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Paediatric vesicoureteral reflux

Case report

A two-year-old male child was referred into the paediatric urology outpatients in Our Lady’s Children’s Hospital, Crumlin with two episodes of cystitis and a single episode of pyelonephritis over the previous 10 months. These were successfully treated without complication initially and the child’s primary care physician is now hoping to elucidate the aetiology of these. The child is otherwise well, with no other past medical history and has attained all milestones with an up-to-date immunisation record. The pregnancy and delivery were unremarkable. He is not yet toilet-trained and has a father who may have had a history of reflux as a child, but is unsure. He also has an older brother and sister, who have not had any urinary tract infections. As per the NICE guidelines, he underwent a renal and bladder ultrasound prior to his referral, which demonstrated unilateral dilatation and therefore he underwent a micturating cystourethrogram (MCUG) in the below image.

””

Discussion

The earliest known mention of vesicoureteral reflux (VUR) in written records supposedly come from the anatomical drawings of Leonardo Da Vinci (see Figure 1) labelled in his own script: “Three views of the bladder, with kidneys, ureters, and urethra and detail of entry of ureter into the bladder.” It is felt in this illustration that ureters enter the bladder abnormally low and without the usual long course through the bladder wall. That severe reflux accompanied this abnormality is shown by the scarred kidneys cranially. That ‘long course’ through the sub-urothelial tunnel is usually five times the diameter of the ureter itself, and is known as ‘Paquin’s law’.

””

Figure 1: Leonardo da Vinci drawing

VUR in the modern era was first detected in 1898, soon after x-ray imaging was described in medicine by Wilhelm Röntgen. As VUR occurred at that time in small mammals in a laboratory setting, including dogs, it was considered normal. However, VUR was then detected in a patient with UTI in 1915. Swedish investigators began to use cystography systematically in the early 1950s in the evaluation of children with hydronephrosis and/or UTI, and posterior urethral valves (PUV) were subsequently discovered in living patients and reflux was often seen to be associated with hydroureteronephrosis, and it was therefore supposed that reflux was simply a consequence of these. Much more commonly, however, the children were female or valves were absent, but the hydronephrosis and reflux were sometimes severe.

The cause, consequences and treatment of VUR began to be debated. Urologists of that era dealt primarily with malignancies and urinary obstruction. Cystoscopy and pyelography were virtually the only diagnostic tools available. Cystoscopy, with fluid running into the bladder, flattened the valves, which were virtually never diagnosed by this means. Endoscopically, the bladder neck always appeared to be the narrowest part of the urethra, especially when distal obstruction was present and the bladder and bladder neck were hypertrophied. Thus, bladder neck obstruction was generally diagnosed, especially when residual urine was present. The interior of a normal child’s bladder is not perfectly smooth when distended, but mild to moderate trabeculation is present, which supported the diagnosis of outlet obstruction.

VUR is one of the greatest and most recent challenges in paediatric urology, with an explosive and relentless growth of knowledge. Prior opinions about VUR causing renal damage (‘reflux nephropathy’) through both mechanical impact (‘water hammer theory’) and children’s’ augmented sensitivity to infections, which in turn trigger off biochemical inflammatory cascade and therefore parenchymal damage and hypertension (‘Big Bang Theory’), were found to be inconclusive, and probably inaccurate.

High grade VUR, prevalent in males, is often connected with prenatal-derived renal dysplasia, whereas most other forms of primitive VUR are not necessarily correlated with kidney damage or long-term consequences.

Over the last few years, pregnancy ultrasound has revealed a new group of VUR-affected patients: Neonates (males more than females) being diagnosed prior to any clinical manifestations through antenatal screening. This has led to the early implementation of treatment and risk stratification. Despite this, retrospective studies on the registries of dialysis and transplant patients show that VUR associated with dysplasia remains today the primary cause of chronic renal failure (CRF) in paediatric age (25.8 per cent of cases) patients and that there have been no substantial differences in the development of the disease in patients diagnosed before or after six months of life.

Current views

It is now known that a deficient valve at the vesicoureteric junction (VUJ) permits retrograde flow of urine to the kidney. A common end-point of the investigation of antenatal hydronephrosis, reflux is usually treated conservatively with prophylactic antibiotics. Maturation of the VUJ gives a high rate of spontaneous resolution during the first five years of life, although this is rare in kidneys with severe dilatation and abnormal function at diagnosis. It is important to rule out posterior urethral valves in boys with reflux, by seeing the whole urethral on an MCUG. A refluxing VUJ is often associated with abnormality kidney development and reduced function on imaging, even without a history of urinary tract infection. VUR is divided into five grades of severity by the International Reflux Committee Grading System, with the first two grades characterised by non-dilated systems, and the latter three by dilating reflux (Figure 2).

””

Figure 2: International Reflux Committee Grading System on VUR

Detection

The diagnostic work-up should aim to evaluate the health and development of the child, presence of UTI, renal status, presence of VUR, and lower urinary tract function. A basic diagnostic work-up comprises a detailed medical history (including family history and screening for lower urinary tract dysfunction (LUTD)), a physical examination including blood pressure measurement, urinalysis (assessing for proteinuria), urine culture as indicated, and measurement of serum creatinine level in patients with bilateral renal parenchymal abnormalities.

The findings from imaging studies are useful for diagnosis and decisions about therapeutic options. The standard imaging tests include renal and bladder ultrasonography, MCUG, and nuclear renal scanning.

Dynamic radionuclide studies, such as mercaptoacetyltriglycine (MAG3), for the detection of reflux have lower radiation exposure than MCUG, but the anatomic detail depicted is inferior. However, despite the concerns about ionising radiation and its invasive nature, conventional MCUG remains the gold standard because the test allows better determination of the grade of VUR (in a single or duplicated kidney) and better assessment of bladder and urethral configuration.

Dimercaptosuccinic acid (DMSA) is the best static nuclear agent for visualising the cortical tissue and differential function between both kidneys. DMSA scanning is used to detect and monitor renal scarring. A baseline DMSA scan at the time of diagnosis can be used for comparison with successive scans during follow-up. DMSA can also be used as a diagnostic tool during suspected episodes of acute pyelonephritis. There is also a higher incidence of reflux in the siblings and children of affected patients.

Screening recommendations have been summarised by the European Association of Urology as follows:

The parents of children with VUR should be informed that there is a high prevalence of VUR in siblings and offspring.

If screening is performed, siblings should be screened by renal ultrasonography.

MCUG is recommended if there is evidence of renal scarring on ultrasonography or a history of urinary tract infection.

In older children who are toilet trained, there is no added value in screening for VUR.

Treatment options

Patients with reflux are at risk of secondary renal damage through ascending infection and intra-renal reflux of infected urine. This produces a characteristic pattern of renal scarring at the poles due to the presence of compound renal papillae, occurring maximally during the first infective episode, but this may be mitigated by prompt antibiotic treatment. Prophylactic antibiotics are given until after toilet training, with surgery indicated for breakthrough infection, non-compliance, deterioration in dilatation or function on follow up imaging and non-resolution of the reflux.

The most frequently used agents for continuous antibiotic prophylaxis (CAP) are single low doses (one-third of the treatment dose) of amoxicillin and trimethoprim (patients aged under two months) or trimethoprim/sulfamethoxazole or nitrofurantoin (for older infants), preferably taken at bedtime. The use of CAP and the duration of follow-up during prophylaxis in reflux patients is another area of major controversy. Although it is difficult to make definitive recommendations based on recent literature, it is clear that antibiotic prophylaxis may not be needed for every reflux patient. While some trials such as the RIVUR study, show no benefit for CAP, especially in low grades of reflux, other trials such as the Swedish Reflux Study show that CAP prevents further renal damage, especially in patients with grades III and IV reflux. What is really difficult and risky is to select the group of patients who do not need CAP. A safe approach would be to use CAP in most instances. Decision making may be influenced by the presence of risk factors for UTI, such as young age, high-grade VUR, status of toilet training/LUTD, female sex, and circumcision status.

First-line surgery is endoscopic injection of an inert paste below the refluxing orifice. Endoscopic surgical treatments of the refluxing vesicoureteral junction in neonates affected by high-grade VUR and dysplasia (virtually all males) are also ineffective in healing the associated parenchymal damage, and in stopping the progression of the nephropathy, and therefore, open surgery is reserved for more severe cases, where injection is not possible, or following failed injection treatment. Several bulking agents have been used over the past two decades. They include polytetrafluoroethylene (PTFE, or Teflon), collagen, autologous fat, polydimethylsiloxane, silicone, chondrocytes, and more recently, there have been some very good results with a solution of dextranomer/hyaluronic acid. Another management approach in boys with VUR and recurrent febrile urinary tract infections is to perform a standard circumcision. A recent meta-analysis by Singh and Grewal found this to be extremely effective with numbers needed to treat (NNT) to prevent further febrile infections of four.

Various intravesical and extravesical techniques have been described for the surgical correction of high-grade VUR. Although each method has specific advantages and complications, all the techniques share the basic principle of lengthening the intramural part of the ureter by submucosal embedding of the ureter. All the techniques have been shown to be safe, with a low rate of complications and excellent success rates (92-98 per cent).

The most popular and reliable open procedure is the Cohen cross-trigonal reimplantation (Figure 3). The main concern with this procedure is the difficulty of accessing the ureters endoscopically if needed when the child is older. In patients with bilateral reflux, an intravesical anti-reflux procedure may be considered, because simultaneous bilateral extravesical reflux repair carries an increased risk of temporary postoperative urine retention. All surgical procedures offer very high and similar success rates for correcting VUR.

””

Figure 3: Cohen’s cross-trigonal ureteric reimplant

Recommendations for management

Regardless of the grade of reflux or the presence of renal scars or symptoms, all patients diagnosed within the first year of life should be treated initially with CAP. During early childhood, the kidneys are at higher risk of developing new scars.

Immediate antibiotic treatment should be initiated for febrile breakthrough infections; treatment may be parenteral in children who are not capable of taking oral medications.

Definitive surgical or endoscopic correction is the preferred treatment in patients with frequent breakthrough infections.

Surgical correction should be considered in patients with persistent high-grade reflux (grade IV/V). There is no consensus about the timing or type of surgical correction. The outcome of open surgical correction is better than endoscopic correction for higher grades of reflux, whereas satisfactory results can be achieved by endoscopic injection in lower grades.

There is no evidence that correction of persistent low-grade reflux (grade I–III) in patients with no febrile UTI and normal kidneys offers a significant benefit. These patients may be candidates for endoscopic treatment.

In all children presenting at age one to five years with dilating reflux (grade III–V), CAP is the preferred option for initial therapy. For patients with high-grade reflux or abnormal renal parenchyma, surgical repair is a reasonable alternative. In patients with lower grades of reflux and no symptoms, close surveillance without antibiotic prophylaxis may be an option.

A detailed investigation for the presence of lower urinary tract dysfunction (LUTD) should be performed in all children after toilet training. If LUTD is detected, the initial treatment should be directed toward LUTD.

If parents prefer definitive therapy to conservative management, surgical correction may be considered. Endoscopic treatment is an option for all children with low grades of reflux.

The traditional approach of offering initial medical treatment after diagnosis and shifting to interventional treatment in case of breakthrough infections and new scar formation must be challenged, because the treatment should be tailored to the risk group.

The choice of management depends on the presence of renal scars, the clinical course, the grade of reflux, ipsilateral renal function, bilaterality, bladder function, associated anomalies of the urinary tract, age, compliance, and parental preference. Febrile UTI, high-grade reflux, bilaterality, and cortical abnormalities are considered to be risk factors for possible renal damage. The presence of LUTD is an additional risk factor for new scars.

In high-risk patients who already have renal impairment, a more aggressive, multidisciplinary approach is needed.

Discussion

The earliest known mention of vesicoureteral reflux (VUR) in written records supposedly come from the anatomical drawings of Leonardo Da Vinci (see Figure 1) labelled in his own script: “Three views of the bladder, with kidneys, ureters, and urethra and detail of entry of ureter into the bladder.” It is felt in this illustration that ureters enter the bladder abnormally low and without the usual long course through the bladder wall. That severe reflux accompanied this abnormality is shown by the scarred kidneys cranially. That ‘long course’ through the sub-urothelial tunnel is usually five times the diameter of the ureter itself, and is known as ‘Paquin’s law’.

VUR in the modern era was first detected in 1898, soon after x-ray imaging was described in medicine by Wilhelm Röntgen. As VUR occurred at that time in small mammals in a laboratory setting, including dogs, it was considered normal. However, VUR was then detected in a patient with UTI in 1915. Swedish investigators began to use cystography systematically in the early 1950s in the evaluation of children with hydronephrosis and/or UTI, and posterior urethral valves (PUV) were subsequently discovered in living patients and reflux was often seen to be associated with hydroureteronephrosis, and it was therefore supposed that reflux was simply a consequence of these. Much more commonly, however, the children were female or valves were absent, but the hydronephrosis and reflux were sometimes severe.

The cause, consequences and treatment of VUR began to be debated. Urologists of that era dealt primarily with malignancies and urinary obstruction. Cystoscopy and pyelography were virtually the only diagnostic tools available. Cystoscopy, with fluid running into the bladder, flattened the valves, which were virtually never diagnosed by this means. Endoscopically, the bladder neck always appeared to be the narrowest part of the urethra, especially when distal obstruction was present and the bladder and bladder neck were hypertrophied. Thus, bladder neck obstruction was generally diagnosed, especially when residual urine was present. The interior of a normal child’s bladder is not perfectly smooth when distended, but mild to moderate trabeculation is present, which supported the diagnosis of outlet obstruction.

VUR is one of the greatest and most recent challenges in paediatric urology, with an explosive and relentless growth of knowledge. Prior opinions about VUR causing renal damage (‘reflux nephropathy’) through both mechanical impact (‘water hammer theory’) and children’s’ augmented sensitivity to infections, which in turn trigger off biochemical inflammatory cascade and therefore parenchymal damage and hypertension (‘Big Bang Theory’), were found to be inconclusive, and probably inaccurate.

High grade VUR, prevalent in males, is often connected with prenatal-derived renal dysplasia, whereas most other forms of primitive VUR are not necessarily correlated with kidney damage or long-term consequences.

Over the last few years, pregnancy ultrasound has revealed a new group of VUR-affected patients: Neonates (males more than females) being diagnosed prior to any clinical manifestations through antenatal screening. This has led to the early implementation of treatment and risk stratification. Despite this, retrospective studies on the registries of dialysis and transplant patients show that VUR associated with dysplasia remains today the primary cause of chronic renal failure (CRF) in paediatric age (25.8 per cent of cases) patients and that there have been no substantial differences in the development of the disease in patients diagnosed before or after six months of life.

Current views

It is now known that a deficient valve at the vesicoureteric junction (VUJ) permits retrograde flow of urine to the kidney. A common end-point of the investigation of antenatal hydronephrosis, reflux is usually treated conservatively with prophylactic antibiotics. Maturation of the VUJ gives a high rate of spontaneous resolution during the first five years of life, although this is rare in kidneys with severe dilatation and abnormal function at diagnosis. It is important to rule out posterior urethral valves in boys with reflux, by seeing the whole urethral on an MCUG. A refluxing VUJ is often associated with abnormality kidney development and reduced function on imaging, even without a history of urinary tract infection. VUR is divided into five grades of severity by the International Reflux Committee Grading System, with the first two grades characterised by non-dilated systems, and the latter three by dilating reflux (Figure 2).

Detection

The diagnostic work-up should aim to evaluate the health and development of the child, presence of UTI, renal status, presence of VUR, and lower urinary tract function. A basic diagnostic work-up comprises a detailed medical history (including family history and screening for lower urinary tract dysfunction (LUTD)), a physical examination including blood pressure measurement, urinalysis (assessing for proteinuria), urine culture as indicated, and measurement of serum creatinine level in patients with bilateral renal parenchymal abnormalities.

The findings from imaging studies are useful for diagnosis and decisions about therapeutic options. The standard imaging tests include renal and bladder ultrasonography, MCUG, and nuclear renal scanning.

Dynamic radionuclide studies, such as mercaptoacetyltriglycine (MAG3), for the detection of reflux have lower radiation exposure than MCUG, but the anatomic detail depicted is inferior. However, despite the concerns about ionising radiation and its invasive nature, conventional MCUG remains the gold standard because the test allows better determination of the grade of VUR (in a single or duplicated kidney) and better assessment of bladder and urethral configuration.

Dimercaptosuccinic acid (DMSA) is the best static nuclear agent for visualising the cortical tissue and differential function between both kidneys. DMSA scanning is used to detect and monitor renal scarring. A baseline DMSA scan at the time of diagnosis can be used for comparison with successive scans during follow-up. DMSA can also be used as a diagnostic tool during suspected episodes of acute pyelonephritis. There is also a higher incidence of reflux in the siblings and children of affected patients.

Screening recommendations have been summarised by the European Association of Urology as follows:

The parents of children with VUR should be informed that there is a high prevalence of VUR in siblings and offspring.

If screening is performed, siblings should be screened by renal ultrasonography.

MCUG is recommended if there is evidence of renal scarring on ultrasonography or a history of urinary tract infection.

In older children who are toilet trained, there is no added value in screening for VUR.

Treatment options

Patients with reflux are at risk of secondary renal damage through ascending infection and intra-renal reflux of infected urine. This produces a characteristic pattern of renal scarring at the poles due to the presence of compound renal papillae, occurring maximally during the first infective episode, but this may be mitigated by prompt antibiotic treatment. Prophylactic antibiotics are given until after toilet training, with surgery indicated for breakthrough infection, non-compliance, deterioration in dilatation or function on follow up imaging and non-resolution of the reflux.

The most frequently used agents for continuous antibiotic prophylaxis (CAP) are single low doses (one-third of the treatment dose) of amoxicillin and trimethoprim (patients aged under two months) or trimethoprim/sulfamethoxazole or nitrofurantoin (for older infants), preferably taken at bedtime. The use of CAP and the duration of follow-up during prophylaxis in reflux patients is another area of major controversy. Although it is difficult to make definitive recommendations based on recent literature, it is clear that antibiotic prophylaxis may not be needed for every reflux patient. While some trials such as the RIVUR study, show no benefit for CAP, especially in low grades of reflux, other trials such as the Swedish Reflux Study show that CAP prevents further renal damage, especially in patients with grades III and IV reflux. What is really difficult and risky is to select the group of patients who do not need CAP. A safe approach would be to use CAP in most instances. Decision making may be influenced by the presence of risk factors for UTI, such as young age, high-grade VUR, status of toilet training/LUTD, female sex, and circumcision status.

First-line surgery is endoscopic injection of an inert paste below the refluxing orifice. Endoscopic surgical treatments of the refluxing vesicoureteral junction in neonates affected by high-grade VUR and dysplasia (virtually all males) are also ineffective in healing the associated parenchymal damage, and in stopping the progression of the nephropathy, and therefore, open surgery is reserved for more severe cases, where injection is not possible, or following failed injection treatment. Several bulking agents have been used over the past two decades. They include polytetrafluoroethylene (PTFE, or Teflon), collagen, autologous fat, polydimethylsiloxane, silicone, chondrocytes, and more recently, there have been some very good results with a solution of dextranomer/hyaluronic acid. Another management approach in boys with VUR and recurrent febrile urinary tract infections is to perform a standard circumcision. A recent meta-analysis by Singh and Grewal found this to be extremely effective with numbers needed to treat (NNT) to prevent further febrile infections of four.

Various intravesical and extravesical techniques have been described for the surgical correction of high-grade VUR. Although each method has specific advantages and complications, all the techniques share the basic principle of lengthening the intramural part of the ureter by submucosal embedding of the ureter. All the techniques have been shown to be safe, with a low rate of complications and excellent success rates (92-98 per cent).

The most popular and reliable open procedure is the Cohen cross-trigonal reimplantation (Figure 3). The main concern with this procedure is the difficulty of accessing the ureters endoscopically if needed when the child is older. In patients with bilateral reflux, an intravesical anti-reflux procedure may be considered, because simultaneous bilateral extravesical reflux repair carries an increased risk of temporary postoperative urine retention. All surgical procedures offer very high and similar success rates for correcting VUR.

Regardless of the grade of reflux or the presence of renal scars or symptoms, all patients diagnosed within the first year of life should be treated initially with CAP. During early childhood, the kidneys are at higher risk of developing new scars.

Immediate antibiotic treatment should be initiated for febrile breakthrough infections; treatment may be parenteral in children who are not capable of taking oral medications.

Definitive surgical or endoscopic correction is the preferred treatment in patients with frequent breakthrough infections.

Surgical correction should be considered in patients with persistent high-grade reflux (grade IV/V). There is no consensus about the timing or type of surgical correction. The outcome of open surgical correction is better than endoscopic correction for higher grades of reflux, whereas satisfactory results can be achieved by endoscopic injection in lower grades.

There is no evidence that correction of persistent low-grade reflux (grade I–III) in patients with no febrile UTI and normal kidneys offers a significant benefit. These patients may be candidates for endoscopic treatment.

In all children presenting at age one to five years with dilating reflux (grade III–V), CAP is the preferred option for initial therapy. For patients with high-grade reflux or abnormal renal parenchyma, surgical repair is a reasonable alternative. In patients with lower grades of reflux and no symptoms, close surveillance without antibiotic prophylaxis may be an option.

A detailed investigation for the presence of lower urinary tract dysfunction (LUTD) should be performed in all children after toilet training. If LUTD is detected, the initial treatment should be directed toward LUTD.

If parents prefer definitive therapy to conservative management, surgical correction may be considered. Endoscopic treatment is an option for all children with low grades of reflux.

The traditional approach of offering initial medical treatment after diagnosis and shifting to interventional treatment in case of breakthrough infections and new scar formation must be challenged, because the treatment should be tailored to the risk group.

The choice of management depends on the presence of renal scars, the clinical course, the grade of reflux, ipsilateral renal function, bilaterality, bladder function, associated anomalies of the urinary tract, age, compliance, and parental preference. Febrile UTI, high-grade reflux, bilaterality, and cortical abnormalities are considered to be risk factors for possible renal damage. The presence of LUTD is an additional risk factor for new scars.

In high-risk patients who already have renal impairment, a more aggressive, multidisciplinary approach is needed.

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