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The prevalence of vesicoureteric reflux (VUR) has been estimated to be 2% of the child population.1 In children with VUR demonstrated on micturating cystourethrography there is a tendency for the grade of VUR to improve or for VUR to disappear with time and with increasing age.2 3 VUR has been identified as a risk factor for the development of urinary tract infections (UTI) and is present in a third of young children presenting with this problem. In addition, it is a risk factor for renal scarring, otherwise called reflux nephropathy.4 5 VUR is also associated with renal dysplasia and other developmental abnormalities of the urinary tract.6 There is now abundant evidence for inheritance by an autosomal dominant mechanism.7
Pathogenesis of reflux nephropathy
Studies have suggested that reflux nephropathy develops following UTI in very early childhood or infancy.8 New scars have been observed relatively infrequently; however, there are sufficient case reports of new scar formation both on intravenous urography and using 99mTc DMSA scans to accept that at least a proportion of renal scars are acquired following UTI.9 10 The probability that most scars develop in this way cannot be proved because relatively few children have serial imaging studies; in particular, few children have had imaging investigations before the first UTI. The link between UTI, VUR, and renal scarring has been confirmed by several independent groups.4 11 Smellieet al have also demonstrated a link between delay in diagnosis and treatment of UTI and the development of new renal scars.9 12
Symptoms and signs of VUR and reflux nephropathy
VUR and reflux nephropathy are silent conditions that do not usually give rise to symptoms or signs except when complications such as UTI develop. They can only be detected by invasive tests that are not routinely carried out in healthy children and are not usually indicated during the acute phase of treatment. Thus knowledge of pathogenesis and natural history has been gleaned from observational studies and additional imaging investigations carried out on the advice of paediatricians in the belief that they are important for management.13 The evolution of reflux nephropathy is a slow process. Most renal scarring develops very early in childhood, but progressive deterioration of damaged kidneys may continue slowly throughout life. The relative contributions of congenital renal dysplasia, acquired reflux nephropathy, and the final common pathway of progressive glomerulosclerosis14 15 are difficult to disentangle in this group of patients. The development of proteinuria is indicative of progressive glomerulosclerosis and is a bad prognostic feature particularly when the patient also has hypertension.
A review of literature in the preantibiotic era suggests that chronic pyelonephritis was a very serious condition in children and adults. Weiss and Parker described a series of postmortem cases16: antecedent clinical features included recurrent fevers, presumably due to persistent untreated infection, anaemia, hypertension, growth failure, and pregnancy complications. There is evidence for a falling prevalence of this condition, which is probably due to a true reduction of reflux nephropathy because of modern medical care, particularly the treatment of acute pyelonephritis with antibiotics; alternatively the decline may represent changing fashions in disease classification. The historical aspects are discussed in detail by MacGregor17 who considered that VUR was crucial to the development of reflux nephropathy.
Long term outcome of VUR
In her elegant long term study Smellie describes the natural history of VUR in 226 children, 85 of whom had renal scarring modified by close medical supervision, including long term, low dose prophylaxis, advice on double micturition, treatment of intercurrent UTI, and management of hypertension.18 In addition 33 patients had surgical procedures (nephroureterectomy or reimplantation of the ureter, or both). Twenty (9%) had hypertension and six (4%) had chronic renal failure, two of whom reached end stage. New scars visible on intravenous urography developed in only a small proportion of the cohort and this was attributed to the benefits of careful medical supervision. The incidence of new scars is lower than in other studies,19-21 but the diagnosis of new scars is imprecise and subjective so that comparisons between studies are difficult. New scars have only rarely been seen to develop after the age of 4 to 5 years.22 If scars are acquired following UTI the prompt treatment of symptomatic episodes particularly in early childhood may be equally or even more important than long term preventative measures. The natural history of asymptomatic bacteriuria is not significantly different in terms of incidence of new scars, although many girls have prolonged periods of exposure to infection.19 23 The long gestation period for scar formation visible on intravenous urography makes it difficult to link new scars to specific episodes of infection.
Surgery for prevention of UTI and reflux nephropathy
Following the original observations by Hodson and Edwards24 of the strong association between UTI, VUR, and reflux nephropathy, surgeons developed operations to correct VUR in the belief that this would reduce the risk of recurrent UTI and prevent the development of reflux nephropathy.25 Although reimplantation of the ureter was quite successful for elimination of VUR, there was a significant complication rate26 and the overall risk of UTI was altered little by successful surgery.20 21 27 Similarly, successful surgery did not benefit glomerular filtration rate or prevent new scar formation. More recently a procedure involving the suburothelial injection of Teflon or collagen has been used to correct VUR endoscopically.28The success rate of this procedure in eliminating VUR is less than for surgery but the procedure is simpler and involves a shorter hospital stay. Long term benefits from this procedure on infection rates and new scar formation have not been evaluated. Teflon has now been abandoned because of concerns about embolisation of particles causing granulomas at distant sites; collagen has been found to be safe but benefits are not permanent and VUR may recur after a period of months or years.
Long term, low dose prophylaxis
An alternative approach to correction of VUR is the use of long term, low dose prophylaxis initially with cotrimoxazole or nitrofurantoin29 and later using trimethoprim. It was postulated that UTI usually develop as a result of ascending infection and that from time to time bacteria ascend the urethra and establish infection in the bladder or kidneys. A nightly dose of a broad spectrum antibiotic can sterilise the urine on a daily basis if the bacteria are sensitive to the drug chosen, reducing the chance that UTI can become established. Breakthrough infections can occur if the child’s gut and perineum are colonised with resistant organisms. Breakthrough with sensitive organisms suggests that prophylaxis has been omitted. There was evidence of effectiveness of this treatment in reducing the rate of reinfection in children with normal urinary tracts,30 but there are no controlled studies demonstrating that long term, low dose prophylaxis is superior to prompt treatment of UTI for the prevention of renal scarring. Thus the basis for widespread use of long term low, dose prophylaxis for the prevention of scarring is based on a hypothesis that has never been proved. Increasing resistance of organisms to trimethoprim raise doubts about effectiveness as a prophylactic agent in 1999. Nitrofurantoin is bitter tasting and less well tolerated than trimethoprim but the development of resistance is uncommon.
Because of the concern about development of reflux nephropathy, the Royal College of Physicians (RCP) published guidelines in 1991 on the diagnosis of UTI in childhood and recommended that imaging investigations should be carried out in every child following the first UTI,31 reflecting the view stated in theLancet 20 years previously.13The working group advised that all children should have an ultrasound examination and that a 99mTc DMSA scan should be carried out on all those younger than 7 years. Micturating cystourethrography was considered mandatory in children younger than 1 year. The indication for these tests was the high risk of VUR, around 30%, and the presumed risk of renal damage in these age groups. However, in the absence of good evidence for benefit from treatments and evidence of poor compliance with long term, low dose prophylaxis,32the benefits of imaging and long term treatment may not be as great as originally expected.
The imaging investigations recommended in the RCP guidelines are in effect screening tests as they are carried out in a high risk population after the acute illness has been treated successfully, in the hope that better knowledge of the underlying anatomy will improve future management and prognosis. Unfortunately, there is no evidence that the prognosis is altered by these tests or by the widespread use of long term, low dose prophylaxis or successful surgery. However, the use of published guidelines has provided a very useful step in the evaluation of current practice, as the guidelines are followed widely throughout the UK and it is now possible to audit and assess the outcome of this standard practice.33 Published studies suggest that many children do not have the recommended management.34
Stark, in 1997, challenged the view that these imaging tests are worthwhile and suggested that they are excessively costly and invasive without giving any benefit to most children.35 Tertiary specialists were heavily represented in the working group of the research unit of the RCP; their views and experiences represented the most severe end of the clinical spectrum of UTI and reflux nephropathy. In contrast, general practitioners and general paediatricians who see most children at the time of their first UTI were in the minority. Although there was no formal attempt to inform general practitioners of the guidelines some general practices are now referring large numbers of children for imaging investigations and a paediatric opinion following simple, non-febrile UTI. This has generated a massive workload for radiology departments and exposed large numbers of children to significant radiation without much evidence of benefit. The proportion of children seen with evidence of renal damage is lower than in earlier studies. This may be because UTI are diagnosed quickly in infants when they are referred to hospital,36 or it may reflect the fact that many more straightforward cases are being referred for further investigation. Unfortunately, there is continuing evidence of delay in diagnosis of UTI in infants and toddlers in primary care where urine collection is perceived as difficult,37 and some children have several consultations before the diagnosis of UTI is considered and further delays before it is confirmed.38
Practice in Sweden
In Sweden, children over 2 years old with simple UTI are not referred for imaging procedures unless there is an additional risk factor such as recurrent UTI or evidence of upper tract involvement.39 In spite of this practice, the prevalence of renal scarring is extremely low and there were no cases of chronic renal failure due to reflux nephropathy in a survey published in 1980,4 40 in contrast to the high incidence of VUR and reflux nephropathy in children in the UK.41 This has been attributed to the excellent facilities for the diagnosis of UTI in infants who are screened for UTI whenever they are febrile.42 The mean age for diagnosis of UTI in Sweden is during the 1st year of life in contrast to the UK where the mean age for diagnosis is around 4 years.
Need for controlled studies
Smellie and colleagues18 state that it would be unethical to carry out a randomised controlled study, and this may have been the view of most paediatricians at the time this study was started. However, now that the results of the two large prospective studies have failed to show superiority of either medical or surgical management, and there is mounting evidence that most scars are acquired very early in childhood, the climate of opinion may have changed. There is increasing pressure to establish the effectiveness of treatments and screening procedures both in the interest of the individual patient and in the interest of the National Health Service as a whole. Mounting costs of new and sophisticated treatments have focused the attention of clinicians, managers, and politicians on the need to ensure that money is well spent. The public is becoming aware of the adverse effect of widespread use of antibiotics on bacterial resistance and of the small but not negligible risk of side effects of drugs used long term. The newly established National Institute of Clinical Excellence will examine new treatments, but it is unlikely that it will be able to examine established practice in retrospect. The use of systematic reviews to provide busy clinicians with a summary of previous studies has also aided critical evaluation of current practice.43The outcome of the systematic review of management of VUR is awaited with interest.
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