Long-Term (>10 Years) Results After Endoscopic Injection Therapy for Vesicoureteral Reflux

Introduction

Vesicoureteral reflux (VUR) occurs in 1% of children. In the presence of a urinary tract infection (UTI), reflux increases the incidence of pyelonephritis, which can lead to renal scarring, hypertension, and end-stage renal disease. ¹ The purpose of diagnosing and treating VUR is to prevent these complications by decreasing the number of febrile UTIs (fUTIs). Current accepted options include observation with or without prophylactic low-dose antibiotics, ureteral reimplantation, or endoscopic treatment using subureteral bulking agents. ²

Although several bulking agents have been or still are used, one of the most widespread products is dextranomer/hyaluronic acid (Dx/HA) copolymer (Deflux^®; Q-Med Scandinavia, Uppsala, Sweden). ³ A meta-analysis published in 2006 showed that reflux resolution rates for grades I and II reflux were 78.5%, 72% for grade III, 63% for grade IV, and 51% for grade V. ⁴ Although its success rate is lower than ureteral reimplantation and it decreases as the grade of VUR increases, injection therapy has the clinical advantages of being less aggressive, with fewer complications and a shorter hospital stay. Furthermore, clinical success, that is, absence of recurrence of fUTI, is higher than the VUR resolution success rate.

Parents, however, often ask the question of long-term efficacy of endoscopic injection using Dx/HA, as this product is biodegradable. There are few very long-term studies centered on Dx/HA, that is, >10 years, yet when parents ask about “long-term” results, this is the time scale they are thinking about.

We, therefore, decided to evaluate the efficacy of Dx/HA copolymer endoscopic injection, in terms of recurrence of fUTIs in children, with a follow-up of at least 10 years.

Materials and Methods

We analyzed the medical data of all children who were diagnosed with VUR and underwent endoscopic injection before 2006 in two University Hospitals. We reviewed their medical files, and then tried to contact each patient by phone to ask them about their postoperative course up to today, to identify clinically relevant events that were not present in the medical files. These included any episode of fUTI, defined as the association of fever and a urinalysis-confirmed UTI, and/or need for further endoscopic or open surgery. We used a telephone interview that is more reliable than just sending a questionnaire and it also improves response rate.

All procedures were performed under general anesthesia. Before injection, the location and type of both ureteral orifices and the condition of the bladder were evaluated. Subureteral injection therapy was carried out by the subureteral transurethral injection (STING) technique. The product used in every case was Dx/HA copolymer (Deflux; Q-Med Scandinavia). In unilateral cases, only the ureter with identified reflux was injected. Injection achieved a satisfactory semilunar appearance of the ureteral orifice in all cases. All patients were injected with 0.5–1 mL maximum per ureter.

All children underwent a postoperative sonogram at 2 and 12 months to detect obstruction. They were seen as outpatients at 6, 12, and 24 months postoperatively. For further follow-up, they were then entrusted to their general practitioner. Postoperative cystograms were not systematically performed, although if a child presented with recurrence of fUTI during follow-up, a sonogram and cystogram were systematically performed. Dimercaptosuccinic acid (DMSA) nuclear scans were not systematically performed before and after surgery in all children, so evolution of renal scarring was not analyzed.

The indication for injection therapy was the presence of at least two breakthrough fUTIs in children with VUR under antibiotic prophylaxis, or children >5 years old, presenting fUTIs after antibiotic prophylaxis was discontinued. In our early experience, endoscopic injection was not performed for high-grade reflux. This study followed the rules and recommendations of our national law concerning the necessary approval warranted for this type of study. None of the children presented with symptoms of bladder and bowel dysfunction, as assessed by history and noninvasive urodynamics (uroflow, postvoid residual urine test), and they were all counseled on hygiene and correct bladder and bowel emptying.

Results

We found 68 patients who had undergone endoscopic treatment of VUR with a follow-up of minimum 10 years. We were able to contact 53 patients of which 38 were girls, and 36 had bilateral VUR with a total of 89 ureteral units. The other families had changed address and were not able to be contacted.

The clinical characteristics of the children we were not able to contact were comparable with those who we were able to contact (Table 1). All patients who were contacted agreed to answer our questions and were asked to verify the information in their child's medical booklet. In our country, each child has a medical booklet containing his or her medical information; this booklet accompanies the child and is filled by the child's doctor during each visit or hospitalization.

The study group comprised 15 grades I, 46 grades II, and 28 grades III VUR. All patients who presented with VUR grade I had associated contralateral reflux of a higher grade.

Mean age at surgery of the patients included in this study was 86 months (26–136). Mean follow-up was 151 months (range: 127–181). No child presented with postinjection obstruction on postoperative sonograms and no child presented clinical signs of obstruction during follow-up. Thirteen patients presented a recurrence of fUTI during the postoperative course of whom 8 presented with persistent VUR (4 initial grade III and 4 initial grade II) (Table 2). The other 5 did not show recurrent VUR on control cystogram. The recurrences of fUTI occurred at a mean of 26 months (range 4–60) after injection. Out of the 8 patients who were diagnosed with recurrent VUR after recurrent fUTI, 4 underwent a second injection and 4 underwent open reimplantation, according to the parents and surgeon's preference. The recurrences concerned 4 out of the 46 grades II and 4 out of the 28 grades III. The clinical success rates, that is, absence of VUR recurrence or absence of fUTI recurrence, were 100% for grade I VUR, 91% for grades II VUR, and 86% for grade III VUR when analyzed per ureteral unit. Clinical success rate per patient was 83%.

Discussion

In the treatment of VUR, the concept of subureteral injection therapy was introduced in the 1980s.^5,6 This treatment is thought to resolve VUR by forming solid support behind the intravesical ureter and increasing the submucosal length of the ureter. ⁵ Since first reported by Stenberg and Läckgren in 1995, ⁷ Dx/HA copolymer has been the most commonly used product for VUR injection treatment in children and the only treatment approved by the Food and Drug Administration. Both constituents of Dx/HA copolymer are biodegradable polysaccharides, and cannot accumulate permanently within the body. With time, the injected product becomes infiltrated with endogenous connective tissue, and follow-up studies have shown that the bolus persists for at least 3 years with no fibrosis or aggressive granulomatous reaction spreading to adjacent tissue.^8,9

The overall early success rate of Dx/HA is relatively good. ⁴ However, there are few reports on “very” long-term results. In 2001, Läckgren reported on long-term follow-up results after Dx/HA injection with a mean follow-up of 5 years, ¹⁰ although the series included children with only 2 years follow-up. Since then there have been various reports including those by Stredele et al., with a mean 3 years follow-up, ¹¹ 4 years follow-up for Fotso Kamdem et al., ¹² and 2.5 years follow-up for Arlen et al., ¹³ yet all include children with relatively short follow-up.

The longest follow-up for Dx/HA injection reported so far is by Stenberg and Läckgren with a follow-up between 7.5 and 12 years, in which parents were sent a questionnaire about their postoperative course. ¹⁴ In their study, they found that up to 96.6% of patients successfully treated with endoscopic injection of Dx/HA experienced no fUTIs during the 7 to 12 years, since follow-up occurred >12 months after treatment. Our success rate is hence comparable with published data.^10–14,15 And in our series, no patient presented a recurrence of fUTI >5 years after surgery. This is probably due to the combined effect of the local infiltration by endogenous connective tissue added to the natural anatomic modifications that occur during growth. This information is interesting as parents can be told that if there are no recurrences within the initial 5 postoperative years, it is unlikely that the child will present one later.

None of our patients were diagnosed with significant obstruction, that is, no child presented with postinjection obstruction on postoperative sonograms or clinical signs of obstruction during follow-up. The reported rate of obstruction after endoscopic treatment is around 1%.^16,17 In the study by Vandersteen et al., the authors proposed that those patients with neurogenic bladder and chronic or recurrent bacteria are at a higher risk for postoperative obstruction. ¹⁶ None of our patients had neurogenic bladders, these were low-grade reflux, we used a STING technique, and we never injected >1 mL per ureter. None of our patients presented with refluxing and obstructive megaureters before injection. These are the reasons for which we believe we did not observe obstruction. Not having performed long-term ultrasonographies (i.e., >5 years) means that there might be asymptomatic undetected obstructions, but these are a rare occurrence and it does not seem reasonable to perform late ultrasonographies systematically.

This study obviously has several limitations. The first includes the retrospective study characteristics, including loss of data. Of course, some children might have experienced a recurrent fUTI and have forgotten it. However, having a medical booklet that retraces each child's medical history limits that risk, and we are quite confident that we did not miss any significant events such as reinjection or reimplantation. There were a few patients lost to follow-up as some families changed address and we were not able to contact them. Their clinical characteristics were not different from those we were able to contact, and we do not believe that losing those who changed address would induce bias toward worse results. Furthermore, our response rate was 100% for those we could contact.

We decided to assess recurrence of fUTI since injection therapy does not decrease the risk of afebrile UTI or cystitis, and because it is more clinically relevant than recurrence of VUR, as the aim of the treatment is to stop fUTIs. We did not perform systematic postoperative cystograms as it would be highly debatable to systematically intervene on an asymptomatic child. We did not perform late sonograms either, but early and midterm sonograms were normal, and children who became symptomatic had repeat sonograms and cystograms. Some might argue that long-term obstructions, even with normal sonograms at 12 months, could be unidentified, but these are a rare occurrence especially in asymptomatic patients, and it does not seem reasonable to perform late ultrasonographies systematically.

DMSA nuclear scans were also not systematically performed before and after surgery in all children, so we were unable to analyze evolution of renal scarring. Our patient population only comprises grades I–III VUR as we did not perform endoscopic injection for high-grade VUR, but this does probably represent the population most treated by this method. Finally, our number of patients is relatively low; however, we believe the 10-year evolution is representative of what happens to these patients. The strength of the study is the minimum follow-up of 10 years.

Conclusion

In our experience, clinical results of endoscopic injection using Dx/HA remain stable over time (>10 years) and recurrence of fUTI occurs within the first 5 years of follow-up.