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Table of Contents
REVIEW ARTICLE
Year : 2021  |  Volume : 32  |  Issue : 2  |  Page : 52-58

Conservative management of vesicoureteral reflux: A literature review


Department of Urology, Faculty of Medicine Universitas Padjadjaran, Hasan Sadikin General Hospital, Bandung, Indonesia

Date of Submission30-Sep-2020
Date of Decision13-Nov-2020
Date of Acceptance05-Jan-2021
Date of Web Publication22-Jun-2021

Correspondence Address:
Safendra Siregar
Department of Urology, Faculty of Medicine Universitas Padjajaran, Hasan Sadikin General Hospital, Bandung
Indonesia
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/UROS.UROS_132_20

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  Abstract 


Vesicoureteral reflux (VUR) is defined as the retrograde flow of urine from the bladder to the upper urinary tract (the ureters and kidneys), caused by ureterovesical junction dysfunction. VUR is the most common congenital urinary tract abnormality; nevertheless, the conservative treatment for VUR remains controversial. In addition, the limited data availability made it difficult to establish a widely accepted treatment protocol. This study aimed to review available treatment modalities and recommendations with regard to the conservative management for VUR. An online literature search was performed on PubMed, PubMed Central, and Google Scholar. Studies were compared with several available guidelines. Based on literature search, the conservative management of VUR involves a multimodality approach, including the bladder-bowel dysfunction management through bladder training, anticholinergics and alpha-blockers, continuous antibiotic prophylaxis, and circumcision in male patients. Operative and other invasive treatment modalities may be considered in treatment failure or breakthrough urinary tract infection and should not be used as a first-line treatment.

Keywords: Conservative, literature review, management, vesicoureteral reflux


How to cite this article:
Siregar S, Kurniawan AP, Mustafa A. Conservative management of vesicoureteral reflux: A literature review. Urol Sci 2021;32:52-8

How to cite this URL:
Siregar S, Kurniawan AP, Mustafa A. Conservative management of vesicoureteral reflux: A literature review. Urol Sci [serial online] 2021 [cited 2021 Sep 22];32:52-8. Available from: https://www.e-urol-sci.com/text.asp?2021/32/2/52/318997




  Introduction Top


Vesicoureteral reflux (VUR) is defined as a retrograde flow of urine from the bladder to the ureters and kidneys, caused by ureterovesical (U-V) junction dysfunction.[1] Under normal conditions, the U-V junction functions as a one-way valve, which prevents the backflow of urine from the bladder during urination. A competent U-V junction function depends on several factors, including the submucosal ureter length, ureteral orifice diameter, muscle function in the trigone, and ureteral peristalsis coordination.[2]

Currently, comprehensive data on the epidemiology of VUR is unavailable. Several studies provide limited data on the VUR prevalence in pediatric populations, i.e., approximately 1%.[2],[3] VUR is more commonly diagnosed in girls, with a ratio of approximately 3:1. Due to its often asymptomatic nature, VUR is commonly diagnosed as an incidental finding to evaluate other urinary tract conditions. For example, in children with urinary tract infection (UTI), the VUR prevalence is approximately 40%[4] and 16% in fetuses diagnosed with hydronephrosis prenatally. VUR is also a common finding in patients with congenital urinary tract abnormalities, such as posterior urethral valves, cloacal deformities, and duplex kidneys.[5]

Generally, VUR management consists of medical or conservative and surgical managements. The conservative management for VUR involves active surveillance, where the disease progression is constantly monitored along with the use of several therapeutic modalities, including bladder training, anticholinergic and alpha-blockers, UTI prophylaxis, and bladder and bowel dysfunction (BBD) management.[6] A large number of VUR cases have been spontaneously resolved without treatment, and in patients with low-grade VUR and good clinical presentation, active surveillance without prophylaxis may be considered, and initiation of other treatments can be adjusted in time.[7]

Surgery for VUR is usually indicated for patients with recurrent UTIs, renal scarring, and high-grade VUR.[8] In addition, patients highly at risk for pyelonephritis, renal scarring, and in which VUR is unlikely to spontaneously resolve may also be considered for surgical treatment, for example, patients with breakthrough UTI during continuous antibiotic prophylaxis (CAP), persistent high-grade reflux, bilateral VUR, progressive renal scarring, and with poor compliance to medical treatment.[6]

Recently, conservative treatment has become more preferred than surgical treatment for VUR, mostly due to the lack of demonstrable advantages of surgery compared to conservative treatment. A meta-analysis had found no clear evidence of added benefits of surgical correction for VUR over antibiotic treatment alone,[9] and several studies have shown that less-invasive approaches have a lower cost compared to open surgery.[10],[11]

Current recommendations by the European Urological Association advocate the use of conservative treatment for the majority of VUR cases, and surgical correction of VUR is reserved for patients with high-grade (Grades IV–V) and high-risk VUR [Table 1]. Nevertheless, the optimal choice of treatment for VUR remains controversial. Although the majority of VUR cases can be successfully treated conservatively, treatment protocols as well as several conflicting results on the effectiveness of the said modalities should be clarified.[12] As an example, two of the largest studies on the effectiveness of CAP for VUR, the RIVUR study and the Swedish Reflux Study, advocated the efficacy of antibiotic prophylaxis to prevent UTI in patients with VUR.[13],[14] In addition, several studies have shown that antibiotic prophylaxis does not increase the incidence of UTIs in VUR.[15],[16]
Table 1: European Urological Association recommendations for the treatment of vesicoureteral reflux

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  Conservative Management for Vesicoureteral Reflux Top


The conservative management for VUR is complex and requires individual considerations to achieve optimal results. In general, conservative management aims to prevent long-term complications, which can be caused by hydronephrosis, pyelonephritis, or UTIs.

Bladder training

Bladder dysfunction plays an important role in the pathogenesis of VUR, where functional obstruction due the urethral sphincter constriction causing elevated intravesical pressure and structural distortions in the bladder and ureterovesical junction. In addition to abnormalities during urination, abnormalities in the urinary filling stage such as involuntary detrusor overactivity can also cause VUR.[17] Thus, bladder training is one of the cornerstone therapies for VUR, in which patients are trained to perform complete, regular, and low-pressure urination, thus preventing reflux.[18]

To our knowledge, currently no bladder training protocols have been designed specifically for patients with VUR. Bladder training can be performed by scheduling fluid intake and urination (timed voiding), educating the patient about the ideal posture and pelvic floor relaxation,[6] and using biofeedback. Regular daytime voiding every 3 h is advised, and parents should be instructed to record the frequency, fluid intake volume, and incontinence if present. Biofeedback is the application of perineal electrodes that can facilitate pelvic floor relaxation and can help train patients to achieve adequate pelvic posture and relaxation during bladder training.[19]

Bladder training is an important part of the BBD treatment. Although current evidence does not show a direct relationship between bladder training and VUR resolution, bladder training is known to be effective in resolving BBD. In a retrospective study, several studies have shown a high rate of BBD resolution after bladder training,[20],[21] and bladder-trained children with VUR also have a lower risk for UTIs.[22] Computer-assisted pelvic floor training has also been described by Herndon et al., noting a decreased rate of breakthrough infection, reduced need for surgical intervention, and elimination of constipation in children with voiding dysfunction and VUR.[23] Therefore, considering the high risk of UTI in patients with VUR, especially with BBD, bladder training should be offered for all patients with VUR. Several studies on bladder training or biofeedback for patients with VUR are described in [Table 2].
Table 2: Studies on bladder training in regards of vesicoureteral reflux

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Anticholinergics and alpha-blockers

Anticholinergics such as oxybutynin, propantheline bromide, hyoscyamine,[18] and alpha-blockers (prazosin)[24] have been used as an adjunctive treatment for VUR, although data on the use of these two drug classes are limited.

In the urinary tract, anticholinergics function as a smooth muscle relaxant, which may help control the detrusor muscle overactivity (DOA). DOA is one of the causative factors of secondary VUR, increasing intravesical pressure that causes urine reflux into the ureters.[21] Bladder training in addition to anticholinergics may reduce bladder and sphincter hyperactivity and reduce intravesical pressure during urination and storage. Aguiar and Franco used oxybutynin with a dose of 0.1–0.2 mg/kg body weight 2–3 times daily with the maximum dose of 5 mg, whereas Snodgrass used 2.5 mg oxybutynin for children aged 3–6 years old and 5 mg oxybutynin for older children, three times daily.[26],[27]

Alpha-blockers such as doxazosin and prazosin have also been used for the management of primary bladder neck dysfunction, one of the causative factors of secondary VUR. Alpha-blockers can aid in VUR resolution and reduce lower urinary tract symptoms by reducing outlet resistance, improving bladder microcirculation, and affecting spinal reflexes. In one study, prazosin in a dose of 0.025 mg/kg daily significantly improves urodynamics of patients with VUR having primary bladder neck dysfunction after 12 months.[24]

The use of anticholinergics and alpha-blockers, although theoretically feasible, is not supported by recent literature, and further study is needed to assess the safety and efficacy of these agents. The use of anticholinergics and alpha-blockers may be considered with careful dosing for specific subsets of patients, including those with DOA and primary bladder neck dysfunction with VUR. Studies by Scholtmeijer and Nijman and Koff and Murtagh started anticholinergic treatment after a confirmed urodynamic abnormality; therefore, a thorough urodynamic study must be performed before considering anticholinergic or alpha-blocker treatment. Results of these studies are described in [Table 3].
Table 3: Summary of studies utilizing anticholinergics and alpha-blocker for vesicoureteral reflux

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Continuous antibiotic prophylaxis

Long-term antibiotic prophylaxis has been used to prevent febrile UTIs, its effect on renal scarring, and prevent UTI recurrences. CAP tends to have a greater benefit in patients with high-risk VUR, which are defined in the American Urological Association guideline as patients aged <1 year and VUR with dilatation (3°–5°), as well as patients with febrile UTI history.[28] In patients aged >1 year, antibiotic prophylaxis is recommended if patients have BBD.

The most widely used antibiotic agents as prophylaxis include amoxicillin, amoxicillin-clavulanic acid, trimethoprim-sulfamethoxazole, and nitrofurantoin. Doses used for long-term prophylaxis are calculated based on the body weight, generally approximately 25% of the antibiotic dose for acute infection, which is continuously administered for 6–12 months after diagnosis. Some antibiotic choices and dosages used in several studies are outlined in [Table 4].[29]
Table 4: Antibiotic options for continuous antibiotic prophylaxis

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Antibiotic prophylaxis should be initiated as early as possible, especially in patients with febrile UTIs. Shaikh et al. showed that antibiotics initiation >48 h after the occurrence of UTIs led to an increased risk of renal scarring by 47%.[30] The success of CAP is defined by the absence of UTI in the patient, no renal scarring, and spontaneous VUR resolution. Nevertheless, the occurrence of UTIs during antibiotic therapy (breakthrough UTI) is quite common, mainly because of the high risk of antibiotic resistance in long-term prophylactic use.[31] It should be noted that patient compliance with antibiotic prophylaxis plays an important role in the effectiveness of prophylaxis.[42]

In the case of breakthrough UTI with ongoing antibiotic prophylaxis, surgical intervention through reimplantation or endoscopic injection of bulking agents needs to be considered. However, a replacement of antibiotic agents can be done in the case of a first breakthrough UTI without UTI history or previous renal cortical abnormality.[18]

CAP is among the most successful yet controversial conservative treatment available for patients with VUR. Its use has been advocated by two of the largest studies in patients with VUR (the RIVUR and the Swedish Reflux Trial),[13],[14] and several studies have shown its effectiveness in reducing the risk of UTIs in patients with VUR.[44] Nevertheless, other studies have shown no statistically significant difference in UTI risk or VUR resolution with CAP, and it has also been shown that CAP is associated with much higher treatment costs, especially for patients with lower-grade VUR.[43] In addition, other drawbacks associated with CAP for VUR include increased risk for multidrug resistant UTI,[44] and adverse reactions associated with long-term antibiotic prophylaxis, such as gastrointestinal symptoms, skin rashes, hepatotoxicity, and hematological complications.[45 ] Therefore, the use of CAP should be reserved only for patients with VUR having high risk for UTI or presenting with UTI. [Table 5] describes some of the studies on CAP effectiveness in patients with VUR.
Table 5: Studies on continuous antibiotic prophylaxis for vesicoureteral reflux

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Probiotics

Probiotics are living microorganisms that are beneficial for human health. Exogenous probiotics are known to have a protective effect against uropathogens and have been used as a modality for preventing UTIs. In this case, the most studied probiotic is Lactobacillus sp., as one of the normal florae in the human urogenital tract. Several mechanisms can explain the activity of Lactobacillus sp. in preventing UTIs including a more acidic pH, interference with pathogen adhesion, biofilm formation, expression of virulence factors such as bacteriocin, hydrogen peroxide and surfactants, and immunity modulation.[46]

Although the use of probiotics for the prevention of UTIs in patients with VUR has not been widely recommended, several studies have shown the positive effect of probiotics on the risk of UTIs in VUR. Lee and Lee showed that infant patients with VUR aged 1–52 weeks who received Lactobacillus acidophilus at a concentration of 1.0 × 108 CFU/g twice a day had a lower incidence of UTIs compared to patients receiving antibiotic prophylaxis, although the difference was not statistically significant. The study also showed that bacterial resistance to trimethoprim-sulfamethoxazole and gentamicin was much lower in the probiotic group compared to antibiotics.[33] Research by showed a reduction in the incidence of UTIs in preterm infants who received Lactobacillus GG, with a statistically insignificant difference. In addition, Mohseni et al. showed that probiotics in tandem with nitrofurantoin CAP is more effective in preventing UTI in patients with VUR compared to nitrofurantoin CAP alone.[47] Although more extensive data are needed regarding the use of probiotics in patients with VUR, available literature shows a good safety profile with a protective effect against UTIs in patients with VUR; therefore, probiotics can be considered as alternatives or as an effective addition to antibiotic prophylaxis in patients with low-grade VUR.[34] [Table 6] describes studies identified on the effectiveness of probiotics in VUR.
Table 6: Summary of studies on probiotic prophylaxis for vesicoureteral reflux

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Circumcision

Circumcision can be one of the additional conservative therapy options for VUR in male patients, especially in under 1-year-old pediatric patients [Table 7]. Circumcision in boys with VUR can reduce the risk of UTIs. As UTIs are generally ascending in nature, the periurethral area is the main source of pathogens. Uropathogenic microorganisms can adhere to the surface of the prepuce mucosa, where colonization is supported by a moist environment, and antibiotic prophylaxis cannot penetrate tissue effectively. Thus, removal of the prepuce will reduce the area that can be colonized around the external urethral meatus and reduce the risk of UTIs.
Table 7: Studies on the effectiveness of circumcision in vesicoureteral reflux

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A study by Gücük et al. showed that circumcision in pediatric patients with VUR significantly decreased the number of periurethral positive cultures, and the number of positive urine cultures in patients undergoing circumcision was much lower than in patients who did not undergo circumcision.[48] Another study by Ellison et al. also showed a reduced risk of UTIs in patients with VUR undergoing circumcision.[49] Thus, circumcision can be considered in all male patients with VUR if possible.

Monitoring of conservative treatment

Although continuous monitoring depends on each patient's needs, several general monitoring steps are recommended for all patients with VUR. For general evaluations, the American Urological Association recommends an annual complete physical examination including blood pressure, height, and weight, including a urinalysis with culture and antibiotic sensitivity tests if UTI is suggested. A renal ultrasonography is also recommended every 12 months to monitor kidney growth and scarring, and voiding cystography may be repeated every 12–24 months for patients with lower chance of spontaneous resolution, including patients with high-grade VUR, BBD, or older patients. An abnormal ultrasound examination warrants a dimercaptosuccinic acid radionuclide scan to further assess renal morphology and function.[3] A summary of monitoring recommendations are presented in [Table 8].
Table 8: Summary of monitoring recommendations for vesicoureteral reflux patients

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Based on available guidelines and our review, the treatment of VUR should be stratified based on the grade, age, and history of breakthrough UTI. Patients with low-grade, asymptomatic VUR may be monitored without CAP due to their high rates of spontaneous resolution. Conservative treatment involving bladder training, anticholinergics, circumcision, or probiotics may be considered in patients aged 1–5-year-old. Bladder training and anticholinergics has been demonstrated in assisting VUR resolution and decreasing the risk of UTI, and their use should be recommended in patients with proven BBD or DOA. Although not widely recommended, the potential benefits of circumcision in male patients and probiotic prophylaxis, including the reduced risk of UTIs warrants further consideration by clinicians. CAP should be reserved only for high-risk cases, including patients aged <1-year-old, with high-grade VUR, and prior history of breakthrough infection. In case of persistent VUR after conservative management, endoscopic or surgical repair may be considered as a definitive treatment. The summary of the conservative treatment of VUR is illustrated in [Figure 1].
Figure 1: Summary of conservative treatment for vesicoureteral reflux

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  Conclusions Top


VUR is the most common congenital urinary tract disorder, and its effective management is essential for clinicians. Overall, VUR has an excellent prognosis, and most cases are spontaneously resolved with conservative management. The current literature supports active monitoring aided by several therapeutic modalities, including BBD management through bladder training accompanied by anticholinergic and alpha-blockers, CAP, prophylaxis with probiotics, and circumcision in male patients. Surgical management can be considered in treatment failure or breakthrough UTI and should not be used as first-line treatment. Although VUR management is complex and requires adjustments for each case, further research is needed to determine the protocol that can be applied to broader cases.[51]

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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    Figures

  [Figure 1]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4], [Table 5], [Table 6], [Table 7], [Table 8]



 

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Conservative Man...
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