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Saudi Journal of Kidney Diseases and Transplantation
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EDITORIAL Table of Contents   
Year : 2003  |  Volume : 14  |  Issue : 2  |  Page : 123-128
Vesicoureteric Reflux


Department of Pediatrics, King Hussein Medical Center, Amman, Jordan

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How to cite this article:
Hazza I, Saca E. Vesicoureteric Reflux. Saudi J Kidney Dis Transpl 2003;14:123-8

How to cite this URL:
Hazza I, Saca E. Vesicoureteric Reflux. Saudi J Kidney Dis Transpl [serial online] 2003 [cited 2019 Dec 12];14:123-8. Available from: http://www.sjkdt.org/text.asp?2003/14/2/123/33020

   Introduction Top


Vesicoureteric reflux (VUR) is defined as the backward passage of urine from the bladder into the ureter, and sometimes into the renal pelvis, calyces and collecting ducts depen­ding on the severity of the disease. VUR can be secondary to abnormal bladder dynamics (high intra vesical pressure) such as urethral obstruction, neuromuscular disease and abno­rmal voiding patterns. In contrast, primary VUR is due to an inherited anatomical defect at the junction between the ureter and the bladder without underlying neuromuscular or obstructive condition. [1] Primary VUR is an important cause of morbidity during infancy and childhood, contributing to acute pyelone­phritis, hypertension, reflux nephropathy and end stage kidney disease (ESRD).

Significant maturation of the kidneys occur during infancy with the glomerular filtration rate (GFR) reaching adult levels by two years of age, thus the infant's kidneys are particu­larly vulnerable to damage during this period. [2] This emphasizes the importance of early dia­gnosis and management of VUR, as reflux nephropathy and progression to ESRD, the main concern in VUR, is believed to be pre­ventable. This review will focus on primary VUR in infancy and early childhood, and the therapeutic options available to treat this condition.

Prevalence

Primary VUR is a highly prevalent disease in infancy and childhood. It is estimated that approximately 1-2% of apparently heal­thy children have this condition. [2] It may occur unilaterally or bilaterally, and is the most common radiological finding in children with urinary tract infection (UTI); it is found in 30­50% of such children, of whom about 30% have radiological evidence of renal scarring. [3] Currently, reflux nephropathy accounts for 15- 25% of children with ESRD in the UK. [3],[4]

Pathogenesis of renal scarring

New scar formation in children with VUR has been well described by several authors. Intra-renal reflux of infected urine during an attack of UTI results in pyelonephritis and eventually in the development of the irregular and asymmetric scarring characteristic of reflux nephropathy. [3] However, this does not explain the finding of small scarred kidneys in some newborn babies with intrauterine hydronephrosis secondary to VUR, as these babies have renal scarring with no evidence of a preceding urinary tract infection (conge­nital renal dysplasia). [2],[3],[4]

It is more convenient, therefore, to describe two subgroups of patients with VUR; those born with abnormal kidney development in association with reflux, and those in whom scars develop later in the post natal life seco­ndary to infection. However, congenital and acquired renal scarring may coexist in the same patient and therefore this subdivision is not universally accepted.

Scar formation has been strongly linked to patient's age; it manifests more in infancy and early childhood, and becomes very rare after the age of 5 years. [5] It is postulated that urinary tract infection is associated with a 70% risk of renal parenchymal disease during the first year of life. [2] In addition, Smellie et al showed a link between the delay in diagnosis and treatment of UTI and the development of new renal scars. [6]

Renal scarring occurs during infancy and early childhood, but progressive deterioration of the scarred kidney may continue through­out life. Factors that contribute to the progress­ion of the disease include further scarring, uncontrolled hypertension and proteinuria, which often indicates the development of secondary glomerulosclerosis. [3]


   Diagnosis Top


VUR is often silent; symptoms and signs appear when complications occur. Diagnosis is usually made during radiological investiga­tions for an attack of UTI. Renal ultrasound, although highly informative, is operator depe­ndant and is not enough alone to diagnose VUR; moreover, ureteric and renal pelvic dila­tation in VUR may be intermittent and can be missed. [7]

Contrast micturitic cystourethrography (MCUG), is still considered as one of the most reliable investigations to diagnose reflux, and should be applied to all infants and children who present with UTI. [8] Despite being distre­ssing to both the child and the parents, it reliably diagnoses reflux, allows grading of the severity of reflux [Table - 1] and visualizes the bladder and the urethra. [7],[8] It is recommended that the MCUG be deferred for 2-3 weeks after the infection has subsided . However, evi­dence to suggest that the MCUG is more positive when conducted earlier is lacking.

Nuclear isotope cystogram is an alternative to the MCUG; it has the benefit of less radiation exposure. A direct isotope cystogram is usually necessary if the child is not toilet trai­ned; this requires the insertion of a catheter. In the toilet trained children, the indirect isotope cystogram is more physiological and does not require the insertion of a urethral catheter. [2],[8] In contrast to MCUG, the indirect isotope cystogram does not allow evaluation of the bladder and urethra. We find isotope nuclear cystograms very helpful for girls and in the follow-up of all the patients with VUR, but we require an initial MCUG for all boys less than the age of five years.

The radionuclide scan that uses dimercapto succinic acid (DMSA) can provide an image of both kidneys and an estimate of the contri­bution by each kidney to total renal function. This helps to outline the degree of renal scar­ring and parenchymal involvement. [7] However, it should be noted that when conducted early after acute UTI, it may show diffuse or patchy defects in isotope uptake, that often resolves over weeks or months and therefore not nece­ssarily indicate progression to renal scarr­ing. [3],[7],[8] To avoid confusion and over diagnoses of renal scarring, it is generally recommended to defer DMSA scan for at least 6 weeks and up to 3 months after the acute infection has subsided.

Infants who present with antenatally detected hydronephrosis should first undergo a postna­tal ultrasound. If hydronephrosis is persistent then the MCUG to rule out reflux should be done.

Management of VUR

The main concern in children with VUR is to prevent reflux nephropathy, which accoun­ts for 15-25% of children with ESRD in the UK. The risk of deterioration of renal function in patients with unilateral involvement and normal contralateral kidney is very small. On the other hand, children with bilateral severe reflux are at maximum risk of progre­ssion. [9] Management of the latter group of pati­ents is by far the most controversial, basically due to the lack of prospective randomized con­trolled trials comparing medical with surgical management of children with bilateral severe reflux and reflux nephropathy.

The long-term outlook of preserving renal function in patients with severe bilateral reflux has been well established in several studies to be linked to instituting effective measures to prevent ascending UTI. This can be accompl­ished by either surgical correction of the reflux or continuous antimicrobial suppressive prop­hylaxis.

The surgical correction by ureter re-implan­tation effectively abolishes reflux. However, evidence regarding its effect on decreasing recurrent attacks of UTI as well as on halting progression of renal scarring, or preventing new scar formation when compared with long term anti-microbial prophylaxis is not so strong. [3],[10],[11]

Knowing that reflux will eventually regress in most patients may implicate that some pati­ents are unnecessarily exposed to surgery. In addition, the ureter re-implantation has a signi­ficant morbidity. The evolution of newer techniques that are carried endoscopically to correct reflux including the suburothelial inje­ction of Teflon or collagen, offers a simpler procedure and a shorter hospital stay. How­ever, Teflon has recently been abandoned because of concerns about embolization of particles to distant sites, and collagen needs more evaluation before recommending its use, as there are concerns about the recurrence of reflux after months to years. [12]

Smellie et al recently published a randomi­zed trial conducted to compare medical and surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephro-pathy. [3] The primary endpoint of the trial was the change in GFR at four years of follow-up. The study failed to show any significant difference between the medically and surgically managed patients. However, the authors admitted that failure to detect a difference might be due to the small size of the samples, insufficient length of follow-up, or the fact that inclusion of children in the study promoted better management. We believe that the results of this trial support the previous reports made by the Birmingham Reflux study Group in 1987 [10] as well as the international study of reflux in children; [11] both studies showed no difference between the surgical correction and medical mana­gement. At present, there is a general con­ensus to manage VUR conservatively with prophylactic antibiotics [Table - 2]. However, ureter re-implantation should be conside­red in children with symptomatic breakth­rough infections or those who have structural abnormality of the urinary tract. [9]

The duration of the suppressive antibiotic therapy for children with VUR is also contro­versial. Some authors indicate that one year may be enough, while others suggest continu­ing therapy for five years or more. [13]

Once VUR is diagnosed and the initial work up is obtained, every effort should be made to prevent the occurrence of UTI. Early diagno­sis and institution of treatment cannot be over­emphasized, as late diagnosis and treatment has been shown to be an independent risk factor for new scar formation. [6]

Although obtaining routine urine cultures for asymptomatic patients is not currently recom­mended, it is important to obtain such speci­mens whenever there is any febrile illness, or whenever there is any symptom suggestive of UTI. [8] Furthermore, the medical management should focus on maintaining appropriate bladder and bowel habits as well as hygiene. This requires parent's cooperation, and comp­liance, which can only be achieved if proper explanation and information about the nature of VUR and the importance of UTI in renal scar formation are made accessible to parents.

In our current practice, infants and young children diagnosed to have VUR are given suppressive antimicrobial therapy until they are at least 5-6 years of age as long as VUR is persistent. We advocate a urinary ultrasound every year to monitor for kidney growth and cortical scarring. A DMSA scan and a nuclear isotope cystogram is obtained every other year. If kidney growth is normal and there is no renal scarring, and the reflux has subsided, then suppressive therapy is stopped, other­wise we continue suppressive therapy until the child is at least 5-6 years of age at which time suppressive therapy is discontinued regar­dless of the presence or absence of reflux, as the chance of new scar formation after this age has been shown to be very remote. If there is no renal scarring after this age then the child is discharged from the clinic. Follow up is continued for those with renal scarring to monitor blood pressure and renal function.

For children who present after the age of five years, a DMSA scan and a urinary ultrasound are obtained. If the ultrasound is abnormal then a contrast MCUG is obtained, otherwise we routinely perform a nuclear isotope cysto­gram. Those with VUR are put on suppressive therapy for one year, and then the DMSA and urinary ultrasound are repeated. If there is no new scar formation then the suppressive ther­apy is discontinued, however for those with evidence of new scar formation, suppressive antibiotics are continued for longer periods.

Recent aspects of VUR

Recently there has been growing and com­pelling evidence that VUR is and inherited disease with an autosomal mode of inherita­nce. About 50% of the siblings of an index case will turn out to have VUR. [14] Further­more, there is a high risk of VUR in the off­spring of individuals already known to have reflux. [2] Feather SA et al recently reported the first genome wide search of VUR and reflux nephropathy in seven families with an auto­somal dominant mode of inheritance and were able to map VUR to chromosome 1p13 locus. This region was significant in analyses for VUR or reflux nephropathy since both conditions may have the same genetic deter­minants. There was also evidence of genetic heterogeneity and 12 additional loci were identified. [4]

With the high prevalence of VUR in the ped­iatric population, these results suggest that it is one of the commonest genetic disorders that affect humans, and puts a special empha­sis on the importance of genetic counseling as well as adopting a well defined screening program for siblings of an index case. In the future, the finding of a reflux gene may have important implications on diagnosis and gene­tic screening by replacing invasive cystograms. [4]


   Conclusion Top


VUR is a highly prevalent disease of infancy and early childhood, with morbidity that exte­nds well into late childhood and adulthood. There is enough evidence to consider VUR an inherited disease with an autosomal domi­nant mode of inheritance. The main concern in management is the preservation of renal function. This can be done either by surgi­cally abolishing the reflux or by medically maintaining sterile urine. Currently the climate is changing in favor of conservative manage­ment for all grades of reflux, and regardless of whether there is concomitant renal scarring or not. Surgical reimplantation is reserved for selected patients. Early diagnosis and mana­gement are essential to prevent the occurrence of renal scars, and hence reflux nephropathy, and progression to ESRD.

 
   References Top

1.Rushton B. Vesicoureteral reflux and renal scarring. In: Holliday MA, Barrett TM, Avner ED, eds. Pediatric Nephrology (3rd ed). Baltimore: Williams and Wilkins 1994:963-86.  Back to cited text no. 1    
2.Vesicoureteric reflux: all in the genes? Report of a meeting of physicians at the Hospital for Sick Children GOS London, Lancet 1996;348:725-8.  Back to cited text no. 2    
3.Smellie JM, Barratt TM, Chantler C, et al. Medical versus surgical treatment in children with severe bilateral vesicoureteric reflux and bilateral nephropathy: a randomised trial. Lancet 2001;357:1329-33.  Back to cited text no. 3  [PUBMED]  [FULLTEXT]
4.Feather SA, Malcolm S, Woolf AS, et al. Primary, non-syndromic vesicoureteric reflux and its nephropathy is genetically heterogeneous, with a locus on chromosome. Am J Hum Genet 2000;66(4):1420-5.  Back to cited text no. 4    
5.Coulthard MG, Lambert HJ, Keir MJ, Lee RE. Detection of renal scarring in children using ultrasound. Clin Radiol 1999;54(7):486.  Back to cited text no. 5    
6.Smellie JM, Poulton A, Prescod NP. Retrospective study of children with renal scarring associated with reflux and urinary infection. BMJ 1994;308 (6938):1193-6.  Back to cited text no. 6    
7.Smellie JM, Rigden SP. Pitfalls in the investigation of children with urinary tract infection. Arch Dis Child 1995;72(3):251-5.  Back to cited text no. 7    
8.Stanley H. Urinary tract infections in children. Pediatr Clin North Am 1995;42:1433-55.  Back to cited text no. 8    
9.Warshaw BL, Hymes LC, Woodard JR. Long-term outcome of patients with obstructive uropathy. Pediatr Clin North Am 1982;29:815-26.  Back to cited text no. 9  [PUBMED]  
10.Birmingham Reflux Study Committee. Prospective trial of operative versus non­operative treatment of severe vesicoureteric reflux in children: five years' observation. Br Med J (Clin Res Ed) 1987; 295:237-41.  Back to cited text no. 10    
11.Smellie JM, Tamminen Mobius T, Olbing H, etal. The International Reflux Study Committee. Five-year study of medical or surgical treatment in children with severe reflux: radiological renal findings. Pediatr Nephrol 1992;6: 223-30.  Back to cited text no. 11    
12.Jones KV. Prognosis for vesicoureteric reflux. Arch Dis Child 1999;81: 287-9.  Back to cited text no. 12  [PUBMED]  [FULLTEXT]
13.Smeillie J. Urinary tract infection. In Textbook of Paediatrics (Campbell AGM & McIntosh N. Eds), Churchill Livingstone, Edinburgh, 1992,4 th edition, pp 1031-46.  Back to cited text no. 13    
14.Parekh DJ, Pope JC 4th, Adams MC, Brock JW 3 rd . Outcome of sibling vesicoureteral reflux. J Urol 2002; 167(1):283-4.  Back to cited text no. 14    

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Correspondence Address:
Issa Hazza
Department of Pediatric, King Hussein Medical Center, P.O. Box 143924, Amman 11814
Jordan
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PMID: 18209436

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