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Four-Point Injection Technique of Polyacrylate/Polyalcohol Copolymer in Vesicoureteral Reflux After KidneyTransplant


Objectives: Vesicoureteral reflux after kidney transplant is mostly asymptomatic, but recurrent urinary tract infections can cause graft rejection. Although the gold standard treatment is open surgical repair, we believe that endoscopic treatment can be further improved. Here, we investigated the long-term outcomes of 4-point endoscopic injection of polyacrylate/polyalcohol copolymer in patients with vesicoureteral reflux after kidney transplant.
Materials and Methods: Patients who had undergone 4-point endoscopic injection of polyacrylate/polyalcohol copolymer for symptomatic vesicoureteral reflux after kidney transplant and were followed for at least 3 years were included. Patients with dysfunctional and/or obstructive voiding patterns, unsuccessful primary endoscopic treatment, concomitant injection of native kidney reflux, and incomplete follow-up were excluded. We evaluated patient characteristics, perioperative data, and clinical and radiological outcomes. Urine culture, serum creatinine, and renal ultrasonography were assessed every 3 months. Voiding cystourethrography was performed at month 3 and when recurrence was suspected. Clinical success was defined as absence of febrile urinary tract infection during follow-up, and radiological success was defined as absence of vesicoureteral reflux in the voiding cystourethrography.
Results: Of 21 study patients, 14 (66.6%) were female and 7 (33.3%) were male patients. Average age was 37.1 years (range, 12-62 years). According to preoperative voiding cystourethrography, 3 patients (14.2%) had grade II, 13 patients (61.9%) had grade III, and 5 patients (23.8%) had grade IV vesicoureteral reflux. Eighteen patients (85.7%) had clinical success with the first injection, and 20 patients (95.2%) had success with the second injection. Eleven patients (52.3%) demonstrated radiological success. The reflux degree of all patients, except 2, had partially or completely regressed. Ureteral balloon dilatation and double J stent implantation was performed in 1 patient (4.7%) due to ureteral obstruction.
Conclusions: The 4-point injection of polyacrylate/­polyalcohol copolymer provided long-term per-manent success for symptomatic vesicoureteral reflux after kidney transplant.

Key words : Endoscopic treatment, Renal transplantation, Urinary tract infection


Studies have reported a 10% to 86% rate of vesico-ureteral reflux (VUR) after kidney transplant.1-3 Posttransplant VUR is mostly asymptomatic, but recurrent urinary tract infections (UTIs), graft pyelonephritis, urosepsis, and graft rejections can be seen in 1% to 3% of these patients. Although asymptomatic VUR cases can be monitored safely, symptomatic cases require surgical treatment because VUR can decrease graft survival.3,4

The gold standard treatment option for symptomatic VUR after kidney transplant is open surgical repair, which has a success rate of 83% to 100%.5,6 However, endoscopic treatment, which is a minimally invasive technique, reduces the morbidity of the procedure.7 The overall success rate of endoscopic injection treatments varies from 60% to 86%.8-10

In previous published studies, the hydrodistention implantation technique (HIT), double HIT, and systematic multiple HIT (SMHIT) have been defined for primary VUR treatment. These studies also compared their clinical and radiological successful rates among each other and also versus subureteric transurethral injection (STING).10-12 The SMHIT technique showed the best results, with 94% radiological and 100% clinical success rates for primary VUR treatment. To our knowledge, although some studies have mentioned that they performed multiple or circumferential subureteric injections, no specific method has been defined for endoscopic treatment of VUR after kidney transplant.13-15 In a previous study that investigated factors affecting the success of endoscopic injection treatment, we showed that an increase in the number of injection points provides a significant increase in clinical success.16

Polyacrylate/polyalcohol copolymer (PPC) is a synthetic, biocompatible, nonabsorbable bulking agent; the first clinical experience of its use was reported in 2010.17 Because of its biocompatible structure, its use in the endoscopic treatment of primary VUR is becoming increasingly common. A first report of PPC for endoscopic treatment of VUR after a kidney transplant showed aclinical success rate of 86.7%.18 We also recently reported that the use of PPC was feasible and safe in this patient group, with a clinical success rate of 70.3% and a radiological success rate of 50%.16

In the present study, we aimed to investigate long-term effectiveness with 3-year results of a modified endoscopic treatment for transplanted kidney VUR, in which PPC injection by the 4-point technique was used.

Materials and Method

The study was conducted in accordance with the principles of the Declaration of Helsinki and approved by the Biruni University Clinical Research Ethics Committee (no. 20-21/61-8), and written informed consent was received from all patients. Included patients were those who had undergone endoscopic 4-point injection treatment for symptomatic VUR after kidney transplant and were followed up for 3 years. Between February 2016 and March 2021, kidney transplant and ureterovesical anastomosis with the Lich-Gregoir technique were conducted in 743 patients. A voiding cystourethrogram (VCUG) was performed when there was a suspicion of VUR in patients who developed recurrent UTI, acute graft pyelonephritis, urosepsis, and/or decreased graft function after kidney transplant.

Study population
A diagnosis of VUR was made in 34 (4.5%) transplant recipients of living related kidney donations (19 donors were first-degree relatives, and 15 were second-degree relatives). Patients who were diagnosed with a dysfunctional and/or obstructive voiding pattern in the preoperative evaluation (pressure flow cytometry and/or uroflowmetry) and/or patients who under-went a second injection treatment due to an unsuccessful primary endoscopic treatment and/or patients who underwent endoscopic treatment due to concomitant native kidney reflux and/or patients who did not complete the 3-year follow-up period were excluded from the study.

Data analyses
Patient age, sex, time between transplant and endoscopic treatment, history of previous endoscopic intervention, duration of operations, number of febrile UTIs, and number of hospitalizations were recorded as sociodemographic and preoperative data. We also recorded preoperative radiological and biochemical findings of patients, including level of VUR (grades I-V), serum creatinine level (in mg/dL), and the resistive index measurements per duplex ultrasonography. All patients had urine culture performed 1 week before surgery, and patients with significant bacteriuria (>100 000 CFU/mL in the urine culture) were treated with appropriate antibiotic therapy 72 hours before the endoscopic procedure.

Endoscopic procedure
After patients received information of the procedure and probability of complications and signed informed consent, endoscopic injection treatment was performed under general or regional anesthesia in lithotomy position. Patients with negative preoperative culture received 1 g ceftriaxone intravenously. A rigid cystoscope with a 30-degree lens was used for the visualization of the neo-orifice. If the neo-orifice could not be seen, maneuvers were performed, such as using a 70-degree lens while optimally filling the bladder, using a flexible cystoscope or placing a Sensor PTFE-nitinol guidewire hydrophilic tip (0.038 inches/150 cm) (Boston Scientific) and applying to suprapubic pressure. When the circumference of the orifice could not be seen with only the Sensor guide and suprapubic pressure, a 6F Axxcess open-end ureteral catheter (Boston Scientific) was used.

Polyacrylate/polyalcohol copolymer, a synthetic, nonabsorbable bulking agent, was applied via a 3.6F metal semirigid needle system with a 22-gauge bevel type (manufactured by Vantris) that passed through a rigid cystoscope with the 4-point injection technique, as described below. Depending on the anatomy of the ureteral orifice, a total of 1 mL (0.25 mL to each corner) PPC was applied intraureteric or subureteric at the 3, 6, 9, and 12 o’clock positions (Figure 1). A pause of approximately 1 minute was given between each application of the bulking agent. A Foley catheter was then inserted for removal after 24 hours.

Follow-up protocol
A renal ultrasonography and measurement of urine output were checked after postoperative day 1 to exclude ureteral obstruction. Urine culture, serum creatinine levels, and renal duplex ultrasonography were evaluated after postoperative month 1 and every 3 months for 3 years. A VCUG was performed after month 3 postprocedure and when suspicion of recurrence or persistence of symptomatic VUR was shown during follow-up.

Clinical success was defined as the absence of febrile UTI during follow-up, and radiological success was defined as the absence of VUR in the VCUG. A second endoscopic injection treatment was performed in patients with febrile UTI, due to persistence or recurrence of VUR after the operation. If the second injection was also unsuccessful, patients received a ureteroneocystostomy.


In our study group, 34 kidney transplant recipients received the 4-point injection technique for symptomatic VUR. According to the exclusion criteria, 13 patients were excluded. Of the 21 included patients, 14 were female (66.6%) and 7 were male (33.3%) patients. The patient’s average age was 37.1 years (range, 12-62 years). All patients had received kidney transplants from living donors. The patients had been diagnosed by VCUG because of different clinical symptoms or findings. Two patients had decreased graft functions (9.5%), 9 patients had recurrent febrile UTI (42.8%), 6 patients had febrile UTI and decreased graft functions (28.5%), and 4 patients had urosepsis (19%). According to the VCUG, 3 patients had grade II (14.2%), 13 patients had grade III (61.9%), and 5 patients had grade IV (23.8%) VUR. Patients were diagnosed with VUR at a mean of 20.6 months (range, 5-140 months) after transplant. The median time of follow-up after VUR treatment was 47.7 months (range, 36-65 months) (Table 1).

The clinical success rate of the 4-point technique was 85.7% (n = 18 patients) with the first injection and 95.2% (n = 20 patients) with the second injection. The radiological success rate was 52.3% (n = 11). The degree of reflux among all patients, except 2, had partially or completely regressed. In the postoperative period, VCUG reported grade I, II, III, and IV VUR in 14.2% (n = 3), 19% (n = 4), 9.5% (n = 2), and 4.7% (n = 1) of patients, respectively.

We observed a statistically significant difference in postoperative levels of mean serum creatinine (1.5 ± 0.4 vs 1.2 ± 0.3 mg/dL; P < .001) compared with preoperative levels. No differences were shown in postoperative serum creatinine levels (P < .05), and no significant difference was shown in the mean postoperative resistive index (0.7 ± 0.1 vs 0.7 ± 0.1; P = .5) compared with preoperative resistive index.

None of the patients with radiological success developed clinical and radiological recurrence during the 3-year follow-up period. Two patients (9.5%) required antimicrobial suppression treatment (at least 12 months) because of radiological failure and significant bacteriuria after 4-point injection treatment. Three patients (14.2%) with both clinical and radiological failure underwent a second endoscopic treatment. Clinical success was achieved in 2 of these patients after the second injection. The patients with an unsuccessful second injection required open ureteric reimplantation 11 months after the first injection treatment.

After the 4-point injection, progressive hydronep-hrosis and oliguria developed in 1 patient (4.7%) due to ureterovesical junction stricture. Ureteral balloon dilatation and double J stent implantation was performed in this patient at postoperative week 18. However, endoscopic treatment was unsuccessful for this patient, and open ureteric reimplantation was performed.


Vesicoureteral reflux is a common condition in transplanted kidneys, and surgical treatment is recommended to extend graft survival in symptomatic cases.3,4 Although endoscopic injection treatment is not the gold standard, it is often the first choice of surgeons because it is a less invasive technique. In this study, the rate of symptomatic VUR was found to be around 1%, similarly to the current literature.

Different bulking agents for VUR after kidney transplant have been reported in previous studies, such as collagen with a 50% to 67% success rate19,20 and polytetrafluoroethylene with a 30% to 53% success rate.21,22 Dextranomer/hyaluronic acid (Dx-HA) is one of the most widely used bulking agents, and its clinical success rate has been reported to be between 56.1% and 85.7%.3,9 To the best of our knowledge, PPC has only been used in 1 study in cases of VUR after kidney transplant, and its clinical success rate was reported (in 6 of 7 patients) as 86.7%.18 Our previously published study, the largest study to our knowledge of PPC use (n = 54), reported a success rate of 70.3% after first injection of PPC. However, the success rate of PPC with multiple injections (double or 4-point), respectively, is higher than the 1-point injection technique (at 85.7% and 87.1% vs 56.2%; P = .047).16 In our present study, in which we present the long-term results of PPC injection with the 4-point method in patients with VUR after renal transplant, we found a clinical success rate of 85.7%.

The first clinical experience with PPC was in 2010.17 Although clinical success was achieved with an injection of Dx-HA in primary VUR cases, recurrence can be seen in the long term due to its biodegradable structure, which leads to the need for repeated injections or open surgery. For this reason, PPC, a synthetic and nonbiodegradable bulking agent, is increasingly used for primary VUR.23 Studies that have investigated the success of the 2 bulking agents in primary VUR cases reported that the success of PPC is superior to Dx-HA, and the rates of recurrence and repeated injection are higher for Dx-HA.24-27 One randomized controlled study reported no statistically significant difference between the 2 bulking agents, although clinical (94.7% vs 90%; P = .579) and radiological (86.4% vs 77.3%; P = .698) success rates of PPC were higher.28 Although there have been only a few studies, radiological success has been reported with a success rate of 14.2% to 26.4% after endoscopic treatment for VUR in the transplanted kidney.3,9 In our study, we performed a 4-point injection technique using PPC with a 52.3% radiological success rate. This is because PPC has a nonbiodegradable structure, and the 4-point technique provides a more controlled and reliable ureteral coadaptation. In addition, this study is the first study to offer long-term follow-up after the use of PPC for endoscopic treatment of VUR after kidney transplant.

Recent studies have reported that multiple and intraureteric injection methods are almost as successful as open surgery in primary VUR cases. A meta-analysis showed that HIT was a more effective method in the treatment of primary VUR, with a 71.4% vs 82.5% success rate compared with the STING method.11 In addition, the double-HIT method, which is defined as coinjection into the ureteral orifice and distal part of the ureter, showed a 93% clinical and radiographical success in the medium and long term for primary VUR.10 Furthermore, a recent study reported that SMHIT provides excellent outcomes with a success rate of 100% in primary VUR patients. This technique is based on the principle of applying multiple injections around the orifice.12 Although excellent results have been demonstrated in the endoscopic treatment of primary VUR, this rate is lower (60% to 86%) in the transplanted kidney.8,9,10,25 This may be because of the relatively larger and atypical orifice structure of transplanted kidney cases, the presence of scar tissue in the ureterovesical anastomosis area, and/or the insufficient length of the antireflux tunnel. According to the development of endoscopic treatment of primary VUR, we showed that the 4-point technique can increase the clinical success rate. In our previously published study, we observed a significant efficacy of 4-point injection compared with other injection techniques in a univariate analysis of clinical success (P = .042). Here, we applied PPC material into the intraureteric area as much as possible so that the perianastomotic scar tissue did not reduce the success of the bulking agent. A higher success rate was achieved in the short and long term (85.7% and 95.2%) after PPC injection with 4-point technique compared with the literature.

Previous studies show that a larger amount of bulking agent has been used to provide ureteric coaptation. Ozkaptan and colleagues reported a clinical success of 52.2% after the first injection and 69.9% after the second injection using an average of 2 ± 0.65 mL Dx-HA.29 Akiki and colleagues reported that an average of 3.1 ± 1.58 mL bulking agent (with Dx-HA and polydimethylsiloxane) was used in the group with clinical success and 2.84 ± 1.63 mL in the group without clinical success, with a success rate of 42.1% for the first and 56.1% for the second injection.3 Another study with 49 cases reported a clinical success of 59.1% with the first injection and 67.3% with the second injection with an average of 2.75 ± 0.66 mL bulking agent.13 Frankiewicz and colleagues reported an 86% success rate for transplanted VUR using PPC for the first time in the literature. They applied 1 mL of the bulking agent to all patients.18 We achieved similar clinical success rates of 85.7% with the first and 95.2% with the second injection by using 1 mL of PPC for all patients.

Recent studies have shown that the multiple-point injection technique is a useful and reliable method in providing coaptation in the treatment of VUR after kidney transplant, which differs from case to case in terms of localization, appearance, diameter of neo-orifice, and structure. To the best of our knowledge, although no specific method has been defined for VUR after transplant, circumferential or multiple injections have been mentioned in the methodology of some studies.14,29 Yucel and colleagues reported that there was no significant difference (52.9% vs 55.5%) between intraureteric and subureteric Dx-HA injections and described that they performed repeated injections until the orifice was completely closed with this technique.15 In addition, they did not try the second injection, which had been unsuccessful in their previous study, because open surgical repair became more difficult and more complicated after the second injection.30

Ureteral obstruction has been reported with a rate of 0 to 23.5% with the Dx-HA bulking agent injection depending on different techniques.7,14 Some studies have demonstrated that they could prevent ureteral obstruction by placing a double J stent during the endoscopic procedure. Frankiewicz and colleagues18 reported that there was no obstruction in their 7 cases with injections of PPC for the endoscopic treatment of VUR secondary to renal transplant. We observed ureteral obstruction in 1 case (4.7%). The patient presented with febrile UTI, elevated serum creatinine, and oliguria at postoperative week 4. He did not benefit from endoscopic ureteral dilatation and double J stent implantation. Therefore, an open redo ureteral implantation operation was performed 18 weeks after the first endoscopic injection. With use of PPC and the 4-point injection method, the double J stent insertion during the procedure could have prevented this complication. This fact should be considered in later cases.

The limitations of this study are as follows: the study was not performed with a randomized controlled design or compared with other injection methods (single or subureteric). Different bulking agents were not compared to PPC with the 4-point method. Furthermore, the process needs to be studied with a larger sample; however, so far, this study has the largest sample group in the literature using PPC bulking agent for the endoscopic treatment of VUR secondary to renal transplant.


Four-point PPC injection is a safe, feasible, and minimally invasive treatment for symptomatic VUR after kidney transplant. The 4-point injection of PPC provided high clinical and radiological success and also maintained long-term efficacy. In the future, if supported by higher series and other randomized controlled prospective studies, it may be the gold standard endoscopic treatment for symptomatic VUR after kidney transplant.


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DOI : 10.6002/ect.2022.0303

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From the 1Department of Urology, Biruni University, Istanbul; the 2Department of Urology, Istanbul Koç University, Istanbul; and the 3Department of Urology, Taksim Education and Research Hospital, Istanbul, Turkey
Acknowledgements: The authors have not received any funding or grants in support of the presented research or for the preparation of this work and have no declarations of potential conflicts of interest.
Corresponding author: Nusret Can Çilesiz, Department of Urology, Faculty of Medicine, Biruni University, Protokol Yolu No:45, 10. Y?l Cd., 34010 Zeytinburnu/?stanbul, Turkey
Phone: +90 5065871934