Predictive factors for the success of subureteric injection in renal transplant patients with vesicoureteral reflux

Abstract

Background

Predicting the success of endoscopic treatment of VUR in transplant patients may not only protect both the physician and the patient from unnecessary investigations and treatment but may also prolong the life of the graft by preventing possible loss of time.

Methods

This retrospective study included 116 patients with vesicoureteral reflux following kidney transplantation between 2014–2022. Demographic data, preoperative and intraoperative clinical aspects, and postoperative 6^th-month success rates were evaluated.

Results

The success rate of the injection treatment in the 6^th month was 41.4%. As the patient age decreased, the success rate of the injection decreased (p = 0.025). While no significant relationship was observed between the preoperative reflux grade, injected volume of the bulking agent, and success (p = 0.109 and 0.222, respectively), a significant decrease in success was observed with an increase in UDR (p < 0.001) in group comparison. Regression analyses demonstrated that pre-injection visual assessment and post-injection orifice mound view influenced the success rate (p < 0.001 and p < 0.001, respectively).

Conclusions

Intraoperative visual assessment of the orifice is a reliable indicator for predicting the success of subureteric injection. It not only provides patients with trustworthy postoperative information but also saves clinicians time by anticipating the next surgical stage, ultimately contributing to the prolongation of graft life.

Background

Kidney transplantation is the gold-standard treatment approach to enhance the survival and quality of life of patients with end-stage renal failure [1]. However, kidney transplantation is associated with a series of urological complications, which may occur at a rate of 8–9.5% [2], requiring intervention for graft function and survival.

Vesicoureteral reflux (VUR), which may lead to complicated urinary tract pathologies such as infection ranging from urosepsis to severe long-term effects with scarring [3], is one of the most common urological complications following renal transplantation. Coulthard and Keir [4] revealed that about 40% of transplanted kidneys, including adult kidneys, may have pyelonephritic scarring in the presence of VUR and urinary tract infection (UTI). Besides, it was also suggested that reflux should be prevented whenever possible. The most successful treatment modality for treating reflux in transplant recipients is surgical reconstruction, which has a success rate of 90–100% [5,6,7]. However, in recent years, endoscopic subureteric injection, which causes less morbidity and has low complication and acceptable success rates ranging from 33 to 87% [8,9,10], has gained popularity as a first-line surgical treatment approach.

According to the literature, no well-known algorithm or recommendation has been described to anticipate the success rate of subureteric injection and related factors for vesicoureteral reflux in transplant kidneys. This study aimed to evaluate the preoperative clinical factors and additional intraoperative assessments that may influence the prediction of the success of endoscopic injection therapy, thereby potentially improving patient care by avoiding unnecessary procedures and loss of time and cost and aiding clinicians in selecting appropriate treatment approaches for transplant patients.

Materials and methods

This study was conducted according to the Declaration of Helsinki and approved by our institutional ethics committee (September 13, 2023; Decision No. KAEK- 699). Written informed consent was obtained from all the participants.

Patient enrollment

A total of 1714 kidney transplants were performed at our center between June 2014 and June 2022, and 139 (8.1%) patients had symptomatic reflux. Patient enrollment was presented in Fig. 1. Patients who had lower urinary tract dysfunction (posterior urethral valve history, neurogenic bladder, and voiding dysfunction), a lack of data in the hospital database, no clear imaging field between L1-L3 vertebrae in VCUG, reflux to the native kidney, a follow-up period of less than 6 months after subureteric injection, and multiple transplanted kidneys were excluded from the study. A total of 116 patients with symptomatic reflux causing recurrent febrile UTI or deterioration in graft function followed by transplantation, who presented to our clinic and underwent endoscopic subureteric injection treatment by two experienced urologists, were included in the present study. The remaining 23 patients of the 139 who did not meet the inclusion criteria were excluded; nonetheless, the same treatment protocol was applied to them. Ten of those 23 patients had conservative treatment (antibiotic prophylaxis) in the transplant clinic. The rest of the 13 patients were performed subureteric injection (5 patients) or redo-ureteroneocystostomy (8 patients).

Fig. 1

Flow diagram in patient enrollment

Transplant technique

In all cases, open surgery was preferred by the transplant team. The ureterovesical anastomosis was created according to the modified Lich-Gregoir technique in an antirefluxive fashion with a detrusor tunnel in a 3:1 ratio. Although ureterovesical anastomosis was performed primarily on the posterolateral or lateral wall of the bladder to prevent technical difficulties due to orifice placement during further endoscopic interventions, this placement was not achieved in all cases (anterior bladder wall or dome). At least a double J stent was routinely inserted to avoid anastomosis leakage and facilitate recovery. In the 3rd or 4 th week postoperatively, the urology team removed the double J stent endoscopically.

Follow-up protocol

All patients were routinely followed via clinical visits at the transplant clinic, consisting of general surgeons and nephrologists. Recurrent UTI was defined as three or more episodes within 1 year, fever greater than 38℃, and documented urine culture with more than 100.000 colony-forming units/mL. Voiding cystourethrography (VCUG) was performed in the presence of one of those primary indications, such as recurrent febrile UTI, progressive hydronephrosis, or elevated serum creatinine levels in suspicion of VUR. Patients diagnosed with VUR were referred to the urology clinic for further evaluation and treatment. However, the management of asymptomatic VUR cases was achieved in the transplant clinic. The urology clinic evaluated each patient for bladder-bowel dysfunction, LUTD, and postvoided volume. After this examination process, patients were informed about the endoscopic and open VUR treatment approaches.

Clinical success was defined as the absence of deterioration in graft function and absence of UTI at the 6 th month or absence of reflux on VCUG or follow-up, similar to a previous study by Akiki et al. [11]. During follow-up, patients with the mentioned symptoms or findings were reassessed and analyzed via the same protocol. In suspicion of VUR, control VCUG or direct radionuclide VUR scintigraphy was applied after excluding other possible reasons, including voiding dysfunction. Patients who had undergone failed subureteric injections were scheduled for open ureteroneocystostomy in follow-up.

Study design

These patients were evaluated retrospectively based on various variables, including age, sex, etiology of renal failure, duration between transplantation and injection, degree of reflux in preoperative voiding cystourethrography (VCUG) according to International Reflux Study Committee [12], ureteral diameter ratio (UDR) in VCUG before subureteric injection, and volume of the injected bulking material. The"Ureteral Diameter Ratio"(UDR), as defined by Cooper et al. [13], was calculated by dividing the maximum ureteral diameter of the transplanted kidney in the false pelvis by the distance between the lower end of the L1 vertebra and the upper end of the L3 vertebra. The authors also examined the anatomy of the transplant orifice, paying particular attention to its shape (such as stadium, horseshoe, or wide-open) and its placement (posterolateral, lateral, anterior, or dome) via operation recordings. Patients with wide-open or poorly positioned orifices identified in the pre-injection assessment were considered ‘unfavorable for injection’ for achieving proper coaptation (Fig. 2A). In addition, those with posterolateral wall placed and stadium orifice were considered ‘favorable for injection’ (Fig. 3C). Moreover, the mound appearance after the injection was assessed and defined as ‘improper coaptation’ (Fig. 2B) and ‘proper coaptation’ (Fig. 3D) to evaluate a well-formed volcano-shaped orifice.

Fig. 2

Anterior wall placed orifice (A: pre-injection wide-open orifice, unfavorable for injection B: post-injection improper coaptation)

Fig. 3

Posterolateral wall placed orifice (C: pre-injection stadium orifice, favorable for injection, D: post-injection proper coaptation, volcano-shaped mound view)

Endoscopic treatment was performed according to the subureteric transurethral injection technique (STING) by injecting a bulking agent into the submucosa just below the transplant ureteral orifice via 3.7 Williams (Cook®) needle [14]. However, the injection was not performed precisely at the 6 o’clock position due to the different placement of the transplanted orifice (posterolateral or lateral wall of the bladder), but the appropriate submucosal plane. In addition, a flexible cystoscope was also used to reach the transplanted orifice in challenging cases. The bulking agent was used in all cases, which was hyaluronic acid/dextranomer (Dx/HA) (Dexell®, Hyadex®).

Statistical analysis

Data are given as mean ± standard deviation and median with (minimum–maximum). We used the Independent Samples t-test and the Mann–Whitney U test to analyze the differences between the two groups. Additionally, the Wilcoxon Signed-Rank Test was employed to compare the distribution of the groups, as they did not meet the criteria for normal distribution. The Spearman correlation test evaluated relationships between numerical data (age, UDR, follow-up period, etc.), and Pearson’s chi-square and Fisher’s exact tests were used for categorical data (reflux grade, pre-injection visual assessment, post-injection volcano-shaped mound view, etc.). Univariate and multivariate Cox proportional hazards regression analysis was performed to specify the independent predictors that affect success. P-value less than 0.05 was considered statistically significant. All analyses were performed using SPSS version 23.

Results

Patients’ characteristics and data of both groups are summarized in Table 1. Subureteric injection was successful in 48 patients (41.4%) and unsuccessful in 68 (58.6%). The regression analyses found no significant relationship between success rate and sex, volume of the bulking agent, age, or reflux grade group (p: 0.108, 0.199, 0.65, 0.195, respectively), although age differed significantly between groups. In addition, the success rate in each reflux grade group (Grade 1–5) was compared, and no statistically significant difference was detected (p = 0.109).

Table 1 Patients’ characteristics and pre- and intraoperative variables of both groups

Out of the patients evaluated, 41 (35.3%) were considered improper for injection due to either a wide-open orifice or difficult orifice placement. In contrast, 75 patients (64.7%) were classified as proper for injection. The success rate in patients deemed proper was significantly higher (57.3% vs. 12.2%) than that in those classified as improper (p < 0.001) (Table 1). Both univariate and Cox’s multivariate regression analyses demonstrated that pre-injection visual assessment is a significant predictor of success (HR 0.103; 95% CI 0.036–0.293; p < 0.001 and HR 0.3; 95% CI 0.152–0.593; p: 0.001). Additionally, the success rate of 81 patients (69.8%) who achieved a volcano-shaped mound view after injection was significantly higher than that of those who did not (53% vs. 14.3%) (p < 0.001) (Table 1). Regression analysis also showed that achieving a volcano-shaped mound appearance influenced the success rate of subureteric injection. (HR 0.147; 95% CI 0.052–0.418; p < 0.001 and HR 1.007; 95% CI 1.000–1.013; p: 0.04, respectively).

According to group comparison, UDR is significantly higher in the unsuccessful group (0.17 vs 0.14, p < 0.001, Table 1). However, neither regression analysis indicated that the UDR is a predictor of success rate (p:0.065).

In addition, the correlation between variables was evaluated in 116 patients. While age was negatively correlated with reflux grade (r = − 0.366, p < 0.001) and UDR (r = − 0.431, p < 0.001), a positive correlation was found between grade and UDR (r = 0.491, p < 0.001). When variables were grouped according to success, a significant negative correlation was observed between age and UDR in both the successful and unsuccessful groups (r = − 0.431, p < 0.001), and age was negatively correlated with grade (r: − 0.440, p < 0.001) in the unsuccessful group.

Discussion

Vesicoureteral reflux is one of the most common complications, even after an anti-refluxive ureterovesical anastomosis during kidney transplantation. It can lead to a range of outcomes, from asymptomatic cases to end-stage renal failure [10, 15]. Hence, care must be taken preoperatively, and a tailored management strategy must be planned to improve graft survival. In recent years, endoscopic subureteric injection has gained popularity as a first-line approach with an acceptable success rate (60–85%) and promising outcomes via various injection techniques in surgical treatment [6, 16, 17]. In contrast, Whang et al. [18] reported that long-term success was not achieved in any patient treated with Dx/HA and that they no longer applied endoscopic injection treatment for transplant reflux. In addition, ureteral redo implantation in an anti-reflux fashion, which is widely preferred [7], can be used for patients who do not benefit from endoscopic injection. In this longitudinal single-center study, we aimed to investigate various preoperative and intraoperative factors that could predict the success rate of endoscopic injection therapy. Our goal was to estimate the success rate before the procedure, which would assist clinicians in managing transplant patients with vesicoureteral reflux and help prevent further unsuccessful procedures.

It has been highlighted in the literature that increasing patient age may be associated with postoperative complications and urinary tract infections after transplantation [16]. In contrast, it was found that the failure of injection treatment increased as patient age decreased in the present study, and a negative correlation was detected between age and the degree of reflux and UDR. This conflict may be associated with the thinner wall of the immature bladder due to low age, which leads to a weaker submucosal tunnel during ureteroneocystostomy. In addition, congenital urinary pathologies and lower urinary tract dysfunction are more common in young patients with chronic kidney disease, which may predispose them to reflux. Therefore, the more frequent occurrence of high-grade reflux in young patients may have contributed to the failure of injection treatment, as previously concluded by Ucar et al. [8] in pediatric renal transplant patients.

Previous studies have shown that the degree of reflux is one of the most critical factors affecting the success of subureteric injection in patients with primary reflux, with findings indicating that treatment success decreases as the degree of reflux increases [19, 20]In contrast to the literature, our study did not establish a statistically significant relationship between the degree of reflux and treatment success, similar to a survey conducted by Tadrist et al. [21].

During subureteric injection, the intraoperative goal is to create a volcano-shaped mound at the orifice, which may relate to either the injection technique, volume, and components of the bulking agent [22,23,24]. In addition to some of these factors, we assessed the success rate using the anatomical shape and placement of the transplant orifice before the injection and the coaptation condition after the injection using operation recordings. Our findings indicated a higher success rate in patients who exhibited ‘proper coaptation’ with a satisfactory volcano-shaped mound appearance after the injection. Similar observations regarding native ureteral reflux have been reported previously in the literature [25]. Moreover, patients considered ‘favorable for injection’ showed higher success rates. Therefore, a visual assessment of the transplant orifice anatomy and mound appearance by the surgeon, both pre- and post-injection, appears to be a critical factor in predicting the success of endoscopic injection treatment. However, this subjective factor, which necessitates experience with transplant patients, may not be as clearly defined or recommended as other objective findings.

Determining the degree of reflux can be challenging in patients with prominent pyelocalyceal and ureteral dilations. The submucosal ureteral tunnel, ureterovesical junction, and trigonal structure play a more significant role in the development of reflux than the upper urinary system [26], and subjective interpretation of the degree of reflux has also led to the need for an objective measurement method. Hence, a recent study suggested the ureteral diameter ratio (UDR) as an alternative indicator [27]. Many authors concluded that the UDR is an essential factor in the prognosis of reflux and in predicting the success of endoscopic treatment conducted in the pediatric population for native ureteral reflux [28,29,30]. In the present study, a correlation was found between UDR and the degree of reflux, and the mean UDR values of the groups were lower than those in previous studies. However, our findings could not address the fact that UDR is a predictor of the success rate in transplant kidneys. This may be related to the adult patient population and the pelvic-placed transplanted kidney. There is a need for a large population series involving different patient groups to obtain nomograms for standardization of UDR. According to our knowledge, the present study is the first one to investigate the UDR and visual subjective assessment in transplant patients.

The present study has several limitations besides its retrospective design, lack of prospective validation, and low number of patients in particular study groups. First, no analysis was performed for the end-stage renal disease etiological factors, which may affect treatment success due to the limited number of patient groups. Despite the necessity of a control VCUG, which allows the precise determination of radiological success, remains a topic of debate in literature [10, 21], was only performed in patients with symptomatic urinary tract infections and/or positive urine cultures and deterioration in graft function after the procedure. Moreover, low-numbered patient groups investigating the reflux grade may cause a statistical bias in an appropriate comparison. Visual assessment of the transplant orifice anatomy and post-injection mound view depends solely on the surgeon’s experience and cannot be clearly defined to establish a standardized definition due to their subjective nature. Despite these limitations, this study effectively highlights the strengths of evaluating UDR and focusing on clinical aspects during surgery for the first time in the literature. There is a need to assess the variables in this study in a prospective, randomized manner with a larger patient group and to obtain threshold values and nomograms for the variables.

Conclusions

Endoscopic subureteric injection is an effective first-line treatment for reflux in transplant patients due to its minimally invasive characteristics, ease of application, and low complication rates. Identifying predictive variables could significantly improve treatment algorithms, saving time and reducing costs. This study found that visually assessing the injection orifice during the procedure and achieving a mound appearance after injection are both associated with successful outcomes. To our knowledge, this study is the largest to date in evaluating the key factors influencing the success rate of endoscopic injection in transplant patients, according to the existing literature.