Key words : Ureteral stenosis, Urinary leakage, Urologic complications

Introduction

Over the decades, most surgical techniques involved in kidney transplant (KTx) have been standardized. The double J stent (JJ stent)^1,2 has been mostly used in draining after ureteroneocystostomy of KTx, and previous studies have demonstrated that it can decrease the incidence of major urologic complications (MUCs), that is, both ureteric obstruction and ureteric leakage, from between 7% and 9% to 1.5%. However, according to the KTx transplant guidelines from the European Association of Urology,³ JJ stents can also increase the risk of urinary tract infections (UTIs) from 6% to 40% if left in place for longer than 30 days. The guidelines also advise centers to remove stents earlier than 6 weeks after transplant rather than later. Thus, the ureteric stent is similar to a double-edged sword for KTx recipients: it is helpful in the prevention of MUCs⁴ but is a high-risk factor in the development of UTIs⁵ and idiosyncratic complications such as hematuria and irritative bladder symptoms.⁶ Appropriate application of the ureteric stent is important in KTx.

There are different opinions among surgeons with regard to timing for stent removal. Some researchers^7,8 have asserted that KTx recipients could only benefit from stents placed for 1 or 2 weeks; however, other researchers^9,10 have suggested that indwelling stents can only prevent complications if left for longer periods of time, with too early removal of stents associated with UTIs as well as ureteric leakage. So far, no consensus on the appropriate time of stent removal has been reached.

In this meta-analysis and systematic review, we aimed to identify the optimal “early” timing of ureteric stent removal after KTx, which could be helpful for clinical decisions among transplant centers.

Materials and Methods

Selection criteria
All studies included in our analyses were published in English and conformed to the following criteria: (1) studies on KTx patients, but not those on stenting of ileal conduits or continent urinary diversions, who had urinary stent removal posttransplant; (2) studies designed as randomized controlled trials (RCTs); and (3) studies that included at least 1 outcome. Duplicated results in different articles, reviews, and animal research studies were excluded.

Search strategy
With use of the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) statement and above selection criteria, we searched PubMed, Embase, and the Cochrane Library databases for studies published from February 2011 to October 2019. Potentially relevant RCTs from references of relative studies were also searched by hand to ensure that no articles were missed. The followed medical subject headings (MeSH) or non-MeSH terms were used in our search: “kidney graft” OR “kidney transplantation” OR “renal transplant” OR “kidney transplant” AND “stent” and “urinary stent.” These search strategies were used to search each database.

Outcome measures
The outcome measure in this meta-analysis was the timing of stent removal and the incidence of UTIs and MUCs (urinary leakage and ureteral stenosis).¹¹ Urinary tract infections were defined as a positive urine culture with a bacterial colony count of more than 10⁵ colony-forming units/mL.¹²

Data extraction
Two reviewers independently assessed all eligible publications, and any disagreements were discussed with a third reviewer and solved by all reviewers. With selection criteria, each reviewer used a standardized extraction form to extract the data from all full-text studies, which included details on author names, the year of publication, country, general patient data, follow-up duration, donor type, type of stent, stent removal methods, immunosuppressive therapies, and outcomes.

Statistical analyses
Review Manager Software (RevMan 5.3) was used for meta-analysis. Differences in outcomes were expressed as relative risk (RR) or odds ratio (OR; with 95% CIs). Heterogeneity across trials was quantified by using the I² statistic. When I² statistic was below 50% by chi-square test, which indicted a low level of heterogeneity, a fixed-effects model was used for estimates. When I² statistic was over 50%, a random-effects model was chosen. Furthermore, subgroup analysis was used to explore possible sources of heterogeneity, and sensitivity analyses were performed to examine the results. P < .05 was affirmed as statistically significant.

Quality assessment
The GRADE tool^13,14 was recommended for assessing the risk of bias and evaluating the methodological quality of each RCT, which included 7 aspects: random sequence generation, allocation concealment, blinding of participants and personnel, blinding of outcome assessment, incomplete outcome data, selective outcome reporting, and other biases. Each reviewer assessed each study to find high, low, or unclear risk of bias. Disagreements were resolved through a third reviewer and discussion.

Results

After careful review of the initial literature search, a total of 7 eligible studies^15-21 from 2012 to 2018 and 1277 patients were found to be within the scope of our study. Figure 1 illustrates the selection strategy, and Table 1 lists the characteristics of the 7 included studies. Figure 2 illustrates the quality assessment of each RCT and provides a qualification of risk of bias. All studies except Parapiboon and colleagues¹⁸ reported the age of the recipients. Five of the 7 articles reported the use of the Lich-Gregoir technique, which was not reported in the remaining 2 studies. Regarding stent removal, cystoscopy was mostly used in the studies. Six studies recorded the use of antibiotic prophylaxis, such as ceftriaxone and sulfamethoxazole/trimethoprim, to protect or to prevent UTIs. Five studies reported the immunosuppressive therapies that patients received. With regard to outcomes, all articles described the incidence of UTIs and 4 articles reported MUCs. Table 2 presents the outcomes for the included studies.

Urinary tract infections
All included studies recorded UTI events with regard to various timing of stent removal. Significant differences were shown between groups with early versus late stent removal in the development of UTIs, with early removal shown to have better outcomes for UTI incidence (RR of 0.42; 95% CI, 0.26-0.685; P < .001) (Figure 3A). With the consideration of high heterogeneity (I² = 56%), sensitivity analysis and subgroup analysis were conducted. To explore appropriate timing, we investigated 2 timelines: 2 weeks and 3 weeks. To avoid low quality and high risk of bias, we excluded Gunawansa and associates21 (the full article was not assessable). This article was also excluded for our continuous analysis of MUC. Our analysis was consistent with the previous conclusion without heterogeneity, which favored early stent removal. At the 2-week timeline, relative risk was 0.36 (95% CI, 0.26-0.52; P< .001; Figure 3B); at the 3-week timeline, relative risk was 0.35 (95% CI, 0.25-0.49; P < .001; Figure 3C).

Major urological complications
Four studies described the incidence of MUCs with a total of 718 patient. As shown in Figure 4, with regard to MUCs, there were no significant differences among the studies between early and late stent removal. The OR for 2-week timeline was 2.79 (95% CI, 0.62-12.52; P = .18), and the OR for 3-week timeline was 1.97 (95% CI, 0.61-6.33; P = .26). As shown in Figure 5, we also observed no significant differences between early and late stent removal groups in risk of developing urinary leakage, with OR for 2-week timeline of 3.02 (95% CI, 0.59-15.51; P = .18) and RR for 3-week timeline of 2.00 (95% CI, 0.59-6.80; P = .27). For ureteral stenosis, only Gunawansa and colleagues²¹ (2 cases) and Patel and colleagues¹⁹ (1 case) reported ureteral stenosis, all at late stent removal. Therefore, because of the low incidence among our findings, this factor was not suitable for the meta-analysis.

Discussion

The universal use of ureteric stents is a good minimally invasive option for urinary drainage after KTx; however, there are still questions on indwelling time. Previous research⁵ has shown that the implanted stent can be accompanied by various complications, including hematuresis, stent migration, and dis-comfort. In addition, it may lead to UTIs, which could result in prolonged hospitalizations, increased costs, and even recurrent surgical interventions. However, the benefits of stents have also been shown, with KTx recipients having a lower incidence of MUCs. A number of studies^22-24 have explored timing of stent removal after KTx, with ureteral stent removal usually occurring from 1 to 6 weeks after the surgery. Because, so far, no consensus has been reached with regard to timing, we explored this aspect with a systematic review and meta-analysis.

In our analysis, we found that early removal of the stent after KTx (that is, not later than 3 weeks) had a significant effect on decreasing the incidence of UTIs. We found that timing at both 2 weeks and 3 weeks had good results; therefore, we suggest 14 to 21 days as a preferred timing. In their study, Yuksel and colleagues¹⁰ reviewed 818 KTx patients and divided them into 4 groups according to the timing of stent removal (5-7 days, 8-14 days, 15-21 days, >22 days). They found that only 0.1% of UTIs were observed at 15 to 21 days versus 1.2% at 8 to 14 days and 3.2% at >22 days, with obvious lower incidence among those who had JJ stent removal before day 14 (10.6% in the combined group of 5-7 days and 8-14 days). Dadkhah and colleagues⁹ also showed a lower rate of UTIs in patients who had stent removal at about 20 days versus those who had removal at about 30 days after KTx (7.2% vs 12.4%, respectively). These results imply that long-duration indwelling stents could lead to high risk of UTIs.

In contrast to the results for UTIs, our analysis showed that development of MUCs was not associated with indwelling time of stents. We also found no significant differences between groups with short and long duration of stent placement with regard to risk of developing urinary leakage, with negligible rate of ureteral stenosis (0.6%). As reported previously,^25-28 the incidence of urinary leakage can range from 1.5% to 6.0%, with most leakages occurring at the site of the ureteroneocystostomy during the early stage due to distal ureteral ischemia. In a meta-analysis from Alberts and colleagues,²⁹ several factors, including graft arterial reconstruction, recipient diabetes, and multiple renal arteries, were concluded to contribute to ureteral leakage after KTx, with the Lich-Gregoir technique suggested to significantly reduce the rate of leakage. Furthermore, Yuksel and colleagues¹⁰ reported that early stent removal (<14 days) led to a higher rate of leakage and stenosis than in the unstented population. Thus, we suggest that more than 2 weeks of the implanted stent could help to prevent leakage, but longer indwelling time may have no effect on the incidence of ureteral leakages after KTx. With these considerations, we recommend removal of the ureteral stent after 2 weeks.

This meta-analysis also carries some limitations that must be considered. First, only 7 RCTs were included in our study, and 1 of the studies carried a high risk of bias, resulting in our minimization or exclusion of those results for some analyses. Second, each RCT contained a small numbers of patients; therefore, larger RCTs may be needed to confirm these results. In addition, only studies written in English were searched in this meta-analysis, which resulted in potential publication bias. Finally, various recipient and donor characteristics of included studies could also have affected our results. Because of these limitations, more trials may be needed to confirm these results.

Conclusions

Our study demonstrated that the early removal of ureteral stent, not later than 3 weeks, significantly decreased the incidence of UTI but did not affect the development of MUCs. We recommend that stent placement of 14 to 21 days is a preferred duration and the appropriate timing of stent removal.

References:

1. Sozen H, Ozen O, Fidan K, Soylemezoglu O, Dalgic A. Outcome of the double-J stent placement in pediatric kidney transplant: a single center experience. Exp Clin Transplant. 2017. doi:10.6002/ect.2016.0280
   CrossRef - PubMed
   
2. Alci E, Ustun M, Sezer T, et al. Comparison of patients in whom double-J stent had been placed or not placed after renal transplantation in a single center: a follow-up study. Transplant Proc. 2015;47(5):1433-1436. doi:10.1016/j.transproceed.2015.04.064
   CrossRef - PubMed
   
3. Rodriguez Faba O, Boissier R, Budde K, et al. European Association of Urology Guidelines on Renal Transplantation: Update 2018. Eur Urol Focus. 2018;4(2):208-215. doi:10.1016/j.euf.2018.07.014
   CrossRef - PubMed
   
4. Gomes G, Nunes P, Castelo D, et al. Ureteric stent in renal transplantation. Transplant Proc. 2013;45(3):1099-1101. doi:10.1016/j.transproceed.2013.02.086
   CrossRef - PubMed
   
5. Maliakkal JG, Brennan DC, Goss C, et al. Ureteral stent placement and immediate graft function are associated with increased risk of BK viremia in the first year after kidney transplantation. Transpl Int. 2017;30(2):153-161. doi:10.1111/tri.12888
   CrossRef - PubMed
   
6. Bzoma B, Kostro J, Hellmann A, et al. Ureteric stenting in kidney transplant recipients, Gdansk Centre experience, Poland. Transplant Proc. 2018;50(6):1858-1862. doi:10.1016/j.transproceed.2018.02.105
   CrossRef - PubMed
   
7. Wingate JT, Brandenberger J, Weiss A, Scovel LG, Kuhr CS. Ureteral stent duration and the risk of BK polyomavirus viremia or bacteriuria after kidney transplantation. Transpl Infect Dis. 2017;19(1). doi:10.1111/tid.12644
   CrossRef - PubMed
   
8. Coskun AK, Harlak A, Ozer T, et al. Is removal of the stent at the end of 2 weeks helpful to reduce infectious or urologic complications after renal transplantation? Transplant Proc. 2011;43(3):813-815. doi:10.1016/j.transproceed.2010.11.016
   CrossRef - PubMed
   
9. Dadkhah F, Yari H, Ali Asgari M, Fallahnezhad MH, Tavoosian A, Ghadian A. Benefits and complications of removing ureteral stent based on the elapsed time after renal transplantation surgery. Nephrourol Mon. 2016;8(2):e31108. doi:10.5812/numonthly.31108
   CrossRef - PubMed
   
10. Yuksel Y, Tekin S, Yuksel D, et al. Optimal timing for removal of the double-J stent after kidney transplantation. Transplant Proc. 2017;49(3):523-527. doi:10.1016/j.transproceed.2017.01.008
    CrossRef - PubMed
    
11. Goldfarb DA. Stented versus nonstented extravesical ureteroneocystostomy in renal transplantation: a metaanalysis. J Urol. 2005;173(3):889. doi:10.1097/00005392-200503000-00075
    CrossRef - PubMed
    
12. Naber KG, Bergman B, Bishop MC, et al. EAU guidelines for the management of urinary and male genital tract infections. Urinary Tract Infection (UTI) Working Group of the Health Care Office (HCO) of the European Association of Urology (EAU). Eur Urol. 2001;40(5):576-588. doi:10.1159/000049840
    CrossRef - PubMed
    
13. Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336-341. doi:10.1016/j.ijsu.2010.02.007
    CrossRef - PubMed
    
14. Cumpston M, Li T, Page MJ, et al. Updated guidance for trusted systematic reviews: a new edition of the Cochrane Handbook for Systematic Reviews of Interventions. Cochrane Database Syst Rev. 2019;10:ED000142. doi:10.1002/14651858.ED000142
    CrossRef - PubMed
    
15. Appiya Ramamoorthy B, Javangula Venkata Surya P, Darlington D. Early versus delayed double j stent removal in deceased donor renal transplant recipients: a prospective comparative study. Cureus. 2018;10(7):e3006. doi:10.7759/cureus.3006
    CrossRef - PubMed
    
16. Huang L, Wang X, Ma Y, et al. A comparative study of 3-week and 6-week duration of double-J stent placement in renal transplant recipients. Urol Int. 2012;89(1):89-92. doi:10.1159/000338075
    CrossRef - PubMed
    
17. Indu KN, Lakshminarayana G, Anil M, et al. Is early removal of prophylactic ureteric stents beneficial in live donor renal transplantation? Indian J Nephrol. 2012;22(4):275-279. doi:10.4103/0971-4065.101247
    CrossRef - PubMed
    
18. Parapiboon W, Ingsathit A, Disthabanchong S, et al. Impact of early ureteric stent removal and cost-benefit analysis in kidney transplant recipients: results of a randomized controlled study. Transplant Proc. 2012;44(3):737-739. doi:10.1016/j.transproceed.2011.11.033
    CrossRef - PubMed
    
19. Patel P, Rebollo-Mesa I, Ryan E, et al. Prophylactic ureteric stents in renal transplant recipients: a multicenter randomized controlled trial of early versus late removal. Am J Transplant. 2017;17(8):2129-2138. doi:10.1111/ajt.14223
    CrossRef - PubMed
    
20. Liu S, Luo G, Sun B, et al. Early removal of double-J stents decreases urinary tract infections in living donor renal transplantation: a prospective, randomized clinical trial. Transplant Proc. 2017;49(2):297-302. doi:10.1016/j.transproceed.2016.12.007
    CrossRef - PubMed
    
21. Gunawansa N, Wijeyaratne M, Cassim R, Sahabandu C. Early bedside removal versus delayed cystoscopic removal of ureteric stents following live donor renal transplantation: a randomized prospective study: O323. Transplant Int. 2015;28.
    CrossRef - PubMed
    
22. Visser IJ, van der Staaij JPT, Muthusamy A, Willicombe M, Lafranca JA, Dor F. Timing of ureteric stent removal and occurrence of urological complications after kidney transplantation: a systematic review and meta-analysis. J Clin Med. 2019;8(5). doi:10.3390/jcm8050689
    CrossRef - PubMed
    
23. Ali Asgari M, Dadkhah F, Tara SA, Argani H, Tavoosian A, Ghadian A. Early stent removal after kidney transplantation: is it possible? Nephrourol Mon. 2016;8(2):e30598. doi:10.5812/numonthly.30598
    CrossRef - PubMed
    
24. Mannu GS, Bettencourt-Silva JH, Gilbert J. The ideal timing of ureteric stent removal in transplantation patients. Transpl Int. 2014;27(10):e96-e97. doi:10.1111/tri.12363
    CrossRef - PubMed
    
25. Rahnemai-Azar AA, Gilchrist BF, Kayler LK. Independent risk factors for early urologic complications after kidney transplantation. Clin Transplant. 2015;29(5):403-408. doi:10.1111/ctr.12530
    CrossRef - PubMed
    
26. ElSheemy MS, Ghoneima W, Aboulela W, et al. Risk factors for urological complications following living donor renal transplantation in children. Pediatr Transplant. 2018;22(1). doi:10.1111/petr.13083
    CrossRef - PubMed
    
27. Bruintjes MHD, d’Ancona FCH, Zhu X, Hoitsma AJ, Warle MC. An update on early urological complications in kidney transplantation: a national cohort study. Ann Transplant. 2019;24:617-624. doi:10.12659/AOT.920086
    CrossRef - PubMed
    
28. Friedersdorff F, Weinberger S, Biernath N, Plage H, Cash H, El-Bandar N. The ureter in the kidney transplant setting: ureteroneocystostomy surgical options, double-J stent considerations and management of related complications. Curr Urol Rep. 2020;21(1):3. doi:10.1007/s11934-020-0956-7
    CrossRef - PubMed
    
29. Alberts VP, Idu MM, Legemate DA, Laguna Pes MP, Minnee RC. Ureterovesical anastomotic techniques for kidney transplantation: a systematic review and meta-analysis. Transpl Int. 2014;27(6):593-605. doi:10.1111/tri.12301
    CrossRef - PubMed