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 Pyelo?
■ VUR UTI? ■ VUR Scarring?
Current Treatment Recs
Workup:
Febrile UTI (any age) UTI <5yo UTI x2 in school-age girls UTI in any boy
Imaging:
Renal US
40% sensitive (VUR)
VCUG
Diagnostic!
DMSA
To treat or not to treat?
AUA Treatment Guidelines
Grade I-II III-IV III-IV V V V V Age (y) Any 0-5 6-10 <1 1-5 1-5 6-10 Scarring +/+/+/+/+ +/Treatment Abx prophy Abx prophy Unilat: abx Bilat: surgery Abx prophy Unilat: abx Bilat: surgery Surgery Surgery Follow-Up No consensus Surgery Surgery Surgery Surgery
Current Treatment Recs
AUA Pediatric VUR Guidelines Panel (1997)
“The panel recommendations to offer continuous abx prophylaxis…are based on limited scientific evidence. To our knowledge controlled studies comparing the efficacy of continuous prophylaxis and intermittent therapy on health outcomes…have 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 UTI? no VUR Scarring? no
■ VUR Pyelo? ■ Degree VUR Scars?
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
Fisher’s 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/fishers.asp
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)
Type of Recurrence
Cystitis (no p value)
VUR – 8.6% No VUR – 13.3%
VUR – 22.4% No VUR – 23.3% VUR – 23.6% No VUR – 8.8%
Pyelonephritis (p=.3781)
Abx (p=0.633)
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)
YES (age, gender, degree of reflux)
Were groups similar at start, & treated equally?
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-β (β = 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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Atala A, Keating MA. Vesicoureteral reflux and megaureter. In Campbell’s Urology Vol 2, 7th ed. Philadelphia: WB Saunders 1988. Behrman Re, Kliegman RB, Jenson HB. Nelson Textbook of Pediatrics, 17th ed. Philadelphia: Saunders, 2004. Biggi A et.al. Prognostic value of the acute DMSA scan in children with first urinary tract infection. Pediatr Nephrol 2001;16:800-804. Bjorgvinsson E, Majd M, Eggli KD. Diagnosis of acute pyelonephritis in children: comparison of sonography and 99mTc-DMSA scintigraphy. Am J Roentgenol 1991;157(3):539-543. Dawson B, Trapp RG. Basic and clinical biostatistics, 3rd ed. New York: Lange Medical Books 2001. DeSadeeler C et.al. A multicenter trial on interobserver reproducibility in reporting on 99mTc-DMSA planer scintigraphy: a Belgian survey. J Nucl Med 2000;41(1):23-26. Elder JS et.al. Pediatric vesicoureteral reflux guidelines panel summary report on the management of primary vesicoureteral reflux in children. J Urol 1997;157(5):18461851. Garin EH et.al. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics 2006;117:626-632. Garin EH, Campos A, Homsy Y. Primary vesicoureteral reflux: review of current concepts. Pediatr Nephrol 1998;12:249-256.
References
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Gordon I et.al. Primary vesicoureteral reflux as a predictor of renal damage in children hospitalized with urinary tract infection: a systematic review and metaanalysis. J Am Soc Nephrol 2003;14:739-744. Guyatt GH et.al. How to use an article about therapy or prevention. A. Are the results of the study valid? JAMA 1993;270:2598-2601. Guyatt GH et.al. How to use an article about therapy or prevention. B. What were the results and will they help me in caring for my patients? JAMA 1994;271:59-63. Lee RS et.al. Antenatal hydronephrosis as a predictor of postnatal outcome: a metaanalysis. Pediatrics 2006;118(2):586-593. Penido Silva JM et.al. Clinical course of prenatally detected primary vesicoureteral reflux. Pediatr Nephrol 2006;21:86-91. Schwab CW et.al. Spontaneous resolution of vesicoureteral reflux: a 15-year perspective. J Urol 2002;168:2594-2599. Williams G et.al. Antibiotics for the prevention of urinary tract infection in children: a systematic review of randomized controlled trials. J Pediatr 2001;138(6):868-874. Yu RN, Roth DR. Treatment of vesicoureteral reflux using endoscopic injection of nonanimal stabilized hyaluronic acid/dextranomer gel: initial experience in pediatric patients by a single surgeon. Pediatrics 2006;118(2):698-703.