Pediatric Vesico-Ureteral Reflexes: Current Management
Published : Feb 05, 2024

Abstract

Vesicoureteral reflux (VUR) is a pediatric disorder and is a retrograde flow of urine to the upper urinary tract from the bladder. Frequently, it is genetic. VUR may show no symptoms at all or be linked to serious nephropathy. Kidney salvage is possible with early diagnosis and prompt treatment of VUR. Diagnostically, a Voiding cystourethrogram (VCUG) is considered the gold standard that determines VUR grades. The VUR grade and clinical presentation dictate the course of treatment. Generally, treatment includes medical and surgical therapies. There is significant disagreement over the best way to treat VUR. Only open surgery and antibiotic prophylaxis (AP) were thought to be viable options for a long time. Ever since its initial reports in the early 1980s, endoscopic therapy (ET), open or laparoscopic or robotic surgical techniques have grown in acceptance. This review focuses on the different treatment modalities for VUR management.

Keywords

Vesicoureteral reflux, Urinary tract infection, Autosomal, Bladder bowel disorder, Renal pelvis reflux, Endoscopic injection, Reimplantation

Introduction

VUR is a urinary tract disorder frequently seen in children. It is an abnormal backflow of urine up to the kidneys from the urinary bladder. It can be caused by pathologically elevated intravesical pressure or secondary type to functional (structural) abnormality of the vesicoureteral junction. This medical condition is mainly because of neurogenic bladder, posterior ureteral valves, or other obstructive uropathies [1]. It was estimated that the prevalence rate of VUR ranges from 0.4% to 1.8% [2].  The incidence rises to 30%–40% in patients with urinary tract infection (UTI) in addition to VUR [3]. Lower urinary tract symptoms (LUTS) and recurrent febrile UTIs and leads to VUR, regardless of whether they are linked to bladder bowel disorders (BBD). VUR affects 30% of children with a history of UTIs and 17% of children with normal kidneys [4,5]. Based on the results of a VCUG, a grading system is used to describe the severity of VUR. The grades range from I (mild) to V (severe) which are represented in Figure 1 [6]. Grade I is diagnosed as ureter reflux without dilation, Grade II as non-dilated ureters and the renal pelvis reflux, Grade III as ureter and pyelocalyceal system reflux with minor dilation, Grade IV as reflux with blunting of the renal fornices and a convoluted, somewhat dilated ureter. Preserved is the papillary impression, and Grade V as papillary impression, dilatation of the pyelocalyces with loss of fornices, and reflux with the tortuous and severely dilated ureter [7]. About 80% of grades I and II, approximately 45% of grades III, and lower than 10% of grades IV and V exhibit spontaneous resolution of VUR [8].

 

Figure 1: VCR Grades from I to V

 

The monozygotic twins have a higher concordance rate (80-100%) than dizygotic twins (35-50%) for VUR, genetic anomalies are a potential cause of VUR. It is believed that VUR has an autosomal dominant inheritance pattern [9]. Even in the absence of a history of UTIs, diffuse parenchymal lesions may occur in children with grade IV or V VUR, which leads to aberrant renal development. Patients with low-grade VUR who have an underlying pathological condition that causes abnormally elevated detrusor pressure may develop reflux nephropathy, even in the absence of infections, according to another clinical finding. Renal scarring in the absence of infection is explained by the impact of high pressure noninfected urine on the renal parenchyma. Reactive oxygen species, hazardous metabolites, and proinflammatory cytokines are released as a result, causing local ischemia [10,11,12].

 

The signs and symptoms of VUR include fever, burning and pain during urinating, abdominal pain, frequently passing small amount of the urine, bedwetting, high blood pressure, detection of protein in the urine [7]. Radionuclide cystography (RNC), x-ray, contrast-enhanced voiding urosonography (ceVUS), and VCUG are diagnostic options for the direct detection of VUR. Further nuclear medicine techniques, such as kidney [99Tc] dimercaptosuccinic acid (DMSA)-scintigraphy was also used to assess potential parenchymal damage [13]. The patient’s age, gender, occurrence of bowel or bladder dysfunction, and type of VUR grade all influence the course of medical care. VUR can spontaneously resolve before the age of five. A lower VUR grade (I–III) and younger age are conducive to spontaneous resolution [14].

 

The current management strategies for patients with VUR are outlined in this review and are antibiotic prophylaxis (medical management), endoscopic therapy (minimally invasive) or ureteral reimplantation (surgical technique).

Current Management Strategies

VUR is treated very individually, with consideration given to the age and gender of the child, grade or classification of reflux, status of renal, screening or UTI, adherence to the prescribed course of care (treatment), chance of VUR resolution, and preferences of both parents and children. The medical management of VUR consists of the following: 1) training of bladder, 2)voiding dysfunction with biofeedback, anticholinergic and B-blocker medications, and constipation treatment, 3) Daily AP versus intermittent therapy (At diagnosis treatment of UTI), and, 4) Periodic evaluation of VUR and child health, comprising repeated urine culture and urinalysis, repeated radionuclide cystogram or VCUG, repeated upper UT tests, and repeated monitoring of blood pressure and renal function [15].

 

Many urine biomarkers are used along with different radiological techniques to accelerate diagnosis, grading, and VUR management. Exactly, certain interleukins or neutrophil gelatinase-linked lipocalin have been associated with the proinflammatory state and innate immune response that describe children with VUR; this information may be used in clinical settings to quickly identify patients who need surgical intervention or AP [16].

Antibiotic Therapy

Continuous Antibiotic prophylaxis (CAP) is a widely used therapy for the treatment of patients with VUR. This therapy is also used for the prevention of febrile UTIs and renal scarring. According to the American Urological Association (AUA) guidelines, 1997, the first line of treatment should be antibiotic prophylaxis, with ureteral reimplantation surgery recommended as the second line of treatment for cases that persist or as the first line of intervention in cases of severe VUR, especially in older children [17]. Because endoscopic injection therapy is starting to show signs of success, there has been a recent shift toward early surgical treatment. Though reflux correction is not always necessary, VUR can be successfully corrected with minimally invasive therapy. Without medical intervention, 50% of Grade III reflux and 80% of low-grade reflux will resolve on their own [18]. North America and Europe conducted clinical trials to assess the usefulness of CAP using trimethoprim and sulfamethoxazole combination. Many clinical studies reported that infants (<2 months old) suffered from thrombotic thrombocytopenic purpura and hemolytic-uremic syndrome when treated with trimethoprim and sulfamethoxazole. Traditional antibiotic Cephem is commonly used in Japan. Before going to bed, a single oral dose (roughly one-third to one-sixth of the typical pediatric daily dose) should be administered. Infants younger than two months old may receive penicillin antibiotics; one-third of the pediatric daily dose should be given orally before bed [19,20]. Additionally, even after a brief exposure to a sub-therapeutic dosage of antibiotics, infants with VUR who had previously received CAP treatment exhibited an altered composition of their gut microbiota, which predisposed them to high concentrations of Enterobacteriaceae, including Klebsiella and Escherichia coli species. This created a significant risk factor for the development of more challenging-to-treat UTIs. It’s important to consider the negative effects of prolonged antibiotic use, which include immune system weakness, allergic reactions, and Clostridium difficile infections [21]. De Bessa et al. (2016) conducted a preliminary meta-analysis of 6 studies that evaluated the effectiveness of CAP in children with Grades I–II (non-dilated) and Grades III–IV (dilated)` VUR. The results indicated that antibiotics are used for recurrent UTIs in both high and low-grade VUR. The gathering of clinical information from the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) study discovered an overall effect showing a stronger protective agent with marginal significance, and reported as the use of CAP in all children with all grades of VUR, even though the no statistical significance results were not observed in meta-analysis [18,22].

 

Antibiotic misuse leads to increasing antibiotic resistance in UTIs and decreases the effectiveness of presently available antibiotics [23]. Moriya K et al. carried out a retrospective study to assess the discontinuation of AP in children through surveillance. During 5 years of active surveillance, the study found that approximately two-thirds of patients with permanent VUR did not experience a febrile UTI. On follow-up voiding cystourethrogram, patients with dilated vesicoureteral reflux have a markedly increased risk of developing a febrile UTI. Therefore, active surveillance appears to be a safe option even for children who have not yet completed toilet training, particularly in patients with non-dilated VUR on follow-up voiding cystourethrogram [24].

Endoscopic Injection

Puri and O’Donnell were first outlined for subureteral polytetrafluoroethylene injection and it is known as STING operation [25]. The material is injected into the terminal submucosal tract of the ureter, which inserts the needle a few millimeters below the ureteral orifice. Upon completion of the process, the ureteral orifice should be visible as a projection resembling a volcano. This technique is described in Figure 2 [26]. The injected material or paste (nonautologous or autologous) should be biocompatible, non-carcinogenic, non-antigenic, and non-migratory. Generally, different types of nonautologous materials are used in the children, such as polytetrafluoroethylene (Teflon or polytef), glutaraldehyde cross-linked bovine dermal collagen (Zyplast or Contigen), polydimethylsiloxane (Macroplastique) and dextranomer microspheres in sodium hyaluronan solution (Deflux). Merckx L et al reported that in 4234 VUR patients (6316 ureters) given polytef, 75.9% of patients were cured successfully after a single injection, although additional injections may enhance the rate upto 84.9% [27].

 

Figure 2: Endoscopic injection

 

Leonard MP et al evaluated that following a single injection, the success rate is close to 60%. Similar to polytef, repeated Glutaraldehyde cross-linked bovine dermal collagen injections can raise cure rate from 65% to 80% [28]. Collagen is probably not as durable as polytef, it used for patient’s permanent cure without needing open surgery or antibiotics prophylaxis [29]. Herz D et al stated that after receiving treatment with Polydimethylsiloxane, 114 rental units or seventy-four children were cured in 76% of the cases with just one injection. The cure rate appeared to be 84% of the children (90% of ureters) with additional injections. The patients under treatment had a 24-month follow-up period, and the cystogram was typically done three months following the last injection [30]. The Swedish group that conducted the first experimental studies mentioned above is the primary source of clinical data about the treatment of Deflux for VUR patients. Sixty-eight percent of the 75 patients (115 ureters) who received treatment showed improvement 3 months following their initial injection. Additionally, they observed that 16 out of 18 ureters that were cured after three months did not experience reflux one year later [31].

Ureteral Reimplantation

In 1993, the first laparoscopic reimplantation was done on a porcine model. It is surgery to fix the tubes that connect the bladder to the kidneys. To properly plan the ureteral reimplantation procedure, the surgeon must ascertain the degree of ureteral pathology and advise to perform an image on the abdomen and pelvis using magnetic resonance imaging (MRI) with specific urographic and arterial phases or a three-phase computed tomography (CT) scan [32]. It’s important to note that the choice of technique and materials for ureteral reimplantation depends on various factors, including the patient’s age, the severity of VUR, anatomical considerations, and the surgeon’s preference and experience. One of the two methods for laparoscopic ureter reimplantation is extravesical (detrusorrhaphy) or intravesical (vesicoscopic). There is no distinction between the open Lich-Gregoir method and extravesical reimplantation. In a recent series, the mean operative time for unilateral was 1.75 h and 3.75 h for bilateral VUR, compared to 0.50 and 1.00 h for opening the Lich–Gregoir technique [33]. Remarkably, the intravesical surgical repair has not shown any postoperative pain or dysuria related to open intravesical surgery [34]. Smith et al. discovered a similar success rate when contrasting the gold standard of an open, intravesical, cross-trigonal ureteral reimplantation with the most widely used method of robot-assisted laparoscopic ureteral reimplantation, known as extravesical Robotic-assisted laparoscopic ureteral reimplantation (RALUR). The success rate of extravesical RALUR was 97%, while the open cross-trigonal technique yielded a 100% success rate. However, in line with an excess of research showing comparable results for the robotic laparoscopic method, it was linked to shorter hospital stays and lower use of painkillers [35]. The Cohen cross-trigonal ureteral reimplantation is a well-established surgical procedure for VUR disease. This procedure involves cross-reimplanting one or both ureters into a new ureteric orifice (UO) located across the bladder trigone. This procedure is commonly used intravesically and has a low rate of post-operative ureteric obstruction. However, it can be difficult to access the ureteric orifice endoscopically subsequently [36]. Additionally, ureteral stents can be used temporarily to maintain ureteral patency and prevent obstruction during the healing process after reimplantation. These stents may be removed after a certain period post-surgery [37].

Conclusion

Over the past few decades, knowledge of VUR has grown. Children who have grade III to V VUR and recurrent fUTI are susceptible to renal decline. The VUR management of these kinds of patients is based on risk assessment and physicians initially preferred CAP treatment. ET is becoming more widely accepted and has shown promise in many cases. ET is now believed to be a significant replacement therapy to AP and open surgery. Numerous studies have listed the advantages of minimally invasive surgery, which include better cosmesis, shorter hospital stays, and less pain following surgery. With the advent of the robot and its continued development, urologists can now execute minimally invasive procedures more precisely and easily. The complexity of the cases performed robotically will probably increase along with the level of comfort that surgeons have with the technology, leading to even better results.

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Acknowledgment

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Sheikh Raziya Begum M. Pharm, Author, medtigo

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DOI

10.5281/zenodo.10890208

Cite this Article

Raziya Begum, S. (2024). Pediatric Vesico-Ureteral Reflexes: Current Management. medtigo Journal, 2(1). https://doi.org/10.5281/zenodo.10890208

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