Diagnosis and Management of VUR after first UTI Ron Keren, MD, MPH Division of General Pediatrics...

Diagnosis and Management of VUR

after first UTI

Ron Keren, MD, MPH

Division of General Pediatrics

Center for Pediatric Clinical Effectiveness

Children’s Hospital of Philadelphia

Case

• 2.5 year old old white girl with 3 days of:– Fever (Tmax = 40°C) – Poor appetite– Fussiness– 2 loose stools a day

• Urine dip shows moderate leukocyte esterase• Treatment with PO TMP/SMZ initiated• Urine culture (cath specimen) grows >105 E. coli• Child defervesces in 2 days and completely well in 3

days.• Next steps?

Screening for VUR

• Infants and children 2 months to 2 years with initial UTI should have either a VCUG or RNC performed to detect the presence and severity of VUR. (Strength of evidence: fair)

(AAP, Practice Parameter: The Diagnosis, Treatment, and Evaluation of the Initial UTI in Febrile Infants and Young Children, Pediatrics, 103:4; 843-852, 1999)

Age at First UTI

0 - 2 years39%

2 - 6 years61%

Conway, P. H. et al. JAMA 2007;298:179-186.

Screening for VUR

• Infants and children 2 months to 2 years with initial UTI should have either a VCUG or RNC performed to detect the presence and severity of VUR. (Strength of evidence: fair)

(AAP, Practice Parameter: The Diagnosis, Treatment, and Evaluation of the Initial UTI in Febrile Infants and Young Children, Pediatrics, 103:4; 843-852, 1999)

No recommendations on how to manage VUR

Management of VURScarring at Dx

No Yes

Age Initial F/U Initial F/U

< 1 Proph Abx III-V: Surgery Proph Abx III-V: Surgery

1-5 Proph Abx

B/L grade V: Surgery

III-V: Surgery V: Surgery III-V: Surgery

6-10 Proph Abx

B/L grade III-IV or U/L V: Surgery

III-IV: Surgery Proph Abx


III-IV: Surgery

(AUA, Report on The Management of Primary VUR in Children, Journal of Urology, May, 1997.)

Management of VURScarring at Dx

No Yes

Age Initial F/U Initial F/U

< 1 Proph Abx III-V: Surgery Proph Abx III-V: Surgery

1-5 Proph Abx

B/L grade V: Surgery

III-V: Surgery V: Surgery III-V: Surgery

6-10 Proph Abx


III-IV: Surgery Proph Abx


III-IV: Surgery

“The recommendations, which generally lack empirical scientific support, reflect the clinical experience and opinion of the panel.”

(AUA, Report on The Management of Primary VUR in Children, Journal of Urology, May, 1997.)

Current Conceptual Model

UTI(s)

VUR

RENALSCARRING

End Stage Renal Disease

Pre-eclampsia

Hypertension

Prophylactic antibiotics prevent recurrent UTI

Surgery corrects VUR

Figure 3. Conceptual Model

What is the evidence to support current model of diagnosing and

treating VUR in children after UTI?

Ecological Evidence• Analyses of dialysis and transplant

registries• Expect reduction in incidence of end

stage renal disease attributable to reflux nephropathy following the diagnosis and treatment of VUR started in the 1960’s

• Not thereBroyer M, Chantler C, Donckerwolcke R, Ehrich JH, Rizzoni G, Scharer K. The

paediatric registry of the European Dialysis and Transplant Association: 20 years' experience. Pediatr Nephrol. Dec 1993;7(6):758-768.

Fenton S, Desmeules M, Copleston P, et al. Renal replacement therapy in Canada: a report from the Canadian Organ Replacement Register. Am J Kidney Dis. Jan 1995;25(1):134-150.

Observational Studies


Incidence Rates and Follow-up

• Incidence Rate of First UTI: 0.007/person-year – Similar to previous estimates

• Incidence Rate of Recurrent UTI after first UTI: 0.12/person-year – Significantly lower than previous estimates of 21- 48%

recurrence with follow-up of 6-12 months

• Mean observation time was 408 days with a median of 310 days (IQR 150 – 584 days), range of 24 - 1600 days

Survival Analysis

• Outcome is time to an event (e.g. death, recurrent infection)

• Observation time varies from one subject to another– Different quantity– Different start and stop times

• Censoring

Types of censoring

• Subject does not experience event of interest

• Incomplete follow-up– Lost to follow-up– Withdraws from

study– Dies

Hazard Ratio

• The hazard ratio in survival analysis is the effect of an explanatory variable on the hazard or risk of an event.

• Consider hazard ratio to be an estimate of relative risk

Clinical Trials

Author, Journal, Year Abx No Abx RR (95% CI)

Savage, Lancet, 1975 7/29 (24%) 4/32 (13%) 1.9 (0.6-5.9)

Garin, Pediatrics, 2006 13/55 (24%) 12/58 (21%) 1.1 (0.6-2.3)

Roussey, JU, 2008 18/103 (17%) 32/122 (26%) 0.7 (0.4-1.1)

Garin: Up to age 18 years, febrile UTI, grades 1-3 VUR, unblinded

Roussey: 1 mo – 3 years, febrile UTI, grades 1-3 VUR, unblinded

In Garin study, recurrent acute pyelo seen in 7/55 (abx) v. 1/58 (placebo) (p=0.03) raising specter of INCREASED risk of APN with prophylactic antibiotics.

No. (%) with Recurrent UTI

Systematic Review

“The evidence to support the widespread use of antibiotics to prevent recurrent symptomatic UTI is weak. Large randomized, double blinded studies are needed…”

Williams et al, Long-term antibiotics for preventing recurrent UTIs in children. Cochrane Database of Systematic Reviews 2006, Issue 3.

What’s a pediatrician/parent to do?

Maintain Status Quo

• Absence of evidence is not evidence of absence of benefit

• Continue to screen all children for VUR after first UTI

• Continue antibiotic prophylaxis for children with VUR until VUR resolves

• Conservative, one size fits all approach

Individualize Care

• 3 y.o. girl with first afebrile UTI concurrent with potty training vs…

• 5 mo. girl with febrile UTI requiring hospitalization; history of other febrile illnesses that got better with antibiotics; mother with duplicated collecting system and h/o bilateral grade 4 VUR that never completely resolved.

Consider Dysfunctional Elimination

• Abnormal elimination pattern (frequent/infrequent voids, urgency, constipation)

• Bladder/bowel incontinence• Withholding maneuvers• Underdiagnosed and undertreated• 40% 1st UTI; 80% recurrent UTI• Treatment decreases UTI recurrence and

speeds resolution of VUR

• Scheduled voids q 2-3 hours• Treat constipation

– Laxatives– Increase fluid intake

• Avoid bladder irritants– Caffeine, food coloring, chocolate, citrus, carbonation

• Urology referral– Further evaluation– Biofeedback for pelvic floor muscle training– Anticholinergics

Dysfunctional Elimination Treatment

“Top Down” Imaging Approach

• You don’t need VUR to develop kidney scars after UTI

• If you have a normal DMSA scan with a febrile UTI, you are VERY unlikely to have high grade (>3/5) VUR

APN Renal ScarringNormal

DMSA Renal Scans

Renal Scarring on DMSA

0%5%

10%15%20%25%30%35%40%45%

Rushton 1992

Jakobsson 1994

Hoberman 2003

Garin 2006

VUR No VUR

Dilating VUR (Grades 3-5)

0%

5%

10%

15%

20%

25%

Tseng 2007 Preda 2007

Normal DMSA Abnormal DMSA

Normal DMSA

Abnormal DMSA

No VUR 36 64

VUR 1-2 5 16

VUR 3-5 0 21

Normal DMSA

Abnormal DMSA

No VUR 133 105

VUR 1-2 7 18

VUR 3-5 1 26

“Top Down” Approach

• Perform DMSA within 30 days of UTI• Normal: reassure parents that kidneys

are normal and child unlikely to have dilating VUR skip the VCUG

• Abnormal: obtain VCUG, consider antibiotics v. surgery if VUR present, repeat DMSA in 4-6 months to diagnose scars

“Top Down” Approach

• Spares a lot of children a VCUG (48% in Preda study)

• DMSA less than half the radiation of a VCUG

• DMSA less invasive than a VCUG• DMSA gives information about the

health of the kidneys, which can be followed over time.

No Work-up

• Defer work-up until 2nd or 3rd UTI• Heightened vigilance

– Educate on early signs and symptoms– Emphasize need for rapid diagnosis– Treat dysfunctional elimination– ?Provide urine collection kits and dip sticks

• Likely that early diagnosis and treatment will prevent most UTI-related scarring.

Copyright ©2007 American Academy of Pediatrics

Doganis, D. et al. Pediatrics 2007;120:e922-e928

DMSA results in the acute phase and day of treatment

Refer to RIVUR study

• Randomized Intervention for Children with VesicoUreteral Reflux

• CMH KC Site PI: Dr. Uri Alon

Study Design• NIDDK funded (U01 contract)• Multi-center

– 15 Clinical Trial Centers across the US– Data Coordinating Center at UNC Chapel Hill

• Randomized Placebo Controlled Trial• Initial UTI, presence of grades I-IV VUR• Effect of prophylactic TMP/SMZ on:

– Recurrent UTI– Renal scarring– Antimicrobial resistance

Inclusion Criteria

• 2 months – 6 years at time of randomization

• Diagnosed 1st or 2nd F/SUTI within 16 weeks prior to randomization

• Presence of Grade I- IV VUR on VCUG

Time Line

• Recruitment started July 2007

• 2 years of recruitment

• 2 years of follow-up

• Plan to recruit 600 patients

Endpoints

• Primary– Recurrence of F/SUTI

• Secondary– Time to first recurrence of F/SUTI– Renal scars on DMSA scan– Stool E. coli resistant to TMP/SMZ– Recurrent F/SUTI caused by TMP/SMZ

resistant organisms

Modified Conceptual Model

VUR

RenalScarring

End Stage Renal Disease

Pre -eclampsia

Hypertension

Prompt diagnosis and treatment of UTI

Prophylactic antibiotics prevent recurrent UTIUTI(s)

VUR

UTI (s)

Congenital VUR and renal

dysplasia

Delayed UTI diagnosis and

treatment

Questions

International Classification of VUR

Renal Ultrasound

Deflux

Endoscopic Correction of VUR

• Deflux procedure– Endoscopic injection of bulking agent

(Dextranomer/hyaluronic acid) into submucosal layer of bladder just beneath or within the ureteric orifice.

– “Minimally invasive” compared with open surgery– Day surgery– Requires sedation

Deflux: Capozza• >1 y.o • Grades II-IV VUR persistent for at least 6

months• Randomly assigned (2:1) to:

– Dextranomer/Hyaluronic Acid (n = 40)– Prophylactic abx (n = 21)

• 12 months later 69% v. 38% (p=0.03) had bilateral grade I or less VUR.

• 11 (25%) needed 2nd injection at month 3, only 2 successful

Capozza, N, Dextranomer/hyaluronic acid copolymer implantation for VUR: a randomized comparison with antibiotic prophylaxis, J Pediatr, 2002 Feb; 140(2):230-4.

Deflux: CapozzaDeflux Proph abx p-value

Recurrent UTI 6/40 (15%) 0/21 (0%) 0.08

New renal scars*

3/80 (4%) 1/42 (2%) 0.6

Renal scars healed*

11/80 (14%) 7/42 (16%) 0.4

Parenchymal kidney damage*

1/40 (3%) 3/21 (14%) 0.11

*As determined by renal US, not DMSA.

PIC VURPatients Renal Units Interpretation

Recurrent febrile UTIs/ No VUR on conventional VCUG

30/30 48/60(all 48 ureteral orifices lateral

and/or patulous)

“Explains” recurrent UTIs

No febrile UTIs/ No VUR on conventional VCUG

0/15 0/30(all 30 ureteral orifices normal

appearing)

Doesn’t show VUR in kids with no h/o UTI

Recurrent febrile UTIs/ VUR on conventional VCUG

12/12 20/24(all 20 ureteral orifices lateral

and/or patulous)

Shows VUR in kids with h/o UTI

PIC VUR

• Invasive – Requires general anesthesia and instrumentation of bladder

• Specificity needs confirmation – 0/15 does not mean no false positives

• % children with febrile UTI found to have PIC VUR after negative VCUG fell to 82% in small prospective validation study (Edmonson, Urol, 2006)

• No evidence that treating those found to have PIC VUR prevents recurrent UTI or renal scarring.

International Reflux Study

Effectiveness of Interventions for VUR

Author, Journal, Year RR recurrent UTI 2 years

RR recurrent UTI 5 years

Wheeler, ADC, 2003

(meta-analysis)

1.1 (0.6-2.1) 0.99 (0.8-1.3)

Open surgical correction of VUR plus prophylactic antibiotics v. prophylactic antibiotics alone to prevent recurrent UTIs

Effectiveness of Interventions for VUR

Author, Journal, Year RR new renal scars (2 years)

RR new renal scars (5 years)

Wheeler, ADC, 2003

(meta-analysis)

1.1 (0.3-3.4) 1.1 (0.8-1.5)

Open surgical correction of VUR plus prophylactic antibiotics v. prophylactic antibiotics alone to prevent renal scarring

“It is not clear whether any intervention for children with primary VUR does more good than harm. Well designed and adequately powered placebo controlled randomized trials of antibiotics alone in children with VUR are now required.” (Wheeler et al, Antibiotics and surgery for VUR: a meta-analysis of RCTs, ADC, 2003)

RIVUR Study

Definitions

Appropriately treated UTIAntibiotic therapy continues for a minimum of 7

days AND:1) There is documented sensitivity of the

organism to the antibiotic used for treatment OR

2) There is a documented test of cure (negative urine culture) 1-14 days after initiation of therapy.

Febrile or SymptomaticUTI

Check Preliminary Eligibility Criteria

Complete Study Screening / Baseline Imaging

US(within 6 weeks of

index UTI)

VCUG(within 6 weeks of

index UTI)

RANDOMIZATION VISIT

1. Confirm Eligibility2. Treatment Phase Consent3. Randomize4. Baseline Data Collection5. Specimen Collection

Scheduled Follow-up Contacts

UTI Evaluation Visits(unscheduled visits)Calls

(Every 2 months)

Routine Visits6, 12, 18 months

Specimen Collection

END OF STUDY - EXIT EXAM24 months

1. Scheduled Data Collection2. Specimen Collection3. VCUG4. DMSA

Screening Phase

Treatment Phase

DMSA(If VUR; within 8 weeks of

index UTI)

Definitions

UTI• Pyuria on urinalysis

–>10 WBC/mm3 (uncentrifuged specimen) OR–>5 WBC/hpf (centrifuged specimen), OR–>1+ leukocyte esterase on dipstick

• Culture proven infection with a single organism

–>5 x 104 CFU/mL (catheterized or suprapubic aspiration urine specimen) OR

–>105 CFU/mL (clean voided specimen).

DefinitionsFever• Documented temperature of at least 100.4 °F (38

°C), measured anywhere on the body either at home or at doctor’s office

Symptoms• Suprapubic, abdominal, or flank pain or tenderness• Urinary urgency, frequency, hesitancy, or dysuria,

or foul smelling urine• In infants < 4 months old: failure to thrive,

dehydration, or hypothermia

Endpoints

Treatment Failures• Occurrence of 2 recurrent FUTIs within

the study period, OR • Total of 4 recurrent F/SUTIs within the

study period • Additional renal segment involvement at

12 mo. DMSA scan

Study Month Type of Contact

0 (Visit)

Randomization/ Baseline

6 month (Visit)

Follow-up

12 month (Visit)

Follow-up

18 month (Visit)

Follow-up

24 month (Exit Visit) Follow-up

Every 2 months (Phone)

Follow-up

Informed Consent X

DMSA X* X

Contrast VCUG X

Medical History and Physical Examination

X X X X X

Questionnaires

Dysf Void Symp Score, PACCT (age>3),

QOL assessment X X X

Parent Questionnaire X X X X X

Randomization X

Study medication dispensation

X X X X

Study medication Accountability

X X X X X

Urine tests

Urinalysis, Culture**, Microalbumin/Creatinine, Urine for central Repository

X X

Blood tests

CBC with diff; Creatinine, lytes, SGOT, SGPT; Cystatin ; Blood for central Repository

X X

Rectal Swabs X X

Telephone Follow-up X

X

Renal Scarring

Author, Journal, Year VUR No VUR RR (95% CI)

Rushton, J Urol, 1992 40% 43% 0.9 (0.4-2)

Jakobsson, ADC, 1994 42% 19% 2.2 (1.3-3.8)

Hoberman, NEJM, 2003 15% 6% 2.4 (1.1-5.2)

Garin, Pediatrics, 2006 6% 6% 1.1 (0.4-3.1)

Renal Scarring Less Common

Author, Journal, Year N # (%) F/U

Rushton, J Urol, 1992 33 16 (48) 11 mo (mean)

Jakobsson, ADC, 1994 76 28 (37) 2 years

Stokland, J Peds, 1996 157 59 (38) 1 year

Hoberman, NEJM, 2003 275 26 (9) 6 mo

Garin, Pediatrics, 2006 118 6 (5) 1 year

Decreasing rates of renal scarring possibly due to increased awareness and earlier Dx and Rx of UTIs in febrile infants?

Potential Harms and Costs

• VCUG and RNC are invasive and cause physical discomfort and psychological distress.

• VCUG involves exposure to ionizing radiation.• Diagnosis of VUR and perceived risk of renal scarring

causes anxiety to patient and family.• Prophylactic antibiotics contribute to antimicrobial

resistance in the patient and the community.– Recurrent UTIs with bacteria resistant to Cefotaxime = 27%

in children receiving prophylactic antibiotics v. 3% in children not receiving them (RR=9.9; 95% CI [4-24.5]). (Lutter et al., Antibiotic resistance patterns in children hospitalized for UTIs, APAM, 2006)

• Costs of diagnosis and treatment potentially great.

Diagnosis and Management of VUR after first UTI Ron Keren, MD, MPH Division of General Pediatrics...

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