Evaluation and management of pediatric vesicoureteric reflux: Clinical guidelines review and introduction of the primary reflux evaluation and severity scoring severity score for vesicoureteric reflux

INTRODUCTION

Vesicoureteric reflux (VUR) in children constitutes a challenging problem in therapy. The inherent nature of the disorder necessitates invasive imaging procedures for diagnosis and follow-up. The anatomical derangement, the severity of disease, and renal affection in each case are highly variable. Similarly, the natural history is also variable, with the possibility of spontaneous resolution in some cases and the potential for worsening reflux with progressive renal functional deterioration in others. These factors contribute to the complexity of decision-making in evaluation and therapy. A greater understanding of the nuances regarding anatomical and physiological alterations in VUR has enabled the use of a more streamlined, stepwise, and escalating protocol for therapy. However, no stratification system for primary VUR integrates various factors that determine the severity of the disease and prognosis. Such a severity scoring would help incorporate all the anatomical and functional criteria that influence the outcome of primary VUR. This would help to integrate and corroborate the findings of various investigations. This would also provide a more comprehensive picture of the disease’s extent than any grading in isolation and help guide management decisions.

MATERIAL AND METHODS

A thorough review of current concepts in the management of VUR was conducted by analyzing the standard literature, current guidelines, recommendations, and landmark reviews. The relevant PubMed and Scopus-indexed articles pertaining to “diagnosis,” “classification,” “evaluation,” and “management” of “primary VUR” were reviewed. The cardinal points were summarized as part of the review for clarity of background data. A need was felt for a categorization of VUR that combines the different critical parameters, such as the grade of VUR and renal scarring, which determine the likelihood of resolution, the need for intervention, and the overall prognosis, especially the risk of progression to end-stage renal disease. The critical factors that determine the severity and prognosis of primary VUR to be used for the scoring system (Primary Reflux Evaluation and Severity Scoring [PRESS]) were identified on the basis of the literature review and clinical experience. The severity scoring system elaborated here combines the key prognostic factors that dictate the outcome.

PRIMARY AND SECONDARY VUR

It is important to distinguish primary VUR from secondary VUR. Primary VUR refers to the reflux that occurs commonly as an isolated pathology, with no specific etiological factor or causative urological disease. It occurs due to an abnormality of the uretero-vesical junction (UVJ), characterized by a deficiency of the submucosal tunnel of the ureter in the bladder, and can be unilateral or bilateral. When used in general, the term VUR, unless otherwise specified, usually refers to primary VUR. It can also be seen as commonly associated with conditions like voiding disorders, especially bladder and bowel dysfunction (BBD). It may also be occasionally associated with other urological anomalies such as ureteropelvic junction obstruction.^[1-3] Secondary VUR refers to the reflux that occurs due to an underlying etiological or causative factor such as neurogenic bladder, posterior urethral valves (PUVs), duplex system with lower moiety reflux, and post-operative or iatrogenic reflux. Here, the reflux is secondary to the derangement of UVJ due to the underlying abnormality or a high-pressure state of the bladder. The treatment of the underlying etiological factor takes precedence in these instances, while the follow-up and treatment of VUR are equally vital.^[1-4]

THE INVESTIGATIVE AND DIAGNOSTIC MODALITIES IN VUR

THE CLINICAL PRESENTATION OF VUR

The diagnosis of VUR is generally made at the VCUG performed for the evaluation of one of the following conditions:^[1,2,7,8]

1. Prenatally detected fetal hydronephrosis/hydroureteronephrosis

2. Urinary tract infections (UTI) in children

3. Postnatal diagnosis of hydronephrosis on sinology

4. Lower urinary tract disorders (LUTD) and BBD

5. Other: Neurogenic bladder, PUV, duplex system, multicystic dysplastic kidney.

VUR PRESENTING AS PRENATALLY DETECTED FETAL HYDRONEPHROSIS

In cases of fetal hydronephrosis, VUR is to be suspected in the presence of the finding of ureteral dilatation on sinology. The incidence of VUR in neonates with a history of prenatal hydronephrosis is about 16%, based on the outcome analysis. Female infants are seen to have a significantly higher incidence of VUR compared to males. Following the postnatal US, VCUG is to be done in all neonates with Society for Fetal Urology grade 3 and 4 hydronephrosis, ureteral dilatation, suspicion of bladder abnormalities, and those developing UTI.^[9-11]

POSTNATAL CLINICAL PRESENTATION OF VUR

Some children can have normal prenatal scans but present in early life with UTI or incidentally detected hydroureteronephrosis on the US. Recurrent UTI is the most common clinical indication for the performance of a VCUG. The general indications to perform a VCUG are (1) first UTI episode in a <2-month-old child, (2) second episode of UTI in children above 2 months of age, and (3) abnormality on renal US detected after the first UTI. Those with abnormal bladder (PUV) should undergo an early VCUG, while others can undergo elective testing at 4–6 weeks. Those children awaiting VCUG should be placed on continuous antibiotic prophylaxis (CAP).^[9-11]

VCUG should be done only under antibiotic cover and with complete aseptic precautions to prevent infection. The use of VCUG in neonates and early infancy is associated with the general risks of exposure, such as hypothermia and infection, and complications of bladder catheterization. The purpose of patient selection is to restrict the use of VCUG to cases with the highest probability of a positive yield, due to the invasive nature of the procedure, along with the risk of radiation exposure. Early initiation of CAP helps to abate the risk of UTI and pyelonephritis in these children while awaiting VCUG.^[10,12,13]

THE COMPLICATIONS ASSOCIATED WITH VUR

The common issues and complications associated with VUR, especially in bilateral and severe disease, are surmised below:^[2,3,12,13]

1. Inherent renal dysplasia (Developmental)

2. Recurrent UTI

3. Complications due to BBD

4. Increased plasma renin activity (PRA) and hypertension

5. Metabolic and endocrine abnormalities (acidosis)

6. Reflux nephropathy with progressive renal scarring

7. Chronic kidney disease

8. Renal osteodystrophy and growth retardation.

THE ESSENTIAL PRINCIPLES OF EVALUATION AND MANAGEMENT OF VUR

The essential principles of evaluation and management of VUR are summarized here:^[11,13-15]

1. To make an early and accurate diagnosis and to precisely grade the reflux and identify renal scarring

2. To prevent recurrent UTI

3. To identify and treat comorbidities such as LUTD and BBD

4. To individualize therapy, considering the natural history and possibility of spontaneous resolution of VUR

5. To use investigations and therapy selectively and appropriately during follow-up, to minimize morbidity

6. To institute medical/endoscopic/surgical therapy only for those likely to have maximum benefit

7. To identify and treat systemic complications such as hypertension and growth failure

8. To offset the progression of reflux nephropathy.

GENERAL EVALUATION OF A CHILD WITH VUR

The following factors should be noted in the general evaluation of a child, during the evaluation, and periodic follow-up:^[13-15]

1. Growth (height and weight)

2. Blood pressure

3. Presence of symptoms of bladder and bowel dysfunction (BBD)

4. Renal function tests (RFT) and glomerular filtration rate estimation

5. Urine analysis for bacteriuria, proteinuria, and urine culture studies

6. Serum electrolytes and bicarbonate, especially in bilateral disease

7. PRA

8. To identify and treat complications such as metabolic acidosis, hypertension, and renal rickets.

THE ASSOCIATION OF PRIMARY VUR WITH BBD IN OLDER CHILDREN

Bladder and bowel dysfunction (BBD) refers to the common complex of symptoms including diurnal urinary incontinence, recurrent UTI, infrequent voiding, and functional constipation. The child with this combination of conditions is at greater risk of renal injury due to UTI. The presence of BBD has an adverse effect on the resolution of VUR and its response to therapy. Hence, it is vital to identify the presence of symptoms of BBD during the initial evaluation and establish a proper diagnosis. This association is more common in children more than 5 years of age.^[14-18]

Investigations such as uroflowmetry and urodynamic assessment will be required for the diagnosis of the type of lower urinary tract disorder. It is important to initiate the management of BBD along with that of VUR for the optimal result. If evidence of BBD is present, its treatment is indicated before any interventional therapy. The prompt and effective treatment of BBD can result in a lower incidence of UTI, a better possibility of spontaneous resolution, and better results for therapy.^[16-18]

GENERAL MANAGEMENT PRINCIPLES IN THE INITIAL MANAGEMENT OF REFLUX

The general management principles in the initial management of reflux are summarized here:^{[10,13,14,19,20]}

1. DMSA scan is to be done for the assessment of renal cortical involvement as baseline, generally at 6 weeks– 3 months

2. Cystoscopy is done if there is a high index of suspicion of other pathology, and for high-grade reflux to assess the UO

3. CAP is initiated for those with Grade III–V VUR, renal scarring, and a history of febrile UTI

4. CAP may also be considered in Grade I–II VUR based on risk assessment and parental preference

5. Periodic reassessment is necessary with regular urine analysis and US. VCUG and DMSA scans are generally repeated after 1 year to assess progression.

MANAGEMENT OF VUR AFTER THE 1^ST YEAR OF LIFE

If VUR is observed to persist on reassessment after 1 year of age, further therapy depends on the following factors:^[15-17]

1. Age of the child and period since the initial diagnosis

2. Grade of reflux: static/progressive

3. Laterality: unilateral/bilateral

4. Renal scarring: static/progressive

5. Association with BBD

6. Incidence of breakthrough UTI (BT-UTI)

7. Presence of systemic complications (hypertension/metabolic/growth failure)

The other clinical considerations in older children include:^[16-18]

1. There is a lesser likelihood of spontaneous resolution in the older age group

2. The frequent association with functional constipation and BBD negatively impacts reflux resolution

3. There is a greater probability of early clinical diagnosis of UTI and a lower risk of morbidity from UTI in older children, thus permitting more selective use of CAP.

Broad management principles in the management of reflux in older children include:^[15-18]

1. CAP for those with Grade III- V VUR, renal scarring, BBD, and history of febrile UTI

2. CAP can be avoided for those with low-grade reflux without renal scarring/BBD/UTI

3. If BBD is present, concomitant treatment of the same, with monitoring of response to therapy. Treatment of BBD in a child with VUR forms an integral part of reflux management

4. Periodic reassessment with urine analysis, US, VCUG, DMSA scan, and cystoscopy as narrated below

5. Consider endoscopic/surgical intervention in cases not responding to observational treatment.

FOLLOW-UP EVALUATION OF A CHILD WITH VUR

The general guidelines in the follow-up of VUR include the following:^[17,18,21]

1. Urine analysis and culture studies are done periodically to exclude UTI

2. US is done every 6 months to monitor renal size and grade of hydronephrosis, if present

3. VCUG is done after 1 year, to look for resolution/downgrading of reflux

4. DMSA scan is repeated in the instance of progressive reflux/pyelonephritis to look for progressive renal scarring

5. Cystoscopy is done to assess the nature of the orifice, likelihood of spontaneous resolution, and feasibility of endoscopic therapy (favorable/unfavorable orifice)

6. Biochemical markers such as beta-2 microglobulin, urinary cytokines, and urinary microalbumin have been proposed as early indicators of reflux nephropathy.

THE DIAGNOSIS AND MANAGEMENT OF BT-UTI

The occurrence of a febrile BT-UTI while on CAP should raise the suspicion of failure of therapy and alert to the possibility of progressive reflux nephropathy and the need for a change in therapy. All children with febrile BT-UTI should be started on parenteral antibiotics at the earliest. The adequate treatment of BBD, if present, should be ensured. CAP should be commenced if the patient has not already been on the same.^[16,17] If symptomatic BT-UTI while on CAP occurs in the absence of progressive renal scarring, a change in the antibiotic used for prophylaxis may be effective. In the event of BT-UTI while on CAP occurs in the setting of high-grade reflux with scarring, endoscopic/surgical correction should be considered.^[18-20]

FACTORS ASSOCIATED WITH HIGHER LIKELIHOOD OF NEED FOR ENDOSCOPIC/SURGICAL INTERVENTION IN PRIMARY VUR

Factors associated with a higher likelihood of the need for endoscopic/surgical intervention in primary VUR include the following:^{[2-4,20,22-25]}

1. Grade IV and V reflux

2. Progressive reflux

3. Bilateral high-grade reflux

4. Golf hole type and laterally placed UO on cystoscopy

5. Presence of paraureteric (Hutch) diverticulum on cystoscopy

6. Presence of significant renal scarring

7. History of BT-UTI/pyelonephritis.

ENDOSCOPIC THERAPY FOR VUR

Endoscopic therapy classically involves the sub-ureteric injection of a bulking agent, with the aim of creating a backing for the intramural ureter that restores the integrity of the UVJ. It is important to select the right patient for the procedure, considering the grade of reflux and the type of UO. It is advisable to perform a cystoscopic examination of the bladder to assess the feasibility of the procedure before planning for endoscopic injection.^[20,22]

The procedure may be more suitable for an intermediate-grade reflux with a relatively favorable UO. Repeat procedures may be required in certain cases of persistent reflux after injection. The double hydrodistension implantation technique may have increased efficacy in achieving a successful result. The procedure has a success rate of about 80%, with minimal morbidity.^[20,22-24]

SURGICAL CORRECTION OF VUR

If the orifice is very patulous and laterally placed with poor muscle backing, along with high-grade reflux and significant renal scarring, surgical correction may be more appropriate. Operative intervention for VUR entails ureteric reimplantation that advances the ureteral meatus to create a competent UVJ. This involves the creation of a submucosal tunnel with a 5:1 ratio between the diameter of the ureter and the length of the tunnel (Paquin’s principle) with adequate muscle backing.^[25,26]

The more commonly employed infrahiatal repairs (Cohen’s trans-trigonal technique) involve preservation of the original ureteral hiatus, while suprahiatal repairs (Leadbetter) involve changing the ureteral hiatus, especially in cases with grossly dilated ureters. The approaches can be intravesical or extravesical (Lich-Gregoir) and open/laparoscopic. The surgery has a high success rate (>90%) with a low incidence of complications. Follow-up after endoscopic/surgical intervention involves an US done after 3–6 months and VCUG done after 1 year to confirm the resolution of reflux.^[25-27]

Long-term follow-up after resolution of VUR

The concerns with regard to resolved VUR in the long term are UTI, recurrent VUR, hypertension (especially during pregnancy), and renal functional loss. These issues are more likely with the history of high-grade reflux with renal scarring or with recurrent UTI after reflux resolution. Hence, these children require regular follow-up and general evaluation with additional investigations where necessary, continuing into adolescence.^[28-30]

PRESS; A NEWLY PROPOSED SEVERITY SCORING SYSTEM FOR PRIMARY VUR

This depends on various factors such as grade of reflux on VCUG, laterality of disease, presence of renal scarring on DMSA scan, distal ureteric morphology on VCUG/cystoscopic findings, and metabolic/systemic complications [Table 1].

Score 1: Unilateral/Bilateral; Grade I/II VUR; Favorable ureteric morphology*; No cortical scarring; No metabolic/systemic complications

Score 2: Unilateral; Grade III/IV/V VUR; Unfavorable ureteric morphology*; Unilateral renal scarring present; No metabolic/systemic complications

Score 3: Bilateral; Grade III/IV/V; Unfavorable ureteric morphology; Bilateral renal scarring; Presence of metabolic/systemic complications**.

*Ureteral morphology as assessed by cystoscopy or distal ureter diameter on VCUG; a significant variation in the anatomy is deemed as unfavorable ureteric morphology.

**Elevated RFT, metabolic acidosis, hypertension, renal osteodystrophy, growth failure.

The scoring is to be done at the time of initial diagnosis and reviewed on re-evaluation during the regular follow-up to assess resolution/progression of the disease. The scoring integrates various prognostic factors and estimates the likelihood of spontaneous resolution/progression to chronic renal failure or renal insufficiency. This will aid in the timely institution of appropriate therapy.

DISCUSSION

The assessment of the severity of primary VUR depends on multiple variables, including the grade of reflux, laterality, abnormality of ureteric morphology, extent of renal scarring, and presence of systemic complications. None of the present grading systems or severity scores integrates these different factors to provide a holistic view of the severity of the disease. Such an assessment has a significant bearing on the therapeutic measures necessary, possible prognosis, and outcome. The individual factors or criteria in isolation can convey only part of the picture, while the combination of these can help to improve the accuracy of the assessment significantly.

There is a lack of a unified scoring or grading system for VUR at present that incorporates the different factors associated with the disease, which significantly impact the severity of the disease. The treatment cannot be based on a single factor such as grade of reflux, laterality, or renal scarring. The therapeutic decisions should rely on a combined assessment of the severity based on the usually performed investigations. This would ensure that all the major contributing factors to the severity of the disease are accounted for during long-term management.

The PRESS scoring system proposed here attempts to integrate the critical factors that influence the outcome of primary VUR. These factors have been identified on the basis of literature review and clinical experience, including those that reflect the severity of the development and anatomic and functional derangement. The scoring criteria were thus determined on the basis of the clinically significant aspects of reflux on detailed evaluation that includes DMSA scan, cystoscopic, and systemic evaluation. These factors directly influence the practical considerations pertaining to VUR, such as the possibility of spontaneous resolution, therapeutic options to be employed, and prognostic significance.

Among the factors used for the scoring system, cystoscopic grading of the abnormal ureteral anatomy can be subjective. However, the assessment of distal ureteral diameter on VCUG can help bring more objectivity to the same. The limitations of the study include the lack of clinical validation of the scoring system proposed here. Hence, it is recommended that validation by prospective studies should be done to establish the clinical significance of the scoring system.

It is important to recognize VUR as a disorder with significant systemic problems and the potential for chronic and long-term functional sequelae. A deep understanding of the physiology and natural history of the disorder is key to the treatment of reflux. The treatment protocol has to be tailored to the specific situation of each patient, with the aim of minimizing morbidity and maximizing therapeutic benefit.

CONCLUSION

The broad management pathways presented here with regard to the diagnosis, evaluation, and management of VUR in various patient groups can serve only as an outline for the decision-making process, as the therapy needs to be highly individualized. The PRESS severity scoring system proposed here integrates various critical anatomical and functional criteria that determine the severity of disease. This will help to guide management decisions and also function as a comprehensive prognostic indicator.