1. 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

2. 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?
So now that we’ve discussed the epidemiology and pathogenesis of UTIs, let’s proceed to a case and answer some specific questions using the best evidence found in the literature.

3. 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; , 1999)

4. 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; , 1999)

5. Age at First UTI
Conway, P. H. et al. JAMA 2007;298:

6. Screening for VUR No recommendations on how to manage 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; , 1999)
No recommendations on how to manage VUR

7. Management of VUR Scarring at Dx No Yes Age Initial F/U < 1
Proph Abx
III-V: Surgery
1-5
B/L grade V: Surgery
V: Surgery
6-10
B/L grade III-IV or U/L V: Surgery
III-IV: Surgery
(AUA, Report on The Management of Primary VUR in Children, Journal of Urology, May, 1997.)

8. Management of VUR
Scarring at Dx No
Yes
Age
Initial
F/U
< 1
Proph Abx
III-V: Surgery
1-5
B/L grade V: Surgery
V: Surgery
6-10
B/L grade III-IV or U/L V: Surgery
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.)

9. Current Conceptual Model

10. What is the evidence to support current model of diagnosing and treating VUR in children after UTI?

11. 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 there
Broyer 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):
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):

12. Observational Studies
Conway, P. H. et al. JAMA 2007;298:

13. Incidence Rates and Follow-up
Incidence Rate of First UTI: /person-year
Similar to previous estimates
Incidence Rate of Recurrent UTI after first UTI: 0.12/person-year
Significantly lower than previous estimates of % 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 days

15. Conway, P. H. et al. JAMA 2007;298:

16. Conway, P. H. et al. JAMA 2007;298:

17. Conway, P. H. et al. JAMA 2007;298:

18. Conway, P. H. et al. JAMA 2007;298:

19. 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

20. Types of censoring Subject does not experience event of interest
Incomplete follow-up
Lost to follow-up
Withdraws from study
Dies
X = dies

21. 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

22. No. (%) with Recurrent UTI
Clinical Trials
No. (%) with Recurrent UTI
Author, Journal, Year
Abx
No Abx
RR (95% CI)
Savage, Lancet, 1975
7/29 (24%)
4/32 (13%)
1.9 ( )
Garin, Pediatrics, 2006
13/55 (24%)
12/58 (21%)
1.1 ( )
Roussey, JU, 2008
18/103 (17%)
32/122 (26%)
0.7 ( )
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.

23. 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.

24. What’s a pediatrician/parent to do?

25. 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

26. 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.

27. 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

28. Dysfunctional Elimination Treatment
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 28

29. “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

30. DMSA Renal Scans
Normal
APN
Renal Scarring 30

31. Renal Scarring on DMSA

32. Dilating VUR (Grades 3-5)
Normal DMSA
Abnormal DMSA
No VUR 36 64
VUR 1-2 5 16
VUR 3-5 21
Normal DMSA
Abnormal DMSA
No VUR
133
105
VUR 1-2 7 18
VUR 3-5 1 26

33. “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

34. “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.

35. 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.

36. DMSA results in the acute phase and day of treatment
Doganis, D. et al. Pediatrics 2007;120:e922-e928
Copyright ©2007 American Academy of Pediatrics

37. Refer to RIVUR study
Randomized Intervention for Children with VesicoUreteral Reflux
CMH KC Site PI: Dr. Uri Alon

38. 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

39. 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

40. Time Line Recruitment started July 2007 2 years of recruitment
2 years of follow-up
Plan to recruit 600 patients

41. Endpoints Primary Secondary Recurrence of F/SUTI
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

42. Modified Conceptual Model
Prompt diagnosis and
Delayed UTI
treatment of UTI
End Stage Renal
diagnosis and
Disease
Prophylactic antibiotics
treatment
UTI ( s )
prevent recurrent UTI
Renal
UTI ( s )
Hypertension
Scarring
VUR
Congenital
Pre -
eclampsia
VUR and renal
dysplasia
VUR 42

43. Questions

44. International Classification of VUR44

45. Renal Ultrasound

46. Deflux

47. 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

48. 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.

49. Deflux: Capozza Deflux 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.

50. PIC VUR Recurrent febrile UTIs/ No VUR on conventional VCUG 30/30
Patients
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

51. 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.

52. International Reflux Study

53. Effectiveness of Interventions for VUR
Open surgical correction of VUR plus prophylactic antibiotics v. prophylactic antibiotics alone to prevent recurrent UTIs
Author, Journal, Year
RR recurrent UTI 2 years
RR recurrent UTI 5 years
Wheeler, ADC, 2003
(meta-analysis)
1.1 ( )
0.99 ( )

54. Effectiveness of Interventions for VUR
Open surgical correction of VUR plus prophylactic antibiotics v. prophylactic antibiotics alone to prevent renal scarring
Author, Journal, Year
RR new renal scars (2 years)
RR new renal scars (5 years)
Wheeler, ADC, 2003
(meta-analysis)
1.1 ( )
1.1 ( )
“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)

55. RIVUR Study

56. Definitions Appropriately treated UTI
Antibiotic therapy continues for a minimum of 7 days AND:
There is documented sensitivity of the organism to the antibiotic used for treatment OR
There is a documented test of cure (negative urine culture) 1-14 days after initiation of therapy.

58. 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).

59. Definitions
Fever
Documented temperature of at least °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

60. 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

61. X

62. 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 ( )
Hoberman, NEJM, 2003
15% 6%
2.4 ( )
Garin, Pediatrics, 2006
1.1 ( )

63. 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)
Decreasing rates of renal scarring possibly due to increased awareness and earlier Dx and Rx of UTIs in febrile infants?

64. 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.