the management of primary vesicoureteral reﬂux in children

Report onReport on

Clinical Practice Guidelines

The American Urological AssociationPediatric Vesicoureteral RefluxClinical Guidelines Panel

The Managementof PrimaryVesicoureteralReflux in Children

The Managementof PrimaryVesicoureteralReflux in Children

Jack S. Elder, MD(Panel Chairman)Director of Pediatric UrologyRainbow Babies/University HospitalProfessor of Urology and PediatricsCase Western Reserve University

School of MedicineCleveland, Ohio

Craig Andrew Peters, MD(Panel Facilitator)Assistant Professor of Surgery

(Urology)Harvard University Medical SchoolAssistant in Surgery (Urology)Children’s HospitalBoston, Massachusetts

Billy S. Arant, Jr., MDProfessor and ChairmanDepartment of PediatricsUniversity of Tennessee College of

Medicine—Chattanooga UnitMedical DirectorT.C. Thompson Children’s HospitalChattanooga, Tennessee

David H. Ewalt, MDClinical Assistant ProfessorDepartment of UrologyChildren’s Medical Center of DallasDallas, Texas

Charles E. Hawtrey, MDProfessor of Pediatric UrologyVice Chair, Department of UrologyUniversity of IowaIowa City, Iowa

Richard S. Hurwitz, MDHead, Pediatric UrologyKaiser Permanente Medical CenterLos Angeles, California

Thomas S. Parrott, MDClinical Associate Professor of

Surgery (Urology)Emory University School of

MedicineAtlanta, Georgia

Howard M. Snyder, III, MDAssociate DirectorDivision of UrologyChildren’s HospitalProfessor of UrologyUniversity of PennsylvaniaSchool of MedicinePhiladelphia, Pennsylvania

Robert A. Weiss, MDAssociate Professor, PediatricsDirector, Pediatric NephrologyNew York Medical CollegeValhalla, New York

Steven H. Woolf, MD, MPHMethodologistFairfax, Virginia

Vic Hasselblad, PhDStatisticianDuke UniversityDurham, North Carolina

Gail J. Herzenberg, MPAProject DirectorTechnical Resources International, Inc.Rockville, Maryland

Michael D. Wong, MSInformation Systems DirectorTechnical Resources International, Inc.Rockville, Maryland

Joan A. SaundersWriter/EditorTechnical Resources International, Inc.Rockville, Maryland

Pediatric Vesicoureteral Reflux Clinical Guidelines Panel Members and Consultants

The Pediatric Vesicoureteral Reflux Clinical Guidelines Panel consists of board-certified urologistsand nephrologists who are experts in vesicoureteral reflux in children. This Report on the Manage-ment of Primary Vesicoureteral Reflux in Childrenwas extensively reviewed by over 50 urologiststhroughout the country in the summer of 1996. The Panel finalized its recommendations for theAmerican Urological Association (AUA) Practice Parameters, Guidelines and Standards Committee,chaired by Joseph W. Segura, MD, in November 1996. The AUA Board of Directors approved thesepractice guidelines in November 1996.

The Summary Report also underwent independent scrutiny by the Editorial Board of theJournalof Urology, was accepted for publication in November 1996, and appeared in its May 1997 issue. AGuide for Parentsand Evidence Working Papershave also been developed; both are available fromthe AUA.

The AUA expresses its gratitude for the dedication and leadership demonstrated by the membersof the Pediatric Vesicoureteral Reflux Clinical Guidelines Panel and by the consultants affiliated withTechnical Resources International, Inc., in producing this guideline.

Members Consultants

ISBN 0-9649702-2-8

Page iiiCopyright © 1997 American Urological Association, Inc.

Vesicoureteral reflux refers to the retrograde flow of urine from the bladder into the ureter and, usu-ally, into the collecting system of the kidney. In most individuals, reflux results from a congenitalanomaly of the ureterovesical junction, whereas in others it results from high-pressure voiding sec-ondary to posterior urethral valves, neuropathic bladder or voiding dysfunction. Between 3–5 percentof girls and 1–2 percent of boys experience a urinary tract infection before puberty (Jodal and Winberg,1987). Approximately 40 percent of children with a urinary tract infection have reflux (Bourchier,Abbott and Maling, 1984; Drachman, Valevici and Vardy, 1984). Urinary tract infection is the mostcommon bacterial disease during the first 3 months of life (Krober, Bass, Powell, et al., 1985) andaccounts for approximately 6 percent of febrile illnesses in infants (Hoberman, Chao, Keller, et al.,1993). Reflux is a predisposing factor for pyelonephritis, which can result in renal injury or scarring,also termed reflux nephropathy. The most serious late consequence of reflux nephropathy is renal insuf-ficiency or end-stage renal disease. Between 3.1–25 percent of children and 10–15 percent of adultswith end-stage renal disease have reflux nephropathy (Arant, 1991; Avner, Chavers, Sullivan, et al.,1995; Bailey, Maling and Swainson, 1993). In addition, reflux nephropathy may result in renin-medi-ated hypertension and cause morbidity in pregnancy (Martinell, Jodal and Lidin-Jason, 1990).

The primary goals in the management of vesicoureteral reflux in children are to preventpyelonephritis, renal injury and other complications of reflux. Children with reflux may be managedeither medically or surgically. The rationale for medical management is prevention of urinary tractinfection with daily antimicrobial prophylaxis, regular timed voiding and, in some cases, anticholin-ergic medication. These children also undergo periodic screening of the urine for infection and radio-logic reassessment of the urinary tract for reflux and renal injury. Many children show spontaneousreflux resolution while receiving medical management. Surgical management of reflux consists ofrepair of the ureterovesical junction abnormality.

Although vesicoureteral reflux is common, there is disagreement regarding the optimal manage-ment, even among specialists caring for these children (Elder, Snyder, Peters, et al., 1992; InternationalReflux Study Committee, 1981). Because of the lack of consensus regarding management of thiscommon condition, the American Urological Association (AUA) convened a panel of experts todevelop treatment guidelines for children with vesicoureteral reflux. The panel was charged with thetask of producing practice recommendations based primarily on outcomes evidence from the scientificliterature. This Report on the Management of Primary Vesicoureteral Reflux in Childrenis the result ofthe panel’s efforts. The panel members represent various geographic areas, ages, professional activities(academic medical centers, private practice, health maintenance organizations) and expertise (pediatricurology, pediatric nephrology), allowing a broad perspective on the management of reflux.

The recommendations in this report are to assist physicians specifically in the treatment of vesi-coureteral reflux in children diagnosed following a urinary tract infection. The recommendations applyto children aged 10 years and younger with unilateral or bilateral reflux with or without scarring. Thereport therefore deals only peripherally with the diagnostic methods of identifying vesicoureteralreflux, renal scarring and management of children with reflux identified incidentally or by screening ofasymptomatic siblings. In addition, the report does not pertain to reflux associated with neuropathicbladder, posterior urethral valves, bladder exstrophy or fixed anatomic abnormalities, such as ectopicureterocele and ectopic ureter.

Because treatment recommendations are made jointly with the parents of the child,A Guide forParents,based on this report, is available to assist the physician in discussing treatment options withthe parents. A summary of this report has been published in the Journal of Urology, May 1997.

Introduction

Page iCopyright © 1997 American Urological Association, Inc.

Table of Contents

Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .iExecutive Summary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1

Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1Treatment alternatives and outcomes analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .1Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .3Literature limitations and research priorities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .4

Chapter 1: Pediatric vesicoureteral reflux and its management . . . . . . . . . . . . . . . . . .9Background . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .9Pathophysiology of renal injury . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .11Diagnosis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .12Treatment methods . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .13Surveillance and follow-up . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .15

Chapter 2: Methodology . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16Literature search . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .16Article selection and data extraction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17Limitations of the literature . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .17Combining the evidence . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18Dataset analysis . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .18Analytic process . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .19

Chapter 3: Outcomes analysis for treatment alternatives . . . . . . . . . . . . . . . . . . . . . . .20Intermediate outcomes and health benefits and harms . . . . . . . . . . . . . . . . . . . . . . . . . .20Analysis of data quality . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20Analysis of outcomes . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .20

Chapter 4: Treatment recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49Assumptions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49Special considerations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .49Recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .50Rationale for recommendations . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .54

Chapter 5: Research priorities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .56References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .59Appendix A: Literature review—Papyrus references . . . . . . . . . . . . . . . . . . . . . . . . . .66Appendix B: Data extraction form . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .73Appendix C: Methodology for combining parameters . . . . . . . . . . . . . . . . . . . . . . . . .75Appendix D: Recommendations questionnaire–Sample page . . . . . . . . . . . . . . . . . . . .78Appendix E: Data presentation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .79Index . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .87

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In developing recommendations for the manage-ment of primary vesicoureteral reflux in children,the AUA Pediatric Vesicoureteral Reflux GuidelinesPanel extensively reviewed the available literatureon the treatment of pediatric reflux from January1965 through December 1994 and extracted all rel-evant data to estimate as accurately as possibledesirable and undesirable outcomes of the alterna-tive treatment modalities. The panel followed anexplicit approach to the development of practicepolicies, supplemented by expert opinion. Thepanel synthesized the evidence using techniquesdescribed by Eddy, Hasselblad and Schachter(1992) and Cooper and Hedges (1994). Themethodology for these analyses was described byHasselblad (in press). For a full description of themethodology, see Chapter 2.

Vesicoureteral reflux refers to the retrogradeflow of urine from the bladder into the upper uri-nary tract. Reflux is a birth defect but also may beacquired. Vesicoureteral reflux predisposes an indi-vidual to renal infection (pyelonephritis) by facili-tating the transport of bacteria from the bladder tothe upper urinary tract. The immunologic andinflammatory reaction caused by a pyelonephriticinfection may result in renal injury or scarring.Extensive renal scarring causes reduced renal func-tion and may result in renal insufficiency, end-stagerenal disease, renin-mediated hypertension, reducedsomatic growth and morbidity during pregnancy.

The primary goals of treatment in children withreflux are to prevent renal injury and symptomaticpyelonephritis. Medical therapy is based on theprinciple that reflux often resolves with time. Thebasis for surgical therapy is that, in select situa-tions, ongoing vesicoureteral reflux has caused orhas a significant potential for causing renal injury

or other reflux-related complications and that elimi-nation of the reflux condition will minimize theirlikelihood. Chapter 1 documents the variousmethods of diagnosis, treatment and surveillanceand follow-up for children with primary vesi-coureteral reflux.

Grading of reflux severity is important becausemore severe reflux is associated with higher ratesof renal injury, and treatment success varies withreflux grade. The International Study Classificationis the most common and is the grading system usedin this report (International Reflux Study Commit-tee, 1981).

The panel considered 7 modalities as treatmentalternatives, including:

• No treatment (intermittent antibiotic therapy forUTI);

• Bladder training (including timed voiding andother behavioral techniques);

• Antibiotic prophylaxis (continuous);

• Antibiotic prophylaxis and bladder training;

• Antibiotic prophylaxis, anticholinergics (forbladder instability), and bladder training;

• Open surgical repair; and

• Endoscopic repair.Outcomes were identified as criteria by which

effectiveness of treatment would be analyzed (seeevidence matrix on page 21, Chapter 3), and thereview of evidence was organized around thisframework. The outcomes included intermediateoutcomes (those not directly perceived by thepatient or family but that are associated with orprecede health outcomes), health outcomes (effectsdirectly perceived in some way by patient orfamily), and harms of various forms of manage-ment. The following represents a brief summary of

Treatment alternativesand outcomes analysis

Background

Methodology

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Executive Summary:Management of primary vesicoureteral reflux in children

the statistical analysis that was conducted and thatformed the basis of the treatment recommenda-tions.

Intermediate outcomes

Reflux resolution—medical therapy(continuous antibiotic prophylaxis)

The database included 26 reports with data per-taining to reflux resolution after medical therapy,comprising 1,987 patients (1,410 girls and 304boys273 were not identified) and 2,902 ureters. Theindividual databases of Skoog, Belman and Majd(1987) and Arant (1992) and the data reported fromthe International Reflux Study, European Branch(Tamminen-Mobius, Brunier, Ebel, et al., 1992)were used to estimate the probability of reflux reso-lution with continuous antibiotic prophylaxis (seeFigure 3 on page 24, Chapter 3). In general, alower reflux grade correlated with a better chanceof spontaneous resolution. Data for Grades I and IIreflux showed no differences in regard to age atpresentation or laterality (unilateral vs. bilateral).For Grade III, age and laterality were importantprognostic factors, with increasing age at presenta-tion and bilateral reflux decreasing the probabilityof resolution. Bilateral Grade IV reflux had a par-ticularly low chance of spontaneous resolution. Allof these estimates are subject to 2 restrictions: (1)estimates are only valid for up to 5 years after diag-nosis; and (2) for Grade IV disease, estimates onlyapply to the time of diagnosis and are not age spe-cific. No data were available for reflux resolutionwith intermittent antibiotic therapy.

In children with reflux and voiding dysfunction(frequency, urgency, urge incontinence, incompletebladder emptying), available results from the serieswith control groups suggested that the reflux reso-lution rate increased with anticholinergic therapyand bladder training.

Reflux resolution—surgical therapyIn the articles reviewed by the panel, overall sur-

gical success was reported in 959 of 1,008 patients(95.1 percent) and 7,731 of 8,061 ureters (95.9 per-cent). Surgical success was achieved in 108 of 109ureters (99 percent) for Grade I, 874 of 882 (99.1percent) for Grade II, 993 of 1,010 (98.3 percent)for Grade III, 386 of 392 (98.5 percent) for GradeIV and 155 of 192 (80.7 percent) for Grade Vreflux.

For endoscopic therapy, most reports in the liter-ature describe results of the use of polytetrafluoro-

ethylene (Teflon™). Overall reflux was corrected in77.1 percent of ureters after a single injection.Reflux was resolved after initial treatment in only 6of 19 ureters (31.6 percent) with Grade V disease.Currently, no injectable substance has beenapproved for endoscopic antireflux surgery by theU.S. Food and Drug Administration.

Renal scarringThe panel felt that relevant data pertaining to

renal scarring should be analyzed primarily fromstudies with a minimum of 5 years of follow-up.Four prospective trials comparing the outcomes ofmedical and surgical management included analysisof new renal scarring (Birmingham Reflux StudyGroup, 1987; Elo et al., 1983; Olbing et al., 1992;Weis et al., 1992). None of these trials showed astatistically significant difference in the rate of newrenal scarring. In the European arm of theInternational Reflux Study, the rate of scarring wassimilar in patients receiving continuous antibioticprophylaxis and those treated surgically (Olbing,Claesson, Ebel, et al., 1992). However, 80 percentof the new renal scars in the surgical groupappeared by 10 months after randomization,whereas new renal scars appeared throughout the 5years in the group managed medically (Tamminin-Mobius, Brunier, Ebel, et al., 1992). TheBirmingham Reflux Study (1987) identified newscars after 5 years in only 6 percent and 5.2 percentof those treated medically and surgically, respec-tively, with no additional scars detected after 2years of follow-up. In the prospective study by theSouthwest Pediatric Nephrology Study Group ofchildren younger than 5 years of age with Grades I,II or III reflux, normal kidneys at entry and withcontinuous antibiotic prophylaxis, 16 percent devel-oped new scars (Arant, 1992). On the other hand,the International Reflux Study found new scars in15.7 percent (medical) and 17.2 percent (surgical)of refluxing children in Europe and 21.5 percent(medical) and 31.4 percent (surgical) in NorthAmerica (Olbing, Claesson, Ebel, et al., 1992;Weiss, Duckett and Spitzer, 1992). Few data wereavailable to analyze the relationship between bac-teriuria and new renal scarring in children withreflux.

Renal growth and functionOn the basis of studies available to date, there is

no evidence that renal growth is impaired inunscarred kidneys exposed to sterile reflux of anygrade or that surgical correction of reflux facilitatesgrowth of the kidney postoperatively. Surgical

Page 2 Executive Summary Copyright © 1997 American Urological Association, Inc.

correction of reflux stabilizes the glomerular filtra-tion rate but has not been shown to lead to long-term improvement.

Health outcomes

Urinary tract infectionThe panel reviewed 41 articles that described the

incidence of urinary tract infection in children withvesicoureteral reflux treated with antibiotic prophy-laxis or reimplantation surgery. In children withGrades III to IV reflux, the incidence of pyelo-nephritis was approximately 2.5 times higher inpatients treated with antibiotic prophylaxis than inthose treated surgically. The incidence of cystitis inpatients with vesicoureteral reflux was not signifi-cantly different in patients treated medically or sur-gically. In children treated medically, recurrentsymptomatic urinary tract infections were morecommon in children with voiding dysfunction thanin those with normal bladder function.

HypertensionIn the reports reviewed by the panel, no statisti-

cally significant difference was found in the risk ofhypertension related to treatment modality. How-ever, these studies indicated that renal scarringincreases the relative risk of hypertension to 2.92(95 percent confidence interval 1.2–7.1), comparedto the risk without renal scarring.

UremiaIt was not possible to demonstrate that even

optimal treatment of reflux and urinary tract infec-tion can prevent progressive renal failure and ulti-mately uremia after severe bilateral refluxnephropathy has been diagnosed.

Somatic growthNo evidence substantiated an effect of reflux

treatment on somatic growth.

Morbidity during pregnancyThe panel performed a limited search of perti-

nent literature pertaining to reflux, renal insuffi-ciency and adverse outcomes of pregnancy. Al-though the available data suggest a greater risk ofmorbidity from pyelonephritis in women who havepersistent reflux during pregnancy, the sample sizeis small and only limited conclusions can be basedon this evidence. The panel reviewed 5 studies thatdemonstrated that women with renal insufficiency

exhibit an increased incidence of toxemia, pretermdelivery, fetal growth retardation, fetal loss anddeteriorating renal function.

Harms of medical treatment

Adverse drug reactionsPotential adverse reactions to antimicrobial pro-

phylaxis include minor effects, such as skin rash,nausea, vomiting, abdominal pain, a bad taste inthe mouth, marrow suppression as well as moreserious side effects. Few studies dealing with themedical management of reflux included informa-tion on any drug reaction.

Harms of surgery

ObstructionA total of 33 studies provided rates of obstruc-

tion after ureteral reimplantation for reflux. Thelikelihood of obstruction in the 33 series rangedfrom 0 to 9.1 percent with a combined rate of 2percent in studies published after 1986. The reoper-ation rate ranged from 0.3 to 9.1 percent with anoverall prevalence of 2 percent. There was no dif-ference among various surgical techniques.

A total of 15 series provided detailed informa-tion about postoperative ureteral obstruction fol-lowing endoscopic treatment of reflux. The 15series included refluxing ureters treated using poly-tetrafluoroethylene or collagen as the injected sub-stance. Seven (0.40 percent) persistent obstructionswere reported.

Contralateral refluxThe development of contralateral reflux after

unilateral ureteral surgery has been reported innumerous series. Of 1,566 ureters considered atrisk there was an overall incidence of 142 reportednew cases (9.1 percent) of contralateral reflux. Thesurgical method of reimplantation did not influencethe likelihood of new contralateral reflux. Contra-lateral reflux generally resolves with time and sur-gical intervention is not usually recommended forat least 1 year.

The panel generated its practice policy recom-mendations on the basis of evidence-based out-comes and panel opinion, reflecting its clinical

Recommendations

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experience in pediatric urology and pediatric neph-rology. In this report, statements based on opinionare explicitly identified, and evidence-based recom-mendations are accompanied by appropriate refer-ences. Only a few recommendations could bederived purely from scientific evidence of a benefi-cial effect on health outcomes.

As a result, the recommendations were derivedfrom a panel survey of preferred treatment optionsfor 36 clinical categories of children with reflux.The treatment recommendations were classified asguidelines, preferred options and reasonable alter-natives. Treatment options selected by 8 or 9 of the9 panel members are classified as guidelines. Treat-ment options that received 5 to 7 votes are desig-nated as preferred options, and treatment optionsthat received 3 to 4 votes are designated as reason-able alternatives. Treatments that received no morethan 2 votes are designated as having no support.

AssumptionsThe recommendations listed on pages 5–7 are

intended to assist physicians specifically in thetreatment of vesicoureteral reflux in children diag-nosed following a urinary tract infection. Theyapply only to children 10 years and younger withunilateral or bilateral reflux and with or withoutscarring. The recommendations assume that thepatient has uncomplicated reflux (e.g., no voidingdysfunction, neuropathic bladder, posterior urethralvalves, bladder exstrophy or fixed anatomicalabnormalities).

Rationale for recommendationsSpecific treatment recommendations for children

with reflux with or without scarring are providedon pages 5–6. The panel’s overall recommendationsfor all children follow. The panel’s recommenda-tions to offer continuous antibiotic prophylaxis asinitial therapy are based on limited scientific evi-dence. Controlled studies comparing the efficacy ofcontinuous antibiotic prophylaxis and intermittenttherapy on health outcomes in children with refluxhave not been performed. However, the opinion ofthe panel is that maintaining continuous urinesterility is beneficial in reducing the risk of renalscarring and this benefit outweighs the potentialadverse effects of antibiotics.

Recommendations to proceed to surgery in chil-dren with reflux that has not resolved sponta-neously are supported by limited scientific evi-dence: open antireflux surgery is 95–98 percent

effective in correcting reflux, and in children withGrades III–IV reflux the risk of clinical pyeloneph-ritis is 2–2.5 times higher in children treated withcontinuous prophylaxis than in those treated surgi-cally. Nevertheless, randomized controlled trials ofsuch children have shown that most childrentreated medically do not develop a urinary tractinfection while receiving prophylaxis.

Recommendations for more aggressive treatmentof girls than boys (e.g., for persistent Grades III–IVreflux in school-aged children) are based on epi-demiological evidence that girls have a higher riskof urinary tract infection than boys. Recommenda-tions for more aggressive treatment of Grade Vreflux (e.g., surgical repair as initial therapy) arebased on panel opinion that such cases are unlikelyto resolve spontaneously over time, surgery iseffective in resolving severe reflux and these bene-fits outweigh the potential harms of surgery. Moreaggressive recommendations for children who haverenal scarring at diagnosis are based on panelopinion that such patients have a higher risk of pro-gressive scarring and decreased renal-functionalreserve.

An important variable in the scope of treatmentis the presence of voiding dysfunction, a commonoccurrence among children with reflux. Such chil-dren may require more aggressive treatment withanticholinergics and bladder training in addition toantibiotic prophylaxis. Surgical repair of reflux isslightly less successful in children with voidingdysfunction and, thus, a higher threshold is neces-sary before surgery is recommended in suchpatients. Consequently, children with reflux shouldbe assessed for voiding dysfunction as part of theinitial evaluation.

Limitations of the literatureThe panel attempted to rely on published evi-

dence whenever possible. Many studies thataddressed a particular issue could not be usedquantitatively in the various syntheses because ofinconsistent reporting of data, limited follow-up,incomplete description of treatments or poorlydefined patient populations. Analyses were alsocomplicated by the existence of at least 5 methods

Literature limitations and research priorities


(continued on page 8)

Executive SummaryCopyright © 1997 American Urological Association, Inc.

Treatment recommendations for children without scarring at diagnosis

Age at diagnosis: Infants (<1 year)

Initial treatment. Infants with Grades I–IV reflux should be treated initiallywith continuous antibiotic prophylaxis. In infants with Grade V reflux, continuousantibiotic prophylaxis is the preferred option for initial treatment.

Follow-up treatment. In infants who continue to demonstrate uncomplicatedreflux, antibiotic prophylaxis should be continued. For patients with persistentGrades I–II reflux after this period of prophylaxis, there is no consensus regardingthe role of continued antibiotic therapy, periodic cystography or surgery. Surgicalrepair is the preferred option, however, for patients with persistent unilateral GradesIII–IV reflux. Patients with persistent bilateral Grades III–IV reflux or Grade Vreflux should undergo surgical repair.

Age at diagnosis: Preschool children (ages 1–5 years)

Initial treatment. Preschool children with Grades I–II reflux or unilateralGrades III–IV reflux should be treated initially with continuous antibiotic prophy-laxis. Continuous antibiotic prophylaxis is the preferred option in preschool childrenwith bilateral Grades III–IV reflux. In patients with unilateral Grade V reflux, con-tinuous antibiotic prophylaxis is the preferred option for initial treatment, althoughsurgical repair is a reasonable alternative. In patients with bilateral Grade V reflux,surgical repair is the preferred option and continuous antibiotic prophylaxis is a rea-sonable alternative.

Follow-up treatment. In children who continue to demonstrate uncomplicatedreflux, antibiotic prophylaxis should be continued. In children with persistent GradesI–II reflux, there is no consensus regarding the role of continued antibiotic therapy,periodic cystography or surgery. Surgery is the preferred option for children withpersistent Grades III–IV reflux. Patients with persistent Grade V reflux shouldundergo surgical repair.

Age at diagnosis: School children (ages 6–10 years)

Initial treatment. School children with Grades I–II reflux should be treated ini-tially with continuous antibiotic prophylaxis. Continuous antibiotic prophylaxis isthe preferred option for initial treatment of patients with unilateral Grades III–IVreflux. In patients with bilateral Grades III–IV reflux, surgical repair is the preferredoption, although continuous antibiotic prophylaxis is a reasonable alternative.Patients with Grade V reflux should undergo surgical repair.

Follow-up treatment. In children who continue to demonstrate uncomplicatedreflux, antibiotic prophylaxis should be continued. In patients with persistent GradesI–II reflux after this period of prophylaxis, there is no consensus regarding the roleof continued antibiotic prophylaxis, periodic cystography or surgery. Surgery is thepreferred option for persistent reflux in children with Grades III–IV reflux.


Executive Summary Copyright © 1997 American Urological Association, Inc.

Treatment recommendations for childrenwith scarring at diagnosisAge at diagnosis: Infants (<1 year)

Initial treatment. Infants with scarring at diagnosis and Grades I–IV refluxshould be treated initially with continuous antibiotic prophylaxis. In infants withGrade V reflux and scarring, continuous antibiotic prophylaxis is the preferredoption for initial treatment, and surgical repair is a reasonable alternative.

Follow-up treatment. In infants who continue to demonstrate uncomplicatedreflux, antibiotic prophylaxis should be continued. In patients with persistent GradesI–II reflux after this period of prophylaxis, there is no consensus regarding the roleof continued antibiotic prophylaxis, periodic cystography or surgery. In boys withpersistent unilateral Grades III–IV reflux, surgical repair is the preferred option.Boys with persistent bilateral Grades III–IV reflux, girls with persistent GradesIII–IV reflux, and boys and girls with persistent Grade V reflux should undergo sur-gical repair.


Initial treatment. Preschool children with scarring at diagnosis and eitherGrades I–II reflux or unilateral Grades III–IV reflux should be treated initially withcontinuous antibiotic prophylaxis. Antibiotic therapy is the preferred option in chil-dren with bilateral Grades III–IV reflux and scarring, and surgical repair is a reason-able alternative. Surgery is the preferred option for patients with unilateral Grade Vreflux. Patients with bilateral Grade V disease and scarring should undergo surgicalrepair as initial treatment.

Follow-up treatment. In children who continue to demonstrate uncomplicatedreflux, antibiotic prophylaxis should be continued. In patients with persistent GradesI–II reflux after this period of prophylaxis, there is no consensus regarding the roleof continued antibiotic prophylaxis, periodic cystography or surgery. Girls with per-sistent Grades III–IV reflux and boys with persistent bilateral Grades III–IV refluxshould undergo surgical repair. Surgery is the preferred option for boys with persis-tent unilateral Grades III–IV reflux. For patients with persistent Grade V reflux whohave not undergone surgery as initial treatment, surgical repair is the preferredoption.

Age at diagnosis: School children (ages 6–10 years)

Initial treatment. School children with scarring at diagnosis and Grades I–IIreflux should be treated initially with continuous antibiotic prophylaxis. In childrenwith unilateral Grades III–IV reflux and scarring, antibiotic therapy is the preferredoption. Patients with bilateral Grades III–IV reflux or Grade V reflux shouldundergo surgical repair as initial treatment.

Follow-up treatment. In children who continue to demonstrate uncomplicatedreflux, antibiotic prophylaxis should be continued. In patients who have persistentGrades I–II reflux after this period of prophylaxis, there is no consensus regardingthe role of continued antibiotic prophylaxis, periodic cystography or surgery.Patients with persistent unilateral Grades III–IV reflux who have not undergonesurgery as initial treatment should undergo surgical repair.


Executive SummaryCopyright © 1997 American Urological Association, Inc.

Other recommendations for children with reflux

In children with vesicoureteral reflux, urethral dilation and internal urethrotomyare not beneficial. In addition, cystoscopic examination of the ureteral orifices doesnot appear to aid in predicting whether reflux will resolve. In children with symp-toms of voiding dysfunction, urodynamic evaluation may be helpful, but evocativecystometry is unnecessary in children with reflux and a normal voiding pattern.

In children with reflux who are toilet trained, regular, volitional low-pressurevoiding with complete bladder emptying should be encouraged. If it is suspectedthat the child is experiencing uninhibited bladder contractions, anticholinergictherapy may be beneficial.

The clinician should provide parents with information about the known benefitsand harms of available options, including continuous antibiotic prophylaxis,surgery and intermittent antibiotic therapy. The clinician should indicate to whatextent the estimates of benefits and harms are based on scientific evidence or onopinion and clinical experience. Given the general lack of direct evidence that anyone treatment option is superior to another (especially when total benefits, harms,costs and inconvenience are considered), parent and patient preferences regardingtreatment options should generally be honored.

In children for whom antireflux surgery is chosen, the panel does not recom-mend the endoscopic form of therapy because of the lack of proven long-termsafety and efficacy of the materials used for injection and the lack of approval ofsuch materials by the U.S. Food and Drug Administration.

Follow-up evaluation should be performed at least annually, at which time thepatient’s height and weight should be recorded and a urinalysis should be per-formed. If the child has renal scarring, the blood pressure should be measured. Indeciding how often to obtain follow-up cystography in children managed med-ically, the clinician should take into consideration the likelihood of spontaneousresolution (see Figure 3 on page 24, Chapter 3), the risk of continued antibioticprophylaxis and the risks of radiologic study. In general, cystography does notneed to be performed more than once per year.

used for grading reflux, nonuniformity in character-izing reflux grade and patient population, and lackof a standard method for reporting outcomes. Only3 prospective randomized controlled trials com-pared medical to surgical therapy—the Birming-ham Reflux Study (1987), the International RefluxStudy in Children (Olbing, Claesson, Ebel, et al.,1992; Weiss, Duckett and Spitzer, 1992), and astudy from Erasmus University, Rotterdam, TheNetherlands (Scholtmeijer, 1991). The literature oncertain issues, such as complication rates of surgeryand adverse drug reactions, was limited and insome cases so sparse that judgments were made onthe basis of expert opinion.

Research prioritiesThe panel identified many research areas as

needing further investigation. Presently, there islittle information regarding health outcomes per-taining to reflux, and a significant priority shouldbe to continue to acquire this information.

Basic research into the pathogenesis as well asthe genetics of vesicoureteral reflux is needed.Further randomized controlled trials studying therole of medical and surgical therapy using dimer-captosuccinic acid scan for evaluation of renal scar-ring are indicated. Future studies should stratifyresults by patient gender, age and reflux grade,reporting reflux resolution both by rate of ureteraland patient resolution. Also worthwhile would bestudies to confirm the panel’s finding that resolu-tion of Grade III reflux depends on patient age orlaterality (unilateral vs. bilateral) and the finding

that resolution of Grades I and II reflux does notdepend on age or laterality.

The extent to which reflux increases the risk ofrenal scarring associated with urinary tract infec-tion and the mechanism of this effect deservesinvestigation. Comparison of the efficacy of inter-mittent and continuous antibiotic therapy would bebeneficial. The role of voiding dysfunction in thepathogenesis of reflux and its risk on reflux compli-cations, such as renal scarring and the complica-tions of surgery, also deserve further investigation.Matched controlled studies of anticholinergictherapy and bladder training on reflux-related out-comes in children with voiding dysfunction arenecessary.

Less traumatic methods of determining whetherreflux is present should be developed as well astechniques of voiding cystourethrography thatresult in less radiation exposure. Analysis of thecosts of reflux treatment and surveillance is impor-tant, particularly comparing those associated withmedical and surgical therapy. The impact ofscreening at-risk populations and early medical orsurgical intervention on reflux-related outcomes insuch patients should be analyzed.

Development of minimally invasive techniquesof antireflux surgery is indicated. Newer materialsthat can be used for endoscopic subureteral injec-tion and that are safe in children should be studied.

The natural history of vesicoureteral reflux inadult women with persistent reflux deserves investi-gation, including an analysis of the morbidity ofpersistent reflux, and need for and efficacy of pro-phylaxis in pregnant and nonpregnant women.


Vesicoureteral reflux (VUR or “reflux”) refers tothe retrograde flow of urine from the bladder intothe upper urinary tract. Normally, the ureter isattached to the bladder in an oblique direction, per-forating the bladder muscle (detrusor) laterally andproceeding between the bladder mucosa anddetrusor muscle (the “intramural” or submucosaltunnel) before entering the bladder lumen. As thebladder fills, the ureteral lumen is flattened betweenthe bladder mucosa and detrusor muscle, creating aflap-valve mechanism that prevents VUR. Refluxoccurs when the submucosal tunnel between themucosa and detrusor muscle is short or absentand/or there is weak detrusor backing (Figure 1,page 10). In general, the severity of reflux corre-lates with the degree of deformity of the uretero-vesical junction. Reflux is usually a birth defect. Insome cases, reflux will disappear as the childgrows. Reflux was described in the writings ofGalen (Polk, 1965) and da Vinci (Lines, 1982). Itwas not until the observations of Hutch in 1952,however, that the relationship between reflux andacute pyelonephritis was appreciated (Hutch,1952).

VUR predisposes an individual to renal infection(pyelonephritis) by facilitating the transport of bac-teria from the bladder to the upper urinary tract.The inflammatory reaction caused by a pyeloneph-ritic infection may result in renal injury or scarring.Extensive renal scarring impairs renal function andmay result in renin-mediated hypertension, renalinsufficiency, end-stage renal disease (ESRD),reduced somatic growth, and morbidity duringpregnancy.

VUR may be primary or secondary. PrimaryVUR refers to reflux resulting from an anatomicdeformity of the ureterovesical junction without acausative urinary tract abnormality that may causereflux. Secondary VUR can result from increasedbladder pressure (e.g., detrusor-sphincter discoordi-nation, neuropathic bladder, posterior urethralvalves), which destabilizes the ureterovesical junc-tion; abnormal attachment of the ureter (ectopic

ureter); or associated lower urinary tract abnormali-ties (e.g., ectopic ureterocele, prune belly syn-drome, bladder exstrophy) that affect ureteral inser-tion.

The prevalence of reflux in healthy children isunknown but is estimated to be 1 percent (Arant,1991). In 1993, in the United States approximately15,000 individuals under 15 years of age wereadmitted to the hospital for a total of 62,000 days fortreatment of pyelonephritis, and reflux was present inapproximately 40–50 percent of these patients (U.S.Department of Health and Human Services, 1993).

Approximately 44,000 children are treated (inpa-tient and outpatient) for urinary tract infection(UTI) associated with VUR each year in the UnitedStates (Woodwell, 1993). Woodwell (1993)observed that of the 9.8 million outpatient visitsmade to urologists annually, 492,000 (5 percent ofurologic practice) involve the health of childrenunder age 15. Of these children seen for a varietyof urinary complaints, 369,000 were boys and123,000 were girls under 15 years. Other data(based on the 9.8 million reported visits) suggestedthat voiding symptoms, urine abnormalities, painfulurination, enuresis, bladder symptoms, and UTI (allsymptoms not initially related to a diagnosis ofVUR) account for 3 million visits to urologists andrepresented 25.6 percent of symptoms requiringevaluation. Assuming uniform distribution of thesecomplaints within urologic practice, 125,952 visits(492,000 2 0.256 = 125,952) to urologists caringfor children would encompass the symptoms listedabove. Data from Lindberg, et al. (1975) estimatethat 20 percent of symptomatic individuals willhave reflux; therefore, 25,190 visits a year to urolo-gists would include encounters for care and assess-ment of reflux (125,952 2 0.2 = 25,190). HealthCare Financing Administration data indicate thatVUR is diagnosed in 7,000–14,000 hospitalizedpatients, and that 2 to 3 times as many children areseen as outpatients for evaluation and treatment ofreflux.

The typical patient with VUR is a child youngerthan 10 years old who develops a UTI, either clin-ical pyelonephritis with fever, abdominal/flankpain, malaise and/or nausea, vomiting, or cystitis

Background

Page 9Copyright © 1997 American Urological Association, Inc.

Chapter 1:Pediatric vesicoureteral reflux and its management

with dysuria, frequency, urgency, and often urgeincontinence. Neonates and infants with VUR andpyelonephritis may have nonspecific symptoms.

The average age for diagnosis of reflux in chil-dren is 2–3 years. Approximately 75–80 percent ofchildren with primary reflux diagnosed following aUTI are girls, presumably because the incidence ofUTI in girls is greater than in boys after 6 monthsof age. The mean age for the onset of UTI in chil-dren is 2–3 years, corresponding to the average agewhen toilet training occurs. It is thought, by some,that during the process of toilet training, bladder-sphincter dyssynergia occurs, which predisposes toUTI, allowing children who also have VUR to bediagnosed.

A substantial proportion of children with VURhave incomplete maturation of bladder function,with symptoms of bladder instability characterizedby urgency, frequency, and diurnal incontinence(van Gool, Hjalmas, Tamminen-Mobius, et al.,1992; Koff, 1992). Because the associated highintravesical pressures can contribute to reflux,assessment of voiding habits is important in evalu-ating children with VUR.

In recent years, reflux has been discovered pre-natally by detection of fetal hydronephrosis,although the diagnosis of VUR is not made until

postnatal studies are performed. Approximately 80percent of these neonates are boys (Elder, 1992),and most have more severe reflux than do femaleswith VUR discovered after UTI. This phenomenonmay result from higher voiding pressures in maleinfants (and presumably fetuses) than in females(Hjalmas, 1976; Sillen, Bachelard, Hermanson, etal., 1996).

Reflux appears to be an inherited trait. Forexample, in 1 study of 354 siblings of 275 knownpatients with prior diagnosis of reflux, 34 percenthad reflux, and 75 percent of these children wereasymptomatic (Noe, 1992). In that study, 13 per-cent of siblings with reflux already had evidence ofrenal scarring, and 66 percent of these children hadnot had a documented UTI. In addition, as many as67 percent of offspring of women with reflux alsohave reflux (Noe, Wyatt, Peeden, et al., 1992).Reflux is less common in African-American than incaucasian children (Skoog and Belman, 1991).

Reflux severity can be graded (Figure 2). Refluxgrade is important because more severe reflux isassociated with higher rates of renal injury, andtreatment success varies with reflux grade. In addi-tion, the reflux grade is an indirect indication of thedegree of abnormality of the ureterovesical junc-tion. Numerous grading systems have been used.

Page 10 Copyright © 1997 American Urological Association, Inc.

Figure 1.

A B

(A) Normal ureterovesical junction. Demonstration of length of intravesical submucosalureteral segment. (B) Refluxing ureterovesical junction. Same anatomic features as nonre-fluxing orifice, except for inadequate length of intravesical submucosal ureter, are shown.Some orifices reflux intermittently with borderline submucosal tunnels (Politano, 1975).

Intramuralureter

Submucosalureter

Reflux

Possible reflux

No reflux

The most common classifications are shown inTable 1. These classifications are based on a stan-dard contrast voiding cystourethrogram. TheInternational Study Classification, which wasadopted by the International Reflux StudyCommittee in 1981, is the most common and is thegrading system used in this report.

The likelihood of renal injury after a UTIdepends on bacterial virulence factors, the presenceor absence of reflux, adherence characteristics of

the uroepithelium, anatomic characteristics of theinfected kidney, and host inflammatory response.During infection, certain bacteria, particularly thosewith P-fimbria, may ascend the ureter and enter therenal pelvis and calyces. Bacterial ascent is pro-moted by the presence of reflux. Intrarenal reflux(reflux from the minor calyx into the collectingduct) of infected urine results in renal parenchymalinfection (pyelonephritis). In previously normalkidneys, this initial infection often occurs in theupper or lower poles, because these typically con-tain compound papillae that favor intrarenal reflux(Ransley and Risdon, 1979). Bacteria often producean endotoxin, which causes a cellular and humoralimmune response as well as an inflammatoryresponse (Roberts, 1992). The sequel of the hostreaction is renal parenchymal fibrosis, a renalinjury termed reflux nephropathy.

Pathophysiology ofrenal injury


Table 1. Common classifications of vesicoureteral reflux

Description Grade/classification

International Study Classification1 0 I II III IV VDwoskin-Perlmutter 0 1 2a 2b 3 4Birmingham 0 1 2 3Australia/NZ Mild Moderate SevereGreat Britain I II III IV

(Voiding) (Filling and voiding) (Dilatation)

1 Classification used in this Report.

Figure 2.

I II III IV V

International Study Classification (International Reflux Study Committee, 1981)

Reflux is an important risk factor for developingpyelonephritis. Pyelonephritis occurs in childrenwith and without VUR, as well as in children inwhom reflux has resolved spontaneously and inchildren whose reflux is undetected on a voidingcystourethrogram. In children who develop pyelo-nephritis, renal scarring results in as many as 40percent (Rushton and Majd, 1992). Childrenyounger than 5 years old appear to be at greatestrisk of renal injury from pyelonephritis, but olderchildren also may develop renal scarring. In 1report of 34 children older than age 5 who hadnormal kidneys and who later developed renal scar-ring, nearly all had both UTI and reflux (Smellie,Ransley, Normand, et al., 1985).

In the neonate with prenatally diagnosedhydronephrosis, medium- or high-grade refluxoften is diagnosed. In some of these neonates, typ-ical patterns of renal scarring are found eventhough no bacteriuria is present. The cause of therenal abnormality is uncertain but may be sec-ondary to abnormal induction of the metanephricblastema by the ureteral bud (Mackie and Stephens,1975) and/or possibly high voiding pressuresduring renal development.

Although reflux associated with bacteriuria maycause renal scarring, sterile VUR is not thought toresult in renal injury unless abnormally elevatedbladder pressures exist (i.e., with posterior urethralvalves, neuropathic bladder, bladder outlet obstruc-tion, or detrusor-sphincter dyssynergia) (Ransleyand Risdon, 1979).

In most cases, reflux is diagnosed during evalua-tion of a UTI. In some cases reflux is diagnosed“incidentally” during screening of patients at risk,for example, those who have a sibling with reflux(Noe, 1992; Wan, Greenfield, Ng, et al., 1996), amother with reflux (Noe, Wyatt, Peeden, et al.,1992), a multicystic kidney (Selzman and Elder,1995) or hydronephrosis (Elder, 1992).

The panel did not undertake a formal evaluationof the radiologic literature regarding the accuracyof various methods of diagnosing reflux ordetecting upper urinary tract changes secondary toor associated with reflux, because these considera-tions were deemed outside the scope of treatmentguidelines in a child with VUR.

Diagnosis of VUR requires catheterization of thebladder, instillation of a solution containing iodi-nated contrast or a radiopharmaceutical and radio-logic imaging of the lower and upper urinary tract,termed a voiding cystourethrogram (VCUG) orradionuclide cystogram, respectively. The bladderand upper urinary tracts are imaged during bladderfilling and voiding. Reflux occurring during bladderfilling is termed low-pressure or passive reflux, andreflux occurring during voiding is termed high-pressure or active reflux. Children with passivereflux are less likely to show spontaneous refluxresolution than children who exhibit only activereflux (Mozley, Heyman, Duckett, et al., 1994).Radiation exposure during radionuclide cystog-raphy is less than with standard contrast cystog-raphy. In the past, many children underwent cys-tography under general anesthesia. However, thismethod is flawed because normal micturition doesnot occur under anesthesia. Other methods fordetecting reflux, such as indirect cystography andrenal ultrasound, are thought to be less accurate(Blane, DiPietro, Zerin, et al., 1993; de Sadeleer,de Boe, Keuppens, et al., 1994).

Assessment of upper urinary tractThe goal of upper tract imaging is to assess

whether renal scarring and associated urinary tractanomalies are present. In a child with VUR, theupper urinary tract can be evaluated by one of sev-eral techniques, including renal cortical scintig-raphy (renal scan), excretory urography (intra-venous pyelography, or IVP), and renal ultrasound.Radiopharmaceuticals used for renal scanninginclude dimercaptosuccinic acid (DMSA), gluco-heptonate, and mercaptoacetyltriglycine (MAG-3).On an IVP, renal scarring is evident from reductionin the thickness of the renal cortex. Several specificpatterns of renal scarring have been described(Smellie, Edwards, Hunter, et al., 1975). Renalsonography, a noninvasive method of evaluating thekidney, can show hydronephrosis, renal duplicationwith an obstructed upper pole and gross renal scars.The surface areas of the kidney on renal sonog-raphy roughly correlate with differential renal func-tion (Sargent and Gupta, 1993).

Following an episode of pyelonephritis, renalscarring usually is apparent on scintigraphy within3 months, but may not be apparent on an IVP orsonography until 1–2 years later.

Diagnosis


Assessment of lower urinary tractThe goal of lower urinary tract assessment is to

determine whether the bladder empties satisfacto-rily, whether a bladder abnormality such as a para-ureteral diverticulum is present, and in males, toassure that no bladder outlet obstruction such asposterior urethral valves is present. This informa-tion is often obtained from the voiding cysto-urethrogram. At times, bladder trabeculation maybe present and suggest that voiding dysfunction ispresent. Cystoscopic examination of the ureteralorifices has not been helpful in predicting whetherspontaneous resolution of a child’s reflux is likely(Bellinger and Duckett, 1984; Mulcahy and Kelalis,1978). Evocative cystometry also does not appearto provide useful information in children withnormal voiding function. However, urodynamicsmay be beneficial in children with voiding dysfunc-tion.

The primary goals of treatment in children withreflux are to prevent pyelonephritis, renal injuryand other complications of reflux. Medical therapyis based on the principle that VUR often resolvesover time, and that the morbidity or complicationsof reflux may be prevented nonsurgically. The basisfor surgical therapy is that in selected situations,ongoing VUR has caused or has a significantpotential for causing renal injury or other reflux-related complications and that elimination of refluxwill minimize the likelihood of these problems.The 7 treatment modalities for VUR considered bythe panel follow:

• No treatment (intermittent antibiotic therapy forUTI);

• Bladder training (including timed voiding andother behavioral techniques);

• Antibiotic prophylaxis (continuous);

• Antibiotic prophylaxis and bladder training;

• Antibiotic prophylaxis, anticholinergics (forbladder instability), and bladder training;

• Open surgical repair; and

• Endoscopic repair.

Neither urethral dilation nor urethrotomy havebeen found to be beneficial in the treatment of chil-

dren with reflux (Forbes, Drummond, and Nogrady,1969; Hendrey, Stanton, and Williams, 1973;Kaplan, Sammons, and King, 1973).

No treatmentThis management modality involves treating

patients with UTI with antibiotics at each occur-rence. The philosophy of this therapy is thatprompt diagnosis and treatment of UTI will elimi-nate or minimize the risk of reflux-associated renalinfection. Because the continuous antibiotic pro-phylaxis approach has been used in recent years,few data are available on the intermittent treatmentapproach.

Bladder trainingBladder training refers to regular, volitional,

complete emptying of the bladder through behav-ioral conditioning to achieve balanced, low-pres-sure voiding with coordinated relaxation of theexternal sphincter and pelvic floor during voiding.Measures include a voiding schedule (e.g., every2–3 hours), complete emptying of the bladderduring micturition, re-education in proper voidingdynamics if voiding dysfunction is present, andelimination of constipation. The practice alsoincludes genital and perineal hygiene. The goal ofbladder training is to reduce the likelihood ofdeveloping UTI and reduce voiding pressure.Infrequent voiding, detrusor-sphincter dyssynergia,and constipation can increase the likelihood of bac-teriuria (Smith and Elder, 1994).

Antibiotic prophylaxisContinuous antibiotic prophylaxis has become

the cornerstone in the initial management ofpatients with reflux. This form of therapy is basedon the observations of Lenaghan, Whitaker, Jensen,et al. (1976), who reported that 21 percent of previ-ously normal refluxing kidneys showed scarring onfollow-up with intermittent antibiotic therapy, andSmellie, Edwards, Hunter, et al. (1975), who foundthat children on continuous antibiotic prophylaxiswho were kept free of infection did not developnew renal scarring.

Drugs commonly used for prophylaxis includesulfamethoxazole-trimethoprim, trimethoprimalone, and nitrofurantoin, generally administeredonce daily at a dose calculated to be one-fourth toone-third of the dose necessary to treat an acuteinfection (Birmingham Reflux Study Group, 1987;Cardiff-Oxford Bacteriuria Study Group, 1978;

Treatment methods


Goldraich and Goldraich, 1992; Hannerz, Wikstad,Celsi, et al., 1989; Hanson, Hansson, and Jodal,1989; Pinter, Jaszai, and Dober, 1988; Smellie,Gruneberg, Bantock, et al., 1988). Prophylaxis usu-ally is continued until reflux resolves or until therisk of reflux to the individual is considered to below. Many clinicians treating children with refluxobtain urine specimens periodically for urinalysisand/or culture, although the frequency of urinesampling varies widely (Elder, Snyder, Peters, etal., 1992).

Medical management with antibiotic prophylaxisis considered to be successful if the child remainsfree of infection, develops no new renal scarring,and the reflux resolves spontaneously. On the otherhand, breakthrough UTI, the development of newrenal scars, or failure of reflux to resolve would beconsidered failure of medical management. Non-compliance (Smyth and Judd, 1993), allergic reac-tion, or side effects to the prescribed medicationmay preclude medical management or lead to itsfailure.

Antibiotic prophylaxis and bladder training

Many clinicians emphasize the principles ofbladder training when placing children with VURon antimicrobial prophylaxis. Most studies in theliterature do not specify whether attention tobladder training was emphasized in the treatmentplan, and assessment of the contribution of bladdertraining to outcome has not been studied in anycontrolled trials.

Antibiotic prophylaxis, anticholinergicsand bladder training

Before toilet training, voiding is an automaticprocess. During toilet training, however, childrenmay demonstrate a discoordinated pattern, withincomplete relaxation of the external sphincterduring voiding, resulting in high intravesical pres-sure and incomplete bladder emptying. The termsbladder instability, uninhibited bladder contrac-tions, and pediatric unstable bladder refer to reflexdetrusor contractions at low bladder volumes.Children with bladder instability typically experi-ence frequency, urgency, and urge incontinence,and girls with this condition may cross their legs orsquat down to try to avoid incontinence. Anti-cholinergic medication, in conjunction with timedvoiding, is thought to improve the symptoms ofdysfunctional voiding. Typical anticholinergic med-

ications (also often classified as antimuscarinic/antispasmodic agents) include oxybutynin chloride,propantheline bromide, and hyoscyamine.

Open surgical repairOpen surgical management involves modifying

the abnormal ureterovesical attachment to create a4:1 to 5:1 ratio of length of intramural ureter toureteral diameter. Numerous techniques have beendescribed, and each has undergone minor modifica-tions. The primary techniques evaluated by thepanel include intravesical operations, including thePolitano-Leadbetter (Politano and Leadbetter,1958), Glenn-Anderson (Glenn and Anderson,1967), Cohen transtrigonal (Cohen, 1975) andPaquin and Gil-Vernet procedures, and extravesicaloperations, including the Lich-Gregoir procedure(Gregoir, 1974) and detrusorrhaphy (Zaontz,Maizels, Sugar, et al., 1987). Surgical techniquesfor management of children with refluxing mega-ureter and reflux associated with ureteral duplica-tion were evaluated separately. Studies dealing withlaparoscopic correction of reflux, bladder neckplasty/Y-V plasty, and nephrectomy or partialnephrectomy as management for reflux were notreviewed.

Endoscopic repairThe technique of endoscopic injection of polyte-

trafluoroethylene paste (polytef, Teflon™), for thecorrection of VUR was reported in 1986 byO’Donnell and Puri (1986). The technique involvesinjecting 0.1–1 ml of polytef paste into the submu-cosa deep to the affected ureter. The injected bolusprovides a firm buttress against which the uretericroof may be compressed with rising intravesicalpressure. This operative procedure, termed the“STING” (subtrigonal injection) has become verypopular, particularly in Europe, because it is lessinvasive than open surgical techniques and can beperformed as an outpatient procedure under generalanesthesia. If the initial injection fails to correctreflux, the procedure can be repeated. Polytef is aninert material, yet the long-term safety of this for-eign material in the bladder has not been docu-mented (Aaronson, 1995; Puri, 1995). Furthermore,polytef has not been approved by the U.S. Foodand Drug Administration for use in the treatment ofreflux.

Another substance that has been used for endo-scopic therapy is cross-linked bovine collagen(Leonard, Canning, Peters, et al., 1991). Othermaterials for injection currently under investigation


include autologous collagen, a mixture of cross-linked dextran and hyaluronadan, polyvinyl alcoholfoam (Ivalon), polydimethylsiloxane, blood, fat,chondrocytes embedded in biodegradable polymer,bioactive glass, and detachable balloons. The paneldid not review studies focusing on the use of thesematerials. Until an injectable substance is devel-oped with acceptable known risks, open surgicalcorrection of reflux remains the surgical treatmentof choice. Nevertheless, the appeal of a safe andeffective outpatient procedure for the correction ofreflux will undoubtedly continue to stimulate inves-tigation of this technique.

In a child with VUR, periodic surveillance isgenerally recommended to monitor for UTI,because the complications of reflux often occurwhen infection is present. No guidelines exist forfrequency of monitoring (e.g., monthly, every 3months) or type of surveillance (urine dipstick, dip-stick with microscopy, urine culture, or a combina-tion) (Elder, Snyder, Peters, et al., 1992). If thechild has symptoms of a UTI, a urine cultureshould be performed, even if the urinalysis isnormal.

Follow-up radiologic testing is performed tomonitor the status of reflux, that is, whether it ispresent (worse, improved, no change) or absent. Inaddition, studies to determine whether renal injuryhas occurred may also be performed. In children

undergoing medical or surgical therapy, no guide-lines exist for frequency or type of follow-up(Elder, Snyder, Peters, et al., 1992).

In a child receiving medical therapy, follow-upcystography is generally performed every 12–18months. The radionuclide cystogram is preferred bymany, because the radiation dose to the gonads issignificantly lower than that with a standard con-trast cystogram (Conway, King, Belman, et al.,1972). The 2 techniques are sufficiently dissimilar,therefore, the assessment of reflux severity may notbe comparable. With digital fluoroscopy equipmentand a “tailored” or individualized contrast cys-togram performed by a pediatric radiologist, theradiation dose also is significantly lower than thatwith a standard VCUG (Kleinman, Diamond,Karellas, et al., 1994). In a child with reflux thatappears to have resolved spontaneously by cystog-raphy, as many as 20 percent might show reflux ifthe study were repeated in 1 year (Arant, 1992).Most clinicians do not obtain a second cystogram,unless recurrent urinary tract infections haveoccurred. In addition, periodic upper tract imagingstudies (ultrasound, IVP, renal scintigraphy) areoften performed, although the ability of these teststo detect renal scarring and growth is variable. In achild treated surgically, follow-up lower and uppertract studies are generally performed at least onetime to assess the success of the surgical procedureand to determine whether any complications haveoccurred.

The panel did not perform an assessment of theaccuracy of these tests, nor is there any agreementon the effect these tests have on outcomes. Suchstudies do, however, document the status of thereflux problem.

Surveillance andfollow-up


The AUA Pediatric Vesicoureteral Reflux Paneldeveloped the recommendations in thisReport onthe Management of Primary Vesicoureteral Refluxin Childrenfollowing an explicit approach to thedevelopment of practice policies (Eddy, 1992) sup-plemented by expert opinion. The explicit approachprovides mechanisms that take into account the rel-evant factors for making selections from alternativeinterventions. The use of scientific evidence in esti-mating the outcomes of intervention is emphasized.

To develop recommendations for this report, thepanel undertook an extensive review of the litera-ture on vesicoureteral reflux and extracted data.

The panel reviewed the evidence tabulated in thedatabase and focused attention on randomized, con-trolled studies wherever possible. The level ofavailability and quality of the data from which out-comes could be estimated are displayed on the evi-dence matrix on page 21.

Expert opinion was polled by questionnaire orsurvey in a blinded fashion when scientific evi-dence was lacking. The panel generated its practicepolicy recommendations on the basis of evidence-based outcomes and on expert opinion. In thisreport, statements based on opinion are explicitlyidentified, and evidence-based recommendationsare accompanied by appropriate references. Therecommendations were derived from a survey ofpreferred treatment options for 36 clinical cate-gories of children with reflux. The treatment rec-ommendations were classified as follows:

• Guidelines: Treatment recommendationsselected by 8 or 9 of the 9 panel members areclassified as guidelines and are strongly wordedusing “should”; e.g., “Children with Grade Vreflux should undergo surgical repair.”

• Preferred options: Treatment recommendationsthat received 5 to 7 votes are worded with thisclassification.

• Reasonable alternatives:Treatment recommen-dations that received 3 to 4 votes are wordedwith this classification.

• No consensus:Treatment recommendations thatreceived no more than 2 votes are worded with

this classification and are not to be consideredrecommendations.

The reference database was developed fromMEDLINE literature searches encompassing theperiod January 1965 through December 1994. Thesearch strategy was all-inclusive, using vesico-ureteral-reflux as the major or minor medical sub-ject heading (MeSH keyword). It was important touse this specific form of vesico-ureteral-refluxbecause similar alternatives (e.g., vesicouretericreflux) do not capture all reflux articles. All of thecitations were imported into a Papyrus Bibliog-raphy System (Research Software Design, Portland,OR) and assigned a Papyrus Reference Number.Articles were accepted on the basis of specific cri-teria (outlined on page 17), as well as the inter-pretability of the data and inclusion of new data(relative to older published reports updatingongoing studies). A total of 3,207 references wereretrieved and reviewed. Of these, 413 (13 percent)were selected for initial panel review. From thisgroup, 168 were accepted for analysis (5.2 percentof initially retrieved articles). Bibliographies ofreflux literature from 1960–1965 were reviewedmanually to identify any relevant articles thatwould not have been retrieved electronically; how-ever, no articles from which data could be extractedwere identified in this manner. The articles fromwhich outcomes data were extracted are listed inTable A-1 (Appendix A) and are the basis for thepanel’s analysis of vesicoureteral reflux.

Evidence on some outcomes was reviewed fromselected articles that were not analyzed systemati-cally, due to the nature of the material or the lackof a significant number of adequate articles. Theseareas included the impact of reflux on pregnancy,hospitalization due to antireflux surgery and due topyelonephritis, adverse drug reactions, adverseeffects of surveillance testing, and other surgicalharms.

Literature search


Chapter 2: Methodology

After identifying articles from the literaturesearch, the panel reviewed the abstracts andselected relevant citations for data extraction. Cri-teria for admissible evidence included (1) Englishlanguage and (2) peer-reviewed studies of primaryVUR in children younger than 10 years old. Theinitial exclusions were based on article title, key-words (other than vesicoureteral reflux) or reviewof the abstract, if present. Specific exclusion cri-teria included review articles, non–English lan-guage studies, non–peer-reviewed studies, olderduplicate studies, animal studies, adult studies, casereports with fewer than 5 patients, laboratorystudies, studies without treatment outcomes, studiesof secondary reflux, letters, editorials, and datafrom unpublished material.

Each article was accepted for inclusion orrejected on the basis of the treatment outcome datait contained. Inclusion or exclusion of each articlewas verified by 2 panel members in consultationwith the panel chair. Articles were rejected by con-sensus of the 2 reviewers and the panel chair. Twoindividual panel members extracted data from eachaccepted article, and the data were tabulated on thedata retrieval form developed by the panel (Appen-dix B). Each data retrieval sheet was reviewed bythe panel chair, providing triple review for eacharticle. Figures A-1–A-4 (Appendix A) list the arti-cles reviewed and accepted by year, the source ofthe articles, the type of study for the accepted arti-cles, and the reason for article rejection. From thisreview, reports were accepted for inclusion in theworking bibliographic database.

The data were entered into a FoxPro™ (Micro-soft Corp.) database. All computer entries werereviewed to ensure accuracy. The tabulated datawere categorized according to the pediatric vesi-coureteral reflux evidence matrix to facilitatereview and to identify areas where limited or nodata exist.

The panel attempted to rely on published evi-dence whenever possible. Many studies thataddressed a particular issue could not be used

quantitatively in the various syntheses because ofinconsistent reporting of data, limited time offollow-up, incomplete description of treatments uti-lized, or poorly defined patient populations. Inaddition, many of the datasets that were extractedstill contained some deficiencies. Practical prob-lems were encountered in analysis of the scientificliterature as follows:

• Only 3 prospective randomized controlled trials(RCTs) compared medical with surgical therapy:the Birmingham Reflux Study, the InternationalReflux Study in Children, and a study fromErasmus University, Rotterdam, TheNetherlands. The strongest evidence for thecomparison of efficacy of treatments comes fromthese RCTs. Because even RCTs can havemethodological problems, additional analyseswere conducted on cohort studies for selectedissues. In general, the results from these analyseswere consistent with those of the RCTs.

• At least 5 different methods are used for gradingreflux (see Table 1, page 11). The InternationalStudy Classification is currently the mostcommon method for reporting data on reflux,and the Dwoskin-Perlmutter System correspondsclosely to this grading system. The other sys-tems tend to combine higher reflux grades, fre-quently making it difficult to extract outcomesdata for specific grades of reflux.

• Many studies did not report outcomes by sepa-rate reflux grade, and instead combined variousgrades. Often, the results were not broken downby initial grade of reflux. In some cases, anattempt was made to adjust for this statistically;in other cases, the results were excluded fromthe analyses. (See Appendix C.)

• Although reflux is diagnosed more frequently ingirls than in boys and the sequelae of reflux maybe different in girls and boys, most outcomeswere not reported separately by patient gender.The literature and data available suggested nodifference in resolution by gender.

• No standard method was used for reporting out-comes in children with reflux. Some studiesreported selected outcomes on reflux by patientgrade, and other studies reported outcomes byureteral grade. Some studies reported demo-graphic data by patient data and outcome byureteral data, or vice versa. Consequently, thepanel had to assess which information was moreimportant. For example, are patients with unilat-eral Grade II or III reflux more likely to show

Limitations of theliterature

Article selection anddata extraction


reflux resolution than those with bilateral GradeII or bilateral Grade III reflux? Are patients withbilateral reflux, Grade IV on one side and GradeIII on the other, as likely to show reflux resolu-tion as patients with Grade IV reflux on one sideand Grade I or II reflux on the other side?

• In series reporting outcomes of surgical correc-tion of reflux, the duration of follow-up tendedto be shorter than that in series of medicaltherapy. Thus, determining the long-term inci-dence of outcomes such as renal scarring andUTI after surgical therapy was difficult.

• In most series of reflux resolution on medicaltherapy, the resolution rate by year of follow-upwas not provided, and patients were includedwith varying lengths of follow-up. This factormade combining the data in these series difficult.

• Few studies reported side effects of medicaltherapy or provided the reasons for changing theprophylactic medication. In addition, moststudies of medical therapy did not stratify out-comes by specific antibiotic prophylaxis, makingit impossible to analyze whether a particularform of prophylaxis is better than another.Issues such as adverse drug reactions or compli-cation rates from surgery are most accuratelyestimated from large cohort samples taken fromthe same populations about which inferences areto be made. The literature on issues such ascomplication rates and adverse reactions wasusually based on a convenience sample. In somecases, the information was so sparse that judg-ments had to be made on the basis of expertopinion.

• Most studies of reflux resolution on medicaltherapy did not stratify results by patient age,making it difficult to determine whether, for aspecific grade of reflux, younger children aremore likely than older children to experiencereflux resolution. In addition, some studiesreported the number of children who had refluxresolution at specific ages, but the initial refluxgrade and the age at diagnosis in these patientswere not provided.

To generate an evidence matrix (see page 21),estimates of the probabilities and/or magnitudes of

the outcomes are required for each alternative inter-vention. Ideally, these come from a synthesis of theevi]dence, either from all available studies or asubset of high-quality data. Some cells in the evi-dence matrix were derived from a single dataset. Ifseveral studies had some degree of relevance to aparticular cell or cells of the evidence matrix, thepanel used more complicated methods of data syn-thesis—the Confidence Profile Method (Eddy,Hasselblad, and Shachter, 1992)—as a generalframework, and the FAST*PRO software computerpackage (Eddy and Hasselblad, 1992) for calcula-tions. The more complicated analyses were con-ducted using logistic models with random effects(Hasselblad, in press), and these calculations wereperformed using EGRET software (Statistics andEpidemiology Research Corp., 1993). The use ofthese logistic models for estimating parameterswith dichotomous outcomes is described inAppendix C.

Panel members used expert opinion to addressoutcomes in the evidence matrix for which directevidence was lacking, recognizing the limitationsof opinion as a basis for reaching conclusionsabout effectiveness. They completed a mailed ques-tionnaire in which they were asked to contrast, onthe basis of their opinions and clinical experience,the relative effectiveness of several treatmentoptions (e.g., anticholinergic therapy, bladdertraining, continuous antibiotic prophylaxis, surgery)in relation to various intermediate and health out-comes. The questionnaire also explored their opin-ions regarding the natural history and pathogenesisof VUR and the risk of adverse effects from contin-uous antibiotic prophylaxis and surgical repair.These pooled estimates, which were later presentedat a panel meeting to help the group fill in the evi-dence matrix, are cited in this report along with anexplicit statement that they originate from a panelsurvey and are gross estimates based on expertopinion and not on scientific data.

In addition, the panel was able to obtain thedatasets of the large studies of Skoog and Belman(1991)1 and Arant (1992). Analysis of thesedatasets provided a unique chance to answer somespecific questions about resolution of reflux. In par-ticular, the studies were used to determine whether

Dataset analysis

Combining the evidence


1 Provided by Regina O’Donnell of Washington, D.C.

age of presentation affected resolution rates.Standard survival analyses were completed, andparametric analysis was used so that results couldbe combined across the 2 studies where appro-priate. In general, a Weibull hazard model wasused, and in many cases the exponential model (aspecial case of the Weibull model) was appropriatebecause it involved fewer parameters. Goodness offit statistics were used to determine the adequacy ofeach model.

The recommendations in this report were devel-oped on the basis of the scientific evidence andexpert opinion, summarized according to the abovemethodology. A structured approach was used totranslate the information into recommendations:confidential voting on standardized questions wasconducted to give each panel member an equalvoice in the recommendations, and explicit lan-guage was used to clarify the rationale for the rec-ommendations and to document whether theassumptions were based on scientific evidence orexpert opinion. After systematically reviewing thestrengths and limitations of the evidence for eachof the principal outcomes in the evidence matrix,panel members completed a confidential survey inwhich they designated preferred treatments for chil-dren presenting initially with reflux and for thosewith persistent reflux following initial treatment.Separate survey forms (see example in Appendix

D) were completed for 36 clinical scenarios thatincorporated all possible combinations of patientage (infancy, ages 1–5, ages 6–10), reflux severity(Grades I–II, Grades III–IV, Grade V), laterality(unilateral, bilateral) and the presence or absence ofrenal scarring at diagnosis. Voting was conductedin September 1995 and again in May 1996 afternew data on spontaneous resolution rates becameavailable. Recommended treatments were classifiedas guidelines, preferred options, reasonable alterna-tives, or no consensus, as defined on page 16.2

The text that resulted from this protocol was pre-sented to the panel for review. Although the paneledited the text to improve consistency and read-ability, the panel did not deviate from the aboveprotocol, either in determining what to recommendor in the wording of the recommendations. Forexample, even if some panel members believed thatsurgical repair is a reasonable alternative for spe-cific clinical situations, the group did not recom-mend surgery if it received fewer than 3 votes onthe survey. Finally, working with a facilitator, thepanel listed individually the explicit arguments thatformed the rationale for each of its recommenda-tions. These arguments are summarized inRationale for Recommendations (page 53), whichalso specifies whether the assumptions are based onscientific evidence or expert opinion. Specialcaveats about the limited scope of the recommen-dations (e.g., applying only to patients with uncom-plicated reflux) also were made explicit. The finaltext that resulted from this process appears onpages 49–53.

Analytic process


2 An exception occurred in evaluating treatments for patients with persistent reflux, because the denominator (the number of panel members voting)was less than 9 if any panel members recommended surgery as initial treatment (i.e., they would not participate in voting for additional treatments).Accordingly, votes for persistent reflux were classified as guidelines if a treatment received 85–100 percent of the total votes or as preferred optionif it received 50–84 percent of total votes. No treatments for persistent reflux were classified as reasonable alternatives; if a treatment received nomore than 50 percent of the votes, the text stated that there was no consensus. Because of the small sample size in this voting process, a change inthe vote of a single panel member could affect the strength of the recommendations (e.g., making a “preferred option” a “guideline”). When differ-ences due to rounding error resulted in illogical discrepancies in the recommendations (e.g., recommending more aggressive treatment for unilateralthan for bilateral reflux), the response rate for the overall class of patients was used to calculate the strength of the recommendations.

Health outcomes are the effects of a medicalcondition or intervention on patients that aredirectly perceived in some way by the patient orfamily. Harms are health outcomes that have a neg-ative impact on the well-being of the patient, rang-ing from the impact of an acute illness or diag-nostic testing (such as a VCUG), to the need forsurgery or hospitalization, to death. Health benefitsare generally expressed as a reduction in the sever-ity or frequency of a harm.

It is important to distinguish between outcomesdirectly experienced and appreciated by a patient orparent (health outcomes) and those that patientscannot feel or experience but that are either associ-ated with or precede health outcomes (intermediateoutcomes). A patient or parent is only concernedabout reflux if it causes symptoms that negativelyaffect them or if it has the potential to cause suchproblems. For example, although a direct relation-ship may be evident between reflux and pyeloneph-ritis, it is the clinical condition of pyelonephritiswith fever, pain, and hospitalization that is experi-enced by the patient. Similarly, renal scarring itselfmay not affect a patient’s well-being, but possiblesequelae of hypertension, renal insufficiency, clin-ical renal failure, symptoms of azotemia, or theneed for dialysis, have direct impact. Consequently,reflux and reflux grade are intermediate outcomes,as are renal scarring, serum creatinine, or asympto-matic bacteriuria. In contrast, symptomatic UTI,azotemia, growth failure, as well as the need for x-ray studies, medications, surgery, or dialysis arehealth outcomes.

Many studies reported in the literature recordonly intermediate outcomes because the causalconnection between intermediate outcomes andhealth outcomes is assumed or inferred. Analysesof intermediate outcomes are important in devel-oping practice guidelines, but a firm causal connec-tion with health outcomes is essential for validityand relevance.

The evidence matrix on page 21 presents theoutcomes of interest, indicating health outcomes,intermediate outcomes and harms for various formsof management, including no treatment, medicaltherapy and surgical therapies. Areas in which good(defined as 2 or more datasets available), fair (1well-done dataset), and poor (very little) data areavailable are indicated. In some areas, a significantamount of interpretable information is available tointegrate into a clinical decision, while in others asurprising lack of evidence was found. The areaslacking useful outcomes data highlight the deficien-cies in the literature on VUR and emphasize theneed for well-developed studies to address areas ofuncertainty. The text following the evidence matrixnotes areas in which relative benefits and harmsmay differ by patient population (e.g., differentpatient ages and grades of reflux).

The following sections detail the analysis of thevariables included on the evidence matrix. Theinformation is organized in relation to outcomeslisted on the left side of the evidence matrix, begin-ning with intermediate outcomes.

Intermediate outcomes

Resolution and diminution of refluxOver time a considerable proportion of children

with reflux will experience resolution or diminutionin reflux grade. Because the significance of diminu-tion in reflux grade was difficult to assess, thepanel used reflux resolution as an indication of suc-cess.

Medical therapy.The database included 26reports with data pertaining to reflux resolutionafter medical therapy, encompassing 1,987 patients

Analysis of outcomes

Analysis of data qualityIntermediate outcomes andhealth benefits and harms


Chapter 3:Outcomes analysis for treatment alternatives


Evidence matrix: quality of data–studies of primary vesicoureteral reflux

Key: Good Fair Poor NA Not applicable No dataGood = 2 or more datasets, Fair = one well-done dataset, Poor = very little data

No Bladder Antibiotic Antibiotic Antibiotic Open Endo-treatment1 training 2 prophylaxis prophylaxis prophylaxis, anti- surgical scopic

& bladder cholinergics & repair 3 repair4

training bladder training

Decrease grade of reflux

Duration of reflux

Renal scarring

Renal growth

Renal function

UTI

Pyelonephritis

Cystitis

Hypertension

Uremia

Growth

Morbidity during pregnancy5

Death

Adverse drug reactions

Hospitalization

Adverse effects of surveillance testing

Obstruction

Bleeding/transfusion

Infection

Contralateral reflux

Bladder injury

Pain

Hospitalization


Health benefitsare positive outcomes that patients can feel or experience directly.Intermediateoutcomes are pathophysiological outcomes that lead to, or are associated with, the development of health outcomes.1. Includes intermittent antibiotic therapy for episodic UTI.2. Includes timed voiding and other behavioral techniques.3. Politano-Leadbetter, Glenn-Anderson, transtrigonal (Cohen), Lich-Gregoir, Paquin, Gil-Vernet, detrusorrhaphy, etc. Also includes repair

of duplication anomalies (e.g., common sheath reimplant, ureteroureterostomy, partial nephrectomy).4. Teflon™, collagen, Ivalon, blood, fat, etc.5. Women with reflux/reflux nephropathy appear to have a higher risk of UTIs and/or pyelonephritis during pregnancy. UTIs during pregnancy can

result in eclampsia, premature delivery, reduced fetal growth and possible fetal loss. Pyelonephritis would require maternal hospitalization. If thereis pre-existing renal functional impairment secondary to reflux nephropathy, deterioration of renal function may occur during pregnancy.


NA

Harms (medical treatment)

NA

Intermediate outcomes (not considered admissible evidence of effectiveness)

Health outcomes

Harms (surgery)

(1,410 girls and 304 boys or a ratio of girl to boy,4.3:1) and 2,902 ureters. In those studies in whichthe reflux could be classified as unilateral or bilat-eral, the distribution of ureters was almost equal(767 and 763, respectively). To accommodate aclinically relevant management strategy, childrenwere divided into groups by age at diagnosis as fol-lows: younger than age 1 year; preschool (1–5years); and school age (6–10 years). The panelexcluded from its consideration teenage youths andadults.

The data in these reports were difficult to collatebecause: (1) the minimum length of follow-up wasoften 6 months or less; (2) some studies did notreport reflux resolution specifically but rather com-bined resolution and reduction in reflux grade; (3)some studies reported reflux resolution by ureter,and others reported reflux resolution by patient; (4)data showing reflux resolution often combined mul-tiple grades of reflux, particularly in the older liter-ature that did not use either the International or theDwoskin-Perlmutter System of grading reflux; (5)reflux was not usually assessed annually for allpatients, making it difficult to evaluate reflux byyear in the majority of studies; and (6) somestudies only reported the age at resolution of reflux,making it impossible to determine the actual rangeof time to reflux resolution.

For these reasons, 3 datasets were used to esti-mate the probability of reflux resolution as a func-tion of initial grade, age at presentation and initialgrade of reflux and laterality (unilateral/bilateral).The individual databases from the studies ofSkoog, Belman, and Majd (1987) and Arant (1992)allowed analysis of these specific parameters,whereas the study of Tamminen-Mobius, Brunier,Ebel, et al. (1992) only provided summary resolu-tion curves and sample sizes. The Arant datasetprovided information on children with initial gradesof I, II and III for ages 0–60 months. The Skoogdataset provided information primarily on Grades IIand III for all ages. The Tamminen-Mobius studyprovided information primarily on Grade IV for allages, but the results were not available by age. Thestudy of McLorie, McKenna, Jumper, et al. (1990)was also analyzed for Grades III and IV reflux in amanner similar to Tamminen-Mobius, but was notincluded because the study data were not ade-quately described for analysis using the Weibullmodel determined to be the most appropriate forthe analysis of the other studies.

The survival curves of these studies were fittedto the data. The results were pooled using anempirical Bayes model (Hedges and Olkin, 1985)

when 2 or more studies provided information for asingle risk category. The data for Grades I and IIdid not show any differences by age or laterality.For Grade III reflux, however, age and lateralitywere important.

Table 2 (page 23) shows the estimated chance ofresolution for a child with reflux of a given grade,age and laterality (unilateral/bilateral). Forexample, assume that a child aged 30 months (2½years) is diagnosed with unilateral Grade III reflux.Table 2 indicates that the chance of that child’sreflux resolving in the next year is 13.4 percent.The chance of that same child experiencing refluxresolution in 3 years is 35.1 percent. The chance ofresolution does not depend on how long the childhas had reflux before diagnosis or treatment. Ifreflux does not resolve in the child described previ-ously in the first year, the chance of resolution forthe next year is still 13.4 percent. However, thetable indicates 25 percent due to patients droppingout once their reflux resolved. For example, 100patients, age 25–60 months, are diagnosed withGrade III, unilateral reflux. The first year, 13.4 per-cent will resolve. Therefore, approximately 87patients remain. During the second year, another13.4 percent of the 87 patients will resolve, leaving75 patients with reflux, which means 25 percent ofthe original 100 patients resolved. A graphic pre-sentation of the data is provided in Figure 3 onpage 24.

All of these estimates are subject to 2 restric-tions: (1) the estimates are only valid for up to 5years after diagnosis; and (2) for Grade IV, the esti-mates only apply to the time of diagnosis, and theyare not age specific. Children younger than 1 yearwith Grade IV reflux may have a higher chance ofresolution, and children older than age 5 may havea lower probability.

The mean age at reflux resolution is 4.6–6.8years (Skoog, Belman, and Majd, 1987; Bellingerand Duckett, 1984). The age beyond which refluxis unlikely to undergo spontaneous resolution is notwell documented, however. Goldraich andGoldraich (1992) reported that almost all 10-year-old girls with persistent Grade I or II reflux under-went reflux resolution by age 13. In contrast, only50 percent of 10-year-old boys with Grade I or IIreflux showed resolution by age 13. Few 10-year-old girls or boys with Grade III or IV showedreflux resolution between 10 and 13 years of age.Lenaghan, Whitaker, Jensen, et al. (1976) reportedthat of 83 refluxing ureters that resolved, reflux res-olution occurred after age 14 in 22 (27 percent).


Medical resolution of reflux in patients withvoiding dysfunction.Many children have voidingdisorders exhibited by bladder and externalsphincter discoordination along with bladder insta-bility that contribute to VUR (Hinman andBaumann, 1973; Hinman, 1986; Allen, 1977,1978). Clinically, these children in addition tohaving reflux and UTIs also have a combination ofday and night-time enuresis, holding maneuvers,constipation, encopresis, and abdominal pain. Thevoiding disturbances are primarily a learned phe-nomenon that significantly increase voiding pres-sures resulting in decompensation of theureterovesical junction and reflux. Inappropriatecontraction of the voluntary external sphincterduring detrusor contraction causes a functionalobstruction to urinary flow with the development ofelevated intravesical pressure. Many children per-form this maneuver to delay bladder emptying

while playing games, watching television, or beinginvolved in other activities.

The cornerstone of treatment of patients withvoiding dysfunction includes bladder retraining(timed voiding, relaxed voiding, biofeedback) withor without pharmacologic intervention directed atdecreasing bladder or sphincter hyperactivity.Children with concomitant constipation or enco-presis are often placed on a bowel program. Threeprospective studies have found that neither urethraldilatation nor urethrotomy benefited children withVUR (Forbes, Drummond, and Nogrady, 1969;Kaplan, Sammons, and King, 1973; Hendry,Stanton, and Williams, 1973).

The panel selected 2 series that specificallyexamined the impact of voiding dysfunction on thecourse of reflux resolution without any intervention


Table 2. Medical therapy–Percent chance of reflux resolution after specified number of years1

Percent chance(95% confidence interval)

Risk category (age in months)(number of patients on which 1 year 2 years 3 years 4 years 5 yearsestimates are based)

Grade I2 39.3 63.1 77.6 86.4 91.8(N=15) (24.6–51.1) (43.2–76.1) (57.2–88.3) (67.7–94.3) (75.7–97.2)

Grade II2 28 48.1 62.7 73.1 80.6(N=250) (24.1–31.7) (42.3–53.4) (56.2–68.1) (66.8–78.2) (74.8–85.1)

Grade III, unilateral, age 0–24 21.4 38.2 51.5 61.9 70(N=27) (10.8–30.8) (20.4–52.1) (29–66.8) (36.6–77.1) (43.5–84.1)

Grade III, unilateral, age 25–60 13.4 25 35.1 43.8 51.3(N=27) (4.6–21.4) (8.9–38.3) (13.1–51.5) (17.1–61.9) (20.9–70.1)

Grade III, unilateral, age 61–120 10.8 20.5 29.1 36.7 43.6(N=15) (3.5–17.5) (6.9–32) (10.2–43.9) (13.4–53.8) (16.5–61.9)

Grade III, bilateral, age 0–24 12.7 23.8 33.5 41.9 49.3(N=62) (7–18.1) (13.5–32.9) (19.5–45) (25.1–55) (30.3–63.1)

Grade III, bilateral, age 25–60 7 13.5 19.6 25.2 30.5(N=53) (3.1–10.8) (6.1–20.4) (9–28.9) (11.8–36.6) (14.6–43.4)

Grade III, bilateral, age 61–120 2.6 5.2 7.7 10.1 12.5(N=14) (0.7–4.5) (1.4–8.8) (2.1–13) (2.8–16.9) (3.5–20.7)

Grade IV, unilateral3 16.1 29.7 41 50.5 58.5(N=28) (8.5–23.1) (16.4–40.8) (23.5–54.5) (30–65) (36–73.1)

Grade IV, bilateral3 4.5 6.4 7.8 8.9 9.9(N=96) (1–7.9) (2–15.1) (3–21.8) (4–28) (4.9–33.7)

1 The yearly rate of reflux resolution remains constant for each group.2 No difference shown by age or laterality (unilateral/bilateral); therefore, these categories were combined.3 Estimates only apply to the time of diagnosis and are not age specific.


Copyright © 1997 American Urological Association, Inc.

Grade IV - Bilateral

Grade IV - Unilateral

Grade II

Grade I

100

80

60

40

20

Per

cen

tag

e o

f C

hild

ren

wit

h R

eflu

x

0 1 2 3 4 5

Figure 3-a.

Years Since Presentation

Percent chance of reflux persistence, grades I, II and IV, for 1 to 5 years following presentation

100

80

60

40

20

0

Per

cen

tag

e o

f C

hild

ren

wit

h R

eflu

x

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Figure 3-b.

Years Since Presentation

Bilateral Age 6-10

Bilateral Age 3-5

Bilateral Age 1-2Unilateral Age 6-10

Unilateral Age 3-5Unilateral Age 1-2

Percent chance of reflux persistence by age at presentation, grade III, for 1 to 5 years following presentation

Source:Based on the databases from the studies of: Arant, 1992; Skoog, Belman, andMajd, 1987; and Tamminen-Mobius, Brunier, Ebel, et al., 1992.


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IIIIV

V

directed at abnormal bladder function (van Gool,Hjalmas, Tamminen-Mobius, et al., 1992; Koff andMurtagh, 1983) (Table 3, page 25). In the Interna-tional Reflux Study in Children, the rate of sponta-neous reflux resolution in 37 patients with mildvoiding dysfunction was 11 percent (4/37) com-pared with 25 percent (36/147) in a similar groupwithout voiding dysfunction (p < 0.05) at 5 yearsof follow-up (van Gool, Hjalmas, Tamminen-Mobius, et al., 1992). In addition, recurrent symp-tomatic UTIs were more common in the group withvoiding dysfunction (44 percent) compared withthose with normal bladder function (25 percent)during 5 years of follow-up. Despite the increasedpropensity for symptomatic infections, the Inter-national Reflux Study in Children could not dem-onstrate a correlation between new renal scarringand the presence or absence of voiding dysfunc-tion. Koff and Murtagh (1983) demonstrated a lowreflux resolution rate in a small group of 8 childrenwith voiding dysfunction who were noncompliantwith treatment of their bladder dysfunction. Thereflux resolution rate was 33 percent (4/12 ureters:Grade I, 0/3; Grade II, 1/4; Grade III, 2/3; GradeIV, 1/2) at a mean follow-up of 3.9 years. The rateof symptomatic and asymptomatic infections was63 percent in this group over the same follow-up.These studies suggest that non-treatment of voidingdysfunction is associated with a lower spontaneousreflux resolution rate and an increased risk of UTI.

Resolution in patients receiving antibiotic pro-phylaxis, anticholinergics and bladder retraining.Improving voiding dynamics with bladder retrain-ing and pharmacologic intervention can bring aboutdiminution of both voiding and storage pressures.Five clinical series (not randomized controlledtrials) specifically examined the role of bladdertraining and/or pharmacologic intervention in addi-tion to antibiotic prophylaxis in the treatment ofchildren with VUR (Table 4 on pages 27-28). Ineach study, different inclusion criteria were used todefine each treatment group. In addition, each useda variety of techniques to improve bladder training(timed voiding, relaxed voiding, or biofeedback)with single or multiple pharmacologic agents (oxy-butynin, imipramine, baclofen, flavoxate, dicy-clomine, and diazepam) directed at decreasingbladder or sphincteric hyperactivity. The rate ofUTIs for each group over the same period was 16,63 and 71 percent, respectively. This study con-cluded that treatment of voiding dysfunction, asdemonstrated by uninhibited contractions on urody-namic evaluation, increased the reflux resolution

rate and decreased the rate of UTI. Seruca (1989)compared a group of patients prospectively studiedand treated for voiding dysfunction with a retro-spective control group of patients who were nottreated. The overall reflux resolution rate (byureter) was 92 percent for the former group and 54percent for the latter. The follow-up period was notspecified. Reflux resolution rates in the other 3studies, which did not include any controls, are alsosummarized in Table 4. The wide variation inresults (37–83 percent) is likely due to differencesin inclusion criteria, treatment regimens, andfollow-up period.

Available results from the series with controlgroups suggest that the reflux resolution rateincreases with active treatment of those patientswith a clinical history suggestive of voiding dys-function. Given the variability of treatment regi-mens and the disparity of results, there is a need forcontrolled, matched studies in this area.

Medical resolution of reflux in patients withduplicated systems.Among the 168 articlesreviewed by the panel, 14 included data on patientswith duplicated collecting systems. Five studiesincluded data on spontaneous resolution of refluxin patients receiving medical prophylaxis. The 14studies reporting data on ureteral duplicationincluded 498 patients or at least 546 affected renalunits. Three studies, representing a total of 45patients, did not report data on renal units. Assum-ing that each of the 45 patients had at least 1affected renal unit, the total units would approxi-mate 591 renal units or more. Duplication wasidentified predominantly in girls, with a ratio of 1male (57) to 5.6 female (322) individuals.

Although 2 reports presented controlled studiescomparing single ureteral reflux to duplicated sys-tems (Husmann and Allen, 1991; Ben-Ami, Gayer,Hertz, et al., 1989), limited data are available onmedical treatment of reflux in the patients withduplicated systems. The data show that within thepopulation of patients with duplicated systems,Grades I–II may be treated medically whereasGrades III, IV, and V have been treated surgicallyin most cases. Data on resolution by grade inpatients receiving medical treatment are minimalcompared with those in patients with duplicatedsystems treated surgically. Table 5 on page 29 pro-vides data from the 5 studies, including data on res-olution in patients with duplicated systems receiv-ing medical therapy.



Tabl

e 4.

M

edic

al r

esol

utio

n of

refl

ux in

pat

ient

s w

ith v

oidi

ng d

ysfu

nctio

n (t

reat

ed)

# P

atie

nts

Res

olut

ion

by g

rade

and/

orR

esol

utio

nR

esol

utio

nTr

eatm

ent

Follo

w-u

pIn

clus

ion

crite

ria#

uret

ers

(pat

ient

s)(u

rete

rs)

regi

men

perio

d

Kof

f an

d P

atie

nts

with

voi

ding

26/4

319

/43

(44%

)5/

93/

107/

112/

102/

3D

aily

ant

ibio

ticR

ange

1.5

-

Mur

tagh

,198

3dy

sfun

ctio

n w

ith u

ninh

ibite

d pr

ophy

laxi

s7

year

sco

ntra

ctio

ns o

n ur

odyn

amic

trea

tmen

t for

voi

ding

(mea

n,3.

9 ev

alua

tion

(com

plia

nt w

ithdy

sfun

ctio

n:ye

ars)

tr

eatm

ent

of v

oidi

ng•

antic

holin

ergi

c dy

sfun

ctio

n)m

edic

atio

n(o

xybu

tyni

n)•

Bow

el a

nd b

ladd

erre

trai

ning

pro

gram

.

Kof

f an

d N

orm

al u

rody

nam

ic

28/4

78/

47 (

17%

)1/

33/

114/

170/

90/

7A

ntib

iotic

Ran

ge 1

.5 -

Mur

tagh

,198

3ev

alua

tion

(con

trol

gro

up f

or

prop

hyla

xis

7 ye

ars

abov

e 2

grou

ps)

(mea

n,3.

9ye

ars)

Ser

uca,

1989

Ele

vate

d bl

adde

r pr

essu

res

53/7

446

/53

68/7

4 (9

2%)

8/8

33/3

326

/27

1/4

0/2

Dai

ly a

ntib

iotic

Unk

now

n du

ring

blad

der

fillin

g an

d/or

prop

hyla

xis

for

6 vo

idin

g,w

ith o

r w

ithou

tm

onth

s,th

en

abno

rmal

per

inea

l mus

cle

stop

ped.

B

aclo

fen,

activ

ityfla

voxa

te,

dicy

clom

ine,

or

diaz

epam

giv

en

indi

vidu

ally

or

in

com

bina

tion

for

each

type

of

blad

der

dysf

unct

ion

seen

on

urod

ynam

ic

eval

uatio

n fo

r 12

-30

mon

ths.

2 pa

tient

s tr

eate

d fo

r co

nstip

atio

n.

Ser

uca,

1989

Ret

rosp

ectiv

e “c

ontr

ol”

48/6

736

/67

(54%

)12

/12

22/3

52/

180/

2—

Dai

ly a

ntib

iotic

Unk

now

n gr

oup

from

198

0-85

(fo

r th

epr

ophy

laxi

sab

ove

grou

p)


III

IIIIV

V


III

IIIIV

V

Tabl

e 4.

M

edic

al r

esol

utio

n of

refl

ux in

pat

ient

s w

ith v

oidi

ng d

ysfu

nctio

n (t

reat

ed)

(con

tinue

d)

# P

atie

nts

Res

olut

ion

by g

rade

and/

orR

esol

utio

nR

esol

utio

nTr

eatm

ent

Follo

w-u

pIn

clus

ion

crite

ria#

uret

ers

(pat

ient

s)(u

rete

rs)

regi

men

perio

d

Hom

sy,N

soul

i,U

rody

nam

ic d

emon

stra

tion

40/5

327

/53

(51%

)4/

518

/32

5/8

0/8

—D

aily

ant

ibio

ticU

nkno

wn

Ham

burg

er,

of d

etru

sor

hype

rrefl

exia

prop

hyla

xis.

et

al.,

1985

(15)

or

detr

usor

O

xybu

tinin

for

3-1

8hy

perr

eflex

ia o

r dy

ssyn

ergi

a m

onth

s(2

5)C

onst

ipat

ion

trea

ted

with

die

t an

d so

ftene

rs.

Nas

ralla

h an

dH

isto

ry c

onsi

sten

t w

ith15

/18

15/1

8 (8

3%)

4/4

6/7

3/4

2/3

—D

aily

ant

ibio

tic

2 ye

ars

Sim

on,1

984

void

ing

dysf

unct

ion

prop

hyla

xis.

min

imum

Det

ruso

r hy

perr

eflex

ia:

oxyb

utyn

inS

phin

cter

spa

sm:

coun

selin

g an

d bl

adde

r re

trai

ning

N

octu

rnal

enu

resi

s:im

ipra

min

eS

mal

l bla

dder

sy

ndro

me:

imip

ram

ine

&

blad

der

retr

aini

ngD

etru

sor

arefl

exia

:B

etha

neco

l and

tim

ed v

oidi

ng.

Sch

oltm

eije

r D

etru

sor

inst

abili

ty o

n20

/27

10/2

7 (3

7%)

1/1

6/13

3/8

0/5

—D

aily

ant

ibio

tic1

year

and

Grif

fiths

,vi

deo-

urod

ynam

icpr

ophy

laxi

s.

1990

Ant

icho

liner

gic

med

icat

ion

The 5 studies, representing 234 patients, includ-ed data on follow-up of patients considered med-ically stable for variable periods from 1–5 years.Reflux resolution occurred in 24 percent of patients(55/234). The range of time to resolution variedfrom 24 months (Husmann and Allen, 1991) to39–68 months (Lee, Diamond, Duffy, et al., 1991).The studies including matched control populationsshowed that the chance of resolution in patientswith duplicated systems is lower or equal to that inpatients with single systems (Husmann and Allen,1991; Ben-Ami, Gayer, Hertz, et al., 1989).

Resolution—Open surgery.The panel reviewed86 reports outlining open surgical success, encom-passing 6,472 patients and 8,563 ureters (see TableE-1, Appendix E). Because results were reported in1 of these 2 categories, the data represent differentpopulations. Surgical success is defined as an openoperation performed through an abdominal incisionthat corrected VUR without postoperative ureteralobstruction and that was confirmed by postopera-tive cystography. Surgical success was obtainedboth with “standard” techniques such as thePolitano-Leadbetter procedure (16 reports), Cohentranstrigonal procedure (12 reports), Lich-Gregoirwith modifications (13 reports) and Gil-Vernet (4reports), and with mixtures of the above procedures(that could not be separated) or unique operationsthat could not be classified within the above proce-dures (44 reports).

Overall, surgical success was reported bypatients in 959 of 1,008 patients (95.1 percent), orreported by ureter in 7,731 of 8,061 ureters (95.9

percent). When surgical success was reported byreflux grade, a smaller database was available foranalysis. Surgical success was achieved in 108 of109 ureters (99 percent) for Grade I reflux, 874 of882 ureters (99.1 percent) for Grade II, 993 of1,010 (98.3 percent) for Grade III, 386 of 392 (98.5percent) for Grade IV, and 155 of 192 (80.7 per-cent) for Grade V. Surgical success in Grade Vreflux, which was treated using a wide variety ofprocedures, is shown in Table E-2, Appendix E.Surgical success was also analyzed by surgicaltechnique when that information was available(Table E-3, Appendix E).

Overall, the data on surgical success by anytechnique suggest a narrow range of success ratescentering around 95 percent. Surgical success ismost likely in Grades I–III, with at least mediansuccess in Grade IV reflux. For Grade V, the suc-cess rate ranges from 34 to 100 percent.

Resolution—Endoscopic therapy.Endoscopictherapy is a newer form of surgical treatment forreflux and refers to the subureteric injection ofsome material under the refluxing ureteral orifice.The technique and its limitations are described inChapter 1. Most reports in the literature describeresults of the use of polytetrafluoroethylene(Teflon™) (Table 6 on page 30). If the procedure isunsuccessful, as assessed by postoperative VCUG,it may be repeated. The results of this type oftherapy are difficult to interpret because success isoften described as resolution or reduced grade ofreflux after 1, 2, 3, or even 4 injection procedures.Most reports focus on reflux resolution by ureter


Table 5. Reflux resolution in patients with duplicated systems treated medically

Patients in whom Patients treatedStudy Grade reflux resolved medically Follow-up

Husmann and Allen, 1991 II 7 (10%) 71 0.5–5 years

Peppas, Skoog, Canning, et al., I–V 10 (14%) 70 Not stated1991

Kaplan, Nasrallah, and King, Not stated 5 (22%) 23 Not stated1978

Lee, Diamond, Duffy, et al., I–V 19 (50%) 38 1–11 years1991

Ben–Ami, Gayer, Hertz, et al., I–IV 14 (44%) 32 Min. 1 year1989

Total 55 (24%) 234


rather than by patient. Overall, reflux was correctedin 77.1 percent of ureters after a single injection.However, reflux was resolved after the initial treat-ment in only 6 of 19 ureters (32 percent) withGrade V reflux. In patients with a completely dupli-

cated system, reflux was corrected in 58.1 percentof ureters after 1 injection (Table 7 on page 31).

Success with collagen injections is even moredifficult to interpret because reflux correction maynot be durable. For example, in 1 report of 60

Table 6. Results of endoscopic correction (Teflon™) for vesicoureteral reflux

Procedures1 PatientStudy Grade cure

1st 2nd 3rd Obstruction (1 injection)

Puri and O’Donnell, 1987 IV-V 28/42 6/12 3/6 0/42

Sweeney and Thomas, 1987 All 99/153 1/1532

King and Gollow, 1988 III-IV 31/36 4/5 0/36

Farkas, Moriel, and Lupa, 1990 All 79/88 44/52

II-IV 79/84 4/5 0/1 0/84 44/49

V 0/4 0/3

Lacombe, 1990 All 132/174 6/8 67/100

Sauvage, Saussine, All 159/210 0/210Laustriat, et al., 1990

I-II 25/33 0/33

III 76/93 0/93

IV 52/70 0/70

V 6/14 0/14

Dodat and Takvorian, 1990 All 181/213 2/213

I-II 84/94

III 80/93

IV 23/29

V 0/1

Puri, 1990 II-V 113/143 19/23 3/4 1/143

Schulman, Pamart, Hall, All 139/173 2/173et al., 1990

Davies and Atwell, 1991 All 26/40 6/7 1/40

Bhatti, Khattak, and Boston, 1993 All 152/206 28/41 1/1 0/206 65/88

Total 1139/1478 73/101 7/12 7/1300(77.1%) (72.3%) (58.3%) (0.5%)

1 Results by ureter; lst, 2nd, and 3rd refer to specific treatment.2 Eight other ureters reported to be obstructed, but did not need surgical correction.

ureters with primary reflux, 47 (78 percent) showedresolution 1 month after treatment, but only 29 of47 (61 percent) still showed resolution at 1 year(Leonard, Canning, Peters, et al., 1991). In anotherseries, all 97 treated ureters showed resolutionimmediately after injection, but reflux recurred in40 ureters (41.2 percent) at 1 month and in 5 moreureters (5.2 percent) at 1 year following therapy(Frey, Berger, Jenny, et al., 1992). Whether moresystems would begin to reflux with time because ofimplant degradation or migration is uncertain.

At present, endoscopic treatment remains an inves-tigational procedure in the United States, awaitingtesting of a material that has proven benefit and safety.

Renal scarringRenal scarring is an important outcome in the

long-term assessment of results of medical or sur-gical therapy. Renal scarring may predispose tohypertension requiring medical therapy. Extensiverenal scarring may cause renal insufficiency andend-stage renal disease, with its attendant mor-bidity and mortality.

The presence of renal scarring is documented onimaging studies, including renal scan (DMSA,MAG-3), excretory urography (IVP) and renalsonography. These techniques have certain limita-tions. For example, there is variable sensitivityamong these studies in their ability to detect renalscars. Furthermore, timing of the imaging study isimportant; a renal scar may be evident on DMSAscan within 6 months of an episode ofpyelonephritis, whereas it may not be apparent on

IVP or sonography for 1–2 years. Early identifica-tion of renal inflammation by DMSA during anepisode of pyelonephritis does not necessarily indi-cate that these areas will later develop scarring,however. Interpretation of the studies is variableamong radiologists (Patel, Charron, Hoberman, etal., 1993). In an individual with renal scarring, itmay be difficult to distinguish between a new scaradjacent to the existing one and progression of anold scar. Finally, in an individual who is found tohave a renal scar on the first imaging study of thekidney, it is impossible to determine whether thescar resulted from infection or was congenital,since 20–40 percent of neonates with prenatallydiagnosed hydronephrosis secondary to VUR haverenal parenchymal abnormalities at birth (Elder,1992).

Renal scarring may be new or progressive. Thefinding of new renal scarring suggests that a newrenal injury has occurred since the previousimaging study. Progressive renal scarring, on theother hand, may represent either extension of theoriginal renal injury or may result from a newerrenal insult.

Prevention of new renal scarring is one of theprimary goals of treatment of VUR. Most studies ofreflux have not assessed this specific outcome.When interpreting the results of various studiespertaining to reflux, it is important to understandthe limitations of each type of imaging study usedin the evaluation of renal scarring (see page 12).Unless otherwise indicated, studies that combinedpatients with both new and progressive renal scar-ring have not been included in the panel’s analysis.


Table 7. Reflux resolution following endoscopic correction (Teflon™) for vesicoureteral reflux,duplicated systems

Procedures1

Study Grade 1st 2nd 3rd Obst

Farkas, Moriel, and Lupa, 1990 III-IV 13/16 0/16

Sauvage, Saussine, Laustriat, et al., 1990 All 9/13 0/13

Dodat and Takvorian, 1990 All 8/10

Schulman, Pamart, Hall, et al. 1990 All 11/19

Dewan and O’Donnell, 1991 All 13/35 6/19 6/19 1/35

Total 54/93 1/64(58.1%) (1.6%)

1 Results by ureter; lst, 2nd, and 3rd refer to specific treatment.

Four prospective trials comparing the outcomesof medical and surgical management includedanalysis of new renal scarring (Table 8 on page 32).None of these trials showed a statistically signifi-cant difference in the rate of new renal scarring.The combined relative risk slightly favored medicalmanagement but was not statistically significant(see Figure 4 on page 33). In the European arm ofthe International Reflux Study (Olbing, Claesson,Ebel, et al., 1992), the rate of scarring was similaramong those managed medically and those treatedsurgically; however, 80 percent of the new renalscars in the surgical group appeared by 10 monthsafter randomization, whereas new renal scarsappeared throughout the 5 years in the group man-aged medically.

Several single-arm studies also reported rates ofnew scarring after medical or surgical treatment.The combined risk for new scarring for 14 suchmedical reports was 4.1 percent (range, 0–24.7 per-cent) (Aggarwal, Verrier-Jones, Asscher, et al.,

1991; Arant, 1992; Bellinger and Duckett, 1984;Ben-Ami, Sinai, Hertz, et al., 1989; BirminghamReflux Study Group, 1987; Burge, Griffiths,Malone, et al., 1992; Cardiff-Oxford BacteriuriaStudy Group, 1978; Edwards, Normand, Prescod,et al., 1977; Homsy, Nsouli, Hamburger, et al.,1985; Husmann and Allen, 1991; Jakobsen,Genster, Olesen, et al., 1977; Koff and Murtagh,1983; Scholtmeijer and Griffiths, 1988; Shah,Robins, and White 1978), and for 7 such surgicalreports was 4.6 percent (range, 0–16.7 percent)(Beetz, Schulte-Wisserman, Tröger, et al., 1989;Birmingham Reflux Study Group, 1987; Burge,Griffiths, Malone, et al., 1992; Carpentier, Bettink,Hop, et al., 1982; Hjalmas, Lohr, Tamminen-Mobius, et al., 1992; Scholtmeijer and Griffiths,1988; Scott, Blackford, Joyce, et al., 1986). Thesereports are difficult to compare directly, however,because the length of follow-up and distribution ofreflux grades varied among the studies. In themajority of these studies, the minimum follow-up


Table 8. Scarring after treatment in prospective trials of surgery compared with antibiotictreatment for vesicoureteral reflux

Method of NewStudy Population evaluation Treatment Follow-up scarring

Elo, Tallgren, Matched uncontrolled IVP Medical— 4.3 years 7.5%Alfthan, et al., follow-up study with antibiotic, (average) (3/40)1983 40 girls in each arm. primarily

Mean age of 5.2 years sulfisoxazole

Surgery— 4.3 years 17.5%Politano- (average) (7/40)Leadbetterprocedure

Birmingham 161 children younger IVP Medical 5 years 6%Reflux Study than age 15 years, treatment (5/84)Group, 1987 allocated randomly to

either surgery or Surgical 5 years 5.2%antibiotic treatment treatment (4/77)

Olbing, Claesson, 306 children younger IVP Medical 5 years 15.7%Ebel, et al., 1992 than age 11 years, treatment (19/121)

with nonobstructive Grades III or IV VUR Surgical 5 years 17.2%and with previous treatment (20/116)UTI

Weiss, Duckett, Infants and children IVP Medical 4½ years 21.5%and Spitzer, 1992 with Grades III and IV treatment (14/65)

primary VURSurgical 4½ years 31.4%treatment (16/51)

was 3 months. Furthermore, identification of renalscarring in most studies has depended on intra-venous urography, but the quality of films andexpertise of radiologists were probably inconsis-tent. The Birmingham Reflux Study (1987) identi-fied new scars after 5 years in only 6 percent and5.2 percent of children treated medically and surgi-cally, respectively, with no additional scars detectedafter 2 years of follow-up. On the other hand, theInternational Reflux Study found new scars in 15.7percent (medical) and 17.2 percent (surgical) ofrefluxing children in Europe and 21.5 percent(medical) and 31.4 percent (surgical) in NorthAmerica (Table 8). When patients with VUR dis-covered before 5 years of age whose kidneys wereof normal size by planimetry and had no evidenceof renal scarring on initial intravenous urographywere treated medically and followed for 5 years,renal scarring was detected in 10 percent ofpatients with Grades I or II reflux and 28 percent ofthose with Grade III VUR. Of the scars, 42 percentwere detected after 1 year of follow-up, 25 percentafter 3 years and 33 percent after 5 years (Arant,1992). More recently, renal scarring has been con-firmed on DMSA scan within 6 months after acutepyelonephritis in children (Rushton and Majd,1992).

Renal scarring: Relationship to bacteriuria.Because VUR is most frequently diagnosed after an

infant or child presents with UTI and animalmodels of ascending pyelonephritis (via surgicallycreated VUR) reliably produce renal scarring, the 2events, when they occur clinically, are oftenthought to be causally related. Renal scarring isoften detectable on the initial renal imaging studyobtained following the diagnosis of UTI, and isproportional to the severity of VUR and the sensi-tivity of the technique. This observation suggeststhat previous undiagnosed UTIs may have occur-red, which resulted in pyelonephritic injury. How-ever, new or progressive renal scarring duringfollow-up is less common, despite additionalepisodes of bacteriuria.

The panel attempted to analyze the relationshipbetween bacteriuria and new renal scarring in chil-dren with reflux. However, few data are availablethat would permit such an analysis. Only 14 reportsdescribed the frequency of UTI in children withand without new or progressive renal scarring(Aggarwal, Verrier-Jones, Asscher, et al., 1991;Anderson and Rickwood, 1991; Arant, 1992; Beetz,Schulte-Wissermann, Tröger, et al., 1989; Birming-ham Reflux Study Group, 1983; BirminghamReflux Study Group, 1987; Cardiff-Oxford Bacteri-uria Study Group, 1978; Edwards, Normand,Prescod, et al., 1977; Goldraich and Goldraich,1992; McLorie, McKenna, Jumper, et al., 1990;Shah, Robins, and White, 1978; Skoog, Belman,


Weiss, Duckett, and Spitzer, 1992

Olbing, Claesson, Ebel, et al., 1992

Birmingham Reflux Study Group, 1987

Elo, Tallgren, Alfthan, et al.,1983

Combined

0.0625 0.25 1.0 4.0 16.0

Relative Risk of Scarring

Figure 4. Relative risk of new scarring for surgery compared with antibiotic treatment

Analysis from 4 prospective trials of the risk of new scarring after surgery compared to that aftermedical treatment showed that the combined relative risk slightly favored medical management butwas not statistically significant.

and Majd, 1987; Smellie, Gruneberg, Leakey, et al.,1976; Weiss, Duckett, and Spitzer, 1992). Most ofthese studies provided information only for thepresence or absence of bacteriuria in those withnew or progressive scarring, and not for those whodid not develop such scarring. Using the empiricalBayes method of Hedges and Olkin (1985), an esti-mated odds ratio of 1.18 (95% CI 0.52–2.68) isderived (see Figure 5 on page 34). In other words,the risk of developing new or progressive scarringfor an individual with UTI is 1.18 times as great asthat for an individual without infection, that is, therisk of developing new or progressive scarring isonly slightly increased.

Several factors may contribute to this surprisinglack of association between scarring and infectionin children with reflux. First, few of the reportscharacterized the types of infections (febrile, non-febrile, asymptomatic) in these children. FebrileUTIs are more likely to represent renal paren-chymal inflammation, and thus place the patient atgreater risk for scarring than does nonfebrile UTI.In the study by Goldraich and Goldraich (1992), all7 of the children with new renal scars by DMSAscan had a febrile UTI in the previous year. The

remainder of the reports were not as precise. Inaddition, the progressive scarring recorded mayhave been the result of a UTI that occurred beforetreatment (medical or surgical) was initiated. Theradiologic technique used to detect new or progres-sive scarring may not have been sufficiently sensi-tive to evaluate this parameter properly. Further-more, once the initial diagnosis of UTI and VURhas been made, most parents/patients are morelikely to be attuned to the symptoms of UTI (par-ticularly fever), and patients are more likely toreceive prompt diagnosis and treatment. In addi-tion, it is possible that UTIs were under-reported tothe investigator by referring physicians, or that sus-pected UTIs (or episodes of unexplained fever)may have been treated with an antibiotic withouturine culture. For example, in a study of 50 febrileinfants, all of whom underwent protocol urine cul-ture, 15 ultimately found to have bacteriuria ini-tially had received diagnoses other than UTI(Hoberman, Chao, Keller, et al., 1993).

Renal growthA clinical impression, supported by many

reports, is that renal growth is impaired when VUR


Beetz, Schulte-Wisserman, Troger, et al., 1980

Birmingham Reflux Study Group, 1983

Edwards, Normand, Prescod, et al., 1977

Anderson and Rickwood, 1991

Goldraich and Goldraich, 1992

Weiss, Duckett and Spitzer, 1992

Combined

0.0625 1.0 16 256 4096

Figure 5. New or progressive scarring and bacteriuria

Odds Ratio

Analysis of the relationship of bacteriuria and renal scarring in children with reflux showed that therisk of developing new or progressive scarring was 1.18 times as great for an individual with UTI asthat for an individual without infection (i.e., the risk is only slightly increased).

is present (Scott and Stansfield, 1968; Lyon, 1973;Redman, Scriber, and Bissada, 1974), especiallywith Grades IV and V reflux (Pinter, Jaszai, andDober, 1988; McRae, Shannon, and Utley, 1974),or recurrent infection (Peratoner, Messi, and Fonda,1984; Scott and Stansfield, 1968; Kelalis, 1971).Moreover, accelerated renal growth has beenrecorded after reflux was corrected (Carson,Kelalis, and Hoffman, 1982; Atwell and Vijay,1978; Willscher, Bauer, Zammuto, et al., 1976;Scott and Stansfield, 1968) or during adolescence(Claesson, Jacobsson, Jodal, et al., 1981). Moststudies with useful data on renal growth have beenconducted retrospectively without an appropriatecontrol group and for durations of follow-up inwhich some patients may have been followed nomore than 1 year (Atwell and Cox, 1981; Atwelland Vijay, 1978; Willscher, Bauer, Zammuto, et al.,1976). Standardized methods for assessing renalgrowth have seldom been used, making compar-isons among studies difficult. Furthermore, manypatients have renal scarring when reflux is recog-nized or develop new or progressive scarringduring follow-up (Birmingham Reflux StudyGroup, 1987; Bellinger and Duckett, 1984; Weiss,Duckett, and Spitzer, 1992; Olbing, Claesson, Ebel,et al., 1992; Smellie, Edwards, Normand, et al.,1981).

Renal growth is most often assessed as renallength measured from intravenous urography or,more commonly in recent years, by renal ultra-sonography. Before interpreting data obtained usingthese techniques, it must be recognized that the dis-tance between the table top and tray alters the renalimage projected onto the film (Riggs, 1977). Renaldimensions are distorted when the distance be-tween the x-ray source and film is altered and mag-nified when urographic films are taken when thepatient is in the prone position. Poor technique orinadequate bowel preparation may obscure theexact margins of the renal outline. With renal ultra-sonography, the angle of the transducer to the lon-gitudinal aspect of the kidney may distort renaldimensions.

Of the various estimates of renal size from renallength, standards exist only for normal—notscarred—kidneys (Hodson, Drewe, Karn, et al.,1962; Hodson, Davies, and Prescod, 1975; Eklofand Ringertz, 1976; Rosenbaum, Korngold, andTeele, 1984). Moreover, some kidneys are “shortand fat” while others are “long and thin.” Renalscarring is noted most often in upper or lower poles(Hannerz, Wikstad, Johansson, et al., 1987). Renalsize can be assessed more reproducibly by esti-

mating planimetric surface area (Claesson, Jacobs-son, Olsson, et al., 1981). This two-dimensionalmeasurement of renal parenchyma surface areafrom a standardized urographic film is not compro-mised by differences in renal width or hydroneph-rosis. In addition, identification of parenchymalthinning may be a more sensitive indicator of renalscarring in the small but growing kidney (Olbing,Claesson, Ebel, et al., 1992). Even when aparenchymal scar is not obvious, discrepancies inrenal size between kidneys suggest unilateral dis-ease in the smaller kidney, especially when com-pensatory hypertrophy in the contralateral kidneyresults in its being larger than expected for age,body length, or vertebral height (Claesson, Jacobs-son, and Jodal, 1981). Renal size cannot be esti-mated from any radionuclear study currently in use.Even when a kidney contributes more than 50 per-cent of total renal function on a radionuclide scan,normal renal size cannot be presumed.

Two reported studies provide data on renalgrowth in patients with reflux treated either med-ically or surgically; each was conducted prospec-tively and had a minimum of 5 years of follow-upin every patient. The Birmingham Reflux Study(1987) used renal length whereas the InternationalReflux Study (Weiss, Duckett, and Spitzer, 1992)employed planimetric surface area—both takenfrom intravenous urography. At the outset of bothstudies, each treatment group included manypatients with previous renal scarring. No differ-ences in renal growth were detected betweengroups in either study. Another study that was notconducted prospectively reported similar findings—no difference in renal growth during medical man-agement or after surgical correction of reflux(Peratoner, Messi, and Fonda, 1984). However,patients in both treatment groups had kidneys thatwere smaller than normal or that grew suboptimallyduring the follow-up period. The number of kid-neys that were small because of renal scarring orparenchymal thinning was not reported. On thebasis of clinical studies available to date, there isno evidence to support the notion that in theabsence of voiding dysfunction, renal growth isimpaired in unscarred kidneys exposed to sterilereflux of any grade (Arant, 1992; Smellie,Edwards, Normand, et al., 1981) or that surgicalcorrection of reflux facilitates growth of the kidneypostoperatively (Birmingham Reflux Study Group,1987; Peratoner, Messi, and Fonda, 1984; Beetz,Hohenfellner, Schofer, et al., 1991; Weiss, Duckett,and Spitzer, 1992).


Renal functionThe rationale for identifying reflux early is to

introduce treatment that best prevents scarring andpreserves renal function. Scott, Blackford, Joyce, etal. (1986) reported marked improvement in glom-erular filtration rate (GFR) for most patients inwhom reflux was corrected surgically. Using thesame technique for measuring GFR, however,Poulsen, Johannesen, Nielsen, et al. (1989) foundthat GFR was preserved during nonsurgical man-agement of children with reflux. During long-termobservations, others have found no adverse effectof continued sterile reflux on kidney function(Birmingham Reflux Study Group, 1987; Weiss,Duckett, and Spitzer, 1992). In prospective, con-trolled treatment trials, surgical correction of evensevere reflux has had no benefit on GFR 5 yearslater (Birmingham Reflux Study Group, 1987;Weiss, Duckett, and Spitzer, 1992).

When renal scarring is severe but unilateral,renal function would be expected to be normal.Even when both kidneys are scarred, overall renalfunction may be preserved by compensatorychanges in structure and function of remainingnephrons (Berg, 1992). In fact, the degree of renalfunctional impairment in patients with refluxnephropathy has been related directly to paren-chymal size of both kidneys (Claesson, Jacobsson,Jodal, et al., 1981). Serum creatinine concentrationwill remain within the range of normal values forage until scarring reduces functional nephron masssufficiently to lower GFR. When renal function isdecreased below normal for age, one must con-clude that maximal functional compensation hastaken place already in kidneys that are small orscarred.

A radionuclide study that reports an allocation ofthe percent of isotope excreted by right and leftkidneys cannot be used to interpret overall renalfunction. Total GFR should be corrected to 1.73 m2

body surface area and calculated by timed urinecollection and clearance methodology, from serumcreatinine and height (Schwartz formula) or fromanother radionuclide study that measures andreports actual GFR as well as split functions. Nodecision to remove a kidney or surgically correctVUR can be made on the basis of split functionsalone. When a patient has bilateral renal scarring,every functioning nephron should be conservedbecause each contributes to overall renal function.

Health outcomes

Urinary tract infectionMost infants and children with VUR present

with UTI, usually acute pyelonephritis with theattendant risk of renal parenchymal injury (Weiss,Tamminen-Mobius, Koskimies, et al., 1992). Therelationship between renal injury (presumablypyelonephritic scarring) and UTI complicated byacute pyelonephritis has been examined (Martinell,Claesson, Lidin-Janson, et al., 1995). UTIs werecharacterized retrospectively by conventional cri-teria (e.g., fever) as either acute pyelonephritis, cys-titis or unspecified. Of the 45 patients with renalscarring, 33 (73 percent) had acute pyelonephritisas their first UTI, compared with 18/42 (43 per-cent) who did not have renal scarring (p < .001).

Pyelonephritis can result in destruction of one ormore lobes of the kidney with replacement ofnormal kidney by fibrotic tissue (renal scarring). Inaddition to short-term morbidity, the long-termconsequences of renal scarring include hyperten-sion and functional impairment, both most fre-quently seen after loss of critical mass of kidneytissue. Thus, prevention of UTI, and particularlyacute pyelonephritis, is an important goal in themanagement of infants and children with VUR.

UTI may occur following diagnosis of reflux andinitiation of therapy. If it occurs in a child receivingantibiotic prophylaxis, the infection may occurbecause of antibiotic resistance to the prophylacticantibiotic (in which case the organism is resistantto the antimicrobial) or because of non-compliancewith therapy (in which case the organism is usuallysensitive to the antimicrobial). Children who haveundergone successful surgical therapy often do notcontinue to receive antibiotic prophylaxis after theimaging studies demonstrating reflux resolutionhave been performed. In these children, develop-ment of UTI is independent of the previous struc-tural abnormality and secondary to host uroepithe-lial adherence characteristics and bacterialvirulence factors.

The panel reviewed 41 articles that reported theincidence of UTI (as defined by bacteriuria, regard-less of clinical symptoms) in children with VURtreated either with antibiotic prophylaxis or reim-plantation surgery. The International Reflux Studyin Children randomized infants and children withGrades III and IV VUR to either medical or sur-gical management. In the European branch of thestudy (Jodal, Koskimies, Hanson, et al., 1992), 59



Analysis of the risk of acute pyelonephritis after surgery compared to that after medical treatment showed thecombined relative risk significantly favored surgical treatment. The combined relative risk of acute pyelo-nephritis with surgical treatment is 0.39 (95% CI 0.26–0.58) compared with medical treatment.

Jodal, Koskimies, Hanson, et al., 1992

Elo, Tallgren, Alfthan, et al., 1983

Weiss, Duckett and Spitzer, 1992

Combined

0.0625 0.25 1.0 4.0 16.0

Relative Risk of Pyelonephritis

Figure 6. Relative risk of pyelonephritis for surgery compared with antibiotic treatment

of 151 surgical patients (39.1 percent) had at least1 UTI during the 5-year follow-up (0.65 per 100patient-months), compared with 59 of 155 medicalpatients (38.1 percent) (0.63 per 100 patient-months). In the U.S. branch (Weiss, Duckett, andSpitzer, 1992), 21 of 64 surgical patients (32.8 per-cent) (1.8 per 100 patient-months) compared with20 of 68 medical patients (29.4 percent) (2.3 per100 patient-months) had at least 1 UTI during the5-year follow-up. There was no significant differ-ence in UTI rate between medical and surgicaltreatment either in the European or the U.S. data.The incidence of UTI in a third uncontrolled, butmatched (n = 40 each) study was 2.81 per 100patient-months following surgery and 3.34 per 100patient-months with medical management with acomparable duration of follow-up (Elo, Tallgren,Alfthan, et al., 1983). Combining data from all 3studies yields a relative risk of 0.97 (95% CI0.79–1.19), indicating almost no difference be-tween the 2 treatments with respect to the risk ofbacteriuria. In support of this observation, anotherstudy (Beetz, Schulte-Wissermann, Tröger, et al.,1989) reported an incidence of UTI after surgeryalone that was comparable to the surgical arms ofthe 2 randomized controlled trials, and a study ofUTI with antibiotic prophylaxis alone (Hanson,Hansson, and Jodal, 1989) reported rates compa-rable to those in the medical arms of the 2 random-ized controlled trials.

Because the risk of renal injury is related toacute pyelonephritis rather than to UTI in general,incidence rates of acute pyelonephritis were com-pared in both the European and U.S. branches ofthe International Reflux Study in Children. In theEuropean branch (Jodal, Koskimies, Hanson, et al.,1992), acute pyelonephritis was observed in 15 of151 surgical patients (9.3 percent) (0.17 per 100patient-months) compared with 33 of 155 medicalpatients (21.3 percent) (0.35 per 100 patient-months) (p = 0.03). In the U.S. branch (Weiss,Duckett, and Spitzer, 1992), 5 of 64 surgical pa-tients (7.8 percent) (0.3 per 100 patient-months)compared with 15 of 68 medical patients (22.1 per-cent) (0.7 per 100 patient-months) had at least 1episode of acute pyelonephritis (p = 0.085). In thenonrandomized and uncontrolled, but matchedstudy (Elo, Tallgren, Alfthan, et al., 1983), 72.5percent medical patients compared with 22.5 per-cent surgical patients (1.41 per 100 patient-monthsmedical and 0.44 per 100 patient-months surgical)had acute pyelonephritis. Combining the data fromthe 3 studies, the relative risk of acute pyeloneph-ritis with surgical treatment is 0.39 (95% CI0.26–0.58) compared with medical treatment (Fig-ure 6). An additional uncontrolled and unmatchedstudy examined the incidence of acute pyeloneph-ritis with either surgery or medical therapy (Amar,Singer, and Chabra, 1976). Follow-up varied from1–14 years. Acute pyelonephritis was reported in

none of 111 surgical patients compared with 5 of99 medical patients. In a study of surgical patientsonly (Willscher, Bauer, Zammuto, et al., 1976), 223children were followed postoperatively for 0.5–7years. Three of 175 girls (1.7 percent) had acutepyelonephritis. In a study of medical patients only(Hanson, Hansson, and Jodal, 1989), 12 of 44 (27.3percent) girls who were treated for 860 monthsdeveloped acute pyelonephritis (1.44 per 100patient-months).

In summary, of the few studies that were ade-quate for analysis, the overall incidence of UTI inpatients with VUR was not significantly different inpatients treated with antibiotic prophylaxis (med-ical management) or ureteral reimplantation (sur-gical management). The incidence of acute pyelo-nephritis was significantly greater with medicalmanagement. Despite the risk of renal parenchymalinjury from acute pyelonephritis and its potentialfor healing with scarring, the incidence of scarringwas no greater in medical than in surgical patients(Jodal, Koskimies, Hanson, et al., 1992; Weiss,Duckett, and Spitzer, 1992). The factors that mayaccount for the surprising lack of an associationbetween new or progressive renal scarring andpyelonephritis in the literature are discussed onpages 33–34.

HypertensionReflux nephropathy is considered one of the

most common causes of severe hypertension inchildren, when it is examined in a retrospectivefashion (i.e., of those who present with severehypertension, reflux nephropathy is a frequent diag-nosis). The panel reviewed 10 studies that reportedblood pressure (BP) measurements after reimplan-tation surgery. Only 2 characterized the patientpopulation sufficiently to provide meaningfulanalysis. Wallace, Rothwell, and Williams (1978)reported longer than 10-year follow-up of 166 chil-dren with VUR treated surgically. Of 158 preopera-tive BP measurements that were compared with theAmerican Academy of Pediatrics 1977 BP norms,24 (15.2 percent) had BP higher than the 95th per-centile for age and sex (either systolic, diastolic, orboth.) Hypertension was defined as a BP of≥140/90 in their follow-up, because all 141 sub-jects were older than 14 years of age. Eighteen(12.8 percent) were hypertensive. Of these, 7 hadpreoperative bilateral renal scarring (of 38 with thisfinding on IVU) and 7 had preoperative unilateralrenal scarring (of 62 with this finding on IVU). InBeetz’ series (Beetz, Schulte-Wissermann, Tröger,

et al., 1989), 189 children were evaluated at least 5years after successful VUR surgery. Ten patients(5.3 percent), all of whom were older than age 14,were found to be hypertensive (BP > 140/90). Of61 patients with renal scarring (all preoperative), 7(11.5 percent) were hypertensive at the time offollow-up compared with 3 of 128 patients (2 per-cent) of those without scarring. Preoperative BPlevels were not reported.

Lenaghan, Whitaker, Jensen, et al. (1976)reported hypertension (defined as >140/90) in 10 of102 children (9.8 percent) treated nonsurgically,who were followed-up for 5–18 years. Patients withscarred kidneys were not distinguished from thosewithout scarring.

Thus, no statistically significant difference wasfound in the risk of hypertension related to treatmentmodality (medical or surgical). These studies indi-cated that renal scarring increases the relative risk ofhypertension to 2.92 (95% CI 1.2–7.1), comparedwith the risk in patients without renal scarring.

Numerous medications are used to treat hyper-tension in children and adults with renal scarring.Angiotensin-converting enzyme inhibitors, whichmay be used for treatment of those with renin-mediated hypertension, may be associated withsome side effects (Kim and Swartz, 1993). In addi-tion, use of these drugs during pregnancy maycause oligohydramnios and irreversible neonatalrenal failure (Rosa, Bosco, Graham, et al., 1989).

UremiaSince 1987, the North American Pediatric Renal

Transplant Cooperative Study has registered virtu-ally all children with end-stage renal disease(ESRD), defined as a GFR so low that only kidneydialysis or transplantation will sustain life. Al-though overlap of diagnostic categories (e.g., hypo-plasia, dysplasia, obstructive uropathy) is likely,VUR was the primary diagnosis in 3.1 percent ofthis population (Avner, Chavers, Sullivan, et al.,1995). Those with VUR who develop ESRD typi-cally have been those who present with reducedGFR and bilaterally small, scarred kidneys. It isthought that independent of further pyelonephriticinjury, these patients have sustained the loss of acritical mass of renal tissue, such that progressiveloss of function due to glomerulosclerosis is medi-ated by maladaptive hemodynamic events(Neuringer and Brenner, 1993).

Although UTI is the most frequent presentationof VUR, it is less commonly the presentation ofthose patients with impaired GFR, virtually all of


whom have bilateral extensive renal scarring on theinitial kidney imaging study. Also, antenatal detec-tion of bilateral hydronephrosis has identified apopulation of neonates with severe bilateral VURand impaired GFR before any UTI has occurred.How many patients develop uremia from congenitalreflux nephropathy (or dysplasia associated withVUR), rather than after acquired reflux neph-ropathy from 1 or more pyelonephritic events, re-mains unknown. Thus, it would not be possible todemonstrate that even optimal treatment of VURand UTI can prevent progressive renal failure and,ultimately, uremia, once bilateral reflux neph-ropathy has been diagnosed.

Somatic growthTwo studies mentioned somatic growth associ-

ated with nonsurgical VUR treatment and follow-up (Pinter, Jaszai, and Dober, 1988; Smellie,Preece, and Paton, 1983). Neither study substanti-ated an effect of VUR treatment on somatic growth.

Morbidity during pregnancyBecause of the known association between bac-

teriuria and adverse outcomes in pregnancy, there isa common perception that the increased risks ofpyelonephritis and renal scarring in patients withvesicoureteral reflux may potentially result inincreased morbidity during pregnancy in womenwho have persistent reflux. The panel did notundertake an extensive literature search of refer-ences pertaining to the association between refluxand adverse outcomes of pregnancy. However,based on a more selective review, what follows isthe panel’s current understanding of this associa-tion.

One of the potential late complications of VURand/or pyelonephritic scarring in females ismaternal and fetal morbidity. Maternal problemsinclude pyelonephritis, septicemia, renal scarring,hypertension, toxemia, and reduction in renal func-tion, which in some women progresses to ESRD.Fetal complications include preterm delivery, lowbirth weight, and fetal loss.

On the basis of a retrospective review of 26studies that included a total of 82,364 pregnancies,approximately 4–7 percent of pregnant womenhave asymptomatic bacteriuria (Sweet, 1977). Ifasymptomatic bacteriuria is not treated, pyelo-nephritis is common. From a combination of 18studies of pregnant bacteriuric women who werenot treated with antibiotics, 28 percent of 1,699women developed pyelonephritis (Sweet, 1977).Kass (1960) observed a 42-percent incidence of

pyelonephritis in 48 patients when asymptomaticbacteriuria in pregnancy was not treated. Whenbacteriuria was eliminated, pyelonephritis did notoccur (Kass, 1960). Women with a history of UTIin childhood appear to have a higher risk of asymp-tomatic bacteriuria. Martinell, Jodal, and Lidin-Janson (1990) and Sacks, Roberts, Verrier Jones, etal. (1987) found an incidence of 37 percent (24/65pregnancies) and 50 percent (24/48 pregnancies),respectively. If renal scarring was present, the riskincreased to 47 percent (9/19) (Martinell, Jodal,and Lidin-Janson, 1990) and 60 percent (9/15)(Sacks, Roberts, Verrier-Jones, et al., 1987).

Pregnant women with pyelonephritic renal scar-ring appear to be at higher risk for pyelonephritisthan those without renal scarring. In a study of 41pregnant women with a history of childhood UTI,Martinell, Jodal, and Lidin-Janson (1990) reportedan incidence of 21 percent (4/19) in those withscarring compared with 5 percent (1/22) in thosewithout renal scarring. Jacobson (1991) reportedthat 3 of 30 pregnant women with renal scarringdeveloped pyelonephritis.

The relationship between asymptomatic bacteri-uria and maternal/fetal complications is controver-sial. A meta-analysis of 17 cohort studies including23,298 patients showed that in women with asymp-tomatic bacteriuria, the risk of preterm delivery was2 times higher and the risk of having a low-birth-weight baby was 1.5 times higher compared withwomen without bacteriuria (Romero, Oyarzun,Mazor, et al., 1989). Kincaid-Smith and Bullen(1965) demonstrated that women with bacteriuriaat their first prenatal visit had a 2.9 times higherrisk of fetal loss during the second and thirdtrimesters, the risk of preterm delivery was 2.7times higher and the risk of pre-eclampsia was 1.8times higher than that in women without bacteri-uria. Many of these women also had underlyingrenal scarring. Schieve, Handler, Hershow, et al.(1994) reported on the effects of pyelonephritisduring pregnancy on maternal and fetal outcome.Of the 25,476 mother/infant pairs studied, 7.7 per-cent had a documented UTI. In those with pyelo-nephritis, the risk of perinatal death was 2.6 timeshigher and the risk of preterm delivery or low birthweight was 2.5 times higher than in those withoutUTI.

In women with reflux nephropathy and reducedrenal function, the risk of complications is consid-erable. In addition to pyelonephritis, potential prob-lems include further reduction in GFR, toxemia,preterm delivery, and fetal loss (see Table 9 onpage 40). Women with renal scarring and chronic


hypertension who are receiving angio-tensin-con-verting enzyme inhibitor therapy (captopril, enala-pril) are at particular risk for oligohydramnios andneonatal renal failure, which may be irreversible(Rosa, Bosco, Graham, et al., 1989). This class ofdrugs, which often is extremely effective, shouldnot be used during pregnancy (Cunningham andLindheimer, 1992).

The morbidity of persistent reflux during preg-nancy has not been studied extensively. Williams,Davies, Evans, et al. (1968) found that 21 percent

of women with asymptomatic bacteriuria duringpregnancy had reflux on VCUG performed 6months postpartum, compared with 1.7 percent in arandomly selected group of women examinedimmediately postpartum (Heidrick, Mattingly, andAmberg, 1967). Martinell, Jodal, and Lidin-Janson(1990) reported that pyelonephritis occurred duringpregnancy in 3 of 8 women with reflux, but only 2of 33 in those without reflux. In the 8 patients withreflux, pyelonephritis occurred in 3 of 9 of preg-nancies managed with continuous antibiotic pro-phylaxis and 2 of 4 managed without prophylaxis.


Table 9. Maternal and fetal complications in patients with moderate or severe renal insufficiency

Further Fetaldecrease in Preterm growth Fetal

Study renal function Toxemia delivery retardation loss

Kincaid-Smith and Fairley, 198795 women - 227 pregnancies, normal renal

function 2% 13% — — 9%42 women - 118 pregnancies, SCr > 1.25 mg%

8% 36% — — 24%

Becker, Ihle, Fairley, et al., 198620 women, SCr 2.3–4.5 mg%, including:

6 women preg. duration >12 wk. 100%1 — — — —14 women preg. duration <12 wk 29%2 — — — —

Cunningham, Cox, Harstad, et al., 199037 women, SCr 1.4–9.4 mg% 16%3, 4 60% 40% — —

+ chronic htn 24% 80% 57% 38% 54%+ toxemia, — — 53% — —

including:26 women, SCr 1.4–2.5 mg% (ave. 1.7) 19% — 30% 35% 8%+ chronic htn 29% 79% 43% 36% —11 women, SCr >2.6 mg% (ave. 4.8) 9% 86% 43% 18%+ chronic htn 14% 86% 86% 43% —

Jungers, Houillier, Forget, et al., 1991104 women with reflux nephropathy- — — — — 13%

254 pregnancies14 women, 19 pregnancies,

SCr >1.5 mg% at conception — — — — 63%+ htn — — — — 75%

14 women, SCr 2–5.5 mg% atconception 36%5 — — — —

Jones and Hayslett, 199667 women - 82 pregnancies,

SCr≥1.4 mg% 43%6 — 59% 37% 7%67 pregnancies, SCr 1.4–2.4 mg% — — 55% 31% 9%15 pregnancies, SCr ≥2.5 mg% — — 73% 57% 0%

1 Rapid deterioration in renal function in all 6 women; 4 progressed to ESRD within 2 years post delivery.2 Four with uncontrolled hypertension had rapid deterioration in renal function with progression to ESRD; 10 had slow deterioration in renalfunction over 7 years but not to ESRD.

3 Renal deterioration defined by an increase in SCr of 50% during pregnancy.4 Of 7 patients without deterioration of renal function during pregnancy, 6 later had deterioration of renal function and 4 required dialysiswithin a mean interval of 39 months.

5 Five of 14 patients had accelerated deterioration of renal function with progression to ESRD in 6 months to 4 years.6 During pregnancy and up to 6 weeks postpartum; 31% after 6 months postpartum.

In this series, reflux generally was Grade I or II.Heidrick, Mattingly, and Amberg (1967) reportedthat 3 of 9 women with reflux developed pyelo-nephritis during pregnancy compared with 15 of312 women without reflux. Although the data sug-gest a greater risk of morbidity from pyelonephritisin women who have persistent reflux during preg-nancy, the sample size is small and only limitedconclusions can be made on the basis of this evi-dence.

Few studies have focused on the outcomes ofpregnancies of women with surgically treatedreflux. Fryczkowski, Maruszewska, Paradysz, et al.(1991) reported that in 59 pregnancies in 34women who had undergone antireflux surgery inchildhood, 65 percent (22/34) had a UTI duringpregnancy, but the incidence of pyelonephritis wasnot reported. Mansfield, Snow, Cartwright, et al.(1995) studied 62 women who underwent antire-flux surgery as children and compared them with21 women with uncorrected childhood reflux whohad not had radiologic follow-up and whose refluxstatus was unknown. In the surgically treatedgroup, 40 percent (57/141) of pregnancies werecomplicated by a UTI (18 percent pyelonephritis;22 percent cystitis). In the uncorrected group, 1.3percent (1/75) had pyelonephritis and 13.3 percent(10/75) had cystitis. The 2.5 times higher incidenceof UTIs demonstrated in the surgically treatedgroup has not yet been explained adequately butmay be related to host factors that subject them to ahigher inherent risk of UTI. In this retrospectivestudy, no data were presented concerning the initialpresentations, voiding dysfunction, indications forpatient selection for surgery, or extent of renal scar-ring. Antibiotic prophylaxis during pregnancy wasinconsistently prescribed. There was no significantdifference in the rate of fetal loss in the 2 groups.Although these studies indicate that UTIs are com-mon during pregnancy in patients who have under-gone antireflux surgery, data are not presented onthe effect of antireflux surgery on subsequentpyelonephritis.

DeathDeath can be attributed to VUR only indirectly.

Unrecognized or inadequately treated UTI mayresult in urosepsis and death, which occurred fre-quently in the pre-antibiotic era. Moreover, deathcould occur as a complication of anesthesia orsurgery performed to correct VUR. In a patientwith renal scarring who develops hypertensionwhich, after a period of being asymptomatic, mayresult in heart failure or encephalopathy, death

could result if treatment were unsuccessful. Womenwith bilateral renal scarring, even those with noprevious symptoms, may exhibit acute deteriorationof renal function during pregnancy and requireaggressive treatment to prevent death; some ofthese women regain renal function after delivery,while others do not (Jacobson, Eklof, Eriksson, etal., 1989). Progressive deterioration of renal func-tion over many years in patients with severe bilat-eral renal scarring is a major cause of ESRD inpatients younger than 30 years of age (Arant, 1991;Pistor, Scharer, Olbing, et al., 1985; Salvatierra,Kountz, and Belzer, 1973; Mathew, 1987). Theaverage mortality rate for patients on chronic dial-ysis in the United States is about 25 percent eachyear (Bloembergen, Port, Mauger, et al., 1994).Others die as a complication of renal transplanta-tion. While none of these causes of death is theimmediate consequence of untreated VUR, the pos-sibility of an association cannot be ignored.

Harms of medical treatment

Adverse drug reactionsAntibiotic prophylaxis.One of the mainstays of

the medical management of VUR is antimicrobialprophylaxis. The usual medications administeredare trimethoprim/sulfamethoxazole, trimethoprimalone, and nitrofurantoin. The dose prescribed forprophylaxis typically is one-fourth to one-third ofthe dose recommended for full therapy. The inci-dence of drug-related adverse effects is lower withreduced dosages. Most reports describing adversedrug reactions pertain to adult patients taking thefull dosage of the medication (Lawson and Paice,1982).

Potential adverse reactions to antimicrobial pro-phylaxis include minor effects such as nausea,vomiting, abdominal pain, and bad taste in themouth, as well as more serious side effects (Table10 on page 42). Very few studies dealing with themedical management of reflux have reported minoreffects. Determining whether abdominal complaintsare related to medication or some other factor isoften difficult. Underreported side effects may con-tribute to the lack of compliance with medication insome cases, and the need to change antibiotic pro-phylaxis because of side effects is also probablyunderreported. Bacterial resistance to antibioticprophylaxis may also occur and is discussed in thesection on UTI (page 36).

Reported side effects of trimethoprim/sufameth-oxazole prophylaxis are uncommon. Uhari, Nuutinen,


and Turtinen (1996) reported that medication waschanged because of adverse effects in 15 percent ofchildren receiving sulfonamides and 8 percentreceiving trimethoprim. The most common adverseeffect is allergic skin reaction, usually from thesulfa, and accounts for 90 percent of nonfatal drugreactions (Lawson and Paice, 1982). Uhari, et al.(1996) reported that 4.5 percent of children receiv-ing prophylaxis developed urticaria, with an inci-dence of 7.4 events per 100 years at risk. Allergicskin reaction may occur after several weeks ormonths of therapy, but anaphylaxis is rare. Al-though neutropenia, thrombocytopenia and/oreosinophilia occur in 12–34 percent of childrentaking full-dose trimethoprim/sulfamethoxazole foronly 10 days (Asmar, Maqbool, and Dajani, 1981),the incidence of these side effects in childrenreceiving prophylactic dosages for periods as longas 1 year ranged from 0 percent (Smellie,Gruneberg, Normand, et al., 1982; Uhari, Nuutinen,and Turtinen, 1996) to 41 percent (Holland, Kazee,Duff, et al., 1982). In the latter study, in childrenwith a white blood count (WBC) less than5000/mm3, the WBC level normalized by the fol-lowing visit in all cases. Another potential problemis dental caries related to the fructose in the liquidpreparation, but this can be prevented by having thechildren brush their teeth after taking the drug.Other side effects include nausea, vomiting, ab-dominal pain, hepatotoxicity, and significant hyper-sensitivity reaction, but these effects have beenreported only anecdotally in children. Although sul-famethoxazole and trimethoprim compete for

sequential sites in the metabolic pathway of bacte-rial folic acid synthesis, children receiving prophy-laxis have not developed folic acid deficiency.Trimethoprim/sulfamethoxazole is the mostcommon drug associated with reactions requiringhospital admission, although the drug accounted foronly 0.07 percent of hospital admissions (Mitchell,Lacouture, Sheehan, et al., 1988).

Trimethoprim alone has been reported to causeside effects in as many as 27 percent of patients(Brendstrup, Hjelt, Petersen, et al., 1990). Reportedside effects included nausea, vomiting, or abdom-inal pain in 14 percent of patients, bad taste in themouth in 6 percent, and headache, dizziness, der-matitis and pruritus in 8 percent. Of childrenreceiving trimethoprim prophylaxis, 8 percentchanged the drug because of side effects (Uhari,Nuutinen, and Turtinen, 1996). Hematologic andallergic reactions are uncommon (Smellie,Gruneberg, Normand, et al., 1982).

The incidence of side effects associated withnitrofurantoin depends on the drug preparation.Nitrofurantoin suspension is tolerated poorly, andas many as 55 percent of children taking this med-ication experience a side effect, including nausea,vomiting, or abdominal pain in 34 percent, badtaste in the mouth in 27 percent, and headache,dizziness, dermatitis, pruritus or fever in 12 per-cent; 30 percent changed the medication because ofside effects (Brendstrup, Hjelt, Petersen, et al.,1990). Many of these effects may be eliminated byadministering nitrofurantoin macrocrystals. Thecapsule may be opened and placed in the children’s


Table 10. Adverse effects of antimicrobials commonly prescribed for antibiotic prophylaxis inchildren

Antibiotic Adverse reactions

Cotrimoxazole Skin rash/urticaria, nausea, vomiting, anorexia, dental caries (1–4%)

Rare (<0.1%): serious dermatologic, hematologic, cardiovascular, central nervous system,endocrine, renal, hepatic effects

Trimethoprim Skin rash/urticaria, nausea, vomiting, anorexia (2.5–7%)

Rare (<0.1%): serious dermatologic, hematologic, cardiovascular, central nervous system,endocrine, renal, hepatic effects

Nitrofurantoin Nausea, vomiting, abdominal pain 34% (less with macrocrystals)Headache, dizziness (less with macrocrystals); skin rash/urticaria

Rare (<0.1%): hematologic, cardiovascular, central nervous system, gastrointestinal, hepatic, respi-ratory, dermatologic effects

Source: Computerized Clinical Information System, March 1996 (Micromedex, Inc., Denver CO); American HospitalFormulary Service Drug Information, 1995.

food if they are unable to swallow the capsules.One group of children using the macrocrystalsexperienced no adverse effects (Lohr, Nunley,Howards, et al., 1977). Hematologic side effectsare infrequent (Holland, Kazee, Duff, et al, 1982).More serious adverse reactions are extremely rare,with 1 study documenting only 40 reports out of8.6 million uses (Coraggio, Gross, and Roscelli,1989). Approximately 32 percent of childrenyounger than age 2 years and 10 percent older than2 years of age taking nitrofurantoin prophylaxischanged therapy because of adverse reactions(Uhari, Nuutinen, and Turtinen, 1996). In thatstudy, it was not indicated whether children werereceiving the suspension or macrocrystal prepara-tion.

Anticholinergics. In children with bladder insta-bility and VUR, anticholinergic therapy and timedvoiding are often recommended in addition toantibiotic prophylaxis. Although several reportsdescribe the frequency of reflux resolution in thesepatients, few descriptions of the adverse effects ofanticholinergic medications are available. Onereason for this lack of information may be that thedosage of anticholinergic medication is usuallytitrated to the lowest effective dose in each child,providing the maximum therapeutic effect inreducing bladder instability while minimizing theside effects. Facial flushing can be brought on moreeasily in warm or hot temperatures; thus, a lowerdose may be necessary in summer or warm cli-mates. A dry mouth is common. This side effectmay be particularly bothersome to some children,yet have minimal effect on others. Table 11 listspossible adverse effects of the most commonly pre-scribed anticholinergic medications.

Hospitalization of patients receivingmedical treatment

Many studies reported occurrences of UTI inchildren with reflux who received medical therapy,and some distinguished between episodes of clin-ical pyelonephritis and cystitis (Cardiff-OxfordBacteriuria Study Group, 1978; Hanson, Hansson,and Jodal, 1989; Weiss, Duckett, and Spitzer,1992). However, none of the studies reported onthe proportion of children experiencing clinicalpyelo-nephritis who required hospitalization.

Children with clinical pyelonephritis often havefever, and flank or abdominal pain, and may experi-ence nausea, vomiting, and diarrhea. Decisionsabout whether to admit a child to the hospital forintravenous antibiotic therapy and rehydration vary,and may depend on duration and severity of symp-toms, hydration status, sensitivity pattern of thebacterial strain and the child’s age. If a child is hos-pitalized for pyelonephritis, in 1992 the meanlength of stay was 4.1 days (U.S. Department ofHealth and Human Services, 1993).

Harms of surgeryUreteral obstruction is a recognized complica-

tion following ureteral reimplantation. The otherharms of surgical treatment of VUR occur less fre-quently. Many reports do not describe harmsexplicitly. Others indicate isolated events within theseries, and these reports were used to review thetypes and approximate frequencies of surgical com-plications of antireflux surgery. The panel recog-nizes, however, that due to underreporting, theabsence of reported complications in many studiesmay be misleading and that the actual complicationrates may exceed reported values.


Table 11. Adverse effects of anticholinergic medications most commonly prescribed forbladder instability in children

Antibiotic Adverse reactions

Oxybutynin chloride Xerostomia (usually dose related) 40–45% vasodilation, facial flushing, mydriasis, decreasedsweating, tachycardia, blurred vision, drowsiness, constipation (5–30%)

Rare (< 0.1%): urinary retention, urticaria, hallucinations

Hyoscyamine Xerostomia, decreased sweating, mydriasis, drowsiness, restlessness, blurred vision, tachycardia(5–30%)

Rare (< 0.1%): Central nervous system effects, urinary retention, urticaria, speech disturbances

Propantheline Xerostomia, constipation, cycloplegia (5–30%)

Rare (<0.1%): Central nervous system, cardiovascular, endocrine, renal effects

Source:Computerized Clinical Information System, March 1996 (Micromedex, Inc., Denver, CO); American Hospital FormularyService Drug Information, 1995.

ObstructionThirty-three studies provided rates of obstruction

after ureteral reimplantation for VUR (Table E–4,Appendix E). Figure 7 (page 44) shows the rate ofobstruction in studies before and after 1986. Allstudies used either renal ultrasonography or intra-venous pyelography to detect hydronephrosisindicative of obstruction. The likelihood of obstruc-tion in the 33 series ranged from 0–9.1 percent,with a combined rate of 2 percent after 1986 (95%CI 1–4). The rate of obstruction was similar for dif-ferent types of repair. Fourteen studies provideddata regarding reoperation for obstruction (Table E-5, Appendix E). The reoperation rate ranged from0.3–9.1 percent, with an overall incidence of 2 per-cent. On the basis of these studies, nearly everycase of obstruction leads to reoperation so that thebest estimate of obstruction is probably the propor-tion of patients requiring reoperation (2 percent).

Obstruction following endoscopic treatment ofreflux.Fifteen series provided detailed informationabout postoperative ureteral obstruction followingthe subureteric injection technique as described byO’Donnell and Puri (1984) (Farkas, Moriel, andLupa, 1990; Sauvage, Saussine, Laustriat,Becmeur, et al., 1990; Dodat and Takvorian, 1990;Puri, 1990; King and Gollow, 1988; Schulman,Pamart, Hall, et al., 1990; Sweeney and Thomas,1987; Dewan and O’Donnell, 1991; Kaminetskyand Hanna, 1991; Davies and Atwell, 1991;Leonard, Canning, Peters, et al., 1991; Bhatti,Khattak, and Boston, 1993; Frey, Berger, Jenny, etal., 1992; Dewan and Guiney, 1992; Lipsky andWurnschimmel, 1993). Using renal ultrasound orexcretory urography, the incidence of transient dila-tion was reported in 2 series at 17 and 23 percent

(Sweeney and Thomas, 1987; Bhatti, Khattak, andBoston, 1993). The 15 series included a total of1,741 refluxing ureters treated using either Teflon™

(1,437 ureters) or collagen (304 ureters) as theinjected substance. Seven (0.40 percent) persistentobstructions were reported, requiring ureteral reim-plantation in 5, ureteral catheter drainage (5 days)in 1, and an unknown treatment in 1 (Dodat andTakvorian, 1990; Puri, 1990; Schulman, Pamart,Hall, et al., 1990; Sweeney and Thomas, 1987;Dewan and O’Donnell, 1991). All persistent ob-structions reported occurred in patients with refluxwho were treated with Teflon™. The amount ofexperience with the technique that the centers hadgained when the obstructions occurred was notreported. In 10 of the 15 centers, persistent obstruc-tions were not reported.

BleedingAlthough hematoma was reported in only 2 of

771 patients (0.26 percent) undergoing Politano-Leadbetter or Cohen transtrigonal ureteral reim-plantation (Brandell and Brock, 1993; Ehrlich,1985; Ehrlich, 1985; Broaddus, Zickerman,Morrisseau, et al., 1978; Price, Johnson, andMarshall, 1970; Garrett and Switzer, 1966; So,Brock, and Kaplan, 1981; Jonas, Many, Boichis, etal., 1974; Pypno, 1987; Ahmed and Tan, 1982), itoccurred in 15 of 1,257 patients (1.2 percent) whoreceived surgery using the Lich-Gregoir method(Arap, Abrao, and Menezes-de-Goes, 1981; Zaontz,Maizels, Sugar, et al., 1987; Funke, Chiari, andPlanz, 1980; Marberger, Altwein, Straub, et al.,1978; McDuffie, Litin, and Blundon, 1977;Hampel, Richter-Levin, and Gersh, 1977; Hohen-fellner, 1971; Houle, McLorie, Heritz, et al., 1992;


Analysis of 33 studies showed that the rate of obstruction after ureteral reimplanta-tion for VUR was 2 percent in studies after 1986 compared to a rate of approximately4 percent in studies before 1986.

Studies published before 1986

Studies published after 1986

0 10 20 30 40

Rates of Obstruction (%)

Figure 7. Combined rates of obstruction after surgery

Wacksman, Gilbert, and Sheldon, 1992). In 1 studyof the Lich-Gregoir technique, hematoma wasreported in 13 of 371 patients (3.5 percent) (Mar-berger, Altwein, Straub, et al., 1978). Althoughbleeding from the bladder is thought to be lesscommon after the Lich-Gregoir method than afterthe intravesical methods (Politano-Leadbetter,transtrigonal Cohen, or Glenn-Anderson advance-ment), specific data relating to this factor are notavailable.

InfectionSurgical wound infection following antireflux

surgery was reported explicitly in only 2 cases(Garrett and Switzer, 1966). Other series did notreport the occurrence or specific absence of thiscomplication.

Bladder injury/voiding dysfunctionSeveral reports of temporary voiding dysfunction

after extravesical ureteral surgery for reflux havebeen published. The incidence was as high as 15percent in several series (Houle, McLorie, Heritz,et al., 1992; Wacksman, Gilbert, and Sheldon,1992; Zaontz, Maizels, Sugar, et al., 1987). In mostcases, the voiding dysfunction was associated withbilateral ureteral surgery and was self-limiting.However, intermittent catheterization, which maybe problematic for families, was required duringthe period of voiding dysfunction. Late follow-upsuggests that essentially all patients are likely tofully regain voiding efficiency (Fung, McLorie,Jain, et al., 1995). The overall incidence associatedwith the Lich-Gregoir method was 10 of 125 (8%),in contrast to no reported cases after intravesicaltechniques.

Contralateral refluxThe occurrence of contralateral reflux (CLR)

after unilateral ureteral surgery has been reported innumerous series. It is important to determine notonly the initial incidence (usually found at firstpostoperative cystography) but also the persistenceof CLR over time. The presence of resolved VURin the non-operated ureter has been thought to be amajor risk factor for recurrence with contralateraloperation, but evidence for this clinical impressionis lacking. A recent report demonstrated this rela-tionship in a small group of patients with unilateralantireflux surgery (Ross, 1995).

The incidence and persistence of contralateralreflux were estimated from reports that specificallyindicated the occurrence of CLR, including some inwhich the incidence was zero. By definition this

included only unilateral reimplantation or unilateralsubureteric injection of Teflon™ in which a con-tralateral ureter was present. A total of 1,566ureters were considered at risk, with an overallincidence of 142 reported new CLR (9.07 percent).Not all of these reports included adequate follow-up information, which was used to estimate persis-tence of the reflux. When specified, the type of sur-gical procedure was examined in terms of its effecton new CLR.

The rate of new CLR in studies reported before1986 (13.4 percent) was higher than that reportedafter 1986 (4.7 percent). Although the reasons forthis difference are unclear, an increase in the prac-tice of contralateral reimplantation in case of anysuspicion of prior reflux after 1986 and recognitionof the influence of voiding dysfunction in refluxmanagement in recent years may also have con-tributed to the difference. Reflux grade did not sig-nificantly affect the rate of contralateral reflux,although the rate was highest for Grade IV reflux at3.7 percent compared with 1.5 percent for Grades Iand II (Table 12). The surgical method of reimplan-tation did not influence the likelihood of new CLR.The rate of CLR after endoscopic treatment usingTeflon™ was 2.9 percent and was not significantly

different from that for other open surgical methodsof correction.

Recent studies have offered some new insight.Ross, Kay, and Nasrallah (1995) reported a highincidence of CLR in ureters with previously dem-onstrated VUR. Diamond, Rabinowitz, Hoenig, etal. (1996) indicate that CLR is related to the gradeof VUR rather than to the surgical technique.


Table 12. Estimated percentage chance of contralateral reflux for studies reportedin 1987 or later (by grade and surgicalmethod)

Factor Estimate(95% confidence interval)

Grade

Grade I/II 1.52% (0–5.49%)Grade III 2.80% (0–12.73%)Grade IV 3.66% (0–12.67%)Grade V 2.53% (0–9.77%)

Surgical method

Politano-Leadbetter 5.21% (1.29–10.31%)Transtrigonal 1.90% (0.25–4.24%)Lich-Gregoir 2.33% (0.26–5.39%)Open surgery - other 5.07% (1.47–9.63%)Teflon™ 2.95% (0–10.58%)

Although uniform duration of follow-up is notavailable, the overall resolution rate of new CLRwas 52.1 percent with 28.7 percent persisting attime of follow-up.

Follow-up was usually 1–2 years after surgicalreimplantation; 13.8 percent of patients with newCLR underwent surgical correction at varyingpoints of follow-up. Little follow-up data are avail-able for patients reported after 1986. Clearly, anearly decision to operate would mask possiblespontaneous resolution.

Postoperative painNo specific data are available regarding pain

after surgical repair of VUR. Recent advances inpediatric pain management have altered theapproach to pain management in children aftermajor surgery. The increasingly widespread use ofepidural analgesia and patient-controlled analgesiahave markedly improved pain control after manysurgical procedures (Cain, Husmann, McLaren, etal., 1995). Continuous epidural analgesia is particu-larly well suited to antireflux surgery because itreduces incisional pain as well as the intensity andfrequency of bladder spasms, a common occur-rence after reimplantation surgery. Urethral cath-eterization is necessary while the epidural catheteris in place. Although no objective data are avail-able, these complications appear to be less severeafter extravesical reimplantation, in part because ofthe usually shorter period of catheterization. Sev-

eral studies have reported the use of intravesicalrepairs without postoperative catheter drainage(Brandell and Brock, 1993).

Hospitalization after antireflux surgeryThe length of hospitalization in children under-

going open antireflux surgery was reported in 10studies, with a total of 637 patients and 826 ureters(Table 13). The mean stay varied from 2.4 days(Zaontz, Maizels, Sugar, et al., 1987) to 13.9 days(Rezmi, Ozen, Erkan, et al., 1984). The length ofstay appeared to vary with the surgical techniqueand whether postoperative ureteral stents wereused.

Following extravesical forms of ureteroneocys-tostomy (e.g., detrusorrhaphy), Zaontz, Maizels,Sugar, et al. (1987) reported a mean length of stayof 2.4 days. Wacksman, Gilbert, and Sheldon(1992), reporting a similar surgical technique, had alonger hospital stay of 4.2–5.2 days. Patientsundergoing intravesical techniques of antirefluxsurgery (Cohen, Leadbetter-Politano, Glenn-Anderson) had hospital stays averaging 2.7–10.6days (Brock, 1983; Burbige, 1991; Fort, Selman,and Kropp, 1983).

Temporary ureteral stents generally are usedafter ureteroneocystostomy with tapering, a tech-nique utilized in children with Grade V and somewith Grade IV reflux. Some clinicians also usepostoperative stents in lower grades of reflux tomaintain the patency of the newly-created


Table 13. Mean and range of hospital stay for surgical therapy of vesicoureteral reflux

Hospital stayMean range with/

Reimplantation hospital withoutStudy Patients Ureters type1 stay (days) catheterization

Hampel, Richter-Levin, and Gersh, 1977 51 83 LG 4 Not stated

So, Brock, and Kaplan, 1981 52 87 GA, LP 5 3 to 9 days

Fort, Selman, and Kropp, 1983 63 GA, LP, Cohen, Hutch 10.6/9.3 6–12/3–16 days

Remzi, Ozen, Evkan, et al., 1984 89 143 LP 13.94 11.6/15.3 days2

Ehrlich, 1985 63 74 Kalicinski 6 Unstated

Pypno, 1987 43 80 Cohen 8.6 5–14 days

Zaontz, Maisels, Sugar, et al., 1987 79 120 Detruss. 2.4 1 to 6 days

Burbige, 1991 120 180 LP, Cohen 4.2/5.6 5–7/3–5 days

Wacksman, Gilbert, and Sheldon, 1992 132 211 Detruss. 4.2–5.2 Not stated

Brock, 1993 34 57 GA, LP, Cohen 5.4/2.7 4–8/2–4 days

Totals 637 8261 GA=Glenn-Anderson; LP=Leadbetter-Politano.2 Remzi reports the average stay with a urethral catheter/suprapubic tube. His patients had no ureteral catheters.

ureterovesical junction. In general, patients withureteral stents have had a longer length of stay(5.4–5.6 days) than nonstented patients (2.7–4.2days) (Brock, 1993; Burbige, 1991).

Concerns regarding length of stay were notraised in the United States until relatively recentlyand now are emphasized because of the increasingcost of medical care in this country. In a review of 186 children undergoing ureteroneocystostomyfrom 1986 to 1994, McCool and Joseph (1995)found that the mean length of stay had decreasedfrom 3.6–2.3 days. It is likely that average lengthsof stay for children undergoing open antirefluxsurgery will continue to decrease.

Most endoscopic interventions for reflux aretreated as outpatient procedures or require less than24-hour in-hospital stays.


Risk of urinalysisRoutine urinalysis and urine cultures carry very

little risk except skin sensitivity to cleansingagents. There is potential for misinterpretation ofurinalysis and/or urine culture due to inappropriatecollection and/or contamination that may result inerroneous diagnosis of UTI and therefore inappro-priate therapeutic decisions.

Risk of radiologic evaluationSurveillance evaluation using radiologic tech-

niques represents a major component of follow-upin patients with reflux. Risks of surveillance for thevarious methods can be divided into risks related tophysical manipulation in the performance of thetest and risk from contrast or radiation.

Renal imaging

Harms from physical manipulation.Allimaging techniques using contrast or radioactivetracer require administration via venipuncture,which may be stressful to infants and children andtheir parents to a variable degree. In addition,extravasation of the imaging agent into the soft tis-sues may cause inflammation, particularly with iod-inated contrast, but this complication is uncommon.Ultrasonographic studies appear to have little sig-nificant impact on children, either from the directmanipulation or from the transmitted sound waves.

Risk of contrast.Adverse reactions to intra-venous contrast media are uncommon in the pedi-atric population. Minor reactions with IVP (ioniccontrast media) occur in 6 percent and includenausea, vomiting, urticaria, flushing, pruritus, andheadache (Gooding, Berdon, Brodeur, et al., 1975).Major reactions, including cardiac arrest, pul-monary edema, apnea, seizures, bronchospasm,


Table 14. Radiation exposure in upper urinary tract imaging1

Bladder Whole Typical Study Kidney wall Ovaries Testes body dose

Urography (rad/film)

IVP2

6 mo. AP — — 0.0072 0.00092 0.23 —Pelvis — — 0.024 0.023 —

4 yr. AP — — 0.011 0.0012 0.33 —Pelvis — — 0.033 0.055

12 yr. AP — — 0.035 0.0054 0.53 —Pelvis — — 0.038 0.075

Scintigraphy (rad/mCi)

Tc-99m-MAG-3 renogram 0.014 0.48 0.026 0.016 0.007 3.25 mCi

Tc-99m-DTPA renogram2 hr void 0.090 0.12 0.011 0.007 0.006 9.75 mCi4 hr void 0.090 0.27 0.015 0.011

Tc-99m-DMSA renal scan 0.850 0.07 0.014 0.006 0.016 3.25 mCi1 References: IVP—Kirks, 1991; MAG-3 and DTPA—Stabin, Taylor, Eshima, et al., 1992; MPI, 1985.2 Typical IVP is 2–3 films.3 4 films.

Table 15. Radiation exposure in lower tract imaging (rad)1

Bladder Whole Typical Study Kidney wall Ovaries Testes body dose

VCUG2 — — 0.208 — — —

VCUG (tailored; low-dose) 3 — — 0.029 — — —

Tc-99m cystography <0.001 0.025 0.002 <0.001 <0.001 1 mCi

1 References: Bisset, Strife, and Dunbar, 1987; Conway, King, Betman, et al., 1972; Kleinman, Diamond, Karellas, et al., 1994; Willi and Treves, 1983.2 Exposure variable and depends on fluoroscopy time and number of films taken; Bisset et al., 1987.3 Assuming digital fluoroscopic time over the bladder of 3 to 5 seconds; Kleinman et al., 1994.


laryngeal edema, and shock, are rare. In a largegroup of pediatric patients, the incidence of seriousreactions to ionic contrast media was 0.5 percent,but there were no deaths (Gooding et al., 1975).The risk of adverse reaction with nonionic contrastmedia is significantly less (Bisset, Strife, and Kirks,1991). There is no risk of allergy to agents used forscintigraphy.

Radiation exposure.The average radiationexposure in children undergoing upper urinary tractevaluation is shown in Table 14, page 47. Theaverage annual radiation exposure in the environ-ment is 0.250 rad (Mettler and Upton, 1995).

CystographyHarms from physical manipulation and con-

trast.McAlister, Cacciarelli, and Shackelford(1974) describe atypical cases involving complica-tions of cystography, and suggest ways of avoidingcomplications in clinical experience. Zerin andShulkin (1992) studied 228 children who hadvoiding cystourethrograms or radionuclide cys-

tograms and noted irritative voiding symptoms in70 (35.1 percent). Three patients developed fever,and urine cultures were negative in all. Sixty-threeof 228 patients received no postprocedural prophy-laxis, and postcatheterization symptoms were onlyslightly higher (37 percent) compared with 34.5percent in the nonantibiotic group. No significantdifference in symptoms was reported between chil-dren having nuclear cystograms and those havingcontrast cystograms. There is a risk of inducing aUTI if the procedure is not performed using steriletechnique. Individuals allergic to iodinated contrastdo not develop an allergic reaction during VCUG.

The psychological consequences of cystographicstudies have not been formally addressed, but anec-dotal experience suggests that many children sus-tain varying degrees of psychological trauma fromcatheterization.

Radiation exposure. The average radiationexposure in children undergoing lower urinary tractstudies is shown in Table 15.


Only a few recommendations can be derivedpurely from scientific evidence of a beneficial effecton health outcomes (as opposed to intermediate out-comes; see page 20). Evidence of the efficacy ofmedical management on health outcomes is avail-able only for Grades I–IV reflux. Control data arelacking to compare outcomes for intermittent withthose for continuous antibiotic therapy. Open sur-gical repair, although proven to cure reflux in 90–98percent of patients, has not been demonstrated toimprove health outcomes other than pyelo-nephritis;for this outcome, the evidence suggests that childrenwith Grade III or IV reflux receiving continuousantibiotic prophylaxis are 2.5 times more likely todevelop pyelonephritis than children who haveundergone successful antireflux surgery.Accordingly, based on health outcomes data alone,health outcomes for medical and surgical treatmentcan be compared only for children with Grade III orIV reflux. Even for these patients, available out-comes data provide little information on whetherthe benefits of treatment exceed its potential risks,nor do they aid the clinician in selecting the mostappropriate treatment options for initial therapy orfor persistent reflux. Thus, evidence-based recom-mendations provide limited practical guidance forthe clinician. The need for further outcomesresearch is addressed in Chapter 5.

The following more detailed recommendations,which generally lack empirical scientific support,reflect the clinical experience and opinion of thepanel. The panel recognizes the limitations ofrelying on opinion as a basis for generating prac-tice guidelines. This description of practice patternsis instead offered as an aid to clinicians interestedin more detailed recommendations and in the per-spective of pediatric urologists and nephrologistswho specialize in reflux care. Full documentationof the panel’s underlying rationale for the recom-mendations is provided: statements based onopinion are explicitly identified, and evidence-based recommendations are accompanied by appro-priate references to outcomes analyses in Chapter 3(see Rationale for recommendations, page 52).

As outlined in Chapter 2, the recommendationswere derived from a survey of preferred treatmentoptions for 36 clinical categories of children with

reflux. The recommendations are based on the out-comes analysis presented in detail in Chapter 3 andon the clinical experience and opinion of the panel.Treatment options selected by 8 or 9 of the 9 panelmembers are classified as guidelines and given thestrongest recommendation language. (The word“should” is used to indicate treatment options inthis category; e.g., “Children with Grade V refluxshould undergo surgical repair.”) Treatment optionsthat received 5 to 7 votes are designated as pre-ferred options, and treatment options that received3 to 4 votes are designated as reasonable alterna-tives. Treatments that received no more than 2votes are designated as having no consensus andare not recommended.

The treatment modalities considered included (1)no treatment (including intermittent antibiotictherapy); (2) bladder training; (3) continuous anti-biotic prophylaxis; (4) antibiotic prophylaxis andbladder training; (5) antibiotic therapy, bladdertraining and anticholinergics; (6) open surgicalrepair; and (7) endoscopic repair. These modalitiesare described in Chapter 1. The recommendationsassume that the patient has uncomplicated reflux(e.g., no breakthrough UTI, voiding dysfunction,duplex systems, or other comorbid conditions); seeSpecial considerations below regarding the care ofpatients with additional complications. The recom-mendations apply only to the scope of the topic ofthis report (see Chapter 2) and therefore do notaddress diagnosis of reflux, treatment of patientsover age 10, management of reflux complicated byother factors (see Special considerations below) orsurveillance testing.

The treatment recommendations apply only topatients with uncomplicated reflux. More aggres-sive treatment interventions may be indicated forchildren with breakthrough UTI or other medical

Special considerations

Assumptions

Chapter 4: Treatment recommendations


complications, such as renal insufficiency, new orprogressive scarring, obstructive congenital anom-alies of the upper urinary tract (e.g., ureteropelvicjunction), solitary kidney, intrarenal reflux, sec-ondary reflux (e.g., neuropathic or iatrogenicreflux, reflux associated with structural urologicanomalies such as ureterocele, ectopic ureter, pos-terior urethral valves, prune-belly syndrome, orexstrophy), or other medical comorbid conditions.There is limited direct evidence that duplicationanomalies increase the risk of developing persistentreflux; surgical cure rates appear to be comparablewith duplex and single systems (see Chapter 3,page 26). Treatment options may be countermand-ed by such factors as antibiotic allergies, intoler-ance or noncompliance, limitations in surgicalskills and inadequate hospital facilities. Finally, theintensity of treatment may need to be modifieddepending on the nature of the doctor-parent-patient relationship and to accommodate such fac-tors as limited access to care and personal prefer-ence.

An important variable in the scope of treatmentis the presence of concurrent voiding dysfunction, acommon occurrence among children with reflux.Because resolution of voiding dysfunction may beaccompanied by resolution or diminution of reflux,such children may require more aggressive treat-ment with antibiotics, anticholinergics, and bladdertraining (e.g., timed voiding, biofeedback, parentalmonitoring of voided volumes). Surgical repair ofreflux is less successful in children with voidingdysfunction, and thus a higher threshold is neces-sary before surgery is recommended in suchpatients. Children with reflux should therefore beassessed for voiding dysfunction as part of theirinitial evaluation.

The recommendations that follow emphasize theimportance of shared decision-making in the man-agement of reflux. The treatment recommendationsare tabulated in Table 16 on pages 52–53.

Recommendations for childrenwithout scarring at diagnosis

Age at diagnosis: Infants (<1year)Initial treatment.Infants with Grades I–IV reflux

should be treated initially with continuous antibi-

otic prophylaxis. In infants with Grade V reflux,continuous antibiotic prophylaxis is the preferredoption for initial treatment.

Follow-up treatment.In infants who continue todemonstrate uncomplicated reflux, antibiotic pro-phylaxis should be continued (see Duration ofmedical management, page 51). For patients withpersistent Grades I–II reflux after this period ofprophylaxis, there is no consensus regarding therole of continued antibiotic therapy, periodic cys-tography, or surgery. Surgical repair is the preferredoption, however, for patients with persistent unilat-eral Grades III–IV reflux. Patients with persistentbilateral Grades III–IV reflux or Grade V refluxshould undergo surgical repair.


Initial treatment.Preschool children with GradesI–II reflux or unilateral Grades III–IV reflux shouldbe treated initially with continuous antibiotic pro-phylaxis. Continuous antibiotic prophylaxis is thepreferred option in preschool children with bilateralGrades III–IV reflux. In patients with unilateralGrade V reflux, continuous antibiotic prophylaxis isthe preferred option for initial treatment, althoughsurgical repair is a reasonable alternative. Inpatients with bilateral Grade V reflux, surgicalrepair is the preferred option and continuous antibi-otic prophylaxis is a reasonable alternative.

Follow-up treatment.In children who continue todemonstrate uncomplicated reflux, antibiotic pro-phylaxis should be continued (seeDuration ofmedical management, page 51). In children withpersistent Grades I–II reflux, there is no consensusregarding the role of continued antibiotic therapy,periodic cystography or surgery. Surgery is the pre-ferred option for children with persistent GradesIII–IV reflux. Patients with persistent Grade Vreflux should undergo surgical repair.

Age at diagnosis: School children(ages 6–10 years)

Initial treatment.School children with GradesI–II reflux should be treated initially with contin-uous antibiotic prophylaxis. Continuous antibioticprophylaxis is the preferred option for initial treat-ment of patients with unilateral Grades III–IVreflux. In patients with bilateral Grades III–IVreflux, surgical repair is the preferred option,although continuous antibiotic prophylaxis is a rea-sonable alternative. Patients with Grade V refluxshould undergo surgical repair.

Recommendations


Follow-up treatment.In children who continue todemonstrate uncomplicated reflux, antibiotic pro-phylaxis should be continued (see Duration ofmedical management, page 51). In patients withpersistent Grades I–II reflux after this period ofprophylaxis, there is no consensus regarding therole of continued antibiotic prophylaxis, periodiccystography, or surgery. Surgery is the preferredoption for persistent reflux in children with GradesIII–IV reflux.

Recommendations for children withscarring at diagnosis

Age at diagnosis: Infants (<1 year)Initial treatment.Infants with scarring at diag-

nosis and Grades I–IV reflux should be treated ini-tially with continuous antibiotic prophylaxis. Ininfants with Grade V reflux and scarring, contin-uous antibiotic prophylaxis is the preferred optionfor initial treatment, and surgical repair is a reason-able alternative.

Follow-up treatment.In infants who continue todemonstrate uncomplicated reflux, antibiotic pro-phylaxis should be continued (see Duration ofmedical management). In patients with persistentGrades I–II reflux after this period of prophylaxis,there is no consensus regarding the role of con-tinued antibiotic prophylaxis, periodic cystography,or surgery. In boys with persistent unilateral GradesIII–IV reflux, surgical repair is the preferred option.Boys with persistent bilateral Grades III–IV reflux,girls with persistent Grades III–IV reflux, and boysand girls with persistent Grade V reflux shouldundergo surgical repair.

Age at diagnosis: Preschool children(ages 1–5 years)

Initial treatment.Preschool children with scar-ring at diagnosis and either Grades I–II reflux orunilateral Grades III–IV reflux should be treatedinitially with continuous antibiotic prophylaxis.Antibiotic therapy is the preferred option in chil-dren with bilateral Grades III–IV reflux and scar-ring, and surgical repair is a reasonable alternative.Surgery is the preferred option for patients withunilateral Grade V reflux. Patients with bilateralGrade V disease and scarring should undergo sur-gical repair as initial treatment.

Follow-up treatment.In children who continue todemonstrate uncomplicated reflux, antibiotic pro-phylaxis should be continued (see Duration ofmedical management). In patients with persistent

Grades I–II reflux after this period of prophylaxis,there is no consensus regarding the role of con-tinued antibiotic prophylaxis, periodic cystography,or surgery. Girls with persistent Grades III–IVreflux and boys with persistent bilateral GradesIII–IV reflux should undergo surgical repair.Surgery is the preferred option for boys with per-sistent unilateral Grades III–IV reflux and girlswith bilateral Grades III–IV reflux. For patientswith persistent Grade V reflux who have not under-gone surgery as initial treatment, surgical repair isthe preferred option.

Age at diagnosis: School children(ages 6–10 years)

Initial treatment.School children with scarringat diagnosis and Grades I–II reflux should betreated initially with continuous antibiotic prophy-laxis. In children with unilateral Grades III–IVreflux and scarring, antibiotic therapy is the pre-ferred option. Patients with bilateral Grades III–IVreflux or Grade V reflux should undergo surgicalrepair as initial treatment.

Follow-up treatment.In children who continue todemonstrate uncomplicated reflux, antibiotic pro-phylaxis should be continued (see Duration ofmedical management). In patients who have persis-tent Grades I–II reflux after this period of prophy-laxis, there is no consensus regarding the role ofcontinued antibiotic prophylaxis, periodic cystog-raphy, or surgery. Patients with persistent unilateralGrades III–IV reflux who have not undergonesurgery as initial treatment should undergo surgicalrepair.

Duration of medical managementThe recommendations refer to “persistent reflux”

but do not specify the amount of time that mustelapse before VUR is considered persistent. Littlescientific evidence exists for determining how longto continue antibiotic prophylaxis before recom-mending surgical repair, and this decision is there-fore left to clinical discretion in consultation withparents. The duration of reflux is an important con-sideration. As indicated in Table 2 (page 23), whichis based on the model described in Chapter 2 andAppendix C, the probability that reflux will resolvespontaneously depends on the duration and gradeof reflux. Other factors to consider include thepatient’s surgical candidacy, comorbidities, toler-ance of antibiotics, socioeconomic factors, compli-ance to medications and follow-up, and parentalpreferences and concerns.


Recommendations were derived from a survey of preferred treatment options for 36 clinical categories of children with reflux. The recommendations are classified as follows:

Guidelines = Treatments selected by 8 or 9 of 9 panel members, given the strongest recommendation language.Preferred Options = Treatments selected by 5–7 of 9 panel members.Reasonable Alternatives = Treatments selected by 3–4 of 9 panel members.No Consensus = Treatments selected by no more than 2 of 9 panel members.

The treatment recommendations apply to both boys and girls with primary vesicoureteral reflux.

Treatment recommendations for children without scarring at diagnosis

Clinical presentation Treatment(age at presentation) Initial Follow-up 1

(antibiotic prophylaxis or (continued antibiotic prophylaxis,open surgical repair) cystography or open surgical repair)

VUR grade Age Guideline Preferred Reasonable Guideline Preferred Nolaterality (years) option alternative option consensus2

I-II <1 Antibiotic Boys and girlsUnilateral or prophylaxis

bilateral 1-5 Antibiotic Boys and girlsprophylaxis

6-10 Antibiotic Boys and girlsprophylaxis

III-IV <1 Antibiotic Bilateral: Unilateral:Unilateral or prophylaxis Surgery if Surgery if

bilateral persistent3 persistent3

1-5 Unilateral: Bilateral: Surgery ifAntibiotic Antibiotic persistent3prophylaxis prophylaxis

6-10 Unilateral: Bilateral: Surgery ifAntibiotic Antibiotic persistent3prophylaxis prophylaxisBilateral:Surgery

V <1 Antibiotic Surgery ifUnilateral or prophylaxis persistent3

bilateral 1-5 Bilateral: Bilateral: Surgery if Surgery Antibiotic persistent3

prophylaxisUnilateral: Unilateral:Antibiotic Surgeryprophylaxis

6-10 Surgery


Table 16. Treatment recommendations

1For patients with persistent uncomplicated reflux after extended treatment with continuous antibiotic therapy.2No consensus was reached regarding the role of continued antibiotic prophylaxis, cystography, or surgery.3See Duration of Reflux in the text regarding the length of time that clinicians should wait before recommending surgery.

Recommendations were derived from a survey of preferred treatment options for 36 clinical categories of children with reflux. The recommendations are classified as follows:

Guidelines = Treatments selected by 8 or 9 of 9 panel members, given the strongest recommendation language.Preferred Options = Treatments selected by 5–7 of 9 panel members.Reasonable Alternatives = Treatments selected by 3–4 of 9 panel members.No Consensus = Treatments selected by no more than 2 of 9 panel members.

The treatment recommendations apply to both boys and girls with primary vesicoureteral reflux.

Treatment recommendations for children with scarring at diagnosis

Clinical presentation Treatment(age at presentation) Initial Follow-up 1

(antibiotic prophylaxis or (continued antibiotic prophylaxis,open surgical repair) cystography or open surgical repair)

VUR grade Age Guideline Preferred Reasonable Guideline Preferred Nolaterality (years) option alternative option consensus2

I-II <1 Antibiotic Boys and girlsUnilateral or prophylaxis

bilateral 1-5 Antibiotic Boys and girlsprophylaxis

6-10 Antibiotic Boys and girlsprophylaxis

III-IV <1 Antibiotic Girls: Boys:Unilateral prophylaxis Surgery if Surgery if

persistent3 persistent3

1-5 Antibiotic Girls: Boys:prophylaxis Surgery if Surgery if

persistent3 persistent3

6-10 Antibiotic Surgery ifprophylaxis persistent3

III-IV <1 Antibiotic Surgery ifBilateral prophylaxis persistent3

1-5 Antibiotic Surgery Surgery ifprophylaxis persistent3

6-10 Surgery

V <1 Antibiotic Surgery Surgery ifUnilateral or prophylaxis persistent3

bilateral 1-5 Bilateral: Unilateral: Surgery ifSurgery Surgery persistent3

6-10 Surgery


Table 16. Treatment recommendations (continued)

1For patients with persistent uncomplicated reflux after extended treatment with continuous antibiotic therapy.2No consensus was reached regarding the role of continued antibiotic prophylaxis, cystography, or surgery.3See Duration of Reflux in the text regarding the length of time that clinicians should wait before recommending surgery.


Other management recommendationsIn children with VUR, at initial evaluation the

urine should be assessed for infection and protein-uria, and the child’s height, weight, and blood pres-sure should be measured. If the child shows evi-dence of renal scarring, hydronephrosis, or has asolitary kidney, or known underlying renal disease,a serum creatinine should also be obtained.

In children with VUR, urethral dilation andinternal urethrotomy are not beneficial. In addition,cystoscopic examination of the ureteral orificesdoes not appear to aid in predicting whether refluxwill resolve (see Chapter 1, page 12). Furthermore,evocative cystometry is unnecessary in childrenwith reflux and normal voiding function. However,in children with symptoms of voiding dysfunction,urodynamic evaluation may be beneficial.

The personal preferences of parents (and, atolder ages, patients) must be considered in weigh-ing the benefits and harms of treatment options.The clinician should provide parents with informa-tion about the known benefits and harms of avail-able options, including continuous antibiotic pro-phylaxis, surgery, and intermittent antibiotictherapy. The clinician should indicate to whatextent the estimates of benefits and harms are basedon scientific evidence or on opinion and clinicalexperience. Given the general lack of direct evi-dence that any 1 treatment option is superior toanother (especially when total benefits, harms,costs, and inconvenience are taken into considera-tion), parents’ and patients’ preferences regardingtreatment options should generally be honored. Tothe extent that parents seek physicians’ advice onhow to proceed, the specific treatment guidelinesare offered (Table 16 on pages 52–53).

In children with reflux, a urine culture should beobtained if there are symptoms and/or signs of aUTI. In a child with a suspected UTI, proper spec-imen collection is important. In girls and uncircum-cised boys who are not toilet trained, a urinalysis orurine culture obtained from a contaminated bagspecimen may yield an erroneous diagnosis ofinfection and therefore result in inappropriate man-agement decisions. In such children, a urine spec-imen obtained by catheterization or suprapubic

aspiration is encouraged to minimize the likelihoodof a false-positive diagnosis of UTI.

Follow-up evaluation should be performed atleast annually, at which time the patient’s heightand weight should be recorded. In addition, a uri-nalysis should be performed. If renal scarring hasbeen demonstrated, the blood pressure should alsobe measured, irrespective of whether the child hasreflux that is persistent, resolved spontaneously, orhas been corrected surgically.

In deciding how often to obtain follow-up cys-tography, the clinician should take into considera-tion the likelihood of spontaneous resolution (seeTable 2 on page 23), the risks of continued antibi-otic prophylaxis, and the risks of radiologic study.In general, cystography does not need to be per-formed more than once per year.

In children with reflux who are toilet trained,regular, volitional low-pressure voiding with com-plete bladder emptying should be encouraged. If itis suspected that the child is experiencing uninhib-ited bladder contractions, anticholinergic therapymay be beneficial.

In children in whom antireflux surgery is chosen,the panel does not recommend the endoscopic formof therapy because of the lack of proven long-termsafety and efficacy of most materials used for injec-tion and the lack of approval of such materials bythe U.S. Food and Drug Administration.

The following recommendations to offer contin-uous antibiotic prophylaxis as initial therapy arebased on limited scientific evidence. No controlledstudies have demonstrated that continuous antibi-otic prophylaxis achieves better health outcomes inchildren with reflux than intermittent treatment ofUTI. The opinion of the panel, however, is thatmaintaining continuous urine sterility is beneficialin reducing the risk of renal scarring and that thisbenefit outweighs the potential adverse effects ofantibiotics.3 Observational data from patients with

Rationale forrecommendations

3The argument for continuous antibiotic prophylaxis is especially compelling during infancy, when diagnosing UTI is difficult.Recommendations to initiate antibiotic therapy when reflux is diagnosed in school children, even when the reflux is mild (GradesI–II), are based on the panel’s belief that such children continue to face a risk of scarring and that this risk is independent ofgrade.


Grades I–III reflux suggest that at least 50 percentof reflux cases resolve within 3–5 years of contin-uous antibiotic prophylaxis (see Chapter 3). ForGrades I–IV reflux, the panel generally favors con-tinuous antibiotic prophylaxis over immediate sur-gical repair because it is less invasive and is associ-ated with fewer risks over the short term.

Recommendations to proceed to surgery in casesthat have not resolved spontaneously while thepatient was receiving continuous antibiotic prophy-laxis are supported by limited scientific evidence:open antireflux surgery is 95–98 percent effectivein correcting reflux, and the risk of pyelonephritisis 2–2.5 times greater in children with GradesIII–IV reflux managed medically compared withsurgically treated patients. The expert opinion ofmost panel members is that surgery also reducesthe risk of pyelonephritis in girls with Grades I–IIreflux and in boys and girls with Grade V reflux.Panel members believe that breakthrough UTIincreases the risk of renal scarring. Although theInternational Reflux Study showed no differencebetween medical and surgical treatment in the inci-dence of new renal scarring at 5 years, 80 percentof new renal scars in the surgical group appearedby 10 months after randomization, and thus the rateof new renal scarring between 1 and 5 years fol-lowing randomization was higher in the medicalgroup. Some panel members believe that withlonger follow-up, the incidence of new renal scarsin the surgical group will be less than in the med-ical group. Some panel members also believe thatfemales with unresolved reflux are more likely toexperience pyelonephritis during pregnancy thanwomen without reflux, although women who havehad antireflux surgery also develop pyelonephritis.The panel believes that the benefits of immediatecorrection of reflux in patients for whom surgery

was recommended, even when coupled with itsrisks, outweigh the potential harms of continuousantibiotic prophylaxis (e.g., inconvenience of long-term therapy, adverse drug reactions, periodic sur-veillance testing).

More aggressive recommendations for the treat-ment of girls than of boys (e.g., for persistentGrades III–IV reflux in school children) are basedon epidemiologic evidence that girls face a higherrisk of acquiring UTI than do boys (see Chapter 3,page 36). More aggressive recommendations forthe treatment of Grade V reflux (e.g., surgicalrepair as initial therapy) are based on the panel’sopinion that such cases are unlikely to resolvespontaneously on antibiotic therapy, that surgery iseffective in resolving severe reflux and that thesebenefits outweigh the potential harms of surgery.More aggressive recommendations for childrenwho have renal scarring at diagnosis are based onthe panel’s opinion that such patients face a higherrisk of progressive scarring and decreased renalfunctional reserve.

The panel’s treatment recommendations arebased on its opinion that the benefits of treatmentoutweigh the potential harms. There is little scien-tific evidence to confirm these assumptions, how-ever, and therefore clinicians and parents maychoose other options if they assign differentweights to potential outcomes. For example, someclinicians and parents may not share the panel’sopinion that the benefits of one-time surgical cor-rection of persistent reflux, even when coupled withits potential harms, outweigh the inconvenience,cost, and risk of side effects from long-term antibi-otic prophylaxis. Choosing continuous or intermit-tent antibiotic therapy under such circumstances isappropriate given the lack of scientific evidence tosuggest otherwise.


Many aspects of primary VUR remain incom-pletely understood. The panel identified the fol-lowing areas as needing further investigation.

Development of VUR:The cause of the malde-velopment of the ureterovesical junction isunknown. Because VUR is often related to voidingdysfunction, research into the development of theautonomic nervous system of the bladder and itseffect on morphological bladder development mayallow an understanding of the pathoembryology ofVUR.

VUR is greater in severity in newborn boys thangirls. This phenomenon may be secondary to ele-vated voiding pressures in the newborn male(Gierup, 1970; Hjalmas, 1976; Sillen, Bachelard,Harmanson et al., 1996). Whether these differencesresult from dissimilar forms of urethral develop-ment and/or autonomic nervous system develop-ment is unknown. Investigation of the bud theory ofMackie and Stephens (1975) as applied to VUR issuggested to better understand the relationshipbetween reflux and renal scarring that may be pre-sent at birth. Determination of whether fetal refluxhas a “water hammer” effect deserves study.

Further investigation of the neurologic changesof the pediatric bladder with maturation that couldinfluence bladder function and physiology, particu-larly voiding pressures, is needed. Studies shouldevaluate whether anatomic changes at the bladderneck or a functional disorder of the striatedsphincter or bladder neck could account for ele-vated intravesical pressures.

Reflux resolution:The panel found evidence,based on a few large studies, that resolution ofGrades I and II reflux may not depend on patientage or laterality (i.e., unilateral or bilateral). InGrade III reflux, on the other hand, it was sug-gested that patient age and laterality were impor-tant prognostic considerations. In Grade IV reflux,only laterality could be evaluated. Confirmation ofthese concepts by other large centers would beworthwhile. Furthermore, refinement of predictivecriteria for reflux resolution by patient age, refluxgrade, and laterality would be useful. In addition,further study of the likelihood of resolution of low-grade reflux during adolescence, as described byLenaghan, Whitaker, Jensen, et al. (1976) and byGoldraich and Goldraich (1992), is necessary.

Renal scarring: The development of renal scar-ring in children with reflux is incompletely under-stood. Further investigation of the roles of bacterialvirulence factors and host immune and inflamma-tory responses in the evolution of renal scarring isnecessary. Studies should evaluate methods ofaffecting the host immune or inflammatoryresponse that could reduce renal scarring duringpyelonephritis (Roberts, 1992). Investigation ofwhy younger children, particularly those under1–2 years of age, appear to be more likely thanolder children to develop renal scarring from pyelo-nephritis would be useful.

It is well recognized that pyelonephritis andrenal scarring can occur in children without reflux.The extent to which reflux increases the risk ofrenal scarring and the mechanism of this effectdeserve investigation.

The panel attempted to analyze the associationbetween new and progressive scarring in childrenundergoing medical or surgical treatment for refluxand bacteriuria. Because of extremely limited data,this relationship could not be evaluated. Furtherinvestigation into the factors leading to new renalscarring in children with reflux is important. Inaddition, assessment of whether there are long-termdifferences in the incidence of new scars in chil-dren managed medically and surgically is neces-sary.

Further analysis of the risk factors for end-stagerenal disease, particularly the relative contributionsof “congenital” scarring, intervening infection,voiding dysfunction, and hypertension manage-ment, would be useful.

More randomized prospective trials comparingthe incidence and timing of new scarring, asassessed by DMSA scan, in children with GradesIII and IV reflux are important, because previousstudies, which used IVP for scar detection, havebeen difficult to interpret. Whether the risk of newscarring in a child with Grade III or IV refluxdecreases as reflux grade decreases or refluxresolves should also be analyzed.

Voiding dysfunction: The role of voiding dys-function in the pathogenesis of VUR and its risk inreflux complications, such as renal scarring,deserves further investigation. The role of urody-namic studies in infants and children with reflux,

Chapter 5: Research priorities


with or without voiding dysfunction, should beevaluated (Sillen, Bachelard, Harmanson, et al.,1996). Matched, controlled studies of anticholin-ergic therapy and bladder retraining on reflux-related outcomes in children with voiding dysfunc-tion are also necessary.

Medical therapy: A comparative analysis of theefficacy of various forms of antibiotic prophylaxisin preventing infection and renal scarring would beimportant. Furthermore, studies to assess the dura-tion and dosage of prophylaxis are indicated. Anevaluation of the adverse effects of various formsof continuous antibiotic prophylaxis in children andexamination of the proportion who do not tolerateprophylaxis or who develop resistance would beimportant. In addition, compliance with prophy-laxis regimens should be evaluated, in particularcomparing those who have received prophylaxis forless than 6 months with those who have receivedtherapy for more than 2 years. In addition, a trialcomparing reflux-related outcomes in childrenreceiving continuous prophylaxis with those inchildren receiving intermittent therapy, particularlycomparing children younger than age 5 years witholder children, would be prudent. Whether anti-cholinergic therapy is beneficial in children withreflux but no sign of voiding dysfunction should bestudied. The short- and long-term risk of stoppingprophylaxis in individuals with reflux who havebeen infection-free deserves evaluation. The effi-cacy of periodic surveillance, urinalysis, and urineculture in asymptomatic children with reflux shouldbe studied.

Surgical therapy: Development of new tech-niques of antireflux surgery, particularly minimallyinvasive techniques, is indicated. Newer materialsthat can be used for endoscopic subureteral injec-tion and that are safe in children should be studied.Whether current techniques of antireflux surgerycause transient increases in upper tract pressures,potentially resulting in renal injury, should bestudied. In addition, the mechanism for new-onsetcontralateral reflux in children undergoing unilat-eral antireflux surgery should be studied further,and methods of preventing contralateral refluxshould be developed. More effective techniquesshould be developed for surgical therapy in chil-dren with Grade V reflux. In addition, whetherearly correction of reflux in children with Grade Vreflux alters reflux-related outcomes should be ana-lyzed further.

Bladder function/training: Whether bladdertraining alters reflux-related outcomes deserves

study. In addition, whether reflux resolution isenhanced after successful toilet training and matu-ration of bladder function should be evaluated.Whether pharmacologic manipulation, beyondsimple anticholinergic therapy, could be useful innormalizing bladder dynamics should also bestudied.

Imaging: The effect of voiding cystourethrog-raphy on children should be analyzed, and lesstraumatic methods of determining whether reflux ispresent should be developed. Techniques of voidingcystourethrography that result in less radiationexposure, such as the tailored low-dose fluoro-scopic method (Diamond, Kleinman, Spevak, et al.,1996), should be developed. Clinicians shouldrefine the ideal duration of time between cys-tograms in children being treated for reflux. Inaddition, the role of newer forms of renal imaging,such as SPECT, helical CT and power Dopplerultrasound, in the diagnosis of acute pyelonephritisand renal scarring, should be studied. Furthermore,the indications for obtaining a voiding cysto-urethrogram in a child with a UTI should berefined. Efforts should be made to determine prog-nostic criteria for likelihood of reflux resolutionbased on bladder volume and pressure at whichreflux occurs and volume of refluxing urine.

Genetics of reflux:Further evaluation of thegenetics of reflux deserves study. The current litera-ture has not separately analyzed the incidence ofpure primary sibling reflux and reflux associatedwith voiding dysfunction. The gene for VURshould be identified.

Screening for reflux: Many groups of childrenundergo screening for primary reflux, includingsiblings of offspring of index patients with refluxand children with a multicystic kidney or a solitarykidney. The impact of screening and early interven-tion (medical or surgical) on reflux-related out-comes should be analyzed.

Circumcision and UTI: Whether circumcisionof neonates with prenatally detected VUR dimin-ishes the incidence of UTI and other reflux-relatedoutcomes deserves study.

Reflux and pregnancy:The natural history ofVUR in adult women with persistent refluxdeserves study, including a comparison of the mor-bidity of reflux and need for and efficacy of pro-phylaxis in pregnant and non-pregnant women.Such an analysis should compare various grades ofreflux with and without renal scarring. Comparisonof the reflux-related outcomes and morbidity ofpregnancy in women who had spontaneous reflux


resolution or antireflux surgery during childhoodand those with uncorrected reflux is of utmostimportance.

Social and economic factors:An analysis of thecosts of reflux treatment and surveillance is impor-tant, in particular a comparison of the costs associ-ated with medical and surgical therapy of childrenwith various grades of reflux. In addition, studies ofhow reflux and its treatment and the need for sur-veillance affect patient/family dynamics and qualityof life deserves study.

Randomized controlled trials:Although theInternational Reflux Study in children was suc-cessful in analyzing many reflux-related outcomes,data related to scarring were based on assessmentby IVP rather than DMSA renal scan. Further ran-

domized controlled trials studying the role of med-ical and surgical therapy using DMSA scan forevaluation are indicated. The long-term outcomes(>10 years) of previously randomized children withunresolved reflux at 5 years should be comparedwith children undergoing successful surgical ormedical therapy.

Future clinical studies of children with refluxshould analyze specific reflux-related health out-comes and stratify the results by patient gender,age, and reflux grade. Studies should report refluxresolution both by rate of ureteral resolution andpatient resolution. Ideally, reports of UTI and renalscarring will analyze these outcomes for 5–10years after reflux resolution.


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Tabl

e A

-1:

Pap

yrus

Ref

eren

ce B

iblio

grap

hy—

Alp

habe

tic b

y A

utho

rP

apyr

us

Ref

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ages

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674

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ease

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hild

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1991

6612

84-6

C

over

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cter

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ter

m f

ollo

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pA

ggar

wal

,V.K

.,Ve

rrie

r-Jo

nes,

K.,

Ass

cher

,A.W

.,E

vans

,C.,

and

Will

iam

s,L.

A.

252

Jour

nal o

f U

rolo

gy

1983

129

787-

91A

pplic

atio

n of

the

pul

l-thr

ough

tec

hniq

ue o

f tr

ansv

erse

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ed,S

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vanc

emen

t ur

eter

al r

eim

plan

tatio

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6519

8814

010

92-4

Vesi

cour

eter

al r

eflux

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ompl

ete

uret

eral

dup

licat

ion:

Ahm

ed,S

.,B

ouca

ut,H

.A.

surg

ical

opt

ions

345

Jour

nal o

f U

rolo

gy19

7812

033

2-3

Res

ults

of

uret

eral

rei

mpl

anta

tion

in p

atie

nts

with

A

hmed

,S.,

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ith,A

.J.

intr

aren

al r

eflux

301

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nal o

f U

rolo

gy19

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797

0-73

Com

plic

atio

ns o

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adv

ance

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t ur

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al

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.,Ta

n,H

.re

impl

anta

tion:

dive

rtic

ulum

for

mat

ion

321

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iatr

ics

1980

6578

-80

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con

serv

ativ

e m

anag

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ves

icou

rete

ric r

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:A

ladj

em,M

.,B

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.,a

revi

ew o

f 12

1 ch

ildre

nH

ertz

,M.,

Her

zfel

d,S

.,an

d R

aviv

,U.

462

Sou

ther

n M

edic

al J

ourn

al19

7366

305-

7M

odifi

catio

n of

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ure

tera

l adv

ance

men

t pr

oced

ure

for

Alle

n,T.

D.

vesi

cour

eter

al r

eflux

401

Clin

ical

Ped

iatr

ics

1976

1556

2-9

The

pra

ctic

al m

anag

emen

t of

ves

icou

rete

ral r

eflux

in c

hild

ren.

A

mar

,A.D

.,S

inge

r,B

.,an

d A

rev

iew

of

12 y

ears

’exp

erie

nce

with

236

pat

ient

s.C

habr

a,K

.

614

Brit

ish

Jour

nal o

f U

rolo

gy19

9167

267-

71F

eatu

res

of p

rimar

y ve

sico

uret

eric

refl

ux d

etec

ted

by

And

erso

n,P.

A.,

Ric

kwoo

d,A

.M.

pren

atal

son

ogra

phy.

646

Jour

nal o

f U

rolo

gy19

9214

816

83-7

Med

ical

man

agem

ent

of m

ild a

nd m

oder

ate

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cour

eter

al

Ara

nt,B

.S.,

Jr.

reflu

x:fo

llow

up s

tudi

es o

f in

fant

s an

d yo

ung

child

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A

pre

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repo

rt o

f th

e S

outh

wes

t P

edia

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Nep

hrol

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Stu

dy G

roup

.

304

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opea

n U

rolo

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817

263-

7T

reat

men

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d pr

even

tion

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afte

r ex

trav

esic

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p,S

.,A

brao

,E.G

.,an

d an

tirefl

ux t

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ique

Men

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-de-

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s,G

.

305

Eur

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rolo

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817

257-

62G

row

th o

f th

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dney

fol

low

ing

unila

tera

l ant

ireflu

x su

rger

yA

twel

l,J.

D.,

Cox

,P.A

.

75E

urop

ean

Uro

logy

1990

1730

7-9

‘Stin

g’pr

oced

ure

in t

he t

reat

men

t of

sec

onda

ry r

eflux

in

Aub

ert,

D.,

Zou

pano

s,G

.,ch

ildre

nD

estu

ynde

r,O

.,an

d H

urez

,F.

591

Eur

opea

n U

rolo

gy19

9119

39-4

4Lo

ng-t

erm

fol

low

-up

of c

hild

ren

with

sur

gica

lly t

reat

ed

Bee

tz,R

.,H

ohen

felln

er,R

.,ve

sico

rena

l refl

ux:r

enal

gro

wth

Sch

ofer

,O.,

Sin

ghof

,S.,

and

Rie

dmill

er,H

.

42E

urop

ean

Uro

logy

1989

1636

6-71

Long

-ter

m f

ollo

w-u

p of

chi

ldre

n w

ith s

urgi

cally

tre

ated

Bee

tz,R

.,S

chul

te-W

isse

rman

n,H

.,ve

sico

rena

l refl

ux:p

osto

pera

tive

inci

denc

e of

urin

ary

trac

t T

roge

r,J.

,Rie

dmill

er,H

.,in

fect

ions

,ren

al s

cars

and

art

eria

l hyp

erte

nsio

nM

annh

ardt

,W.,

Sch

ofer

,O.,

and

Hoh

enfe

llner

,R.

209

Con

trib

utio

ns t

o N

ephr

olog

y19

8439

81-9

3Ve

sico

uret

eral

refl

ux:

a co

mpa

rison

of

non-

surg

ical

and

B

ellin

ger,

M.F

.,D

ucke

tt,J.

W.

surg

ical

man

agem

ent

Pap

yrus

R

efer

ence

Jour

nal

Year

Volu

me

Pag

esT

itle

Aut

hor

46P

edia

tric

Rad

iolo

gy19

8919

308-

10T

he n

atur

al h

isto

ry o

f re

flux

in t

he lo

wer

pol

e of

dup

licat

ed

Ben

-Am

i,T.

,Gay

er,G

.,H

ertz

,co

llect

ing

syst

ems:

a co

ntro

lled

stud

yM

.,Lo

tan,

D.,

and

Boi

chis

,H.

497

Jour

nal o

f P

edia

tric

Sur

gery

1970

562

2-7

Ure

tero

neoc

ysto

stom

y in

refl

uxin

g ur

eter

ic d

uplic

atio

n:B

ette

x,M

.,K

umm

er-V

ago,

M.,

indi

catio

ns,t

echn

ique

and

res

ults

and

Kuf

fer,

F.

630

Brit

ish

Jour

nal o

f U

rolo

gy19

9371

22

1-5

Effi

cacy

and

cau

ses

of f

ailu

re o

f en

dosc

opic

sub

uret

eric

B

hatti

,H.A

.,K

hatta

k,H

.,an

d in

ject

ion

of T

eflon

in t

he t

reat

men

t of

prim

ary

vesi

co-

Bos

ton,

V.E

.ur

eter

ic r

eflux

245

Brit

ish

Med

ical

Jou

rnal

- C

linic

al R

esea

rch

1983

287

171-

4P

rosp

ectiv

e tr

ial o

f op

erat

ive

vers

us n

on-o

pera

tive

trea

tmen

t B

irmin

gha

m R

eflux

Stu

dy G

roup

of s

ever

e ve

sico

uret

eric

refl

ux:

two

year

s'ob

serv

atio

n in

96

chi

ldre

n

256

Jour

nal o

f U

rolo

gy19

8312

954

3-4

The

use

of

low

er ip

sila

tera

l ure

tero

uret

eros

tom

y to

tre

at v

esic

o-B

ockr

ath,

J.M

.,M

aize

ls,M

.,an

d ur

eter

al r

eflux

or

obst

ruct

ion

in c

hild

ren

with

dup

lex

uret

ers

Firl

it,C

.F.

58B

ritis

h Jo

urna

l of

Uro

logy

1988

6253

1-6

Prim

ary

vesi

cour

eter

ic r

eflux

tre

ated

by

antir

eflux

B

radi

c,I.,

Bat

inic

a,S

. and

Hus

ar,J

.ur

eter

ocys

tost

omy

at t

he v

erte

x of

the

bla

dder

. A

12-

year

fo

llow

-up

and

anal

ysis

of

oper

ativ

e fa

ilure

412

Brit

ish

Jour

nal o

f U

rolo

gy19

7547

525-

30A

ntire

flux

uret

eroc

ysto

stom

y at

the

ver

tex

of t

he b

ladd

erB

radi

c,I.,

Pas

ini,

M.,

and

Vla

tkov

ic,G

.

789

Uro

logy

1993

42 (

12/6

)70

5-7

Ure

tera

l rei

mpl

anta

tion:

post

oper

ativ

e m

anag

emen

t B

rand

ell,

R.A

.,B

rock

,J.W

.,3d

with

out

cath

eter

s

359

Uro

logy

1978

1113

9-41

Inci

denc

e of

late

r ur

eter

al o

bstr

uctio

n af

ter

antir

eflux

B

road

dus,

S.B

.,Z

icke

rman

,P.M

.,su

rger

y in

infa

nts

and

child

ren

Mor

risse

au,P

.M.,

and

Lead

bette

r,G

.W.,

Jr.

93Jo

urna

l of

Uro

logy

1989

142

499-

500

Ope

n ve

rsus

end

osco

pic

surg

ery

in t

he t

reat

men

t of

B

row

n,S

.ve

sico

uret

eral

refl

ux

117

Eur

opea

n U

rolo

gy19

88

314

7-40

Ant

ireflu

x pr

oced

ure

by L

ich-

Gre

goir.

In

dica

tions

and

res

ults

Bru

hl,P

.,va

n-A

hlen

,H.,

and

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lman

n,R

.

333

Jour

nal o

f U

rolo

gy19

79

121

648-

9E

xtra

vesi

cal u

rete

ropl

asty

Bru

skew

itz,R

.,S

onne

land

,A.M

.,an

d W

ater

s,R

.F.

678

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nal o

f U

rolo

gy19

91

146

1352

-3U

rete

ral r

eim

plan

tatio

n:a

com

paris

on o

f re

sults

with

the

B

urbi

ge,K

.A.

cros

s-tr

igon

al a

nd P

olita

no-L

eadb

ette

r te

chni

ques

in 1

20 p

atie

nts.

636

Jour

nal o

f U

rolo

gy19

9214

817

43-5

Fet

al v

esic

oure

tera

l refl

ux:

outc

ome

follo

win

g co

nser

vativ

e B

urge

,D.M

.,G

riffit

hs,M

.D.,

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nata

l man

agem

ent

Mal

one,

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.,an

d A

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l,J.

D.

488

Jour

nal o

f U

rolo

gy19

7110

629

0-4

Ure

tero

uret

eros

tom

y fo

r re

flux

in d

uple

x sy

stem

sB

urns

,A.,

Pal

ken,

M.

355

Lanc

et19

78

188

9-93

Seq

uela

e of

cov

ert

bact

eriu

ria in

sch

oolg

irls.

A f

our-

year

C

ardi

ff-O

xfor

d B

acte

riuria

fo

llow

-up

stud

y.S

tudy

Gro

up

181

Eur

opea

n U

rolo

gy19

8511

181-

3S

urgi

cal t

reat

men

t of

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icou

rete

ral r

eflux

with

bila

tera

l C

arin

i,M

.,S

elli,

C.,

Lenz

i,R

.,m

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ion

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he u

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ral o

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gli,

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and

Cos

tant

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272

Brit

ish

Jour

nal o

f U

rolo

gy19

82

5423

0-3

Refl

ux--

a re

tros

pect

ive

stud

y of

100

ure

teric

rei

mpl

anta

tions

C

arpe

ntie

r,P.

J.,B

ettin

k,P

.J.,

by t

he P

olita

no-L

eadb

ette

r m

etho

d an

d 10

0 by

the

Coh

enH

op,W

.C.,

and

Sch

rode

r,F.

H.

tech

niqu

e

300

Jour

nal o

f U

rolo

gy19

8212

711

46-8

Ren

al g

row

th in

sm

all k

idne

ys a

fter

uret

eron

eocy

stos

tom

yC

arso

n,C

.C.,

Kel

alis

,P.P

.,an

d H

offm

an,A

.D.

495

Jour

nal o

f U

rolo

gy19

7110

572

0-4

Man

agem

ent

of r

eflux

in t

otal

dup

licat

ion

anom

alie

sD

aine

s,S

.L.,

Hod

gson

,N.B

.

612

Brit

ish

Jour

nal o

f U

rolo

gy19

9167

536-

40P

rimar

y ve

sico

uret

eric

refl

ux:

trea

tmen

t w

ith s

ubur

eter

ic

Dav

ies,

N.,

Atw

ell,

J.D

.in

ject

ion

of P

olyt

ef p

aste

688

Jour

nal o

f U

rolo

gy19

9114

663

6-8

Effe

ctiv

enes

s of

trig

onop

last

y to

tre

at p

rimar

y D

e-G

enna

ro,M

.,A

ppet

ito,C

.,ve

sico

uret

eral

refl

uxLa

is,A

.,Ta

lam

o,M

.,C

apoz

za,N

.,an

d C

aion

e,P.

66Jo

urna

l of

Uro

logy

1988

14

010

89-9

1Ve

sico

uret

eral

refl

ux in

boy

sD

ecte

r,R

.M.,

Rot

h,D

.R.,

and

Gon

zale

s,E

.T.,

Jr.

673

Uro

logy

1992

3916

2-4

End

osco

pic

corr

ectio

n of

prim

ary

vesi

cour

eter

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Dew

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Gui

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592

Eur

opea

n U

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gy19

91

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-8P

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ef p

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inje

ctio

n of

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uxin

g du

plex

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Dew

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17E

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Uro

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1990

17

304-

6T

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men

t of

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rete

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c D

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Takv

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n,P.

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Te

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Rev

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xper

ienc

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642

Jour

nal o

f U

rolo

gy19

9214

816

74-5

Sur

gica

l res

ults

:in

tern

atio

nal R

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Stu

dy in

Chi

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n--

Duc

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J.W

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alke

r,R

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and

Uni

ted

Sta

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260

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Jour

nal o

f U

rolo

gy19

8254

672-

6R

esul

ts o

f co

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vativ

e m

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t of

ves

icou

rete

ric r

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D

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Sm

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370

Jour

nal o

f U

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gy19

77

118

826-

8Ip

sila

tera

l ure

tero

uret

eros

tom

y fo

r ve

sico

uret

eral

refl

ux in

D

utho

y,E

.J.,

Sou

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dupl

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rsM

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459

Jour

nal o

f U

rolo

gy19

7310

988

8-90

Vesi

cour

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al r

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a co

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ed r

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wD

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373

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228

5-8

Dis

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uret

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refl

ux d

urin

g lo

ng-t

erm

E

dwar

ds,D

.,N

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and,

I.C.,

prop

hyla

xis

of u

rinar

y t

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ctio

n in

chi

ldre

nP

resc

od,N

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d S

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180

Jour

nal o

f U

rolo

gy19

8513

466

8-70

The

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l fol

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tec

hniq

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rete

r su

rger

yE

hrlic

h,R

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267

Jour

nal o

f U

rolo

gy19

8212

855

4-7

Suc

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the

tran

sves

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adv

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men

t te

chni

que

for

Ehr

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R.M

.ve

sico

uret

eral

refl

ux

670

Brit

ish

Jour

nal o

f U

rolo

gy19

92

6929

4-30

2C

ompa

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DM

SA

sci

ntig

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y w

ith in

trav

enou

s ur

ogra

phy

Elis

on,B

.S.,

Tayl

or,D

.,fo

r th

e de

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enal

sca

rrin

g an

d its

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Va

n-de

r-W

all,

H.,

Per

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,J.K

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sico

uret

eric

refl

uxC

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,R.H

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d M

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257

Jour

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f U

rolo

gy19

8312

934

3-6

Cha

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f ur

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ns a

nd p

yelo

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ritic

E

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llgre

n,L.

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Alft

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l sca

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antir

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Sar

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284

Sca

ndin

avia

n Jo

urna

l of

Uro

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&

1981

15

243-

8T

he r

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oure

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l refl

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pae

diat

ric u

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y-tr

act

Elo

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Tallg

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Nep

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nA

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d S

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trom

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efer

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Jour

nal

Year

Volu

me

Pag

esT

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Aut

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6Jo

urna

l of

Uro

logy

1990

144

534-

6E

ndos

copi

c co

rrec

tion

of v

esic

oure

tera

l refl

ux:

Far

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Mor

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E.Z

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d O

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ienc

e w

ith 1

15 u

rete

rsLu

pa,S

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620

Jour

nal o

f U

rolo

gy19

9114

554

2-6

The

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ectio

n of

refl

ux n

ephr

opat

hy in

infa

nts

by

Far

nsw

orth

,R.H

.,99

mte

chne

tium

dim

erca

ptos

ucci

nic

acid

stu

dies

.R

ossl

eigh

,M.A

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ight

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Ros

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rg,A

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274

Eur

opea

n U

rolo

gy19

828

193-

5B

ilate

ral C

ohen

's a

ntire

flux

proc

edur

e w

ith a

sin

gle

Fau

re,G

.,B

en-S

alah

,S.,

subm

ucos

al t

unne

ldE

scof

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Rev

ol,M

.

477

Jour

nal o

f U

rolo

gy19

7210

786

2-4

Vesi

cour

eter

al r

eflux

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ure

tera

l dup

licat

ion

in c

hild

ren

Feh

renb

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,L.G

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.P.,

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Stic

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.

816

Inte

rnat

iona

l Uro

logy

& N

ephr

olog

y19

9325

(2)

141-

6P

rimar

y ve

sico

uret

eral

refl

ux in

chi

ldre

n un

der

one

year

of

age:

Fic

htne

r,J.

,Iw

asak

i,K

.,th

e ca

se f

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rvat

ive

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Shr

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d Ik

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255

Jour

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f U

rolo

gy19

8312

954

5-7

A r

etro

spec

tive

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the

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rete

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tent

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chi

ldre

nF

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ng u

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Kro

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657

Jour

nal o

f U

rolo

gy19

9214

871

8-23

Sub

uret

eral

col

lage

n in

ject

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the

endo

scop

ic t

reat

men

t

Fre

y,P.

,Ber

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Jenn

y,P.

,and

of

ves

icou

rete

ral r

eflux

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child

ren.

F

ollo

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stu

dy o

f 97

H

erzo

g,B

.tr

eate

d ur

eter

s an

d hi

stol

ogic

al a

naly

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olla

gen

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.

684

Inte

rnat

iona

l Uro

logy

& N

ephr

olog

y19

91

2323

1-6

Eva

luat

ion

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he c

ours

e of

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gnan

cy,d

eliv

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the

Fry

czko

wsk

i,M

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zew

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the

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ted

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d M

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vesi

cour

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al r

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hood

.

141

Inte

rnat

iona

l Uro

logy

& N

ephr

olog

y19

8618

397-

402

Ope

rativ

e tr

eatm

ent

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ilate

ral v

esic

oure

tera

l refl

ux b

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r F

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n m

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ter

reim

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310

Inte

rnat

iona

l Uro

logy

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ephr

olog

y19

8012

119-

22C

ompl

icat

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r ex

trav

esic

al a

ntire

flux

oper

atio

nsF

unke

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i,R

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d P

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Jour

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f th

e A

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Med

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Ass

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1966

195

636-

8A

ntire

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Gar

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150

Jour

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f P

edia

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Sur

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1986

2169

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1F

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Gin

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Mic

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Gen

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com

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stu

dy

184

Jour

nal o

f U

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gy19

8513

430

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Tra

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uret

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t te

chni

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rete

roG

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ngan

i,G

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en r

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Was

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d W

ater

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lt ca

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)

675

Arc

hive

s of

Dis

ease

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hild

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1991

6612

82-3

Imag

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rinar

y tr

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nG

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641

Jour

nal o

f U

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gy19

9214

816

88-9

2F

ollo

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tivel

y tr

eate

d ch

ildre

n w

ith h

igh

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Gol

drai

ch,N

.P.,

Gol

drai

ch,I

.H.

low

gra

de v

esic

oure

tera

l refl

ux:

a pr

ospe

ctiv

e st

udy

418

Uro

logy

619

7527

3-86

Man

agem

ent

of c

hild

ren

with

urin

ary

trac

t in

fect

ions

:G

ovan

,D.E

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air,

W.R

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e S

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eF

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d F

illy,

R.A

.

222

Zei

tsch

rift

fur

Kin

derc

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gie

3919

8452

-4R

enal

gro

wth

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r an

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ux s

urge

ry in

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nts

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Hja

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Jaco

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n,B

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383

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nal o

f U

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gy11

719

7735

5-7

Ext

rave

sica

l rep

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rimar

y ve

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uret

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chi

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nH

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l,N

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Ger

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249

Jour

nal o

f U

rolo

gy12

919

83

1022

-3M

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emen

t of

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late

ral r

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ipsi

late

ral

Han

ani Y

.,G

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asse

r,B

.,Jo

nas,

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eron

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tom

y--is

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Uro

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1819

8156

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Ear

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n of

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uxin

g m

egau

rete

r in

H

anna

,M.K

.ba

bies

by

tota

l ure

tera

l rec

onst

ruct

ion

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reim

plan

tatio

n

90A

cta

Rad

iolo

gica

3019

8939

1-4

Influ

ence

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vesi

cour

eter

al r

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urin

ary

trac

t in

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ion

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Han

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,L.,

Wik

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,I.,

Cel

si,

rena

l gro

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er u

rinar

y tr

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icat

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54S

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ian

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f In

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ious

Dis

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s21

1989

201-

4T

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im-s

ulph

adia

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ren

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anso

n,E

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d ve

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-ure

teric

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uxJo

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294

Uro

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1819

8124

1-3

Bila

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l or

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l ure

tero

neoc

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r un

ilate

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Har

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Birt

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367-

71C

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the

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643

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f U

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gy14

819

9216

57-6

1S

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l Refl

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al45

1971

1063

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-ure

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l refl

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chi

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nH

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felln

er,R

.

177

Jour

nal o

f U

rolo

gy13

419

8511

68-7

1E

ffect

s of

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buty

nin

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esic

oure

tera

l refl

ux in

chi

ldre

nH

omsy

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i,I.,

Ham

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Sch

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658

Jour

nal o

f U

rolo

gy14

819

9270

4-7

Ext

rave

sica

l non

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McL

orie

,G.A

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trus

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:a

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ue t

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t H

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,D.M

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cKen

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vesi

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al r

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Kho

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616

Jour

nal o

f U

rolo

gy14

519

9110

22-3

Res

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l refl

ux in

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plet

ely

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icat

ed

Hus

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Alle

n,T.

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n?

376

Brit

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Jour

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f U

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1977

119-

27Ve

sico

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l refl

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nJa

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enst

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.,O

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n,S

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d N

ygaa

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.

22B

ritis

h Jo

urna

l of

Uro

logy

6519

9041

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Res

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ical

tre

atm

ent

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e ve

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uret

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ux.

Jans

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spec

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s 4

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5

650

Jour

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f U

rolo

gy14

819

9216

50-2

Infe

ctio

n pa

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rete

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Jo

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Kos

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omly

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cate

d to

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-ter

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Han

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Olb

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hyla

xis.

T

he I

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natio

nal R

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Stu

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Chi

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426

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Jour

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f U

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153-

9T

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Isra

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Ure

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n w

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Jona

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Exp

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150

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d ur

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d H

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Uro

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3719

9124

4-7

End

osco

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tmen

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rete

ral r

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y,J.

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Han

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.K.

346

Jour

nal o

f U

rolo

gy12

019

7822

0-2

Refl

ux in

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plet

e du

plic

atio

n in

chi

ldre

nK

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n,W

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Nas

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h,P.

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666

Arc

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s of

Dis

ease

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6719

9250

6-8

Vesi

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eter

ic r

eflux

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ren

al s

cars

in a

sym

ptom

atic

sib

lings

K

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,R.B

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ettic

h,J.

Jof

chi

ldre

n w

ith r

eflux

68A

ustr

alia

n &

New

Zea

land

Jou

rnal

of

Sur

gery

5819

8856

9-71

The

end

osco

pic

corr

ectio

n of

ves

ico-

uret

eric

refl

uxK

ing,

P.A

.,G

ollo

w,I

.

Pap

yrus

R

efer

ence

Jour

nal

Year

Volu

me

Pag

esT

itle

Aut

hor

586

Inte

rnat

iona

l Uro

logy

& N

ephr

olog

y22

1990

531-

5S

urgi

cal m

anag

emen

t of

ves

icou

rete

ral r

eflux

by

mod

ified

K

limen

t,J.

,Fet

isov

,I.,

and

Gil-

Vern

et m

etho

dS

vita

c,J.

230

Jour

nal o

f U

rolo

gy13

019

8311

38-1

The

uni

nhib

ited

blad

der

in c

hild

ren:

effe

ct o

f tr

eatm

ent

on

Kof

f,S

.A.,

Mur

tagh

,D.S

.re

curr

ence

of

urin

ary

infe

ctio

n an

d on

ves

icou

rete

ral r

eflux

re

solu

tion

214

Con

trib

utio

ns t

o N

ephr

olog

y39

1984

211-

20T

he u

ninh

ibite

d bl

adde

r in

chi

ldre

n:ef

fect

of

trea

tmen

t on

K

off,

S.A

.,M

urta

gh,D

.ve

sico

uret

eral

refl

ux r

esol

utio

n

135

Brit

ish

Jour

nal o

f U

rolo

gy60

1987

36-8

Cor

rect

ion

of r

eflux

with

the

ure

teric

cro

ssov

er m

etho

d.

Kon

do,A

.,O

tani

,T.

Clin

ical

exp

erie

nce

in 5

0 pa

tient

s

15E

urop

ean

Uro

logy

1719

9031

8-20

Ure

tero

vesi

cal r

eim

plan

tatio

n af

ter

failu

re o

f en

dosc

opic

Laco

mbe

,A.

trea

tmen

t of

refl

ux b

y su

bmuc

osal

inje

ctio

n of

pol

ytef

pas

te

687

Jour

nal o

f U

rolo

gy14

619

9165

7-9

Dup

lex

reflu

x:a

stud

y of

105

chi

ldre

nLe

e,P.

H.,

Dia

mon

d,D

.A.,

Duf

fy,P

.G.,

and

Ran

sley

,P.G

.

394

Jour

nal o

f U

rolo

gy11

519

76

728-

30T

he n

atur

al h

isto

ry o

f re

flux

and

long

-ter

m e

ffect

s of

Le

nagh

an,D

.,W

hita

ker,

J.G

.,re

flux

on t

he k

idne

yJe

nsen

,F.,

and

Ste

phen

s,F.

D.

622

Jour

nal o

f U

rolo

gy14

519

9111

5-19

End

osco

pic

inje

ctio

n of

glu

tara

ldeh

yde

cros

s-lin

ked

bovi

ne

Leon

ard,

M.P

.,C

anni

ng,D

.A.,

derm

al c

olla

gen

for

corr

ectio

n of

ves

icou

rete

ral r

eflux

Pet

ers,

C.A

.,G

earh

art,

J.P.

,and

Je

ffs,R

.D.

51E

urop

ean

Uro

logy

1619

8920

0-3

Lich

-Gre

goir

anti-

reflu

x op

erat

ion:

a su

rgic

al e

xper

ienc

e an

d Li

nn,R

.,G

ines

in,Y

.,B

olki

er,M

.,5-

20 y

ears

of

fol

low

-up

in 1

49 u

rete

rsan

d Le

vin,

D.R

.

692

Brit

ish

Jour

nal o

f U

rolo

gy18

1993

52

-5E

ndos

copi

c tr

eatm

ent

of v

esic

oure

teric

refl

ux w

ith c

olla

gen.

Li

psky

,H.,

and

Wur

nsch

imm

elF

ive

yea

rs' e

xper

ienc

e

417

Qua

rter

ly J

ourn

al o

f M

edic

ine

4419

7548

1-9

Chi

ldho

od u

rinar

y in

fect

ion

asso

ciat

ed w

ith v

esic

o-M

acG

rego

r,M

.E.,

Fre

eman

,P.

uret

eric

refl

ux

254

Uro

logy

2119

8323

2-5

Man

agem

ent

of m

assi

vely

refl

uxin

g m

egau

rete

rsM

aggi

olo,

L.F.

,Loc

khar

t,J.

L.,

and

Pol

itano

,V.A

.

347

Jour

nal o

f U

rolo

gy12

019

7821

6-19

The

Lic

h-G

rego

ir an

tirefl

ux p

last

y:ex

perie

nces

with

M

arbe

rger

,M.,

Altw

ein,

371

child

ren

J.E

.,S

trau

b,E

.,W

ulff,

S.H

.,an

d H

ohen

felln

er,R

.

372

Uro

logy

1019

77

19-2

2U

rete

ral r

eim

plan

tatio

n:Li

ch m

etho

dM

cDuf

fie,R

.W.,

Litin

,R.B

.,an

d B

lund

on,K

.E.

5Jo

urna

l of

Uro

logy

144

1990

53

7-40

Hig

h gr

ade

vesi

cour

eter

al r

eflux

:an

alys

is o

f ob

serv

atio

nal

McL

orie

,G.A

.,M

cKen

na,P

.H.,

ther

apy

Jum

per,

B.M

.,C

hurc

hill,

B.M

.,G

ilmou

r,R

.F.,

and

Kho

ury,

A.E

.

443

Lanc

et1

1974

1310

-12

Effe

ct o

n re

nal g

row

th o

f re

impl

anta

tion

of r

eflux

ing

uret

ers

McR

ae,C

.V.,

Sha

nnon

,F.T

.,an

d U

tley,

W.L

.

195

Jour

nal o

f U

rolo

gy13

319

8538

8-90

Reo

pera

tive

uret

eron

eocy

stos

tom

y:re

view

of

69 p

atie

nts

Mes

robi

an,H

.G.,

Kra

mer

,S.A

.,an

d K

elal

is,P

.P.



840

Eur

opea

n U

rolo

gy23

(3)

1993

379-

81E

ffect

s of

sub

muc

osal

Tefl

on p

aste

inje

ctio

n in

M

icha

el,V

.,D

avar

is,P

.,Arh

onta

kis,

A.,

vesi

cour

eter

ic r

eflux

:res

ults

with

1-a

nd 2

-yea

r fo

llow

-up

data

.an

d A

ndro

ulak

akis

,P.A

.

817

Eur

opea

n U

rolo

gy24

(1)

1993

111-

15E

ndos

copi

c co

rrec

tion

of v

esic

o-ur

eter

ic r

eflux

in

Miy

akita

,H.,

Nin

an,G

.K.,

and

Pur

i,P.

dupl

ex s

yste

ms.

344

Jour

nal o

f U

rolo

gy12

019

7833

6-7

Non

-ope

rativ

e tr

eatm

ent

of v

esic

oure

tera

l refl

uxM

ulca

hy,J

.J.,

Kel

alis

,P.P

.

286

Brit

ish

Jour

nal o

f U

rolo

gy53

1981

542-

4Im

prov

emen

t in

ren

al f

unct

ion

follo

win

g ur

eter

ic

Mun

dy,A

.R.,

Kin

der,

C.H

.,re

impl

anta

tion

of v

esic

oure

teric

refl

uxJo

yce,

M.R

.,C

hant

ler,

C.,

and

Hay

cock

,G.B

.

205

Uro

logy

2419

8424

3-5

Refl

ux a

nd v

oidi

ng a

bnor

mal

ities

in c

hild

ren

Nas

ralla

h,P.

F.,S

imon

,J.W

.

637

Jour

nal o

f U

rolo

gy14

819

9217

39-4

2T

he lo

ng-t

erm

res

ults

of

pros

pect

ive

sibl

ing

reflu

x sc

reen

ing

Noe

,H.N

.

176

Jour

nal o

f U

rolo

gy13

419

8511

72-5

The

rol

e of

dys

func

tiona

l voi

ding

in f

ailu

re o

r co

mpl

icat

ion

of

Noe

,H.N

.ur

eter

al r

eim

plan

tatio

n fo

r pr

imar

y re

flux

534

Brit

ish

Jour

nal o

f U

rolo

gy41

1969

6-

13Ve

sico

-ure

teric

refl

ux in

infa

nts

and

child

ren:

resu

lts o

f O

Don

nell,

B.,

Mol

oney

,M.A

.,su

perv

isio

n,ch

emot

hera

py a

nd s

urge

ryan

d Ly

nch,

V.

144

Brit

ish

Med

ical

Jou

rnal

- C

linic

al R

esea

rch

293

1986

14

04-6

End

osco

pic

corr

ectio

n of

prim

ary

vesi

cour

eter

ic r

eflux

:O

Don

nell,

B.,

Pur

i,P.

resu

lts in

94

uret

ers

649

Jour

nal o

f U

rolo

gy14

819

9216

53-6

Ren

al s

cars

and

par

ench

ymal

thi

nnin

g in

chi

ldre

n w

ith

Olb

ing,

H.,

Cla

esso

n,I.,

Ebe

l,K

.D.,

vesi

cour

eter

al r

eflux

:a 5

-yea

r re

port

of

the

Inte

rnat

iona

l S

eppa

nen,

U.,

Sm

ellie

,J.M

.,R

eflux

Stu

dy in

Chi

ldre

n (E

urop

ean

Bra

nch)

Tam

min

en-M

obiu

s,T.

,an

d W

ikst

ad,I

.

12E

urop

ean

Uro

logy

1719

9033

0-2

A n

ew a

ntire

flux

oper

atio

nO

rikas

a,S

.

798

Brit

ish

Jour

nal o

f U

rolo

gy72

(9/

3)19

9337

3-5

Intr

aves

ical

ure

teric

plic

atio

n an

d re

impl

anta

tion

for

Oze

n,H

.A.,

Tekg

ul,S

.,E

rkan

,I.,

meg

aure

ters

in c

hild

ren.

and

Bak

kalo

glu,

M.

403

Uro

logy

719

7627

6-8

Refl

ux in

opp

osite

ure

ter

afte

r su

cces

sful

cor

rect

ion

of

Par

rott,

T.S

.,W

ooda

rd,J

.R.

unila

tera

l ves

icou

rete

ral r

eflux

677

Jour

nal o

f U

rolo

gy14

619

9115

94-5

Non

surg

ical

man

agem

ent

of p

rimar

y ve

sico

uret

eral

refl

ux in

P

eppa

s,D

.S.,

Sko

og,S

.J.,

com

plet

e ur

eter

al d

uplic

atio

n:is

it ju

stifi

ed?

Can

ning

,D.A

.,an

d B

elm

an,A

.B.

204

Inte

rnat

iona

l Jou

rnal

of

Ped

iatr

ic N

ephr

olog

y5

1984

83-8

Eva

luat

ion

of k

idne

y gr

owth

in v

esic

o-ur

eter

al r

eflux

Per

aton

er,L

.,M

essi

,G.,

and

Fon

da,E

.

107

Jour

nal o

f U

rolo

gy14

019

8812

1-4

Med

ical

tre

atm

ent

of v

esic

oure

tera

l refl

ux d

etec

ted

in in

fanc

yP

inte

r,A

.B.,

Jasz

ai,V

.,an

d D

ober

,I.

25S

cand

inav

ian

Jour

nal o

f U

rolo

gy a

nd

125

1989

29-3

4Ve

sico

-ure

tera

l refl

ux.

II. T

he lo

ngte

rm o

utco

me

of k

idne

y P

ouls

en,E

.U.,

Joha

nnes

en,N

.L.,

Nep

hrol

ogy

func

tion

in n

on-s

urgi

cal t

reat

men

tN

iels

en,J

.B.,

Jrge

nsen

,T.M

.,an

d A

nder

son,

A.J

.

21La

ncet

335

1990

1320

-2E

ndos

copi

c co

rrec

tion

of p

rimar

y ve

sico

uret

eric

refl

ux b

y P

uri,

P.

subu

rete

ric in

ject

ion

of p

olyt

etra

fluor

oeth

ylen

e

115

Jour

nal o

f P

edia

tric

Sur

gery

2219

8710

87-9

1E

ndos

copi

c co

rrec

tion

of g

rade

s IV

and

V p

rimar

y P

uri,

P.,O

Don

nell,

B.

vesi

cour

eter

ic e

flux:

six

to 3

0 m

onth

fol

low

-up

in 4

2 ur

eter

s

124

Inte

rnat

iona

l Uro

logy

& N

ephr

olog

y19

1987

141-

3A

ntire

flux

oper

atio

ns w

ithou

t ca

thet

erP

ypno

,W.

182

Brit

ish

Jour

nal o

f U

rolo

gy57

1985

406-

9U

nila

tera

l ure

teric

rei

mpl

anta

tion

for

prim

ary

vesi

cour

eter

ic

Qui

nlan

,D.,

OD

onne

ll,B

.re

flux

in c

hild

ren.

A p

olic

y re

-eva

luat

ed

Pap

yrus

R

efer

ence

Jour

nal

Year

Volu

me

Pag

esT

itle

Aut

hor

332

Uro

logy

1319

79

248-

52P

rimar

y m

assi

ve r

eflux

in c

hild

ren

Rab

inow

itz,R

.,B

arki

n,M

.,S

chill

inge

r,J.

F.,J

effs

,R.D

.,an

d C

ook,

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.

461

Uro

logi

a In

tern

atio

nalis

2819

7356

-64

Sur

gica

l cor

rect

ion

of v

esic

oure

tera

l refl

ux.

R

avas

ini,

G.,

Pag

ano,

F.D

escr

iptio

n of

tec

hniq

ue a

nd r

esul

ts

183

Tur

kish

Jou

rnal

of

Ped

iatr

ics

2619

8417

5-9

15 y

ears

of

expe

rienc

e in

the

sur

gica

l tre

atm

ent

of

Rem

zi,D

.,O

zen,

H.A

.,E

rkan

,I.,

vesi

cour

eter

al r

eflux

in c

hild

ren

and

Ken

di,S

.

356

Uro

logy

1119

7823

1-6

Meg

aure

ters

in c

hild

ren

Ret

ik,A

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McE

voy,

J.P.

,and

B

auer

,S.B

.

827

Eur

opea

n Jo

urna

l of

Ped

iatr

ics

152

(6/6

)19

9352

3-5

Prim

ary

vesi

cour

eter

al r

eflux

in in

fant

s w

ith a

dila

ted

feta

l R

ing,

E.,

Pet

rits

ch,P

.,ur

inar

y tr

act.

Ric

cabo

na,M

.,H

aim

-Kut

tnig

,M.,

Vili

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.,R

auch

enw

ald,

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Fue

ger,

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679

Inte

rnat

iona

l Uro

logy

& N

ephr

olog

y23

1991

437-

40S

cree

ning

of

asym

ptom

atic

sib

lings

of

patie

nts

with

S

ahin

,A.,

Erg

en,A

.,B

alba

y,D

.,ve

sico

uret

eral

refl

uxB

asar

,I.,

Oze

n,H

.,an

d R

emzi

,D.

680

Inte

rnat

iona

l Uro

logy

& N

ephr

olog

y23

1991

31-5

The

fat

e of

con

tral

ater

al u

rete

r af

ter

ipsi

late

ral r

eim

plan

tatio

n

Sar

gin,

S.Y

. E

rgen

,A.,

Oze

n,H

.A.,

in u

nila

tera

l ves

icou

rete

ric r

eflux

Ozk

arde

s,H

.,Te

kgul

,S.,

Erk

an,I

.,an

d B

akka

logl

u,M

.

16E

urop

ean

Uro

logy

1719

9031

0-13

Ana

lysi

s an

d pe

rspe

ctiv

es o

f en

dosc

opic

tre

atm

ent

of

Sau

vage

,P.,

Sau

ssin

e,C

.,ve

sico

uret

eral

refl

ux in

chi

ldre

n w

ith a

20-

mon

th f

ollo

w-u

pLa

ustr

iat,

S.,

Bec

meu

r,F.

,B

ient

z,J.

,Chr

istm

ann,

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Roy

,E.,

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Mar

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n,L.

685

Chi

ld.

Nep

hrol

. U

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1119

9129

-32

Tre

atm

ent

of v

esic

oure

teric

refl

ux:

resu

lts a

fter

3 ye

ars

in

Sch

oltm

eije

r,R

.J.

a pr

ospe

ctiv

e st

udy

18Jo

urna

l of

Ped

iatr

ic S

urge

ry25

1990

66

9-71

The

rol

e of

vid

eour

odyn

amic

stu

dies

in d

iagn

osis

and

Sch

oltm

eije

r,R

.J.,

Grif

fiths

,D.J

.tr

eatm

ent

of v

esic

oure

tera

l refl

ux

114

Brit

ish

Jour

nal o

f U

rolo

gy61

1988

205-

9T

reat

men

t of

ves

icou

rete

ric r

eflux

. P

relim

inar

y re

port

of

Sch

oltm

eije

r,R

.J.,

Grif

fiths

,D.J

.a

pros

pect

ive

stud

y

74E

urop

ean

Uro

logy

1719

9031

4-17

Vesi

cour

eter

al r

eflux

in c

hild

ren:

endo

scop

ic t

reat

men

tS

chul

man

,C.C

.,P

amar

t,D

.,H

all,

M.,

Jans

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F.,a

nd

Avn

i,F.

E.

128

Jour

nal o

f U

rolo

gy13

819

8795

0-2

End

osco

pic

trea

tmen

t of

ves

icou

rete

ral r

eflux

in c

hild

ren

Sch

ulm

an,C

.C.,

Sim

on,J

.,P

amar

t,D

.,an

d A

vni,

F.E

.

157

Brit

ish

Jour

nal o

f U

rolo

gy58

1986

119-

24R

enal

fun

ctio

n fo

llow

ing

surg

ical

cor

rect

ion

of v

esic

o-S

cott,

D.J

.,B

lack

ford

,H.N

.,ur

eter

ic r

eflux

in c

hild

hood

Joyc

e,M

.R.,

Mun

dy,A

.R.,

Kin

der,

C.H

.,H

ayco

ck,G

.B.,

and

Cha

ntle

r,C

.



377

Brit

ish

Jour

nal o

f U

rolo

gy49

1977

109-

18T

he m

anag

emen

t of

ure

teric

refl

ux in

chi

ldre

nS

cott,

J.E

.

540

Arc

hive

s of

Dis

ease

in C

hild

hood

4319

6832

3-8

Tre

atm

ent

of v

esic

o-ur

eter

ic r

eflux

in c

hild

ren

Sco

tt,J.

E.,

Sta

nsfe

ld,J

.M.

94Jo

urna

l of

Uro

logy

142

1989

494-

8Ve

sico

uret

eral

refl

ux a

nd v

oidi

ng d

ysfu

nctio

n:S

eruc

a,H

.a

pros

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ive

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y

354

Arc

hive

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Dis

ease

in C

hild

hood

5319

7821

0-17

Ren

al s

carr

ing

and

vesi

cour

eter

ic r

eflux

Sha

h,K

.J.,

Rob

ins,

D.G

.,an

d W

hite

,R.H

.

618

Ped

iatr

ics

8719

91

538-

43P

rimar

y ve

sico

uret

eral

refl

ux in

the

bla

ck c

hild

Sko

og,S

.J.,

Bel

man

,A.B

.

130

Jour

nal o

f U

rolo

gy13

819

8794

1-6

A n

onsu

rgic

al a

ppro

ach

to t

he m

anag

emen

t of

prim

ary

Sko

og,S

.J.,

Bel

man

,A.B

.,an

d ve

sico

uret

eral

refl

uxM

ajd,

M.

611

Ped

iatr

ic N

ephr

olog

y2

1988

12-1

7P

roph

ylac

tic c

o-tr

imox

azol

e an

d tr

imet

hopr

im in

the

S

mel

lie,J

.M.,

Gru

nebe

rg,R

.N.,

man

agem

ent

of u

rinar

y tr

act

infe

ctio

n in

chi

ldre

nB

anto

ck,H

.M.,

and

Pre

scod

,N.

389

Brit

ish

Med

ical

Jou

rnal

219

7620

3-6

Long

-ter

m lo

w-d

ose

co-t

rimox

azol

e in

pro

phyl

axis

of

Sm

ellie

,J.M

.,G

rune

berg

,R.N

.,ch

ildho

od u

rinar

y t

ract

infe

ctio

n:cl

inic

al a

spec

tsLe

akey

,A.,

and

Atk

in,W

.S.

313

Jour

nal o

f U

rolo

gy12

519

8155

1-3

Ure

tera

l rei

mpl

anta

tion

with

out

cath

eter

sS

o,E

.P.,

Bro

ck,W

.A.,

and

Kap

lan,

G.W

.

105

Eur

opea

n U

rolo

gy14

1988

21

4-15

Cor

rect

ion

of v

esic

oure

tera

l refl

ux b

y th

e G

il-Ve

rnet

pro

cedu

reS

olok

,V.,

Ero

zenc

i,A

.,K

ural

,A.,

and

One

r,A

.

96B

ritis

h Jo

urna

l of

Uro

logy

6319

8924

5-50

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sica

l gro

wth

vel

ocity

dur

ing

cons

erva

tive

trea

tmen

t an

d S

utto

n,R

.,A

twel

l,J.

D.

follo

win

g su

bseq

uent

sur

gica

l tre

atm

ent

for

prim

ary

vesi

cour

eter

ic r

eflux

116

Ann

ales

de

Rad

iolo

gie

3019

8747

8-81

Eva

luat

ion

of s

ub-u

rete

ric T

eflon

inje

ctio

n as

an

antir

eflux

S

wee

ney,

L.E

.,T

hom

as,P

.S.

proc

edur

e

648

Jour

nal o

f U

rolo

gy14

819

9216

62-6

Ces

satio

n of

ves

icou

rete

ral r

eflux

for

5 y

ears

in in

fant

s an

d Ta

mm

inen

-Mob

ius,

T.,B

runi

er,E

.,ch

ildre

n al

loca

ted

to m

edic

al t

reat

men

t. T

he I

nter

natio

nal

Ebe

l,K

.D.,

Lebo

witz

,R.,

Refl

ux S

tudy

in C

hild

ren

Olb

ing,

H.,

Sep

pane

n,U

.,an

d S

ixt,

R.

212

Con

trib

utio

ns t

o N

ephr

olog

y39

1984

238-

46U

nsta

ble

blad

der

activ

ity a

nd t

he r

ate

of r

esol

utio

n of

ves

ico-

Tayl

or,C

.M.

uret

eric

refl

ux

262

Brit

ish

Jour

nal o

f U

rolo

gy54

1982

494-

8M

ictu

ritio

n sy

mpt

oms

and

unst

able

bla

dder

act

ivity

in g

irls

Tayl

or,C

.M.,

Cor

kery

,J.J

.,an

d w

ith p

rimar

y ve

sico

uret

eral

refl

uxW

hite

,R.H

.

131

Brit

ish

Med

ical

Jou

rnal

- C

linic

al R

esea

rch

295

1987

23

7-41

Pro

spec

tive

tria

l of

oper

ativ

e ve

rsus

non

-ope

rativ

e

The

Birm

ingh

am R

eflux

tr

eatm

ent

of s

ever

e v

esic

oure

teric

refl

ux in

chi

ldre

n:S

tudy

Gro

upfiv

e ye

ars'

obs

erva

tion.

Birm

ingh

am R

eflux

Stu

dy G

roup

246

Jour

nal o

f U

rolo

gy12

919

83

1198

-9In

itial

res

ults

with

the

Coh

en c

ross

-trig

onal

W

acks

man

,J.

uret

eron

eocy

stot

omy

348

Jour

nal o

f U

rolo

gy11

919

7881

4-6

Man

agem

ent

of v

esic

oure

tera

l refl

uxW

acks

man

,J.,

And

erso

n,E

.E.,

and

Gle

nn,J

.F.

660

Jour

nal o

f U

rolo

gy14

819

9235

9-61

Res

ults

of

the

rene

wed

ext

rave

sica

l rei

mpl

ant

for

surg

ical

W

acks

man

,J.,

Gilb

ert,

A.,

and

corr

ectio

n of

ves

icou

rete

ral r

eflux

She

ldon

,C.A

.

Pap

yrus

R

efer

ence

Jour

nal

Year

Volu

me

Pag

esT

itle

Aut

hor

327

Brit

ish

Jour

nal o

f U

rolo

gy50

1978

479-

84T

he lo

ng-t

erm

fol

low

-up

of s

urgi

cally

tre

ated

W

alla

ce,D

.M.,

Rot

hwel

l,D

.L.,

vesi

cour

eter

ic r

eflux

and

Will

iam

s,D

.I.

479

Jour

nal o

f U

rolo

gy10

719

7246

6-8

Uni

late

ral u

rete

rone

ocys

tost

omy:

the

fate

of

the

War

ren,

M.M

.,K

elal

is,P

.P.,

and

cont

rala

tera

l ure

ter

Stic

kler

,G.B

.

647

Jour

nal o

f U

rolo

gy14

819

9216

67-7

3R

esul

ts o

f a

rand

omiz

ed c

linic

al t

rial o

f m

edic

al v

ersu

s W

eiss

,R.,

Duc

kett,

J. a

nd

surg

ical

man

agem

ent

of in

fant

s an

d ch

ildre

n w

ith g

rade

s III

S

pitz

er,A

.an

d IV

prim

ary

vesi

cour

eter

al r

eflux

(U

nite

d S

tate

s).

T

he I

nter

natio

nal R

eflux

Stu

dy in

Chi

ldre

n.

396

Jour

nal o

f U

rolo

gy11

519

76

722-

5R

enal

gro

wth

and

urin

ary

infe

ctio

n fo

llow

ing

antir

eflux

W

illsc

her,

M.K

.,B

auer

,S.B

.,su

rger

y in

infa

nts

and

child

ren

Zam

mut

o,P.

J.,a

nd R

etik

,A.B

.

388

Jour

nal o

f P

edia

tric

s89

1976

743-

7In

fect

ion

of t

he u

rinar

y tr

act

afte

r an

ti-re

flux

surg

ery

Will

sche

r,M

.K.,

Bau

er,S

.B.,

Zam

mut

o,P.

J.,a

nd R

etik

,A.B

.

129

Jour

nal o

f U

rolo

gy13

819

87

947-

9D

etru

sorr

haph

y:ex

trav

esic

al u

rete

ral a

dvan

cem

ent

to c

orre

ct

Zao

ntz,

M.R

.,M

aize

ls,M

.,ve

sico

uret

eral

refl

ux in

chi

ldre

nS

ugar

,E.C

.,an

d F

irlit,

C.F

.

640

Jour

nal o

f U

rolo

gy14

819

9216

99-1

702

His

toric

al c

lues

to

the

com

plex

of

dysf

unct

iona

l voi

ding

,va

n G

ool,

J.D

.,H

jalm

as,K

.,ur

inar

y tr

act

infe

ctio

n an

d ve

sico

uret

eral

refl

ux.

Tam

min

en-M

obiu

s,T.

,and

T

he I

nter

natio

nal R

eflux

Stu

dy in

Chi

ldre

nO

lbin

g,H

.

Tota

l Num

ber

of A

rtic

les

= 1

68



Appendix B: Data extraction form


Appendix B (continued)

Copyright © 1997 American Urological Association, Inc. Page 79

Combining relative risks from several different studies is problematic. Several meta-analytic techniquescan be used. A fixed effects analysis assumes that the studies all estimate the same parameter (relativerisk). The opposite of a fixed effects model is a random effects model. In a random effects model, the parameter does not remain constant from study to study, but rather varies randomly, and the center of thedistribution of the parameter of interest must be estimated. This methodology is especially appropriate for combining relative risks from pediatric reflux studies, because the populations used by each study havedifferent mixes of grades, laterality and gender.

One standard method of combining parameters using random effects models is the empirical Bayes (EB) method (Hedges and Olkin, 1985). For this method, we assume that each qj estimates a different parameter,qj, with known variance,sj

2. The qj ’s are assumed to be a sample from a normal distributionwith mean m and variance t2. That is, mother nature chooses parameters for each study at random from anormal distribution with mean m and variance t2. The likelihood is proportional to

L µ exp - [ ( qj - m )2 / ( t2 + sj2 ) + ln ( t2 + sj

2 ) ] / 2 .

Maximum likelihood estimates can be calculated directly using a modified Gauss-Newton algorithm(Hasselblad, 1994) or the EM Algorithm (Dempster, Laird, and Rubin, 1977).

For dichotomous outcomes, such as rates of renal scarring, the same model can be used for the parame-ters, but the underlying distribution of the parameters is assumed to be binomial instead of normal. Thiscan be accomplished by fitting a multiple logistic regression model with random effects. The EGRET soft-ware package (Statistics and Epidemiology Research Corporation, 1993) can be used to estimate such mod-els. This model can be generalized to include multiple variables of interest.

The following example illustrates the use of the method to estimate the effect of both treatment andgrade on renal scarring. A dataset was created for each subgroup of each renal scarring study when thestudy gave results by grade (see Table C-1). Dummy variables were created for each grade to indicate theeffect of grade. Grades IV and V were combined because there were so few subjects. Some studies gavetheir results for a group of grades, and these presented special analysis problems. For those studies, thefraction of subjects in each grade was used in place of the dummy variables. To understand this, assumethat one study had 40 percent in grade II and 60 percent in grade III. Then each individual in grade IIshould be assigned a one for the dummy for grade II and a zero for the other dummies. If this was actuallydone for all subjects in both grades and the dummy variables were then averaged, the result would be thefraction for each dummy as proposed. A small number of studies did not give a grade distribution, and forthese studies an average grade distribution was assigned.

The data in Table C-1 were analyzed using multiple logistic regression analysis. The model assumesthat the effects of each content factor are additive (in the log-odds space). Thus, the analysis results mustbe converted back to probabilities and relative risks. The results for this example are shown in Table C-2.

Appendix C: Methodology for combining parameters

û ûSm

j = 1


TABLE C-1. Dataset Created from the Medical and Surgical Studies of New Scarring (per Ureter)

Study New Sample Grade I Grade II Grade III Grade IV/V SurgeryScars Size (1=yes)

Ben-Ami, Sinai, Hertz, 0 4 1 0 0 0 0et al., 1989

0 28 0 .5 .5 0 0

3 5 0 0 0 1 0

Scholtmeijer and Griffiths, 1988 0 12 1 0 0 0 0

1 36 0 1 0 0 0

1 31 0 0 1 0 0

0 12 0 0 0 1 0

Birmingham Reflux Study Group, 1987 5 111 0 .1 .4 .5 0

Homsy, Nsouli, Hamburger, et al., 1985 0 53 .09 .06 .15 .15 0

Bellinger and Duckett, 1984 1 165 .15 .55 .18 .12 0

Koff and Murtagh, 1983 3 47 .06 .23 .36 .34 0

2 55 .21 .25 .25 .26 0

Shah, Robins, and White, 1978 1 13 0 1 0 0 0

4 47 0 0 .40 .60 0

Cardiff-Oxford Bacteriuria 0 28 1 0 0 0 0Study Group, 1978

1 41 0 1 0 0 0

1 12 0 0 .40 .60 0

Edwards, Normand, Prescod, et al., 1977 2 121 .15 .18 .49 .14 0

Jakobsen, Genster, Olesen, et al., 1977 0 193 .21 .35 .17 .25 0

Husmann and Allen, 1991 13 142 0 1 0 0 0

Burge, Griffiths, Malone, et al., 1992 0 6 1 0 0 0 0

0 3 0 1 0 0 0

0 14 0 0 1 0 0

0 17 0 0 0 1 0

0 4 0 0 0 1 0

Arant 1992 1 11 1 0 0 0 0

5 40 0 1 0 0 0

9 33 0 0 1 0 0

Aggarwal, Verrier-Jones, 0 10 1 0 0 0 0Asscher, et al., 1991

0 10 0 1 0 0 0

2 11 0 0 .40 .60 0

Beetz, Schulte-Wissermann, 9 264 .09 .52 .31 .10 1Tröger, et al., 1989

Scholtmeijer and Griffiths, 1988 2 10 0 0 1 0 1

1 24 0 0 0 1 1

Birmingham Reflux Study Group, 1987 4 104 0 .1 .4 .5 1

Scott, Blackford, Joyce, et al., 1986 0 97 0 .1 .4 .5 1

Carpentier, Bettink, Hop, et al., 1982 0 100 .35 .5 .28 .12 1

Burge, Griffiths, Malone, et al., 1992 0 21 .14 .05 .28 .53 1

Hjalmas, Lohr, Tamminen-Mobius, 20 237 0 0 .11 .89 1et al., 1992


TABLE C-2. Results of the Multiple Logistic Regression Analysis With Random Effects Using theData in Table C-1

Variable Coefficient Std.Err.Beta p-value Odds/Odds ratio

Grade I -6.125 (1.57) <.001 .002187

Grade II -3.739 (.397) <.001 .02377

Grade III -3.332 (.770) <.001 .03573

Grade IV or V -2.841 (.538) <.001 .05836

Surgery -.02613 (.452) .954 .9742

Random effect term 1.368 (.316)

The combination of rates, such as complication rates, is a special case of the analysis just described.The general use of a linear model with random effects can be applied to either continuous or dichotomousdata. Most standard meta-analytic methods, such as inverse variance weighting and the Mantel-Haenszelmethod, are special cases of the methods just described.

References for Appendix C

Aggarwal VK, Verrier-Jones K, Asscher AW, Evans C, Williams LA. Covert bacteriuria: long term follow up. Arch Dis Child1991;66:1284–6.

Arant BS Jr. Medical management of mild and moderate vesicoureteral reflux: followup studies of infants and young children. A preliminary report of the Southwest Pediatric Nephrology Study. J Urol 1992; 148:1683–7.

Beetz R, Schulte–Wissermann H, Tröger J, Riedmiller H, Mannhardt W, Schofer O. Long-term follow-up of children with surgically treated vesicorenal reflux: postoperative incidence of urinary tract infections, renal scars and arterial hypertension. Eur Urol 1989;16:366–71.

Bellinger MF, Duckett JW. Vesicoureteral reflux: a comparison of non-surgical and surgical management. Contrib Nephrol 1984; 39:81–93.

Ben-Ami T, Sinai L, Hertz M, Boichis H. Vesicoureteral reflux in boys: review of 196 cases. Radiology 1989;173:681–4.

Birmingham Reflux Study Group. Prospective trial of operative versus non-operative treatment of severe vesicoureteric reflux in children: five years' observation. Birmingham Reflux. BMJ 1987;295:237–41.

Burge DM, Griffiths MD, Malone PS, Atwell JD. Fetal vesicoureteral reflux: outcome following conservative postnatal management. J Urol 1992;148:1743–5.

Cardiff-Oxford Bacteriuria Study Group. Sequelae of covert bacteriuria in schoolgirls. A four-year follow-up study. Lancet1978;1:889–93.

Carpentier PJ, Bettink PJ, Hop WC, Schroder FH. Reflux—a retrospective study of 100 ureteric reimplantations by the Politano-Leadbetter method and 100 by the Cohen technique. Br J Urol 1982;54:230–3.

Edwards D, Normand IC, Prescod N, Smellie JM. Disappearance of vesicoureteric reflux during long-term prophylaxis of urinary tract infection in children. BMJ 1977;2:285–8.

Hjalmas K, Lohr G, Tamminen-Mobius T, Seppanen J, Olbing H, Wikstrom S. Surgical results in the International Reflux Study in Children (Europe). J Urol 1992;148:1657–11.

Homsy YL, Nsouli I, Hamburger B, Laberge I, Schick E. Effects of oxybutynin on vesicoureteral reflux in children. J Urol1985;134:1168–71.

Husmann DA, Allen TD. Resolution of vesicoureteral reflux in completely duplicated systems: fact or fiction?. J Urol1991;145:1022–3.

Jakobsen BE, Genster H, Olesen S, Nygaard E. Vesico-ureteral reflux in children. Br J Urol 1977;49:119–27.

Koff SA, Murtagh DS. The uninhibited bladder in children: effect of treatment on recurrence of urinary infection and on vesi-coureteral reflux resolution. J Urol 1983;130:1138–40.

Scholtmeijer RJ, Griffiths DJ. Treatment of vesicoureteric reflux. Preliminary report of a prospective study. Br J Urol1988;61:206–9.

Scott DJ, Blackford HN, Joyce MR, Mundy AR, Kinder CH, Haycock GB, Chantler C. Renal function following surgical correc-tion of vesico-ureteric reflux in childhood. Br J Urol 1986;58:119–24.

Shah KJ, Robins DG, White RH. Renal scarring and vesicoureteric reflux. Arch Dis Child 1978;53:210–17.


Appendix D: Recommendations questionnaire—Sample page


Appendix E: Data presentation

TABLE E-1. RESOLUTION OF REFLUX AFTER OPEN SURGERY

Author/ Number Number Surgical Surgical SurgicalPapyrus # of of Procedure1 Success Success Grade I/ Grade II/ Grade III/ Grade IV/ Grade V/

Patients Ureters (Patients) (Ureters) Total Total Total Total Total

Linn 51 60 101 L-G 55/60

Beetz 42 189 242 L-G 238/242

Jansen 22 80 106 Mix,P-L,C,L-G 96/106

Fryczkowski 14 50 103 Author's own 103/103 8/8 48/48 44/44 3/3

Bellinger 209 207 338 Mix,P-L,G-A,C 197/207 ?/12 ?/80 ?/102 ?/115 ?/26

Glassberg 184 60 101 C 101/101 1/1 10/10 23/23 32/32 35/35

Remzi 183 89 143 P-L 118/143

Quinlan 182 51 51 Mix, L-P, C 50/51

Sutton 96 22 22 P-L 22/22 1/1 8/8 13/13

Solok 105 14 22 G-V 18/22 4/4 9/9 4/5 1/4

Decter 66 30 Mix P-L,G-A,C 30/30 1/1 5/5 10/10 9/9 5/5

Carini 181 14 G-V 13/14 3/3 8/9 2/2

Ehrlich 120 31 K 31/31

Scott 157 56 97 C 52/56

Kondo 135 32 64 C 57/57 12/12 45/45

Zaontz 129 79 120 D 111/120 57/58 42/47 15-Dec

Birmingham 131 77 107 L-P, C 105/107 105/107

Breuhl 117 146 190 L-G 188/190 46 106 32 6

Pypno 124 43 80 C 80/80 6 53 10

Bradic 58 618 792 Anterior D 792/824 43 378 403

Hanani 249 105 P-L, G-A 98/105

Faure 274 136 272 C 270/272

Carpentier 272 200 100 P-L 88/100 8 46 31 10 5

Carpentier 272 100 C 97/100 12 55 25 8 0

Ehrlich 267 135 229 C 226/229 74 102 53

Maggiolo 254 15 28 TH 24/28 24/28

Ahmed 252 28 38 C 37/38 4/4 12/12 21/22

Wacksman 24 36? 52 C 51/52 5/5 6/6 24/24 11/11 5/6

Hagberg 222 13 15 P-L 14/15

Jakobsen 376 80 L-P Bischoff (2) 68/80

McDuffie 372 51 78 L-G 73/76

Retik 356 8 9 TH 9/9

Marberger 347 371 429 L-G 419/429

Wachsman 348 P-L 10/1 62/67 50/54

Wachsman 348 G-A 2/2 39/40 25/26

Wachsman 348 P 8/8 7/7 misc 10/19

Harty 294 35 35 L-P 35/35 2/2 6/6 23/23

Hanna 288 13 22 TH 21/22 21/22

1L-G = Lich-Gregoir; P-L = Politano-Leadbetter; C = Cohen (transtrigonal); G-A = Glenn-Anderson; K = Kalicinski; D = Detrusorrhaphy; TH = Tailoring Hendren; P = Paquin; G-V = Gil-Vernet; U = Ureterostomy; H = Hutch

Copyright © 1997 American Urological Association, Inc.Copyright © 1997 American Urological Association, Inc.Page 84

TABLE E-1. RESOLUTION OF REFLUX AFTER OPEN SURGERY (continued)



Scott 540 31 46 ? type 38/46

Bradic 412 90 106 Anterior D 91/93

Hohenfellner 4 96 L-G 92/96

Parrott 403 253 P 253/253

Hampel 383 51 83 L-G 78/83

Scott 377 163 Mod. P-L 157/163

Duckett 642 87 154 C, P-L 153/154 18/153 135/153

Burbige 678 33 C 33/33

Burbige 678 37 P-L 37/37

Brandell 789 34 Mixed,G-A,P-L,C 57/57 7/7 12/12 20/20 8/8 5/5

Oezem 798 11 11 Starr Plic 5/11 5/11

Wacksman 660 202 D 202/202 1/1 63/63 112/112 22/22 4/4

De Gennaro 6 47 69 G-V 68/69 25/25 39/39 3/4

Houle 658 45 65 D 62/65 6/6 16/16 23/23 13/14 4/6

Garrett 566 58 96 P-L 95/96

Kliment 586 60 96 G-V 54/60

Bettex 497 27 29 P-L 25/29

Ravasini 461 22 37 Mod. G-A 37/37

Jonas 438 86 150 Mix P-L, G-A 132/150

Hjalmas 643 151 237 191/237

Hjalmas 643 83 131 P-L

Hjalmas 643 39 59 L-G

Hjalmas 643 27 41 C

Hjalmas 643 2 4 G-A

Hjalmas 643 1 2 Mod. H

Willscher 388+ 223 342 P-L 338/342

Hirsch 368 61 91 Unknown 84/91

Broaddus 359 40 73 P-L 73/73 6/6 28/28 15/15 13/13 2/2

Rabinowitz 332 54 80 TH 25/25 25/25

So 313 52 87 Mix G-A, P-L 82/87

Funke 310 142 176 L-G 168/176

Atwell 305 112 106 P-L 106/106 14/14 16/16 43/43 33/33

Arap 304 300 520 L-G 514/520 29/29 307/307 184/184

Ahmed 301 205 296 C 294/296 13/13 101/101 119/121 61/61

Carson 300 200 Unknown 194/200

Mundy 286 73 80 Mix P-L,C 80/80

Elo 284 49 P-L 47/49

Brockrath 256 11 13 U 11/13

Fort 255 63 Mix,G-A,P-L,C,H 47/50

Govan 418 61 105 H 88/105

Govan 418 P-L 14/17

Burns 488 15 U 6/6

Burns 488 H 7/91L-G = Lich-Gregoir; P-L = Politano-Leadbetter; C = Cohen (transtrigonal); G-A = Glenn-Anderson; K = Kalicinski; D = Detrusorrhaphy; TH = Tailoring Hendren; P = Paquin; G-V = Gil-Vernet; U = Ureterostomy; H = Hutch





Lee 687 23 P-L for duplex 18/23

Scholtmeijer 685 49 Unknown 46/49 1/2 3/3 6/10 21/23 6/7

Sargin 680 30 30 MixP-L,G-A,C,P, 30/30 12/12 18/18

Allen 462 20 29 Mod. G-L 18/19

Mc Rae 443 39 63 Mix H,P,L-P 40/53

McGregor 417 4 Unknown 4/4

Amar 401 111 Mod. P-L 109/111

Brown 93 51 79 C 75/76 18 18 15/15 40/3

Johnston 426 17 29 TH 16/29

Peratoner 204 38 50 Unknown 50/50 2/2 17/17 31/31

Ginalski 150 141 229 Mix P-L, C 229/229 10/1 87/87 106/106 26/26

Nasrallah 205 9 16 Unknown 4/16

Fehrenbaker 4 16 Unknown duplic 13/16

Marra 969 3 3 Unknown 3/3 1/1 2/21L-G = Lich-Gregoir; P-L = Politano-Leadbetter; C = Cohen (transtrigonal); G-A = Glenn-Anderson; K = Kalicinski; D = Detrusorrhaphy; TH = Tailoring Hendren; P = Paquin; G-V = Gil-Vernet; U = Ureterostomy; H = Hutch

TABLE E-2. GRADE V REFLUX: RESOLUTION AFTER OPEN SURGERY

Author/ Number Number Surgical SurgicalPapyrus # of of Procedure1 Success Grade V/

Patients Patients (Ureters) Total

Johnston 426 17 29 TH 16/29

Rabinowitz 332 54 80 TH 25/25 25/25

Oezem 798 11 11 Starr Plic 5/11 5/11

Hanna 288 13 22 TH 21/22 21/22

Retik 356 8 9 TH 9/9

Maggiolo 254 15 28 TH 24/28 24/28

Ehrlich 120 31 K 31/31

Total 118 210 131/155 75/86

Percent 84.50% 87.2

1TH = Tailoring Hendren; K = Kalicinski


TABLE E-3. RESOLUTION OF REFLUX AFTER OPEN SURGERY



Scholtmeijer 685 49 Unknown 46/49 1/2 3/3 6/10 21/23 6/7

Brown 93 51 79 C 75/76 18 18 15/15 40 3

Ahmed 301 205 296 C 294/296 13/13 101/101 119/121 61/61

Burbige 678 33 C 33/33

Wacksman 246 36 52 C 51/52 5/5 6/6 24/24 11/11 5/6

Ahmed 252 28 38 C 37/38 4/4 12/12 21/22

Ehrlich 267 135 229 C 226/229 74 102 53

Carpentier 272 100 C 97/100 12 55 25 8 0

Faure 274 136 272 C 270/272

Pypno 124 43 80 C 80/80 6 53 10

Kondo 135 32 64 C 57/57 12/12 45/45

Scott 157 56 97 C 52/56

Glassberg 184 60 101 C 101/101 1/1 10/10 23/23 32/32 35/35

Total 815 1408 85/89 1288/1301 19/19 117/117 185/187 116/116 61/63

Percent 95.50% 99% 100% 100% 98.90% 100% 96.80%

Politano-Leadbetter Procedure

Lee 687 23 P-L for duplex 18/23

Govan 418 P-L 14/17

Elo 284 49 P-L 47/49 5/6 28 8/9

Atwell 305 112 106 P-L 106/106 14/14 16/16 43/43 33/33

Broaddus 359 40 73 P-L 73/73 6/6 28/28 15/15 13/13 2/2

Willscher 388+396 223 342 P-L 338/342

Bettex 497 27 29 P-L 25/29

Garrett 566 58 96 P-L 95/96

Burbige 678 37 P-L 37/37

Scott 377 163 Mod. P-L 157/163

Harty 294 35 35 L-P 35/35 2/2 6/6 23/23

Wachsman 348 P-L 10/10 62/67 50/54

Hagberg 222 13 15 P-L 14/15

Carpentier 272 200 100 P-L 88/100 8 46 31 10 5

Sutton 96 22 22 P-L 22/22 1/1 8/8 13/13

Remzi 183 89 143 P-L 118/143

Total 1091 961 259/272 928/978 32/32 118/124 139/143 67/68 2/2

Percent 95.20% 94.90% 100% 95.20% 97.20% 98.50% 100%

Lich-Gregoir Procedure

Zaontz 129 79 120 D 111/120 57/58 42/47 12/15

Breuhl 117 146 190 L-G 188/190 46 106 32 6

Hampel 383 51 83 L-G 78/83

Wacksman 660 202 D 202/202 1/1 63/63 112/112 22/22 4/4

Allen 462 20 29 Mod. G-L 18/19

Arap 304 300 520 L-G 514/520 29/29 307/307 184/184





Funke 310 142 176 L-G 168/176

Houle 658 45 65 D 62/65 6/6 16/16 23/23 13/14 4/6

Hohenfellner 96 L-G 92/96

Marberger 347 371 429 L-G 419/429

McDuffie 372 51 78 L 73/76

Beetz 42 189 242 L-G 238/242

Linn 51 60 101 L-G 55/60

Total 1550 2235 165/175 2053/2013 36/36 443/4431 361/361 47/51 8/10

Percent 94.30% 97.60% 100% 100% 100% 92.20% 80%

Gil-Vernet Procedure

Solok 105 14 22 G-V 18/22 4/4 9/9 4/5 1/4

Carini 181 14 G-V 13/14 3/3 8/9 2/2

De Gennaro 688 47 69 G-V 68/69 25/25 39/39 3/4

Kliment 586 60 96 G-V 54/60

Total 162 187 67/74 86/91 29/29 48/48 7/9 1/4

Percent 90.50% 94.50% 100% 100% 77.70% 25%

Paquin Procedure

Wachsman 348 Paquin 8/8 7/7 misc. 10/19

Parrott 403 253 Paquin 253/253

Total 253 253/253

Percent 100%


TABLE E-4. STUDIES OF OBSTRUCTION AFTER OPEN SURGERY

Study Rate Estimate (95% (By ureter) Confidence Interval)

Orikasa, 1990 0/92 0.000 (0.000, 0.032)

Ehrlich, 1985 1/78 0.013 (0.000, 0.039)

Bellinger and Duckett, 1984 7/338 0.021 (0.007, 0.038)

Hagberg, Hjalmas, Jacobsson, et al., 1984 1/15 0.067 (0.000, 0.206)

Maggiolo, Lockhart, and Politano, 1983 0/28 0.000 (0.000, 0.105)

Carpentier, Bettick, Hop, et al., 1982 3/200 0.015 (0.001, 0.036)

Ahmed and Tan, 1982 11/304 0.036 (0.016, 0.060)

Arap, Abrao, and Menezes-de-Goes, 1981 5/520 0.010 (0.002, 0.020)

Broaddus, Zickerman, Morrisseau, et al., 1978 4/73 0.055 (0.009, 0.119)

Hampel, Richter-Levin, and Gersh, 1977 0/83 0.000 (0.000, 0.036)

Willscher, Bauer, Zammuto, et al., 1976 4/342 0.012 (0.002, 0.026)

Govan, Fair, Friedland, et al., 1975 8/105 0.076 (0.028, 0.135)

Jonas, Many, Boichis, et al., 1974 3/150 0.020 (0.002, 0.048)

Garrett and Switzer, 1966 4/96 0.042 (0.007, 0.090)

Duckett, Walker, and Weiss, 1992 0/154 0.000 (0.000, 0.019)

Wacksman, Gilbert, and Sheldon, 1992 0/211 0.000 (0.000, 0.014)

Burbige, 1991 1/180 0.006 (0.000, 0.021)

Bradic, Batinica, and Husar, 1988 10/824 0.012 (0.005, 0.021)

Sutton and Atwell, 1989 3/36 0.083 (0.007, 0.197)

Pypno, 1987 0/80 0.000 (0.000, 0.037)

Zaontz, Maizels, Sugar, et al., 1987 0/120 0.000 (0.000, 0.025)

Birmingham Reflux Study Group, 1987 0/107 0.000 (0.000, 0.028)

Kondo and Otani, 1987 2/100 0.020 (0.000, 0.056)

Ehrlich, 1982 0/229 0.000 (0.000, 0.013)

Faure, Ben-Salah, dEscoffier, et al., 1982 1/272 0.004 (0.000, 0.011)

Mundy, Kinder, Joyce, et al., 1981 0/17 0.000 (0.000, 0.171)

Hanna, 1981 1/22 0.045 (0.000, 0.139)

McDuffie, Litin, and Blundon, 1977 1/78 0.013 (0.000, 0.039)

Johnston and Farkas, 1975 3/33 0.091 (0.008, 0.214)

Ravasini and Pagano, 1973 0/37 0.000 (0.000, 0.080)

Allen, 1973 0/29 0.000 (0.000, 0.102)

Hjalmas, Lohr, Tamminen-Mobius, et al., 1992 8/237 0.034 (0.012, 0.060)

Houle, McLorie, Heritz, et al., 1992 0/65 0.000 (0.000, 0.046)


TABLE E-5. STUDIES OF REOPERATION FOR OBSTRUCTION

Study Rate Estimate (95% (By ureter) Confidence Interval)

Ehrlich, 1985 1/78 0.013 (0.000, 0.039)Bellinger and Duckett, 1984 7/338 0.021 (0.007, 0.38)Hagberg, Hjalmas, Jacobsson, et al., 1984 1/15 0.067 (0.000, 0.206)Ahmed and Tan, 1982 1/304 0.003 (0.000, 0.010)Broaddus, Zickerman, Morrisseau, et al., 1978 4/73 0.055 (0.009, 0.119)Govan, Fair, Friedland, et al., 1975 6/105 0.057 (0.016, 0.110)Jonas, Many, Boichis, et al., 1974 3/150 0.020 (0.002, 0.048)Garrett and Switzer, 1966 4/96 0.042 (0.007, 0.090)Burbige, 1991 1/180 0.006 (0.000, 0.021)Bradic, Batinica, and Husar, 1988 10/824 0.012 (0.005, 0.021)Sutton and Atwell, 1989 3/36 0.083 (0.007, 0.197)Hanna, 1981 1/22 0.045 (0.000, 0.139)Johnston and Farkas, 1975 3/33 0.091 (0.008, 0.214)Hjalmas, Lohr, Tamminen-Mobius, et al., 1992 7/237 0.030 (0.009, 0.055)


Index

AAntibiotic prophylaxis (continuous), 13

duration of, 51harms of, 3, 41–43outcomes of, 1–2, 20–28research priorities for, 57with anticholinergics, 2, 13with bladder training, 2, 13, 23, 26with bladder training and anticholinergics,

2, 13, 26Antibiotics

intermittent therapy with, 1, 13during pregnancy, 38–39resistance to, 36

Anticholinergics. See Antibiotic prophylaxis

BBacteriuria. See Urinary tract infectionBirmingham Reflux Study, 2, 4, 11, 17, 32,

33, 34–35Bladder injury

after open surgery, 45Bladder training, 13, 23, 26, 57 See also

Antibiotic prophylaxisBleeding, 44

CCircumcision

relationship to urinary tract infection, 57Compliance with treatment, 36Contralateral reflux, 3

after open surgical or endoscopic repair,45–46

research priorities for, 57Cystitis. See Urinary tract infection (UTI)Cystogram (radionuclide), 12Cystography, 7, 12, 15, 47–48, 52Cystometry (evocative), 7, 12, 52 Cystoscopy, 7, 12, 52Cystourethrogram (voiding, VCUG), 12

DDeath attributable to vesicoureteral reflux, 41Diagnosis, 12Drug reactions

to antibiotics, 3, 41–42to anticholinergics, 42–43

EEndoscopic surgery, 14

harms of, 3, 43–44outcomes of, 2, 29–31relationship to outcomes during pregnancy,

39–41research priorities for, 57status of, 7, 30, 52

End-stage renal disease (ESRD). See UremiaEvidence matrix, 21. See also Vesicoureteral

Reflux Clinical GuidelinesExcretory urography. See Intravenous pyelography

FFollow-up evaluation, 7, 14–15, 52

adverse effects of, 46–48

GGrades, reflux, 10–11, 17, 22Grade V reflux

research priorities for, 57Growth

Renal, 2, 34-35Somatic, 3, 38

HHarms

from medical treatment, 41–43from surgery, 43–46

Hospitalizationwith medical treatment, 43with open surgery, 46–47with endoscopic surgery, 46for pyelonephritis, 43

Hypertension, 3, 37–38risks during pregnancy, 38–41

IInfection, after open surgery, 44Imaging studies

limitations of, 12, 14–15, 31, 34research priorities for, 57risks of, 46–48

Intermittent antibiotic therapy. See Antibiotics,intermittent therapy

International Reflux Study in Children, 1, 2, 4,23, 26, 31–32, 35, 36–37, 53, 58

Intravenous pyelography (IVP), 12

KKidney. See Renal

LLiterature

limitations of, 4, 17–18

MMedical therapy. See Antibiotic prophylaxis

OObstruction, ureteral, 3, 43–44

after open surgery, 43–44after endoscopic surgery, 43–44

Open surgery, 14harms of, 3, 43–46outcomes of, 2relationship to outcomes during pregnancy,

39–41research priorities for, 57

Outcomesanalysis of, 1, 20–48harms, 3, 20–21, 41–48health outcomes, 2–3, 20–21, 36–41intermediate outcomes, 1–2, 20–36

PPain

management in children, 46postoperative, 46

Parental and patient preferences and concerns,ii, 7, 51, 52, 53

Pregnancy, 3, 38–41research priorities for, 57

Pyelonephritis, I, 2–3, 36–37. See also Urinarytract infection

diagnosis of, 57hospitalization for, 16, 43prevention of, 13relationship to vesicoureteral reflux, 9,

11–12, 20and renal scarring, 30–34, 56risk after treatment, 4, 49, 53risk during pregnancy, 38–41, 53

QQuality of data, 21–22

RRadiation exposure data, 48Radiologic evaluation. See Follow-up

evaluation and Imaging studiesRecommendations, 3–4, 5–7, 49–55

assumptions for, 4, 49–50classifications of, 3–4, 16 methods and definitions of, 3–4, 16rationale for, 4, 49, 52–53

Reflux. See Vesicoureteral refluxRenal cortical scintigraphy, 12Renal function, 2, 35–36

relationship to renal scarring, 35–36risks during pregnancy, 38–41

Renal scarring, 2, 30–34, 56detection of, 31relationship to bacteriuria, 33–34relationship to hypertension, 30, 36–37, 38relationship to pyelonephritis, 36–37relationship to renal function, 35–36risks during pregnancy, 38–41

Research priorities, 8, 56–58Resolution of vesicoureteral reflux, 1–2, 20,

22–30, 56with duplicated systems, 26, 29–31with endoscopic repair, 29–30with medical therapy, 1–2, 20–26with open surgical repair, 2, 26, 29with voiding dysfunction, 25–28

SScarring. See Renal scarringScreening for vesicoureteral reflux, 57Socioeconomic factors, 57Southwest Pediatric Nephrology Study Group, 2Surgery. See Open surgery and Endoscopic

surgerySurveillance. See Follow-up evaluation

TTreatment alternatives. See specific treatments

description of, 1, 13–14, 49

U

Ultrasonography, 12Uremia, 3

risks during pregnancy, 38–41


Ureterovesical junction, 10Urethral dilation, 7, 52Urethrotomy (internal), 7, 52Urinalysis, 7, 15, 46, 52Urinary tract infection (UTI), 2–3, 36–37. See

also Pyelonephritisrelationship to circumcision, 57during pregnancy, 38–41relationship to renal scarring, 33–34relationship to uremia, 38

Urine culture, 15, 52Urodynamic evaluation, 7, 12, 52UTI. See Urinary tract infection

VVesicoureteral reflux

background of, 9 classification of, 10–11follow-up evaluation for, 7, 52diagnosis of, 12genetics of, 10, 57grades of, 10–11in neonates, 12natural history of, 9–10pathophysiology of, 11–12, 56prevalence of, 9primary vs. secondary, 9screening for, 57

Vesicoureteral Reflux Clinical Guidelinesanalytic process, 19assumptions for, 4, 49–50

data extraction for, 17dataset analysis, 2, 18, 22evidence matrix, 18–19literature searches used in, 16–18methodology for, 1, 16–19panel selection and diversity, i–iiquality of data, 21–22

Voiding dysfunction, 1, 2, 4, 49and bladder trabeculation, 12and evaluation for reflux, 7, 52after open surgery, 44–45relationship to morbidity, 41and renal growth, 35role in reflux, 8, 56-57treatment for, 13–14, 22–23, 25–28, 50and urinary tract infection, 3

Stephanie MenshDirector

Suzanne Boland PopeGuidelines Coordinator

Julie BowersGuidelines Assistant

Kim HagedornHealth Policy Projects Coordinator

Robin HudsonHealth Policy Projects Secretary

American Urological Association, Inc.

This report on the Management of Primary Vesicoureteral Reflux was developed by thePediatric Vesicoureteral Reflux Clinical Guidelines Panel of the American Urological Association, Inc.

This report is intended to furnish to the skilled practitioner a consensus of clear principles and strategies for quality patient care, based on current professional literature, clinical experienceand expert opinion. It does not establish a fixed set of rules or define the legal standard of care,pre-empting physician judgment in individual cases.

An attempt has been made to recommend a range of generally acceptable modalities of treatment, taking into account variations in resources and in patient needs and preferences. It is recommended that the practitioner articulate and document the basis for any significant deviation from these parameters.

Finally, it is recognized that conformance with these guidelines cannot ensure a successful result. The parameters should not stifle innovation, but will, themselves, be updated and willchange with both scientific knowledge and technological advances.

Board of Directors (1996 – 1997)

Practice Parameters, Guidelines and Standards Committee (1996 – 1997)

Health Policy Department Staff and Consultants

Jack W. McAninch, MD*Roy J. Correa, Jr., MD*Charles F. McKiel, Jr., MD*William R. Turner, Jr., MD*Winston K. Mebust, MD*Thomas P. Ball, Jr. MD*Dennis J. Card, MD*Joseph C. Cerny, MD*

Joseph W. Segura, MD, ChairIan M. Thompson, Jr., MD, Vice-ChairRodney A. Appell, MDHanan Bell, PhD, Methodology

ConsultantReginald C. Bruskewitz, MDCurtis Colby, Medical Editor

Consultant

Jack S. Elder, MDThomas C. Fenter, MD, ConsultantPatrick M. Florer, Database ConsultantJohn B. Forrest, MDCharles E. Hawtrey, MD, ConsultantJack W. McAninch, MD, Ex-officioJohn D. McConnell, MD, ConsultantSharron L. Mee, MD

Winston K. Mebust, MD, Ex-officioDrogo K. Montague, MDGlenn M. Preminger, MDClaus G. Roehrborn, MD, FacilitatorLinda D. Shortliffe, MD, ConsultantJoseph A. Smith, MDWilliam R. Turner, Jr., MD, Ex-officio

Theresa Lincoln__________________

Lisa EmmonsHealth Policy Manager

Tracy KielyHealth Policy Analyst

Betty WagnerHealth Policy Assistant

Megan CohenGovernment Relations Manager

Scott ReidGovernment Relations Policy Analyst

Roger WoodsGovernment Relations Assistant

Randolph B. FenningerWashington Liaison

Justine GermannLegislative Associate

William GlitzPublic Relations Consultant

Joseph N. Corriere, Jr., MDValentine A. Earhart, MDLloyd H. Harrison, MD*J. Logan Holtgrewe, MDLawrence W. Jones, MD*Harry E. Lichtwardt, MDHarry C. Miller, Jr., MD*Martin I. Resnick, MD

Gerald Sufrin, MD*E. Darracott Vaughan, Jr., MDRobert S. Waldbaum, MD*G. James GallagherThomas D. BrockmanMelanie H. Younger

*Voting member

American Urological Association, Inc.1000 Corporate BoulevardLinthicum, Maryland 21090

ISBN 0-9649702-2-8

April 1997

Report on the M

anagement of P

rimary Vesicoureteral R

eflux in Children

the management of primary vesicoureteral reﬂux in children

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