VUR, UTI, and

Antibiotic
Prophylaxis

How to Use an Article About Therapy

or Prevention
Journal Club
Amy K Evans PGY2
August 15, 2006

The Case

Kali is a 14mo female who presents

to WRAMC ED with fever to 102.
Your stellar Peds Intern suggests
obtaining a UA/UCx, which results in
the diagnosis of acute
pyelonephritis.

The Case

Kali is a 14mo female who presents

to WRAMC ED with fever to 102.
Your stellar Peds Intern suggests
obtaining a UA/UCx, which results in
the diagnosis of acute pyelonephritis.
Kali is admitted to Wd51 for 48hrs of
IV abx, then, afebrile, discharged to
complete po course.

The Case

Kali is a 14mo female who presents to

WRAMC ED with fever to 102. Your stellar
Peds Intern suggests obtaining a UA/UCx,
which results in the diagnosis of acute
pyelonephritis.
Kali is admitted to Wd51 for 48hrs of IV
abx, then, afebrile, discharged to complete
po course.
She undergoes renal US and VCUG 3 weeks
later, which reveal grade II VUR on the left.

The Question

Should we treat her

prophylactically?

Short-term:

Will this decrease recurrent infections?

Long-term:
Will this decrease renal scarring?
Why else would it matter?

Background

Vesicoureteral Reflux (VUR)

Primary congenital incompetence
of VU valve (shortened submucosal
tunnel)
Secondary multiple anatomic
abnormalities

Background

Incidence 1-10%
Siblings 30-45% (3/4 asymptomatic)
Diagnosed via VCUG
UTI workup 40% (girls); 70% (infants
<1yo)
Antenatal hydronephrosis 9% (boys)

Why worry?

VUR pyelonephritis renal scarring

HTN, renal insufficiency, ESRD, pre-eclampsia

Background

Natural hx of VUR: spontaneous resolution

UTI VUR? VUR UTI?

VUR Pyelo?
VUR Scarring?

Current Treatment Recs

Workup:
Febrile UTI (any age)
UTI <5yo
UTI x2 in school-age
girls
UTI in any boy

Imaging:

To treat or not to
treat?

40% sensitive
(VUR)

VCUG

Renal US

Diagnostic!

DMSA

AUA Treatment
Guidelines

Grade Age (y)

Scarrin Treatmen
g
t
+/Abx
prophy

I-II

Any

III-IV

0-5

+/-

III-IV

6-10

+/-

<1

+/-

1-5

FollowUp
No
consens
us

Abx
Surgery
prophy
Unilat: abx Surgery
Bilat:
surgery
Abx
Surgery
prophy
Unilat: abx Surgery

Current Treatment Recs

AUA Pediatric VUR Guidelines Panel (1997)

The panel recommendations to offer

continuous abx prophylaxisare based on
limited scientific evidence. To our knowledge
controlled studies comparing the efficacy of
continuous prophylaxis and intermittent
therapy on health outcomeshave not been
performed.

No controlled studies?
Then what are we basing treatment on?

The State of the Art

Williams et.al. (2001)

Systematic review of RCTs on UTI/abx prophy
Five trials, 1968-1978
Best 2: 71 patients total, normal anatomy, 92%
girls

Garin et.al. (1998)

UTI VUR? no
VUR Pyelo?
VUR UTI? no
Degree VUR Scars?
VUR Scarring? no

We Need A Study That

Will help us decide whether or not to

prophylax this patient

Includes patients with symptomatic

VUR
Compares antibiotic prophylaxis to a
control
Looks at clinically important outcomes

Clinical significance of primary

vesicoureteral reflux and urinary
antibiotic prophylaxis after
acute pyelonephritis: a
multicenter, randomized,
controlled
study.
Garin EH, Olavarria F, Garcia Nieto V,
Valenciano B, Campos A, Young L.
Pediatrics 2006;117:626-632.

Study Questions

Does VUR correlate with UTI/renal

scarring?

Does antibiotic prophylaxis correlate

with UTI/renal scarring?

Study Design

Randomized, controlled, multicenter

trial
Inclusion:
3mo-18yo
Acute pyelonephritis

Exclusion:
Grade IV-V VUR
Anatomic abnormalities
Pregnancy

Study Design

Met inclusion criteria VCUG

VUR
Abx

No Abx

No VUR
Abx

No Abx

Pyelo treated: IV abx po for 14-day

course
Abx: TMP/SMX or nitrofurantoin for 1
year

Follow Up

At entry: UA/UCx, DMSA, VCUG, Renal

US
At Q3mo clinic visit: UA/UCx
At 6mo: DMSA
At 12mo: VCUG, Renal US

Endpoints:

Recurrent UTI
Renal scarring

Study Results

Analysis of Results

Fishers Exact Test

2x2 comparison tables
Control vs. variable
Smaller sample size
Gives p value
Does not give CI

Goal: p<.05!

http://www.childrensmercy.org/stats/ask/fish

Study Results

Recurrence of UTIs
Timing
Type

Recurrent Pyelonephritis & Antibiotics

Recurrent Pyelonephritis & VUR
Degree
Renal Scarring
VUR
Antibiotics

Study Results

Recurrence of
UTI

Overall 20.1%
VUR not significant
No abx (p=.9999)

VUR 22.4%
No VUR 23.3%

Abx (p=0.633)

VUR 23.6%
No VUR 8.8%

Type of
Recurrence

Cystitis (no p
value)

VUR 8.6%
No VUR 13.3%

Pyelonephritis
(p=.3781)

VUR 7.1%
No VUR 3.8%

Study Results

Recurrent Pyelo and Antibiotics

No benefit of abx (p=.0291)
7:1 abx:none

Recurrent Pyelo and VUR Degree

6/8 Grade III
(cystitis: 46%)
2/8 Grade II
(cystitis: 40%)
4/4 pts without VUR

Study Results

Renal Scarring

No evidence VUR increased scarring

(p=.9999)

VUR (6.2%) = No VUR (5.7%)

Abx (7.0%) = No Abx (5.1%)

Grade I VUR 5.3% with scars

Grade II VUR 5.2%
Grade III VUR 13.5%

Study Conclusions

Mild/moderate VUR not associated

with UTI, pyelonephritis, or
scarring

Antibiotic prophylaxis not associated

with
UTI, pyeloneprhitis, or
scarring

Critically Evaluating
(JAMA Users Guide)

Are

the results valid?

What were the results?
Will the results help me to
take care of my patient?

Are the results valid?

Primary Guides

Was the assignment of patients to treatment

randomized? YES.
Were all who entered the study accounted
for?

Was follow-up complete?

NO. Enrolled 236, lost 18
Lost from what groups?
Would this change results?

Were patients analyzed in the groups assigned

to?

NO. Exclusion of noncompliants

Are the results valid?

Secondary Guides

Were pts, clinicians, & study

personnel blinded?

NO (no blinding to +/- VUR, abx; no

placebos)

Were groups similar at start, &

treated equally?

YES (age, gender, degree of reflux)

What were the results?

How large was the treatment effect?

ARR risk difference of variable vs. control

RRR variable reduced risk by Z% relative to that
occurring in control patients; bigger = better!

For example, in presence of VUR:

23.6% of those on abx developed UTI (X%)

22.4% without abx developed UTI (Y%)
ARR = X-Y = .236-.224 = .012
RRR = (1-Y/X)x100% = (1-.224/.236)x100% = 5.1%

What were the results?

How large was the treatment effect?

ARR/RRR not reported!

How precise was the estimated

treatment effect?
Confidence Intervals (CIs) not reported!
95% CI:

Range that includes the true RRR 95% of time

Positive? Negative? Zero?

Statistically vs. clinically significant results

What were the results?

POWER!

Ability of a study to detect a true difference

Directly related to sample size
1- ( = type II error)

Study powered to detect a clinically significant

difference of 20% (power 80%), 95% CI
Need 60/group = 240 subjects

Enrolled 236, Completed 218

POWER : research design :: SENSITIVITY :

diagnostic test

Will the results help me

take care of my patient?

Can the results be applied? YES.

Could Kali have been enrolled?

All clinically important outcomes considered?

YES.
Substitute endpoints vs. POEMS
Adverse effects on other outcomes

Are likely benefits worth potential harms/risks?

NNT = 1/ARR
Consider baseline risk without intervention

Criticisms:

Study Population

What about <3mo?

Present earlier = Higher-grade reflux?
Already abx?
Included in study?

Exclusion of noncompliants?
Exclusion of pyelonephritis x2?
Initial presentation with cystitis?
Febrile UTI without DMSA changes?

How many therefore excluded?

Criticisms:

Study Design

DMSA as inclusion criteria (multicenter)?

Account for 18 lost before study end?
Unknown prognostic factors
Recalculate results assuming they did
well/poorly

Blinding of patients/personnel?
Placebo
Diagnosis

Larger sample size?

Criticisms:

Data Analysis

Reporting of CIs, ARR/RRR?

Magnitude/precision of treatment effect
Rule in/out effect different from Ho

Data crunching using Chi-Square?

Different data combinations?
Did not achieve POWER

Further Questions

UTI prophylaxis vs. intermittent

therapy?
And risk of renal scarring
Over time, given resolution VUR
Larger sample size

VUR in context of abnormal anatomy?

Mechanism of scarring in
pyelonephritis?
What else?

Back to our patient

What would you do?

Call Dr.Cartwright and Dr.Lechner

and get those patients enrolled!

References
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