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History reminds us of valuable lessons learned in the treatment of vesicoureteral reflux (VUR). Rates of reflux nephropathy (RN) have decreased remarkably over the past 50 years, owing in various degrees to more rapid detection of urinary tract infection (UTI) in infants and children, improved medical therapy and timely surgical intervention. Reflux nephropathy once accounted for 22% of all pediatric renal transplantations, and now accounts for less than 6%.1 Despite this improvement, 8.5% of chronic renal disease in North American children is still due to RN.2 In some series, there is a history of childhood pyelonephritis with subsequent renal scarring in up to 15% of adult renal transplantation.3 Therefore, the modern day debate on the optimal management of VUR has significant merit in terms of preventing RN, and its impact on pediatric and adult populations.
During the 1950s, Hutch was the first to suggest a link between VUR, pyelonephritis and renal scars based on his work on adult paraplegics, and the benefits of ureteral reimplantation.4 Politano, Leadbetter, Paquin and others improved upon the concept of an adequate length, detrusor-backed submucosal tunnel, cementing ureteral reimplant as a time-tested cornerstone in the management of VUR. 5,6 Reported contemporary success rates of antireflux surgery range from 96% to 98%.7
The VUR treatment paradigm shifted from surgery towards medical management during the late 1970s. Lenaghan and colleagues showed a natural tendency for most VUR to resolve spontaneously. 8 This work, coupled with the work of Smellie and colleagues,9,10 which showed a low rate of new scar formation on daily low dose antimicrobial prophylaxis, provided the rationale for the expectant VUR treatment we have seen for the past 3 decades. The rationale of preventing UTIs and pyelonephritis, while the refluxing kidney is at risk, formed the basis of the 1997 American Urological Association expert panel on VUR,11 where surgery is reserved for patients who failed on antibiotic prophylaxis and with high-grade reflux.
Several recent publications have questioned the efficacy of daily antimicrobial prophylaxis in terms of preventing UTI and new renal scarring (Table 1).12–15 Breakthrough UTIs of up to 25% have been reported. This challenges the current assumption that daily antibiotic prophylaxis “prevents” UTIs, pyelonephritis and subsequent scar formation in affected renal units. Criticisms over the methodology of the aforementioned studies have led to great anticipation for the results of the Randomized lntervention for children with VesicoUreteral Reflux (RIVUR) study (Fig. 1).16
Adequately designed and powered, this study will hopefully answer the question of whether prophylaxis prevents UTI and scarring in VUR patients (and thus potentially validate VUR management for the past 3 decades). Post-RIVUR, lingering concerns will still remain about antimicrobial prophylaxis. These include (1) increased bacterial resistance;17 (2) the inconvenience and risk associated with serial radiologic investigations; (3) decreased cost-effectiveness;18 (4) the clinical versus statistical significance of any result;19 and (5) the fate of those refluxers who do not resolve over time, in that we are shifting the progression of chronic renal disease into adulthood given the known, slow progression of reflux nephropathy.
Some proponents of medical therapy have proposed that early treatment of early pyelonephritis can decrease the risk or lessen scar formation.20 Two recent studies refute this idea. 21,22 Hoberman and colleagues, in a large prospective trial of oral versus intravenous therapy for UTIs in young children, found no significant difference in scarring among children who presented after 24 hours of fever compared with those who presented sooner.21 Hewitt and colleagues used data from 2 multicentre, prospective, randomized controlled trials to demonstrate a 30.7% scar rate on dimercaptosuccinic acid (DMSA) 12 months after an acute pyelonephritis.22 Progressive delay in antibiotic treatment from <1 day to >5 days after onset of fever was not associated with increased scarring. In other words, prompt treatment of febrile UTI does not prevent associated scarring and/or the potential for RN.
While the debate over the efficacy of medical management continues, there must be an overt acknowledgement in any VUR debate that ureteral reimplantation cures reflux. With published minimal acceptable success rates of 95% and reproducible results reported as high as 99%, pediatric urologists have essentially perfected the art of the ureteral reimplant. At our institution, unilateral reimplantation is generally performed extravesically. Bilateral reimplantation is performed by an intravesical, cross-trigonal fashion to avoid the risk of transient postoperatively urinary retention observed with bilateral extravesical reimplantation (4% to 15%). Other reported complications of ureteral reimplantation include mild transient hydronephrosis in 6% to 7%, and an overall rate of ureteral obstruction requiring revision in <1%.
The perioperative management of the child undergoing ureteral reimplantation has changed dramatically. Two-week hospital stays in the early series have evolved into outpatient or overnight stays. Routine placement of suprapubic catheters, ureteral stents and surgical drains have been abandoned, and most patients with uncomplicated ureteral reimplants are discharged on postoperative day 1 with no tubes in place.
Pediatric anesthesia has also improved greatly. Judicious use of anti-inflammatories and anticholinergics decrease narcotic requirements and relieve bladder spasms. Regional blocks and/or continuous epidural infusions help children recover quickly by providing pre-emptive and better pain control; these are the standard at our centre.
Finally, as laparoscopic, vesicoscopic and robotic approaches gain acceptance as equivalent or superior in terms of success, morbidity from ureteral reimplantation will be further reduced.
Endoscopic bulking agents represent an extension of the surgical armamentarium. Originally pioneered over 30 years ago as an alternative to ureteral reimplantation,23 endoscopic injection for VUR has undergone several modifications of technique, and injection material (polytetrafluoroethylene, silicone paste, collagen, dextranomer/hyaluronic acid copolymer). Currently, dextranomer/hyaluronic acid copolymer is the dominant injectable in part due to its biocompatibility (both contents are biodegradeable polysaccharides) and lack of migration (due to infiltration with endogenous connective tissue). Controversy exists as to the exact mechanism by which reflux is prevented, and success rates are highly variable (60% to 90%). At our institution, endoscopic injection has evolved into a common surgical intervention performed for VUR, especially for lower grade reflux. As with any emerging technology, long-term, prospective studies are needed to better define short- and long-term success and complications and to further clarify the role of endoscopic injection in treating VUR.
From the original animal work of Ransley and Risdon,24 we know that reflux in and of itself is not a disease. Add, however, UTI to VUR, with the appropriate confluence of bacterial virulence and host factors, and renal scarring can ensue. Although the exact pathogenesis of renal scarring is not well-understood, the end result, reflux nephropathy, is understood, and could be entirely preventable.
Given that most reflux is self-limited, the key to any management strategy is selecting out the small minority of patients who are at risk for future deterioration. To avoid overtreatment, some authors are advocating a “top-down” approach to investigation of first febrile UTI.25 Rather than starting with voiding cystourethrography and identifying mainly “benign VUR,” ultrasound and DMSA has become the first-line investigation. Recurrent UTI, and/or renal scars motivate cystography, which then contributes to stratification into low- and high-risk groups in terms of the potential for progressive renal damage. The presence of renal scars and reflux at initial presentation is associated with a 17-fold risk of progressive renal damage over the presence of reflux alone. Though we applaud the efforts to characterize at-risk populations, we do not condone an algorithm that waits for the disease process to become macroscopic before initiating therapy. Further prospective studies are necessary to better identify and characterize high-risk populations with VUR, as well as to validate surgical efficacy and other de novo strategies at preventing renal deterioration in these groups. A search at the molecular level for either a genetic or protein marker of susceptibility could be the eventual Rosetta stone for VUR management.
Until then, we believe every patient must be managed on a case-by-case basis. Multiple variables must be taken into account (Fig. 2).26 These variables can then be incorporated into evidence-based constructs, such as recently published nomograms,27 quantifying the likelihood of reflux resolution. A move from experience-based to evidenced-based medicine is essential in moving forward.
Until the role of antimicrobial prophylaxis is clarified, surgical intervention in the form of ureteral reimplantation remains the gold standard for the prevention of reflux nephropathy in susceptible renal units.
Competing Interests: None declared.
This paper has been peer-reviewed.