therapy has been the mainstay, either administered alone or in combination with anticholinergic agents, accompanied by training in bladder control. It was hoped that as the child aged, the natural growth of the bladder-ureteral junction would resolve the reflux. In many cases of mild reflux, this did in fact occur.
For more severe cases, surgical repair was the only therapy. It is a major procedure and involves reimplanting the ureter into the bladder wall, creating a functional valve. It was usually recommended for older children with Grade III or IV reflux. For years, no means of endoscopic repair was available to surgeons. The recommendation by the panel in 1997 in Report on the Management of Primary Vesicoureteral Reflux in Children was that "Newer materials that can be used for endoscopic subureteral injection that are safe in children should be studied."
That has changed. In late 2001, the FDA approved a dextranomer/hyaluronic acid copolymer (Deflux), made of dextranomer microspheres (80–250 nm) that are suspended in a gel of non-animal stabilized hyaluronic acid for use in Grade II through IV VUR in children older than one year of age. The copolymer has been used in Europe since 1998. Both of these substances are polysaccharides, and the non-animal stabilized hyaluronic acid is very similar to the natural hyaluronic acid found in the body. Dextranomer and hyaluronic acid are biodegradable and lack allergenic or immunogenic properties.
During an endoscopic procedure, Deflux is injected into the submucosal area next to the ureter-bladder junction. At this point at the junction, the substance forms a one-way valve, overcoming the backflow pressure from the bladder. The dextranomer facilitates the growth of fibroblasts and collagen between the microspheres as the hyaluronic acid degrades. The artificial valve is consolidated with endogenous tissue that stabilizes the bulk effect for a sustained response.
Initial studies have demonstrated resolution rates of 66 percent to 77 percent. Depending on the grade and age of patient, this is approximately double the rate of resolution compared with antibiotic treatment and is nearly the same as open surgical treatment. Longer-term observation of patients demonstrated that as many as 96 percent of ureters that were free of grade III or greater reflux from three to twelve months after treatment were still free of reflux two to five years post-injection.
In the 1990s alone, there were nearly 10 million outpatient visits reported for urinary tract infections in children in the U.S. Complications from VUR resulted in nearly 15,000 admissions to the hospital for pyelonephritis in patients ages birth through 10. These admissions involve direct infection of the kidney, a situation that can result in bacteremia. Thus, pyelonephritis can lead to death if untreated.
Children born with a defective valve have primary VUR. There is also an acquired or secondary form that I will not discuss here, as it is rare and has multiple causes. The prevalence of primary VUR in healthy children is estimated to be 1 percent. There appears to be a genetic predisposition, as demonstrated by higher rates of VUR in families with siblings or parents with a history of reflux.
Urinary tract infection (UTI) is common in cases of VUR, with estimates suggesting that as many as 1 in 3 children with a UTI are found to have VUR. Most cases of VUR are diagnosed during the clinical workup of an infection. Recurrent infections, even if treated, can often lead to scarring of the kidney. If unchecked, VUR has serious consequences: renal insufficiency, end-stage renal disease, renin-mediated hypertension, and reduced growth in the child. According to the American Urologic Association's Pediatric Vesicoureteral Reflux Clinical Guidelines Panel Report on the Management of Primary Vesicoureteral Reflux in Children (1997), the primary goals of treatment in children with reflux are to prevent renal injury and symptomatic pyelonephritis.
The higher grades associated with VUR reflect the greater dilation of the ureter attributed to high backpressure, as well as the severity of the reflux. The higher the grade, the greater likelihood of permanent scarring and end-stage renal disease. This is significant because as many as 40 percent of children who develop pyelonephritis may develop renal scarring.
Managed care ramifications
Deflux is not associated with a significant risk of migration or toxic reactions. Both of the constituents of Deflux have established medical uses and safety studies demonstrated overall limited issues.
The retail cost of the material is $925 per vial, with one vial used for each ureter that is affected by reflux. The procedure is performed on an outpatient basis, with the patient given mild anesthesia and, barring complications, same-day discharge. This is much less expensive than the open surgical procedure, which requires several days in the hospital and exposes the child to all of the potential complications, such as scarring, infection, and prolonged recovery. In addition, the long term net cost is actually less than chronic antibiotic use.
This is truly an answer to a prayer for the parents and children who face this disorder.
This substance was approved for VUR in Europe and Canada several years before the FDA approval. It is also approved in Canada and Europe for the treatment of stress urinary incontinence (SUI). It is expected that the company will seek permission for the SUI indication in the United States in the near future.
So what is managed care to do? First, get to know the literature and develop coverage policies for Deflux for VUR. Second, medical directors should talk to their pediatric urologists to see if they feel comfortable with this new technology and are willing to use it in lieu of the much more invasive open procedure, saving the child pain and potential surgical complications and saving the MCO the additional cost. Third, rejoice in the progress of having tomorrow's medicine ... today!