Prevention of UTI in Prevention of UTI in children with VU reflux: children with VU reflux:

management management controversiescontroversies

Moshe Efrat MDMoshe Efrat MDSeptember 2006September 2006

Vesicoureteral Reflux (VUR)Vesicoureteral Reflux (VUR)

Retrograde passage of urine from bladder to Retrograde passage of urine from bladder to upper urinary tractupper urinary tract

VUR = most common urologic abnormality VUR = most common urologic abnormality in kidsin kids

1% newborns1% newborns 30 - 45% of children with UTI30 - 45% of children with UTI

UTI (upper) = most common serious UTI (upper) = most common serious bacterial infection of children in the bacterial infection of children in the developeddeveloped world in the age of conjugate world in the age of conjugate pneumococcal and H. flu vaccines pneumococcal and H. flu vaccines (Israel is (Israel is not there yet!! – why?)not there yet!! – why?)

Two clinical presentations Two clinical presentations VURVUR

Prenatal: Prenatal: male > female, VUR diagnosed prenatally male > female, VUR diagnosed prenatally

(by US)(by US) Severe VUR commonSevere VUR common Significant rates spontaneous resolution, Significant rates spontaneous resolution,

butbut Renal hypoplasia and dysplasia frequentRenal hypoplasia and dysplasia frequent Increased risk renal failure and Increased risk renal failure and

hypertensionhypertension Postnatal: Postnatal:

Mostly femaleMostly female Presents as febrile UTIPresents as febrile UTI Spontaneous resolution is a function Spontaneous resolution is a function

of age and grade of age and grade and if 1 or 2 sidedand if 1 or 2 sided

VUR - gradingVUR - grading GRADINGGRADING — The International Reflux Study Group — The International Reflux Study Group

standardized grading the severity of VUR based on standardized grading the severity of VUR based on findings from a contrast voiding cystourethogram findings from a contrast voiding cystourethogram (VCUG).(VCUG).

Grade IGrade I — Reflux only fills the ureter without dilation. — Reflux only fills the ureter without dilation. Grade IIGrade II — Reflux fills the ureter and the collecting — Reflux fills the ureter and the collecting

system without dilation. system without dilation. Grade IIIGrade III — Reflux fills and mildly dilates the ureter and — Reflux fills and mildly dilates the ureter and

the collecting system with mild blunting of the calyces. the collecting system with mild blunting of the calyces. Grade IVGrade IV — Reflux fills and grossly dilates the ureter and — Reflux fills and grossly dilates the ureter and

the collecting system. One-half of the calyces are the collecting system. One-half of the calyces are blunted. blunted.

Grade VGrade V — Massive reflux grossly dilates the collecting — Massive reflux grossly dilates the collecting system. All the calyces are blunted with a loss of system. All the calyces are blunted with a loss of papillary impression and intrarenal reflux may be present papillary impression and intrarenal reflux may be present . There is significant ureteral dilation and tortuosity. There is significant ureteral dilation and tortuosity. .

Principles of managementPrinciples of management Premise:Premise: VUR can cause upper UTI by VUR can cause upper UTI by

bringing bacteria to the kidneysbringing bacteria to the kidneys Results:Results: renal scarring, loss of renal scarring, loss of

parenchyma parenchyma reflux nephropathyreflux nephropathy:: Potential for hypertension, Potential for hypertension,

decreased renal function, decreased renal function, proteinuria, renal failure/ end stage proteinuria, renal failure/ end stage renal diseaserenal disease

Management:Management: based on - based on - Identification of kids with VURIdentification of kids with VUR Prevention of renal damage due to Prevention of renal damage due to

refluxreflux

How to prevent damage due to How to prevent damage due to VUR VUR??

Medical vs surgical approachMedical vs surgical approach Not clear which is more effective!Not clear which is more effective! Medical: Medical:

VUR resolves spontaneously by age 4 -5 VUR resolves spontaneously by age 4 -5 yearsyears

Continuous antibiotics Continuous antibiotics sterile urine sterile urine VUR with sterile urine is VUR with sterile urine is assumedassumed benign benign

Most appropriate antibiotics: TMP-SMX, Most appropriate antibiotics: TMP-SMX, nitrofurantoinnitrofurantoinNot Not ββ-lactams!?!? Why? …-lactams!?!? Why? …

Increased bacterial resistanceIncreased bacterial resistance

More concerns about medical More concerns about medical therapytherapy

Long-term antibiotics may Long-term antibiotics may complicationscomplications: : minor to severe - including bone minor to severe - including bone

marrow suppression, Stevens-Johnson marrow suppression, Stevens-Johnson syndromesyndrome

AdherenceAdherence (compliance) (compliance) Breakthrough infectionBreakthrough infection Need to monitorNeed to monitor reflux with either VCUG reflux with either VCUG

or radionuclide cystography (RNC), or radionuclide cystography (RNC), bothboth with discomfort and radiationwith discomfort and radiation

The main controversyThe main controversy

Does antibiotic prophylaxis of kids Does antibiotic prophylaxis of kids with VUR with VUR reallyreally prevent recurrent prevent recurrent upper UTI and concomitant renal upper UTI and concomitant renal scarring?scarring?

Over the last 5-6 years this has been Over the last 5-6 years this has been increasingly questioned / debated increasingly questioned / debated and to a certain extent studied…and to a certain extent studied…

Antibiotic prophylaxis (ABP) - Antibiotic prophylaxis (ABP) - studiesstudies

Background: ABP recommended forBackground: ABP recommended for all all grades VURgrades VUR

Most studies to date: compare Most studies to date: compare [[ABP ABP withwith surgery surgery]] to ABP alone, or compare to ABP alone, or compare ABP with surgeryABP with surgery

Meta-analysis (Meta-analysis (Wheeler, et al, Arch Dis Child Wheeler, et al, Arch Dis Child

2003; 88:688-5942003; 88:688-594): 1 randomized, controlled ): 1 randomized, controlled study found no difference in UTI risk study found no difference in UTI risk with ABP, either continual or with ABP, either continual or intermittent, vs no ABPintermittent, vs no ABP

No large, randomized, prospective trials No large, randomized, prospective trials comparing ABP+ with ABP- in VUR!!!comparing ABP+ with ABP- in VUR!!!

AimsAims

Evaluate the role of VUR in affecting Evaluate the role of VUR in affecting frequency and severity of UTI and frequency and severity of UTI and renal scarring after APNrenal scarring after APN

Determine whether ABP reduces Determine whether ABP reduces frequency and/or severity of UTI frequency and/or severity of UTI and/or prevents renal parenchymal and/or prevents renal parenchymal damage in patients with mild-damage in patients with mild-moderate VUR (grades I, II, III moderate VUR (grades I, II, III onlyonly))

The studyThe study Randomized, controlled studyRandomized, controlled study N= 236 children, 3 months – 18 yearsN= 236 children, 3 months – 18 years APN = acute pyelonephritis: pyuria, APN = acute pyelonephritis: pyuria,

fever, positive culture (>10fever, positive culture (>1055) + DMSA ) + DMSA confirmationconfirmation

All tested for VUR by VCUG All tested for VUR by VCUG 2 groups: 2 groups: 113 VUR grades I-III and 115 no VUR113 VUR grades I-III and 115 no VUR After initial treatment for APN, both After initial treatment for APN, both

groups randomized: +/- antibiotic groups randomized: +/- antibiotic prophylaxis (ABP)prophylaxis (ABP)

Conclusion:Conclusion: antibiotics antibiotics do notdo not prevent APN nor renal scarring prevent APN nor renal scarring

in patients with mild or no in patients with mild or no VURVUR!!!!!!Results:Results:

Overall UTI recurrence 20.1%Overall UTI recurrence 20.1% - ABP:- ABP: recurrence 22.4% VUR, 23.3% no VUR recurrence 22.4% VUR, 23.3% no VUR

((NSNS)) +ABP:+ABP: recurrence 23.6% VUR, 8.8% no VUR recurrence 23.6% VUR, 8.8% no VUR

((NSNS, but close, p=0.63), but close, p=0.63) Most recurrences at 9-12 months, most cystitis Most recurrences at 9-12 months, most cystitis

(DMSA nl), APN only 5.5%(DMSA nl), APN only 5.5% No clear-cut advantage for +ABPNo clear-cut advantage for +ABP

All recurrences were with resistant All recurrences were with resistant bacteria!bacteria!

More APN in +VUR than in -VUR (8 vs 4, but More APN in +VUR than in -VUR (8 vs 4, but NSNS))

Results, continuedResults, continued 6/8 recurrent APN were in VUR grade III6/8 recurrent APN were in VUR grade III

2/8 in grade II, none in grade I2/8 in grade II, none in grade I 4 recurrences in non-VUR (2 ABP+, 2 ABP-)4 recurrences in non-VUR (2 ABP+, 2 ABP-)

Cystitis also VUR III, II >>VUR ICystitis also VUR III, II >>VUR I

Renal scars:Renal scars: Only 5.9% developed scars (1 year F/U only!)Only 5.9% developed scars (1 year F/U only!)

7 VUR+, 6 VUR- (7 VUR+, 6 VUR- (NSNS)) Similar scarring rates ABP+ and ABP- (Similar scarring rates ABP+ and ABP- (NSNS)) Increased scarring with increase grade VUR Increased scarring with increase grade VUR

((NSNS)) No difference in scarring in VUR vs non-VURNo difference in scarring in VUR vs non-VUR

Conclusions at 1 year endpointConclusions at 1 year endpoint:: 11 . .Antibiotics Antibiotics do notdo not prevent cystitis, prevent cystitis,

APNAPNor renal scarring in patients with mild to or renal scarring in patients with mild to

moderate or no VURmoderate or no VUR!!!!!!22 . .ABP ABP UTIs with resistant bacteria UTIs with resistant bacteria

3. ABP in VUR+ 3. ABP in VUR+ more APN than in more APN than in VUR- (VUR- (NSNS) )

The EditorialThe Editorial::

Fact or fantasy IFact or fantasy I The study is highly problematic:The study is highly problematic:

1 year follow-up only1 year follow-up only 1 year follow-up required, no ITT 1 year follow-up required, no ITT

analysis in those not completing 1 year analysis in those not completing 1 year Low incidence APNLow incidence APN Low rate renal scarringLow rate renal scarring Non-standardized ABP: Non-standardized ABP:

either trimethoprim-sulfamethoxazole either trimethoprim-sulfamethoxazole (TMP-SMX) or nitrofurantoin (TMP-SMX) or nitrofurantoin

no placebo given to controlsno placebo given to controls

Fact or fantasy IIFact or fantasy II Therefore, too few patients, too short a time Therefore, too few patients, too short a time

period, and maybe the period, and maybe the wrong populationwrong population (VUR I-III), maybe wrong antibiotics - to (VUR I-III), maybe wrong antibiotics - to reach conclusions of significance…reach conclusions of significance… Current study: trend for more UTI and Current study: trend for more UTI and

more scarring with increasing grades of more scarring with increasing grades of VUR…VUR… III > II > IIII > II > I

Important:Important: no evaluation of severe VUR no evaluation of severe VUR (grades IV, V) (grades IV, V) Therefore results are not applicable to Therefore results are not applicable to

these patients !these patients !

DiscussionDiscussion UTI pathogenesis related to bacterial UTI pathogenesis related to bacterial

binding to uroepithelial receptors binding to uroepithelial receptors No reason to think that VUR No reason to think that VUR

increases UTI incidence, but…increases UTI incidence, but… Reasonable to think that VUR Reasonable to think that VUR

increases APN (vs lower UTI) increases APN (vs lower UTI) incidence in those with propensity for incidence in those with propensity for UTI = trend but not significant in UTI = trend but not significant in some studiessome studies

Scarring is a function of APN and not Scarring is a function of APN and not sterile reflux: good evidence existssterile reflux: good evidence exists

ABP should prevent recurrent ABP should prevent recurrent UTI – few good data to support UTI – few good data to support

thisthis!! 2 potential barriers to successful ABP for 2 potential barriers to successful ABP for

UTI:UTI: AdherenceAdherence (compliance) difficult over (compliance) difficult over

years, also antibiotic adverse effects, years, also antibiotic adverse effects, though rare, increase with exposure though rare, increase with exposure timetimeMaybe recurrences mostly at 9-12 Maybe recurrences mostly at 9-12 months indicate decline in months indicate decline in adherence?adherence?

Emergence of Emergence of antimicrobial resistanceantimicrobial resistance

Which drugs are usedWhich drugs are used?? Nitrofurantoin or TMP-SMXNitrofurantoin or TMP-SMX

Theory:Theory: absorption high in the in GI tract - absorption high in the in GI tract - colon flora not “exposed” = protected from colon flora not “exposed” = protected from antibiotics antibiotics little induction of resistance little induction of resistance

ProblemProblem – are areas where TMP-SMX cannot – are areas where TMP-SMX cannot be used: high % GI flora resistant (be used: high % GI flora resistant (Israel?Israel?))

Other agents (e.g. Other agents (e.g. ββ-lactams) are theoretically -lactams) are theoretically poor choicespoor choices Colonic bacteria exposed to low AB levels Colonic bacteria exposed to low AB levels Within weeks Within weeks GI colonized primarily with GI colonized primarily with

bacteria inherently or newly resistantbacteria inherently or newly resistant

Another issueAnother issue

Is there any proof that Is there any proof that prevention of UTI by prevention of UTI by continuous ABP prevents continuous ABP prevents scarring better than very early scarring better than very early initiation of therapy for APN?initiation of therapy for APN?No studies performedNo studies performed

Possible solutionsPossible solutions?? Use Use rotating ABP schedulerotating ABP schedule parallel to parallel to

ABP for chronic lung disease, ABP for chronic lung disease, switching drug q2-4 weeksswitching drug q2-4 weeks

Few data for UTI, some potentially Few data for UTI, some potentially encouragingencouraging

Use Use non-antibiotic prophylaxisnon-antibiotic prophylaxis e.g. e.g. methenamine mandelatemethenamine mandelate When urine pH <6, methenamine When urine pH <6, methenamine

formic acid (like formaldehyde) formic acid (like formaldehyde)ProblemProblem: urine acidification : urine acidification requiredrequired

SuggestionsSuggestions?? Additional studies required:Additional studies required:

To clarify ABP use in VUR grades I,II, III To clarify ABP use in VUR grades I,II, III Larger, better designed, longer F/U, Larger, better designed, longer F/U,

ITT…ITT… To study VUR grades III, IV, VTo study VUR grades III, IV, V

Until new data:Until new data: For For allall ( (??) VUR (severe > moderate > ) VUR (severe > moderate >

mild), continue using ABP (or surgery for mild), continue using ABP (or surgery for high grade, non-resolving VUR)high grade, non-resolving VUR)

If TMP-SMX inappropriate If TMP-SMX inappropriate epidemiologically, maybe nitrofurantoin epidemiologically, maybe nitrofurantoin should be used > othersshould be used > others

What about previous What about previous studiesstudies??

Not a lot of dataNot a lot of data Good systematic review of data Good systematic review of data

available up to 2005…available up to 2005…

Our questions: antibiotics, yes Our questions: antibiotics, yes or no, which, and whenor no, which, and when??

Medical vs surgical therapy?Medical vs surgical therapy? Not clear!Not clear! Meta–analysis Meta–analysis ((Wheeler, et al, Arch Dis Wheeler, et al, Arch Dis

Child 2003; 88:688-594Child 2003; 88:688-594((:: found 7 found 7 randomized, controlled studies, ABP vs randomized, controlled studies, ABP vs surgery, n = 859surgery, n = 859 4 studies: no difference after 5 years4 studies: no difference after 5 years 2 studies: less febrile UTI, at 5 years, 2 studies: less febrile UTI, at 5 years,

surgery (10%) vs ABP (22%)surgery (10%) vs ABP (22%)But no difference in scarring!But no difference in scarring!

Meta-analysis, continuedMeta-analysis, continued 4 studies: no differences in scarring 4 studies: no differences in scarring

after 5 yearsafter 5 years5% overall risk of new scars by 5% overall risk of new scars by DMSADMSA

4 studies: no differences in renal 4 studies: no differences in renal growthgrowth

2 studies: no difference in hypertension 2 studies: no difference in hypertension or end-stage renal diseaseor end-stage renal disease

Lack of information about surgical vs Lack of information about surgical vs medical adverse events!!medical adverse events!!

ConclusionsConclusions

9 reimplantations required to prevent 9 reimplantations required to prevent 1 febrile UTI!1 febrile UTI!

No reduction in rate of renal scarring!No reduction in rate of renal scarring!

Hardly seems wise to prefer surgical Hardly seems wise to prefer surgical therapytherapy

Except?...Except?...

Rationale AUA guidelinesRationale AUA guidelines Low grade VUR, VUR in very young Low grade VUR, VUR in very young

kids kids good chance spontaneous good chance spontaneous resolution so prefer ABPresolution so prefer ABP

The older kids get or the higher grade The older kids get or the higher grade the VUR, ABP still recommended but the VUR, ABP still recommended but surgery is an option especially ifsurgery is an option especially if bilateral disease or renal scarring bilateral disease or renal scarring existsexists

Only in children ≥6 years old with Only in children ≥6 years old with grade V VUR is surgery preferred since grade V VUR is surgery preferred since the likelihood of spontaneous the likelihood of spontaneous resolution is very lowresolution is very low

If ABP follow-upIf ABP follow-up……

Close monitoring to identify Close monitoring to identify breakthroughbreakthrough

Urine-analysis and cultures Urine-analysis and cultures whenever UTI possiblewhenever UTI possible

Surveillance cultures q 3-4 monthsSurveillance cultures q 3-4 months RNC > VCUG monitoring of VUR ~ RNC > VCUG monitoring of VUR ~

yearlyyearly

So, in conclusionSo, in conclusion……

UntilUntil newnew data:data:For For allall ( (??) VUR (severe > ) VUR (severe >

moderate > mild)…moderate > mild)… continue using ABPcontinue using ABP

or surgery for high grade, or surgery for high grade, non-resolving VURnon-resolving VUR

Nitrofurantoin preferred!? Nitrofurantoin preferred!?

Thanks!Thanks!

Questions?Questions?Comments?Comments?Protests?Protests?