|Year : 2003 | Volume
| Issue : 3 | Page : 290-295
|Vesicoureteral Reflux in Childhood
Ali Duzova, Seza Ozen
Department of Pediatrics, Hacettepe University Faculty of Medicine, Pediatric Nephrology and Rheumatology Unit, Ankara, Turkey
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|How to cite this article:|
Duzova A, Ozen S. Vesicoureteral Reflux in Childhood. Saudi J Kidney Dis Transpl 2003;14:290-5
| Introduction|| |
Vesicoureteral reflux (VUR), the retrograde flow of the urine from the bladder into the ureters, is present in 18 to 40 % of children evaluated for their first urinary tract infection (UTI).  Eight percent of girls and 2% of boys suffer from UTI during childhood.  The recognition of VUR and its significance has evolved over the past 40 years.
| Epidemiology and Pathogenesis|| |
The prevalence of VUR in healthy children is uncertain. Ransley reported VUR in seven of 535 apparently normal neonates, infants and children (1.3%).  The frequency appears to be inversely proportional to age. Female to male ratio varies between 1:1 to 10:1; femalecircumcision practice further affects this ratio. ,
VUR is a congenital and partially inherited disorder. Genetic factors may be associated with the development or the prognosis of VUR; for example polymorphism in the ACE gene has been associated with scar formation in VUR, as will be discussed below. ,, The mode of inheritance of VUR is not well understood. An autosomal dominant pattern had been suggested.  The prevalence of VUR among siblings of index patients varies between 11% and 67%, with mean prevalence of 32%. , Hollowell performed a retrospective survey of studies which screened the siblings of patients with VUR, over a period of 17 years.  The mean prevalence of reflux in siblings was 32% (570 of 1768). Sibling age varied inversely with the prevalence of reflux. Twin relationship, and absent dysfunctional voiding symptoms in the index patient predicted a higher chance of reflux in a sibling. The prevalence of reflux and renal abnormality in siblings undergoing screening was 3%. Controlled studies are needed to determine the benefit of screening asymptomatic siblings.
Primary VUR associated with prenatal hydronephrosis usually affects males and is severe; on the other hand, VUR diagnosed after UTI is more common in females and is milder. 
Oblique entry of the ureter into the bladder and adequate length of the intramural ureter are the anatomic features which characterize the normal valve mechanism of ureterovesical junction. Primary VUR is not associated with any neuromuscular or obstructive disorder. The orifice of refluxing ureters are usually located laterally and more cephalad. In case of a duplicated collecting system, the lower segment ureteral orifice is abnormally located. Urethral obstruction, neuromuscular diseases and abnormal voiding patterns (dysfunctional voiding) cause secondary VUR. In every child with VUR, voiding dysfunction should be questioned thoroughly for the presence of unstable bladder. VUR is termed secondary in these cases and treatment is directed towards correcting the bladder dysfunction.
The grades of reflux are shown in [Table - 1]. A VCUG showing grade I reflux to the left and grade II reflux to the right kidney is shown in [Figure - 1].
| Clinical Features and Imaging|| |
VUR is usually detected during assessment of children with UTI. With widespread use of fetal ultrasonography (US), increasing numbers of newborns are referred to pediatric nephrologists.
The Swedish guidelines suggest that the initial work-up at first diagnosed febrile upper UTI be as follows: 
Children below 2 years of age
US within 2-4 weeks
Voiding Cystourethrogram (VCU)
within 1-2 months
Children 2 years of age and older
US within 1-2 months
DMSA nuclear scan after 6-12 months.
If there are uptake defects or side distribution with one kidney having below 45 % of the total function, a VCU is added.
Recent findings support the view that DMSA scan may replace VCU in the initial work-up of children below 2 years of age; VCU can be applied when DMSA is abnormal.
Voiding cystourethrography enables the clinician to visualize the urethra, to grade reflux, to detect duplication or ureteral ectopia, posterior urethral valve, bladder trabeculation, bladder diverticula and foreign bodies. High gonadal irradiation is the major disadvantage of this technique.
Radionuclide cystography has limited capacity for grading of VUR, but the radiation dose is 50-200 times less than with VCU. Radio-nuclide cystography is the ideal method for the follow-up of the patient and the screening of the siblings. 
Ilyas et al report that renal ultrasound (RUS) did not correlate with a positive DMSA renal scan; of the 146 children with normal RUS, 89 (61%) had a positive renal scan consistent with acute pyelonephritis.  In the same study, it was shown that VUR was more prevalent in younger children with febrile UTI than the older children: 51% in < 2 years age group, 47% in 2-8 years of age group, and 28 % in >8 years of age group.
Mahant et al reviewed the US and VCU of 162 children under five years of age with first episode of UTI. They showed that the sensitivity and specificity of ultrasound in suggesting VUR were 40% and 76 % respectively. 
VCU can be obtained once the urine is free of infection. Many pediatricians delay VCU for a period of two to six weeks after an acute UTI, believing that UTI per se may result in VUR or exacerbate VUR; i.e. increase its grade. However, recent studies have shown that the rate of detection of VUR in children with first episode of UTI does not increase when VCU is done early.  The advantages of doing the VCU early are convenience, compliance and avoidance of prophylactic antibiotics. Multicenter studies and/or a metaanalysis are needed to reach a final conclusion.
Voiding urosonography (VUS) is far from giving reliable results; anatomical conditions, patient co-operation and contrast medium administration are factors affecting the accuracy of VUS.
 However, VUS can be used as a first diagnostic step in female babies and in the screening for VUR.
| Antenatal Hydronephrosis and VUR|| |
Brophy et al. retrospectively reviewed children referred for evaluation of prenatally detected hydronephrosis. VUR was identified in 40 of 234 infants (21%), the incidence being higher with greater degrees of sonographic dilatation. 
Ismaili et al. prospectively followed 264 infants with antenatal renal pelvis dilatation.  Two US examinations were performed, first on day five and the second at one month after birth. Additionally, VCU was also performed on all patients. US abnormality was defined as pelvic AP diameter of 7 mm, calyceal or ureteral dilation, pelvic or ureteral wall thickening, absence of cortico-medullary differentiation, and signs of renal dysplasia. US was abnormal in 72% of the cases; among them 33% had abnormal VCU. Only five of the 74 patients who had normal US result had VUR (6.7%). They concluded that a urinary tract which appears normal on two successive neonatal ultrasonographic examinations rarely shows abnormal findings on VCU.
| Management|| |
Prophylaxis: Any infant with suspicion of VUR should be put on antibiotic prophylaxis for UTI, until the imaging studies are completed.  Trimethoprim (TMP) + Sulfamthoxazole (SMX) (2 mg of TMP, 10 mg of SMX per kg as single bed time dose or 2 mg of TMP, 10 mg of SMX per kg twice per week), nitrofurantion (1-2 mg/kg as single daily dose), sulfisoxazole (10-20 mg/kg divided every 12 h), nalidixic acid (30 mg/kg divided every 12 h), methanamine mandelate (75 mg/kg divided every 12 h) are some of the antimicrobials used for porphylaxis.
When VUR is identified, children should be maintained on anti-microbial prophylaxis. Urine cultures are recommended every 1-3 months, and at the time of any urinary symptoms. Blood pressure, height and serum creatinine levels should be followed. DMSA scan are repeated following any upper febrile UTI or cessation of prophylaxis.
Secondary reflux due to voiding dysfunction has emerged as an important issue in recent years. Voiding dysfunction should be specially inquired in children with reflux. In patients suffering from bladder instability anticholinergics and appropriate treatment are recommended. Patients with lazy bladder syndrome; i.e. infrequent voiders, may benefit from timed voiding. A high fiber diet, and a daily toilet habit are useful in patients suffering from constipation For patients with grade I-III reflux and for infants below one year of age with any grade of reflux, medical management is suitable.  Uncontrolled, recurrent UTI, non-compliance to medical treatment or intolerance to antimicrobials are reasons to consider anti-reflux surgery.
Severe grade V reflux beyond 1-2 years of age should be surgically corrected. 
When making a decision for a patient with grade IV reflux, age and compliance of the patient, frequency of UTIs, presence or absence of renal scarring should also be considered.
Many authors recommend surgical correction of unresolved VUR in adolescents; some others recommend cessation of prophylaxis and considering surgical intervention only in the presence of pyelonephritis, proven by a renal scan.
Thompson et al reviewed the records of patients with VUR in whom prophylactic therapy was discontinued either due to physician recommendation or patient noncompliance. A total of 122 patients were infection-free while on, and 124 patients were infection-free while off prophylactic therapy. 
The infection rate on and off prophylactic therapy was 0.29 and 0.24 UTI per patients per year. New scars were identified in five patients while on prophylactics and in seven after antibiotics were discontinued. They suggested that discontinuing antibiotics is reasonable and safe in patients in whom VUR fails to resolve.
The success rate of uretero-neocyctostomy exceeds 95%.  In endoscopic correction (injection of polytetrafluoroethylene or teflon paste subureterically at the ureterovesical junction: STING), the success rate is 76% with one injection and 85% after a second injection.  The recurrence rate after a followup period of 2-5.5 years was 12%.  Ureteral obstruction rate was 0.32%. Long-term consequences of the migration of polytetrafluoroethylene or teflon are unknown. A variety of alternative substances are investigated.
| Outcome and prognosis|| |
Smellie et al evaluated the outcome of VUR in 226 adults.  The patients whose mean age was 27 years, were studied for 10-35 years. At presentation (mean age 5 years) all had VUR and UTI; 63% remained free from UTI, no new scar developed after puberty. At follow up, 17 adults had hypertension and/ or raised plasma creatinine, 16 of whom had scarred kidneys. Those with VUR, but no scarring, did not suffer serious consequences as adults.
In low grade (I-II) reflux with undilated ureters, approximately 75 to 85% will stop refluxing. In higher grades (III-IV) with dilated ureters, the cessation rate is in the range of only 25-30%.  The International Reflux Study in Children (European Branch) studied the outcome of VUR grade III or IV, followed over 10 years.  At 10 years, 15% of children had no reflux, 48% had VUR with dilatation and 37% had VUR without dilatation.
Disappearance of VUR was significantly associated with grade III versus grade IV, unilateral versus bilateral and age >5 years at entry versus age <5 years.
In a randomized trial, medical and surgical management of children (25 boys and 27 girls) with bilateral grade III-V VUR and bilateral nephropathy were compared.  The difference in the glomerular filtration rate (GFR) at four years between the two groups was not significant. The authors concluded that the main factor that determines outcome is the extent of renal parenchymal reduction and the degree of functional impairment at the start.
We examined the influence of deletion (D) and insertion (I) polymorphism in angiotensin I-converting enzyme (ACE) gene, PAI-1 on renal scarring in 94 children with III-IV degree reflux nephropathy. 6 On multivariate analysis DD genotype was the only factor that had a significant impact on renal scar formation, introducing a 4.9-fold risk (p<0.05).
Ohmoto et al studied the I/D polymorphisms of ACE gene in 78 patients with primary VUR.  The incidence of congenital unilateral small kidneys was high in DD patients. The GFR was 120.7 (35.7 in II genotype), 111.7 (33.3 in ID genotype) and 88.0 (18.0 in DD genotype). Hohenfellner et al reported a lower renal survival in DD genotypes compared to ID or II genotype [61% versus 89%, p<0.01]. Thus, the DD polymorphism may be regarded as one genetic modifying factor affecting prognosis, at least in the reported populations.
VUR is still the most common cause of chronic renal disease in children in many parts of the world. Careful management at the right time could save many such children and their families from lots of suffering and financial expenses.
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Hacettepe University Faculty of Medicine, Department of Pediatrics, Pediatric Nephrology and Rheumatology Unit, Sihhiye 06100, Ankara
[Figure - 1]
[Table - 1]
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