|Year : 2000 | Volume
| Issue : 1 | Page : 13-24
|Vesicoureteral Reflux - an Update
Baroukh Maurice Assael, Clara Bellosta
Department of Pediatrics, University of Milano Medical School, Milano, Italy
Click here for correspondence address and email
|How to cite this article:|
Assael BM, Bellosta C. Vesicoureteral Reflux - an Update. Saudi J Kidney Dis Transpl 2000;11:13-24
| Introduction|| |
Vesicoureteral reflux (VUR) is a congenital anomaly consisting of a retrograde passage of urine from the bladder into the ureter and, in severe forms, to the renal pelvis and intrarenal structures. Physiologically, during micturition the bladder muscle compresses filling the ureter, however, reflux of urine is prevented by a valve-type mechanism based on the length of the intravesical ureter. In primary cases, VUR can be caused by a short intramural ureter or by anatomical malposition of the ureteral orifice. In others, it may be secondary to urethral valves, neurological disease (i.e. neurogenic bladder) or elevated pressure in the bladder due to outlet obstruction. VUR is associated with upper urinary tract infections, chronic pyelonephritis, renal scarring, chronic renal damage and hypertension. It is recognized as an important and probably preventable cause of chronic renal insufficiency and end-stage renal failure in children and adults.
Correction of the anatomical defect and prevention of the renal damage are the goals of the therapy. Many efforts have been dedicated to early recognition of VUR. However, despite numerous studies, there are major controversies on the need for screening procedures, the role of medical vs surgical treatment, timing of elective surgery and duration of antibiotic prophy-laxis.
In recent years, improvement and diffusion of prenatal diagnostic procedures have revealed that reflux nephropathy is fre-quently present at birth because of abnormal renal development in utero. Together with advances in gene hunting strategies, this has shed new light on the comprehension of the disease.
The present review will principally focus on the recent advances in the understanding of the congenital damage and the possible role of hereditary factors in VUR. There have been several detailed discussions on specific aspects of VUR. ,,,,
| Epidemiology|| |
The estimation of the prevalence of VUR depends on the reasons leading to diagnostic or screening procedures. The incidence of VUR in the general population has been estimated between 1/100 and 1/1000. ,,, However, the true prevalence is difficult to establish since VUR can resolve spontaneously early in life and may remain undetected in the absence of clinical symptoms.
Screening in asymptomatic populations.
According to several studies, screening for fetal renal pelvic diameter of 4 mm or more and then investigating the infants for VUR after birth is effective. Tsai et al,  reported renal sonography in 2,384 healthy asymptomatic neonates in Taiwan. They performed voiding cystourethrogram (VCUG) in those with moderate to severe hydronephrosis. VUR was diagnosed in 1.26%, with a male/female ratio 4:1. The sensitivity, specificity, positive and negative predictive values of ultrasound (US) for diagnosing VUR were 62.2%, 36.1%, 11.0% and 88.2%, respectively.
Anderson et al,  performed a communitybased study. A fetal renal diameter of 4 mm or more on a transverse view of the fetal renal hilum was found at obstetric sonography after 16 weeks' gestation in 426 fetuses from 9,800 consecutive pregnancies. Of these, 264 infants had postnatal sonography and VCUG at a mean age of nine weeks. Primary VUR was detected in 33 infants (13%) and secondary in another five (2%). Only five of the 33 babies would have been detected if a cut off point of 10 mm had been used.
Higher prevalence is found when VCUG is performed in infants with a prenatal diagnosis of renal pelvic dilatation. In the study of Kitagawa et al,  VUR was identified in 14% of such patients. Inclusive criteria were diameter of renal pelvis >4mm before 33 weeks of gestation and >7mm after 33 weeks of gestation. Dysplastic kidneys were excluded. This value included secondary VUR associated with ureterocele or posterior urethral valves (PUV). Horowitz et al,  detected reflux in 8.3% of 109 infants with prenatal diagnosis of hydronephrosis who underwent VCUG within the third month of life. Patients with dilated ureters, bladder wall thickening and underlying urological anomalies were excluded. The prevalence in black and nonblack population was 0 and 17.6 respectively. Thus racial differences may influence the decision of performing VCUG. With similar exclusion criteria in a population of 47 neonates with mild hydronephrosis, we reported a 29.7% prevalence of reflux. 
Since pyelectasis is often found in fetuses, and since it is difficult to establish a threshold to indicate the need for further evaluation, Avni et al  tried to determine whether meticulous ultrasound examination may help detecting VUR. Reviewing the characteristics of 35 neonates they concluded that the presence of a pelvic dilatation >7mm on a transverse scan together with at least one of several sonographic characteristics will permit to detect over 87% of VURs. The sonographic features are: calyceal or ureteral dilatation; pelvic or ureteral wall thickening; absence of the cortico-medullary differentiation and signs of renal dysplasia (small kidneys, thinned or hyperechoic cortex and cortical cysts). A normal urinary tract appearance does not seem usually to coexist with VUR. In such cases VCUG may not be necessary. However, there are reports of high grade reflux coexisting with normal sonogram. , Blane et al,  reported that 12% of children with grade V reflux, 31% with grade IV and 80% with grade III had normal renal ultrasound.
In conclusion, while prenatal screening may identify fetuses with dilated pelvis and probable VUR the definition of a cut-off point of fetal pelvic diameter for further evaluation by VCUG is still controversial. ,
A high prevalence of VUR has been found in asymptomatic siblings of children with reflux. In this case the likelihood of VUR is 26-46%. ,,, Newborns with mothers or siblings who had history of reflux have also a considerably higher prevalence of reflux. Scott et al,  carried out VCUG in newborns with mothers who had, or with family history of reflux. The proportion of newborn babies with VUR among linked index families was 31%.
Screening in children with urinary tract infections (UTI)
VUR is by far the most common urinary tract abnormality associated with UTI. A recent report of the American Academy of Pediatrics-Urinary Tract Subcommittee  identified 77 studies that reported the prevalence of VUR among children (2-24month-old) with UTI. Although the range of reported values varied widely among small studies the prevalence converged at 30-40% in large ones. The Subcommittee has recommended the necessity of imaging procedures in children 2-24-month-old with UTI, including both VCUG and ultrasonography (US). To our knowledge there are no recommendations considering children >2 years old at their first documented UTI. Yet we believe that in the presence of an abnormal US, further imaging diagnosis is warranted.
| Diagnosis|| |
The major reasons for initial evaluation are urinary tract infections, screening for a familial history, presence of other congenital malformations or prenatal diagnosis of pyelic dilatations.  The standard test is voiding cystourethrogam. This test has good anatomical definition, may grade the reflux and visualize bladder outlet and urethra. Furthermore, there is generally excellent agreement by pediatric radiologists in the interpretation of micturating cystography.  The alternative use of isotope cystogram reduces gonadal radiation, but anatomical details are not visualized. Thus, at first evaluation, VCUG seems to be the best choice, while radionuclide cystography may be used for periodic follow-up imaging. VCUG should document the voiding phase, since some reflux appears only during voiding. New techniques have proved useful in the diagnosis of reflux. Sonicated albumin  and galactose suspension  instilled intravesically may enhance sono-graphy.
In the initial and follow-up management, it is important to ascertain the presence of parenchymal damage. Renal growth, echoic differentiation and pelvic dilatation may be evaluated sonographically, but the definitive study is the cortical scan using technetium 99m labeled dimercaptosuccinic acid (DMSA), which localizes specifically in the proximal tubule depending on integrity of the tubular cells. DMSA scanning shows focal defects with high sensitivity  and is also used in the followup to ascertain the appearance of new scars and has been shown to be more sensitive than intravenous pyelography (IVP). ,,,
| Evolution of the Reflux|| |
Most VUR of the lower grades (I-III) will resolve spontaneously, while bilateral grade IV reflux has a low chance of spontaneous resolution. , Therefore conservative treatment is advisable in most cases, the goal being avoiding UTI. This can be achieved by continuous low dose antibiotic prophylaxis. Surgical correction (most commonly the Cohen cross-trigonal technique) is recommended in infants >1 year of age, if they have extensive scars at diagnosis or if they acquire new scars on follow-up; or in cases of breakthrough infections.  The International Reflux Study Committee compared, in a randomized prospective study, the progression of the renal damage after surgical repair or continuous antibiotic prophylaxis. The incidence of UTI was similar in the two treatment groups as reported in the European arm.  New renal scarring was found in 19 and parenchymal thinning in 11 of 155 children treated medically.  We generally recommend surgery in case of persistent high grade (IIIV) reflux after the age of five. However, since the long-term studies of follow-up did not prove any serious deterioration of renal function in adults even if reflux was not corrected during childhood, the option of more prolonged conservative management might also be reasonable. A corollary of our attitude is that we generally stop antibiotic prophylaxis at the age of six. There is no general recommendation on this. Although UTI seems more dangerous in the younger child and can more frequently cause scars, new scars can be acquired at older ages.  In follow-up studies in which antibiotic prophylaxis was suspended at puberty, several patients had persistent reflux, but no progression of renal damage was observed.  As an alternative to open surgery, endoscopic treatment of reflux has been available for a decade. The ideal material to be injected into the submucosa at the refluxing ureteral orifice has probably yet to be developed. Non-autologous substances, such as Teflon, collagen and Deflux and autologous substances such as fat, chondrocytes and muscle, have been used either clinically or are under investigation.  However, this practice is not universally accepted. 
VUR is often associated with a dysfunctional voiding syndrome (bladder instability, constipation and infrequent voiding). This may delay the spontaneous resolution of the reflux, cause breakthrough UTI and adversely affect the results of reimplantation.  Treatment of the dysfunction syndrome may conversely resolve the reflux.  Evaluation of voiding habits and specific treatment should be an integral part of the management of VUR.
| Reflux Nephropathy|| |
The term reflux nephropathy has been introduced to designate reflux associated renal damage. Bernstein and Arant  examined 25 complete and partial nephrectomy specimens from 21 patients with advanced reflux with severe renal atrophy and loss of parenchyma. They concluded that the linear scars are the results of single duct medullary disruptions, mediated perhaps through obstruction of several thousand nephrons subtended by each papillary duct and perhaps through localized disruption of the renal microvasculature. The abnormalities appear to evolve despite severe renal damage and atrophy. Various hypothesis have been put forward to explain the pathogenesis of reflux nephropathy (for discussion see Belman, 1997  ). Briefly, reflux had been first considered the result of elevated pressure due to obstruction of the lower urinary tract. Several patients with PUV or neurogenic bladder exhibit unilateral or bilateral reflux (bladder outlet obstruction theory).  This theory implies that nephropathy is acquired, no matter if antenatally or postnatally, and is caused by increased pressure in the ureter. This view was reinforced by the studies of Hodson et al, , who produced reflux in piglets by cutting back on the vesicoureteral junction and ensuring its persistence by creating a bladder outlet obstruction. Later, Ransley and Risdon  showed that in models where bladder obstruction had not been created, renal scarring could occur only after bacterial parenchymal infection. The bacterial theory is supported by clinical findings showing that in children with reflux, renal scarring followed episodes of urinary tract infection. In the studies of Smellie et al,  Edwards et al,  and Lenaghan et al,  sterile reflux was not associated with new or progressive renal scarring. These studies led to the important conclusion that continuous antibiotic prophylaxis could prevent renal damage. If urinary tract infection occurs during the first year of life then there is a 70% risk of renal parenchymal disease. Beyond this age, development of macroscopic kidney scars after UTI is less common but can still occur. ,
On the other hand there is compelling evidence that renal damage can occur in children who did not experience any UTI. Scars were found in asymptomatic siblings of children with reflux who were screened for reflux and found to exhibit the anomaly. ,,,, In the attempt to determine the incidence of vesicoureteral reflux and of renal damage in asymptomatic siblings of children with reflux at different ages, Connolly et al,  analyzed cystograms of 482 consecutively referred siblings of children with VUR (295 girls and 187 boys two weeks to 12.8 years old). The overall incidence of VUR was 36.5% (39.3% in girls and 32.1% in boys). Children 24 months or younger had the highest incidence (45.7%) of bilateral reflux. From ages 25 to 72 months the incidence of reflux was 33.1% and in siblings older than 72 months it was 7%. Renal damage was observed on sonography or scintigraphy in 4.7% of the siblings with reflux. Silent renal damage has also been found in siblings of children with reflux by other authors, albeit with different frequency. ,,
It is also clear that renal damage associated with reflux can be found at birth, or soon after, in infants showing hydronephrosis by fetal ultrasound. Renal hypoplasia may also be identified in utero. In these cases VUR is more often found in boys, is frequently gross, often bilateral and renal insufficiency may be present at diagnosis. The kidneys in these cases have been described as small with smooth contours, rather than segmentally scarred. ,,,, Anatomically, typical dysplastic elements were frequently associated with congenital reflux. Dysplastic structures generally consist of microcystic glomeruli, primitive ductules and scattered bizarre nephron formation. Such changes are much more extensive in children dying of uremia. 
Congenital reflux nephropathy: a new nosological entity?
Sometimes things need to be rediscovered. In the seventies Mackie and Stephens proposed the ureteral bud theory to explain the ectopic position of the ureteral orifice and the abnormal morphologies of the kidneys and ureters with reflux.  They proposed that a ureteral bud, which arises ectopically from the most caudal and expanding end of the wolffian duct, could be oversized and produce an orifice placed ectopically lateral to the normal limits of the trigone with a short or absent mucosal segment. The ectopic bud penetrates the nephrogenic cord caudal to the zone predestined for the metanephros. The kidney so formed from the scanty population of mesenchymal nephrogenic and stromogenic cells has smaller numbers of nephrons (hypoplasia) or abnormal nephrons and stroma (dysplasia).
The genetic origin of congenital reflux nephropathy
Familial screening and recognition of reflux in siblings has led to the conclusion that VUR is a genetic condition with phenotypic variation. The experience published in the literature has generally supported the concept of autosomal dominant inheritance and has been the basis of formal screening programs. ,,,,,,,, Noe et al,  identified 23 women of childbearing age with known history of reflux and screened their 36 offsprings with voiding cystourethrograms. Of these 36 offsprings, 24 (66%) exhibited vesicoureteral reflux. They concluded that there is a need to screen the offsprings of known reflux patients. These authors also reviewed the literature and evaluated 66 children of 29 affected adults. The overall rate of offspring reflux determined was 43 of 66 patients (65%) A slight increase was noted in the rate of reflux in female offsprings. In one report suggesting X-linked inheritance, three male siblings and the maternal grandfather all had reflux nephropathy. The mother and three siblings were unaffected, but may have been carriers by a process of Lyonization More Details. 
While vesicoureteral reflux can still be a multifactorial genetic trait with a major gene, consideration must also be given to an autosomal dominant inheritance pattern. Candidate genes for reflux and reflux nephropathy have been searched for by several authors. ,, Renal development is regulated by the complex expression of transcription factors, growth survival factors and adhesion molecules. Mutations of genes encoding the synthesis of these molecules cause urinary tract malformation in mice. Mutations were found in PAX 2, a paired domain containing gene, that is critical for urogenital development and which also regulates the development of the brain, eyes, lymphoid system, musculature, neural crest and vertebrae. Human mutations of PAX 3 cause Waardenburg syndromes (white forelock, deafness and facial dysmorphism) and PAX 6 mutations cause aniridia. During development of the renal tract, PAX 2 is expressed in the metanephros, the precursor of the adult kidney, in cell lineages that are forming nephrons, and also in structures destined to form the ureter, renal pelvis and branching collecting duct system. Functional knockout of this gene causes impaired metanephric growth and fewer nephrons than normal as well as megaureter, a finding consistent with gross VUR. ,, PAX 2 gene mutations have been reported in a family with optic nerve colobomas, renal abnormalities and vesicoureteric reflux.  Choi et al,  however were unable to find evidence for PAX 2 mutations in patients with primary VUR. The exclusion was not entirely definitive because only four of the twelve PAX 2 exons were analyzed although all mutations so far identified in PAX 2 had been found in these exons. These results suggest that PAX 2 mutations are not likely to be a major cause of familial primary VUR. However, the authors did not discount the possibility that PAX 2 could be mutated in families with hereditary VUR and visual anomalies.
The use of angiotensin converting enzyme (ACE) inhibitors in pregnant women, which is now avoided, provided tragic insights into the contribution of the renin-angiotensin system to renal ontogeny in developing humans. In addition to the high rate of fetal death, infants born to mothers treated with ACE inhibitors to control hypertension had increased rates of oligohydramnios (56%), hypotension and anuria (52%) as well as neonatal mortality (25%). The kidneys in these infants had structural abnormalities, including tubular dysplasia, persistence of interstitial mesenchyme, Bowman's space dilatation and glomerular immaturity.  Selective disruption of individual genes in the renin-angiotensin system may cause damage to renal development.  Koseki et al,  showed that apoptosis is significant for the normal development of the ureter. Failure or inadequacy of apoptosis of cells in the mesenchyma surrounding the stalk of ureteral epithelium may contribute to the disruption of normal ureteral growth and development. Indeed, angiotensin-type-2null-mutant mice show a spectrum of congenital urinary tract abnormalities, including ureteropelvic junction obstruction, multicystic dysplastic kidney, megaureter, vesicoureteral reflux and renal hypoplasia. In addition to the wide spectrum of abnormalities, a similarity to human congenital anomalies of the kidney and urinary tract in the angiotensin-type-2-null-mutant mice is suggested by male preponderance, since the angiotensin type 2 gene is located on the X chromosome.
| Follow-up of Reflux Nephropathy|| |
In the United States Renal Data System (USRDS) 1998 Annual Data Report,  120 out of a total 5,155 (2.3%) patients younger than 20 years and with end-stage renal disease were categorized as chronic pyelonephritis/reflux nephropathy. This means that although reflux nephropathy may be associated to renal insufficiency, progression to renal failure rarely occurs in infancy, childhood or adolescence. The proportion of children with congenital reflux and reduced renal filtration at birth (as a result of congenital reflux nephropathy) is reported around 5% of those with prenatal diagnosis and early postnatal management.  However these infants have been followed for too short a time to allow conclusions on their longterm prognosis.  A number of long-term follow-up studies have been published and they globally indicate that the risk for deteriorating renal function is attributable to severe damage at diagnosis, breakthrough infections with new-scar formation and development of hypertension. , Renal growth is reduced in the scarred kidney.  Hypertension may develop in less than 10% of patients even after spontaneous disappearance or surgical treatment of VUR,  however there is no relation between the development of hypertension and the degree of scarring.  The results published so far do not sustain the superiority of medical versus surgical approach in the treatment of VUR. Usually children treated for reflux either surgically or medically do well.  The results of the International Reflux Study  show that out of 287 children with severe reflux followed over five years, deterioration of renal imaging occurred in 48 children. There was no difference between the medical vs the surgical arm of the study and impaired renal function was more often seen in children entering the study when younger than two years old. Smellie et al,  recently reported data concerning 226 adults followed up for 10-35 years. Those with VUR but no scarring and carefully managed in childhood did not suffer serious consequences as adults. The Birmingham Reflux Study Group followed for five years 104 patients with reflux; two of them progressed to endstage renal failure and another four, with extensive bilateral renal scarring, became hypertensive. There were no significant differences between treatment groups in the incidence of breakthrough urinary infection, renal excretory function and concentrating ability, renal growth, and progression of existing renal scars or new scar formation. Progressive scarring occurred at all ages but was more common during the first two years of observation. Furthermore, new scars developed exclusively during the first two years of observation. 
| Conclusions|| |
Our knowledge on VUR has greatly augmented in the last several years. The genetic origin of VUR is sufficiently clear and some candidate genes are currently investigated for their importance in humanbeings. It is also clear now that congenital reflux nephropathy is a distinct disease and has an embryological origin. In some case congenital reflux nephropathy may be severe enough to cause renal insufficiency in infancy. This may be an important cause of chronic renal failure in childhood. Long term studies need to be performed. Some old questions however remain unanswered. Optimal management of VUR is still not a matter of consensus, scientific evidences being lacking. We believe that, among these questions, some at least deserve inquiry, namely medical vs surgical treatment of severe reflux, duration of antibiotic prophy-laxis in patients for whom surgery is not envisaged and management of adolescent girls with persistent reflux. Reflux is, in general, a benign condition with a tendency for spontaneous resolution. A minority of patients may present with small scarred kidneys although with normal renal function. These patients need to be closely followed-up owing to the risk of deterio-rating renal function and development of hypertension. Screening for VUR is feasible by meticulous ultrasound either prenatally or in early life, but whether screening in the general population is worth doing has not yet been established. We believe that sibling of an index case and all children with UTI need to be screened. We also recommend that VCUG be performed in all children <2 years old when a diagnosis of UTI has been firmly diagnosed.
| Acknowledgements|| |
The authors wish to thank Huon Snelgrove, University of Rome, for the revision of the manuscript.
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Baroukh Maurice Assael
Department of Pediatrics, University of Milano Medical School, Via Commenda 9, 20122 Milano
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