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PEDIATRICS Vol. 105 No. 6 June 2000, pp. 1236-1241
,,
From * Centre for Kidney Research, New Children's Hospital; and
Department of Public Health and Community Medicine, University of
Sydney, Sydney, Australia.
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ABSTRACT |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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Objective. It is believed that end-stage renal disease (ESRD) attributable to reflux nephropathy is preventable by the active treatment of vesicoureteric reflux in childhood with long-term antibiotics and ureteric reimplantation surgery. We aimed to test this belief.
Methodology. The Australia and New Zealand Dialysis and Transplant Registry of new patients 5 to 44 years of age treated for ESRD between 1971 and 1998, categorized by age and primary renal disease, was used to analyze the age-specific incidences of ESRD attributable to reflux nephropathy using a before-after study design. The early 1960s were regarded as the introduction period for the active treatment of childhood vesicoureteric reflux. A time-delay in treatment effect was expected. Patients with ESRD attributable to other causes were used as a comparative group.
Results. The incidence of ESRD attributable to reflux nephropathy and nonreflux nephropathy has increased. For reflux nephropathy, the rate of change was significantly associated with age, with a downward trend in incidence with decreasing age suggesting a minor treatment effect. This trend was no longer evident when adjustment was made for changing diagnostic practices. An opposite trend was observed for the nonreflux nephropathy group, who demonstrated an upward trend in incidence with decreasing age.
Conclusions. Treatment of children with vesicoureteric reflux has not been accompanied by the hoped-for reduction in the incidence of ESRD attributable to reflux nephropathy. A randomized trial with a control (no-treatment) arm is required to appropriately assess the medical belief that long-term antibiotics and surgery improve the natural history of vesicoureteric reflux. Key words: vesicoureteric reflux, end-stage renal disease, before-after study.
Urinary tract infection in children is a common health
problem, with a cumulative incidence of 2% to 8% by 10 years of
age.1,2 Vesicoureteric reflux has been consistently found
in approximately one third of children who have at least 1 urinary
tract infection.3-5 Human and animal data demonstrate
that urinary tract infection in the presence of vesicoureteric reflux
may cause acute pyelonephritis and renal scarring.6-12 On the assumption that the prevention of bladder and ascending kidney infections with long-term antibiotics and/or surgical correction of
vesicoureteric reflux will improve long-term outcomes, varying combinations of these 2 interventions have become standard clinical practice for children with vesicoureteric reflux. The year in which
Hodson and Edwards10 published the landmark article in
which they described the association between vesicoureteric reflux and
the scarred kidney, 1960, is widely regarded as the watershed year for
the modern management of this condition.11 They referred
to this condition as chronic pyelonephritis, but it has subsequently
been termed reflux nephropathy.12 The gradual introduction
of active treatment for childhood vesicoureteric reflux followed. From
1960, we could not identify any pediatric, pediatric nephrology,
pediatric urology review article or textbook, which has advocated
nontreatment of children with vesicoureteric reflux.13-15
We could not identify any published cohort or case series of children
with vesicoureteric reflux that has included a control,
observation-only group. Because of this prevailing medical belief that
treatment is effective, no controlled trial has been conducted to
determine whether treating children with vesicoureteric reflux improves
the natural history of this disease. Randomized, controlled trials have
instead only evaluated the relative effectiveness of medical and
surgical treatment.16,17
The outcome measures usually analyzed in clinical studies of
vesicoureteric reflux are recurrent urinary tract infection and renal
scarring.16,17 These adverse events are useful for studies
of short- to medium-term outcomes, but their long-term significance is
not known. Published guidelines advocate active treatment of
vesicoureteric reflux in childhood with the intention of preventing
what is clearly the most significant outcome To assess the effectiveness of the current practice guidelines for
children with vesicoureteric reflux as a prevention strategy for ESRD
later in life, we have conducted a before-after study to determine
whether there has been a fall in the incidence of reflux nephropathy
ESRD after the gradual introduction of active treatment of
vesicoureteric reflux from approximately 1960.
The Australia and New Zealand Dialysis and Transplant Registry
(ANZDATA) was used to obtain details of new patients commencing treatment for ESRD in Australia between January 1, 1971 and December 31, 1998.20,22 Data used for this study were age at
treatment commencement, year of entry to an ESRD program, and cause of
ESRD assigned by the attending physician, categorized as reflux
nephropathy or nonreflux nephropathy. In Australia, the details of
patients with ESRD treated by maintenance dialysis and renal
transplantation are recorded by ANZDATA Registry, which is funded by
the Australian Government and the Australian Kidney Foundation and has
been in existence since 1971. The Registry has 2 features important for
this study. First, there is a separate diagnostic category for reflux
nephropathy, which reflects a strong historical research interest in
this disease among Registry members. Between 1971 and 1973 (the year
the term reflux nephropathy entered the medical literature), there was
some retrospective classification of patients. Second, local conditions
favor complete reporting of treated patients to the Registry,
particularly in the age groups of interest. There is universal
participation by the relatively small number of renal units who provide
ESRD treatment in Australia (63 in 1999). The centralized nature of
certain procedures allows for crossvalidation of records. For example,
all states in Australia have regional tissue typing laboratories that
coordinate the national and statewide matching of donors and recipients
for kidney transplantation. These laboratories record the details of
all patients waiting for a kidney transplant or who have received a
transplant, and twice yearly these records are transferred to the
ANZDATA Registry for additional analysis. This system means that it is
not possible to be waiting for a kidney transplant or to have received
a cadaveric kidney transplant and not be on the ANZDATA Registry.
Certain features of the treatment of childhood vesicoureteric reflux
make the assessment of a causal effect on reflux nephropathy ESRD
difficult. Although we used 1960 as the year of introduction of active
treatment of vesicoureteric reflux, it was not possible to measure
directly the extent that active treatment was pursued in Australia. It
is likely that the treatment of children with vesicoureteric reflux
gradually changed from observation to active management with
antibiotics and surgical reimplantation.
Because early childhood The effect of early childhood treatment of vesicoureteric reflux on
ESRD is not abrupt. There is a lag phase that would correspond to the
age at which reflux nephropathy ESRD occurred Because of these 2 effects The potential effect of changing diagnostic practices was also
considered. For this analysis, patients with a diagnosis of renal
hypoplasia/dysplasia and pyelonephritis were combined with the reflux
nephropathy patients to give a composite reflux nephropathy group.
These categories were chosen for inclusion because they share many of
the clinical and radiologic features of reflux nephropathy. Patients
classified as reflux nephropathy may have been reported as renal
hypoplasia/dysplasia or pyelonephritis, depending on the year of
diagnosis.
The frequency of ESRD attributable to reflux nephropathy and nonreflux
nephropathy were divided by the appropriate populations at risk to give
the annual treated incidence rates per million population for each age
group. Australian population estimates were obtained from the
Australian Bureau of Statistics. To examine the relative rates of
change of ESRD incidence, the annual incidence rates were transformed
logarithmically and regressed against time for each combination of age
group and cause of ESRD to give a proportional change in annual
incidence. A test of interaction was used to determine whether slopes
varied by age for each primary renal disease category.
Since 1971, 7376 patients with ESRD between 5 and 44 years of age
with ESRD have been treated with maintenance dialysis and/or renal
transplantation. Reflux nephropathy was assigned the primary diagnosis
by the treating physician in 13.6% (1007/7376).
The age-specific incidences of reflux nephropathy ESRD and nonreflux
nephropathy ESRD from 1971 to 1998 are shown in Figs
1-4. Throughout, there has been no reduction in the incidence of ESRD. However, opposite trends were apparent for the 2 disease groups. Although the effect is small, the proportional change in annual incidence of reflux nephropathy ESRD was significantly modified by age
for the reflux nephropathy group (Table
1). In younger age groups, the trend for
incidence to increase by calendar year is absent. The largest
difference was between the 2 oldest age groups TABLE 1
end-stage renal
disease (ESRD), for which the only treatment is long-term
dialysis and transplantation.13-15,18 Reflux nephropathy
accounts for 7% to 17% of ESRD worldwide.19-21 Neither
the risk of a child with vesicoureteric reflux developing ESRD nor the
protective effect of early active treatment of vesicoureteric reflux is
known.
METHODS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
younger than 5 years of ageis the period
that intervention for vesicoureteric reflux is thought to be most
effective, a beneficial effect would only be observed in patients born
after 1960. Therefore, patients 35 to 44 years of age were regarded as
the pretreatment group. Details of patients older than 45 years of age
were not included because it has been demonstrated that changing
attitudes over this period have resulted in a substantial increase in
the number of older patients accepted into ESRD
program,23-25 which make it difficult to ascertain any
true change in incidence of ESRD for this age group. In comparison,
those patients between 5 and 44 years of age have always been regarded
as most favorable for treatment, and ascertainment will be most
complete for this age group.
shorter for young
patients and longer for older patients. To take account of this
age-dependent lag effect the posttreatment group were divided into 3 age categories: 5-14, 15-24, and 25-34 years of age. Children
younger than 5 years of age at the time of commencement of therapy were
not included because ESRD is rarely attributable to reflux nephropathy
in this age group. If treatment of childhood vesicoureteric reflux was
effective in reducing reflux nephropathy ESRD, there would be stepwise
reduction in reflux nephropathy ESRD with decreasing age. For example,
a beneficial effect of treatment would be evident earliest for the 5- to 14-year age groupfrom the early 1970s and would only occur
relatively latefrom the mid-1980sfor the 25- to 34-year age group.
the gradual introduction of active
treatment and the lag time to observe the first treatment effectit was not possible to predict the onset or point of maximal treatment effect with accuracy. Instead, we could only analyze the incidence of
reflux nephropathy and nonreflux nephropathy over the whole period,
assuming that a treatment effect would be most apparent in the youngest
age group and least apparent in the oldest age group. We used patients
with ESRD attributable to other causes as a comparative group within
each age group.
RESULTS
Top
Abstract
Methods
Results
Discussion
Conclusion
References
the before and after
treatment age group threshold. An opposite trend was apparent for the
nonreflux nephropathy groupthe slope of incidence on calendar year
was smaller in older age groups.
View larger version (12K):
[in a new window]
Fig. 1.
Incidence of ESRD attributable to reflux nephropathy and nonreflux
nephropathy in subjects 5 to 14 years of age: Australia, 1971-1998.
View larger version (12K):
[in a new window]
Fig. 2.
Incidence of ESRD attributable to reflux nephropathy and nonreflux
nephropathy in subjects 15 to 24 years of age: Australia, 1971-1998.
View larger version (11K):
[in a new window]
Fig. 3.
Incidence of ESRD attributable to reflux nephropathy and nonreflux
nephropathy in subjects 25 to 34 years of age: Australia, 1971-1998.
View larger version (11K):
[in a new window]
Fig. 4.
Incidence of ESRD attributable to reflux nephropathy and nonreflux
nephropathy in subjects 35 to 44 years of age: Australia, 1971-1998.
Slope of Regression Line for Log Incidence of ESRD for Reflux
Nephropathy and Nonreflux Nephropathy, on Year of Treatment for
ESRD
The use of pyelonephritis and renal dysplasia/hypoplasia as diagnostic
categories has changed significantly over the study. Thirty-four
patientsprimarily in the older age groupswere reported with a
primary diagnosis of pyelonephritis, and only 1 patient has been
reported since 1982. Hypoplasia/dysplasia was recorded as the primary
diagnosis for 91 patients, of whom 40 were younger than 14 years of
age. The effect of combining renal dysplasia/hypoplasia and
pyelonephritis is shown in Table 2.
Because of the relatively small numbers of patients with these
diagnoses, there was little change in the incidence of nonreflux
nephropathy (Table 2) or in the age-modifying effect on the association
between year of entry and the proportional change in ESRD incidence. In
comparison, for the combined reflux nephropathy group, there was no
significant age-associated difference in the proportional change in
ESRD incidence (Table 2).
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DISCUSSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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These data suggest that the introduction of an active medical and
surgical treatment policy for children with vesicoureteric reflux in
the 1960s has not been accompanied by an important reduction in the
incidence of ESRD attributable to reflux nephropathy. At best, there is
some evidence of a small treatment effect, with no important change in
incidence compared with the increase in other causes of ESRD. There was
a relative reduction in reflux nephropathy incidence that followed the
predicted age-associated lag time between childhood treatment of
vesicoureteric and the later development of ESRD. However, this
trend was explainable by changing diagnostic practices, because it was
no longer evident for the combined reflux nephropathy group. For this
group, which probably best represents the true reflux nephropathy
disease burden, there was no evidence of a reduction in ESRD or of any
other treatment effect. For the comparative groupnonreflux
nephropathy ESRDthere was also no evidence of a reduction in
incidence. The rate of change in incidence was consistently associated
with age, with a trend toward increasing incidence with decreasing age.
There is an alternative theory that may explain the
association among vesicoureteric reflux, reflux nephropathy, and
ESRD, but which removes the potentially preventable
componenturinary tract infectionfrom the equation. Since the advent
of antenatal sonography, it has become apparent that up to 30% of
newborn children with vesicoureteric reflux have renal damage that is
detectable before urinary tract infection has
occurred.26-29 This probably represents congenital renal
dysplasia/hypoplasia, which is not amenable to any form of postnatal
intervention. If this were the group of children who develop ESRD later
in life, it would not be surprising that active treatment has not
resulted in a fall in reflux nephropathy ESRD since 1960. Additional
supportive evidence that the primary pathogenic event in severe reflux
nephropathy is developmental can be found in family studies of
vesicoureteric reflux, the genetic basis of many malformation sequences
with coexistent renal dysplasia/hypoplasia and vesicoureteric reflux, and the embryology of normal kidney development. Renal damage is
present in 12% to 38% of siblings of children with vesicoureteric reflux, who also have vesicoureteric reflux but no history of urinary
tract infection.30-32 Traditionally, this has been
attributed to unrecognized urinary tract infection but may equally
reflect a common congenital and genetic basis of primary vesicoureteric
reflux and renal dysplasia/hypoplasia. This genetic defect has been
well-established for some human kidney malformations which share
vesicoureteric reflux and renal hypoplasia/dysplasia as part of the
phenotype.33,34 Embryologically, it is plausible why
vesicoureteric reflux and renal dysplasia/hypoplasia are frequently
associated. From 5 weeks, the developing human embryo kidney forms from
the complex interaction between the ureteric bud and the nephrogenic
mesenchyme.35 Considerable progress in the understanding
of kidney organogenesis has recently been made by the recognition of
many genesPAX2, RET, Wnt-4, EYA133-36which are
involved in the metanephric cell-ureteric branch interaction and
development. A defect in 1 or more of these genes or a currently unrecognized gene may explain a coexistent congenital ureteric abnormalityvesicoureteric refluxand a renal parenchymal
malformationhypoplasia/dysplasia.
Although these data support the conclusion that no beneficial effect of
treatment is evident over the past 30 years, the observational nature
of the study means that other explanations are possible and may
confound the true association between treatment of vesicoureteric reflux and ESRD attributable to reflux nephropathy. First, the prevalence of vesicoureteric reflux may have increased during the
study. This is difficult to assess because the true prevalence of
vesicoureteric reflux is not known. Although most authorities accept a
figure of <1%, published studies have reported a prevalence of
vesicoureteric reflux varying between 0% and 30%.37-45 The marked variation in prevalence can be attributed to variations in
the study populations and the diagnostic method used rather than the
year of the study. Second, these trends may represent changes in
ascertainmentreporting practices may have become more complete over
time. The structure of the ANZDATA Registry discussed in "Methods"
makes this explanation unlikely. Third, an increase in incidence of
reflux nephropathy ESRD may simply reflect a lower acceptance threshold
for ESRD treatment. This causes an apparent increase in the incidence
of ESRD and has been well-recognized.18-20 This
selection effect is most evident for the very young and the very old
and least evident for the young adults, who are the only age group
analyzed in this study. There may be some residual selection effect
within this age group as a whole, but it would be unlikely that
selection would explain the age-associated changes in incidence seen in
the nonreflux nephropathy group. Fourth, it is possible that despite
consensus in the medical literature during this time that children with
vesicoureteric reflux should be diagnosed and treated, this may not
have occurred. Quantitative assessment of the actual rather than
presumed treatment of children with vesicoureteric reflux over the past
30 years in Australia is not possible. A study of this type cannot
address all possible explanations for the observed increase in
incidence of ESRD attributable to reflux nephropathy. However, in a
medical climate that insists on treating children with vesicoureteric
reflux, preferable study designsrandomized, controlled trials or
prospective cohort studiesare not feasible.
How do these ANZDATA figures for the proportion of ESRD caused by reflux nephropathy compare with other dialysis and transplantation databases from other parts of the world? This comparison is difficult because of differences in the diagnostic and age categories used and variations over time. ANZDATA results are consistent with the Canadian46 and European47 (European Dialysis and Transplant Association) registries and a world-wide review,48 which all report ~20% to 25% of children younger than 15 years of age treated by dialysis or transplantation have reflux nephropathy or pyelonephritis as their primary diagnosis. For all age groups, these registries consistently report that ~5% of ESRD patients have reflux nephropathy or pyelonephritis.46,47 In comparison, the US database (US Renal Data System) reports that only ~2% of children with ESRD have reflux nephropathy and only .5% of patients of all ages with ESRD have reflux nephropathy has their primary diagnosis.49 This may reflect the wider variety of diagnostic categories used by the US Renal Data System or represent true differences in proportions. Hence, as we have done in this study, any time-dependent comparisons must be made within registries rather than among registries.
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CONCLUSION |
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Top
Abstract
Methods
Results
Discussion
Conclusion
References
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In summary, this study suggests that the currently advocated treatment of vesicoureteric reflux in children, which is invasive and costly, may be of no benefit in the prevention of ESRD. This is plausible if the primary pathogenic event in individuals who develop ESRD from reflux nephropathy is a congenital and developmental anomaly rather than an acquired event. These data imply that a reexamination of conventional treatment of vesicoureteric reflux in children is required. A randomized trial with a control, no-treatment arm is needed to appropriately evaluate the efficacy of current practice in the management of vesicoureteric reflux, an important childhood problem.
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ACKNOWLEDGMENTS |
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We gratefully acknowledge the support of the National Health and Medical Research Council and the Children's Hospital Fund. We also acknowledge the provision of data from the Australia and New Zealand Dialysis and Transplant Registry, particularly the kind assistance of Alex Disney, Brian Livingston and Lee Excell. We thank William Feldman, Denis Geary and Norman Rosenblum for critical reading of the manuscript.
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FOOTNOTES |
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Received for publication Oct 2, 1997; accepted Oct 26, 1999.
Reprint requests to (J.C.C.) Department of Nephrology, New Children's Hospital, Box 3515, Parramatta, NSW 2124, Australia. E-mail: jonathanc{at}health.usyd.edu.au
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ABBREVIATIONS |
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ESRD, end-stage renal disease; ANZDATA, Australia and New Zealand Dialysis and Transplant Registry.
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REFERENCES |
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Abstract
Methods
Results
Discussion
Conclusion
References
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1975-1989. In: Bailey RR, ed. Proceedings of the Second C. J. Hodson Symposium on Reflux Nephropathy. Christchurch, New Zealand: 1991:53-56This article has been cited by other articles:
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  M. Pennesi, L. Travan, L. Peratoner, A. Bordugo, A. Cattaneo, L. Ronfani, S. Minisini, A. Ventura, and for the North East Italy Prophylaxis in VUR study Is Antibiotic Prophylaxis in Children With Vesicoureteral Reflux Effective in Preventing Pyelonephritis and Renal Scars? A Randomized, Controlled Trial Pediatrics, June 1, 2008; 121(6): e1489 - e1494. [Abstract] [Full Text] [PDF]
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 G. Williams, J. T. Fletcher, S. I. Alexander, and J. C. Craig Vesicoureteral Reflux J. Am. Soc. Nephrol., May 1, 2008; 19(5): 847 - 862. [Abstract] [Full Text] [PDF]
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T. B. Newman Much Pain, Little Gain From Voiding Cystourethrograms After Urinary Tract Infection Pediatrics, November 1, 2006; 118(5): 2251 - 2251. [Full Text] [PDF]
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T. B. Newman Evidence Does Not Support American Academy of Pediatrics Recommendation for Routine Imaging After a First Urinary Tract Infection Pediatrics, December 1, 2005; 116(6): 1613 - 1614. [Full Text] [PDF]
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 I Moorthy, M Easty, K McHugh, D Ridout, L Biassoni, and I Gordon The presence of vesicoureteric reflux does not identify a population at risk for renal scarring following a first urinary tract infection Arch. Dis. Child., July 1, 2005; 90(7): 733 - 736. [Abstract] [Full Text] [PDF]
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A. Sandell Management of urinary tract infections in children: No evidence exists BMJ, December 6, 2003; 327(7427): 1346 - 1346. [Full Text]
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M. G Coulthard, S. J Vernon, H. J Lambert, and J. N S Matthews A nurse led education and direct access service for the management of urinary tract infections in children: prospective controlled trial BMJ, September 20, 2003; 327(7416): 656. [Abstract] [Full Text] [PDF]
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R A Gbadegesin, S A Cotton, B M Coupes, A Awan, P E C Brenchley, and N J A Webb Plasma and urinary soluble adhesion molecule expression is increased during first documented acute pyelonephritis Arch. Dis. Child., March 1, 2002; 86(3): 218 - 221. [Abstract] [Full Text] [PDF]
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T. B. Newman;, Wm. Lane, M. Robson, R. S. Van Howe;, M. F. Mangano;, and T. E. Wiswell Circumcisions: Again Pediatrics, August 1, 2001; 108 (2): 522 - 524. [Full Text] [PDF]
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