Endoscopic Vesicoureteral Reflux Correction in Transplanted Kidneys: Does Injection Technique Matter?

Introduction

P osttransplant vesicoureteral reflux (VUR) is a common urologic complication after renal transplantation, although its management is controversial. ^1,2 At the time of transplantation, transplant surgeons prefer a wide ureterovesical anastomosis with the fear of ureterovesical anastomosis obstruction. However, VUR complicated by recurrent urinary tract infections (UTI) may also cause premature graft loss in adults and children. ^1,2

Open re-do ureteral reimplantation in transplanted kidneys can be a difficult procedure with relatively higher morbidity. ³ With the advent of nonanimal dextranomer/hyaluronic acid copolymer (NA Dx/HA) as an injection material, endoscopic correction has been a viable alternative in the treatment of VUR. However, the data on the efficacy and technique of endoscopic correction of posttransplant VUR have been limited. We had presented our preliminary results on endoscopic correction of posttransplant VUR with a 70% success rate where we used a recent technique (intraureteral injection). ⁴ Intraureteral injection technique with higher volume of injected material has been reported to increase the success rate of VUR correction in children. ⁵

Herein, we present our 3-year experience on endoscopic NA Dx/HA injection to correct posttransplant VUR with special focus on the injection technique to address the efficacy.

Materials and Methods

This study has been approved by our institutional review board. We retrospectively reviewed the charts of all patients who underwent endoscopic VUR correction by NA Dx/HA injection due to recurrent UTI with posttransplant VUR between July 2005 and March 2009. Patient characteristics were recorded, including date of original transplant, etiology of end stage renal disease (ESRD), age at transplantation, donor classification of transplant, method of original ureteral anastomosis, presenting symptoms, grade of reflux using the International Reflux Study Committee scale, technique of injection, injected volume, follow-up imaging, and results and clinical symptoms after endoscopic correction. Intervals between original transplantation, diagnosis of VUR, endoscopic correction, and the last follow-up time were also recorded.

Patients with underlying urologic abnormalities such as voiding dysfunction, posterior urethral valve, neurogenic bladder, VUR to native ureters, urethral stricture, or hypospadias were excluded. All ureteral reimplantations were performed by extravesical Lich-Gregoir technique with an indwelling Double-J stent.

Results

A total of 39 patients were identified as posttransplant VUR and referred to our clinic for VUR correction. VUR was diagnosed in all patients during febrile or recurrent UTI after renal transplantation. Thirteen were excluded due to concomitant urological abnormalities: Three had posterior urethral valve, two had neurogenic bladder, six had primary VUR, and two had urethral strictures. Of 26 patients, 14 were women and 12 were men. Mean age was 32.2 years (range: 15–55 years).

The diversity of reflux grades in refluxing ureters of transplanted kidneys were grade I in 2, grade II in 8, grade III in 10, and grade IV in 6. VUR was also graded as nondilating reflux in 10 (grade I–II) and dilating reflux in 16 (grade III–IV) (Table 1).

Overall success rate was 53.8% (14 out of 26). We injected 17 transplanted ureters by using intraureteral injection technique and 9 (52.9%) resolved reflux. Also, 9 transplanted ureters were injected by using subureteral injection technique and 5 (55.5%) patients resolved reflux. In nondilating VUR, injection corrected 90% (9 out of 10) of posttransplant patients, whereas in dilating VUR group injection corrected only 31.25% (5 out of 16) of patients. Subureteral injection technique was effective in 4 (80%) out of 5 of nondilating refluxing ureters and 1 (20%) out of 5 of dilating refluxing ureters. Intraureteral injection technique resolved reflux in 5 (100%) out of 5 nondilating refluxing ureters and 4 (33.3%) out of 12 dilating refluxing ureters (Table 1).

We found no statistical significance of the injection technique on the success rate of VUR resolution both for dilating (p = 1.0) and nondilating VUR (p = 0.103, with Yates correction by using Fisher's exact test.

Discussion

Reported rates of posttransplant VUR in adults and children range between 1% and 86%. Although the association between VUR, UTI, and reflux nephropathy has been established, the clinical significance of posttransplant VUR remains controversial. As many as 4.5% of transplant recipients with posttransplant VUR develop symptomatic UTI necessitating hospitalization. ^1,2 It is believed that the indication to correct posttransplant VUR is limited to a small fraction of recipients who are at risk of premature graft loss due to symptomatic UTI. The treatment of choice has been open surgical revision ureteral reimplantation, which may lead to graft loss due to re-do ureteral implantation complications such as stenosis, fistula, or ureteral necrosis. Therefore, a minimally invasive surgery modality would be very helpful in such recipients requiring posttransplant VUR correction.

Minimally invasive VUR correction has been presented since the 1980s in Europe but has recently been popularized worldwide as NA Dx/HA has been approved by U.S. Food and Drug Administration as a safe and effective bulking agent. In a very recent metaanalysis, Elder et al ⁶ reported an 85% success rate of endoscopic correction of VUR in children. There are many factors determining the success rate, but the most statistically significant one is the grade of reflux and the appearance of the mound after injection. ^6,7 In 2004, Kirsch et al ⁵ described a novel injection technique into the ureteral wall and reported higher success rate by this intraureteral injection technique (particularly on grade III VUR) compared with original subureteral injection (89% vs. 71%). We herein also search whether intraureteral injection technique is more effective to correct posttransplant VUR, particularly in dilating refluxing ureters.

There are only very few reports on endoscopic correction of posttransplant VUR. In 1993, Cloix et al ⁸ reported 30% success rate in 21 patients with posttransplant VUR after endoscopic correction by subureteric polytetrafluoroethylene (PolyTef^®) injection. After this discouraging experience, in 2003, Mallett et al ⁹ reported 66% success rate in posttransplant patients with the same bulking agent. Since polytetrafluoroethylene lost its popularity due to its distant migration potential, alternative bulking agents were brought into the market. Latchamsetty et al ¹⁰ reported collagen as a bulking agent with a complete failure to correct posttransplant VUR in 2003. One year later, Joshi and Jha ¹¹ demonstrated 67% success of posttransplant grade II and III VUR when collagen was subureterally injected.

With the advent of NA Dx/HA, the potential for endoscopic treatment of complex VUR has been tested. Perez-Brayfield et al ¹² studied the concept of endoscopic correction of complex VUR including prior ureteral reimplantation, ureterocele, diverticula, ectopic ureter, and duplications and reported 68% overall success with a single injection of NA Dx/HA. Similarly, Jung et al ¹³ noted 70% success in NA Dx/HA injection of refluxing reimplanted ureters.

Promising results in endoscopic correction of reimplanted ureters has encouraged urologists to test its use on transplanted kidneys. In 2007, Seifert et al ¹⁴ reported their series on the use of NA Dx/HA for the treatment of VUR on transplanted kidneys in four female patients with 100% success. All injections were subureterally done around the orifice. In three cases, they used 3 mL, and in one case, they used 4 mL of NA Dx/HA. In two cases, a second injection of 3 mL was required for success. Apart from the small number of patients in their series, authors had reported a drastic ureteral obstruction complication necessitating open revision. In that case, 7 mL of NA Dx/HA was used at and around the neo-orifice, and during surgery an obstructing periureteric bulky mass along a 3 cm length of ureter was found. ¹⁵

Recently, a multicenter experience on the use of NA Dx/HA in refluxing transplanted kidneys in children has also been published. ¹⁶ In 6 (54.5%) out of 11 children, VUR was corrected by a single injection. All injections were subureterally done, and injected material volume was between 0.5 and 1.5 mL. No complications were encountered.

We had reported our first experience on intraureteral injection of NA Dx/HA to correct posttransplant VUR with a 70% (7 out of 10 cases) success rate at American Urological Association (AUA) 2007 meeting. ⁴ Interestingly in our current study, our success has decreased irrespective of injection technique (55.5% vs. 52.9%); nevertheless, this success rate is comparable to results of Vemulakonda et al. ¹⁶ We herein speculate some reasons of the discrepancy with our prior and current results.

First of all, in our first series, we had included four cases with underlying urologic abnormalities (one case of posterior urethral valve, one case of bilateral grade V reflux, and two cases of primary VUR) who had undergone antireflux reimplantation during transplantation. Those cases were all corrected with intraureteral injection. As shown by the literature, ^12,13 injection treatment is successful in those ureters previously reimplanted with antireflux procedure.

Second, more laterally located ureteral orifices are shown to have less resolution of reflux in endoscopic correction. ¹⁷ Transplanted kidneys typically demonstrate location far from trigone and more typically at the right bladder wall and dome junction. Therefore, very short intramural ureter may be very difficult to inject to obtain a satisfactory mound, and also technically it can be hard to reach the orifice with a straight positioned needle.

Third, when we categorize our first cases into nondilating and dilating reflux groups, success rate was six out of six (100%) in nondilating reflux group and one (25%) out of four in dilating reflux group. Hence, there seems to be a bias in patient selection in favor of nondilating VUR leading to overall higher success rate. In the current study, intraureteral injection group showed 100% (five out of five) success, and the subureteral injection group showed 80% (four out of five) success in the nondilating VUR groups (p = 0.103, Fisher's exact test with Yates correction). Moreover, this success rate is similar to our first series results. Therefore, we believe that success with any injection technique to nondilating reflux in transplanted ureters is very high and predictable (overall success 9 out of 10—90%).

Despite very promising results in nondilating reflux group, dilating refluxing unit is an issue with a 31.25% (5 out of 16) success rate. In the subureteral injection group, the success rate was only 25% (1 out of 4) and only 33% (4 out of 12) in the intraureteral injection group (p = 1.0, Fisher's exact test). There is no statistically significant benefit of intraureteral injection technique over subureteral injection. Interestingly, an increase in the injected volume also had no severe impact on the success rates, which is only one-third of cases at the best. This result contradicts with results of Kirsch et al ⁵ in which intraureteral injection technique with higher injected material volume resolves reflux better, particularly in dilating VUR ureters.

In a study of Seifert et al, ¹⁴ they recommend a second injection trial that is effective in two failed cases. Unfortunately, this has not been our experience. In our first series, we tried a second injection in three failures and all unfortunately failed. Besides, during open revision, periureteral mass was massive in those three cases and complicated the revision surgery. We finally stopped doing second injections in failed injected cases. Of note, the case report of Seifert et al ¹⁵ also noted a ureteral obstruction after the second injection with high material volumes (7 cc). It does not appear very wise to use large amounts of bulking agents in those cases with a risk of ureteral obstruction. We have to repeat our observation that the ureters injected twice showed a significant periureteral mass complicating the surgery where we had to transect some of the ureter. It may be directly related to intraureteral injection technique or the immunosuppressive agents received. However, we have not faced a similar experience in our intraureteral injected native ureters. Moreover, we have not seen any obstructing complications with injections with a volume of maximum 4 mL.

Conclusion

Endoscopic correction by using NA Dx/HA seems to be a plausible alternative treatment to correct VUR in posttransplant ureters, particularly in nondilating VUR. Although injection technique does not appear to be a major factor affecting the success, higher patient numbers at different centers are required to make a stronger argument.