how to predict utility of ab prophylaxis in children with vur
TRANSCRIPT
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How to PREDICT utility of AB prophylaxis in
children with VUR?
Giovanni MontiniPediatric Nephrology and Dialysis Unit
University of Milan
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The old conceptThe old concept
G. Montini, I. Hewitt and K Tullus
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Guidelines Antibiotic prophylaxis Others interventions
NICE
Not for routine use
Treat dysfunctional elimination syndromes and constipation
Drink an adequate amount of fluid Do not delay voiding
AAP
Not for routine use Not considered
ISPN
For reflux III-V Recurrent febrile UTI*
Not considered
* ≥3 febrile UTIs within 12 months
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Causes of CKD in children (n=1197)
Hypodysplasia and VUR24.7%
PUV
10.2%
Glomerulopathies
6.8% Other uropathies12.2%
Hypodysplasia13.9%
Others13.2%
Heredithary
nephropathies
15.4%
HUS
3.6%
ItalKid 2003
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VUR and CKD in children
• Incidence of VUR + CKD: 3-4
children/year/one million of pediatric
population (Italkid)
• Incidence of VUR: 10000/year/one million
of pediatric population
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0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12
months
Cu
mu
lati
ve
%
2 3 3, 5 4 5 6 6, 5 7 8 8, 5 9, 5 10 11 12
years
males
f emales
Age at diagnosis of VUR
Age at diagnosis of vesicoureteral reflux (as cumulative percent) by sex in children with CRF
(n:187)
ItalKid 2002
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Gonzalez Celedon PN 2007176 CAKUT children
Progression of CKD
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Current Understanding of Febrile Urinary Tract Infections and Renal Scarring.
Montini G et al. N Engl J Med 2011
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PREDICTing utility of AB Prophylaxis
1. Recurrence of febrile UTIs
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6.7%
5.7%
8%
27.5%
42.8%
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J De Bessa, J Urol 2015
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RESULTS: primary endpoint
The treatment proved statistically significant, but of doubtful clinical
value: requiring 16 or 22 patient years of antibiotics to prevent 1 UTI
or 1 febrile UTI, respectively
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Hoberman, NEJM 2014
71/126
toilet-
trained
children
VUR GRADE II-III = 80%
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PREDICTing utility of AB Prophylaxis
1. Recurrence of febrile UTIs
2. Risk of new renal scarring
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Montini et al 2008
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Hoberman, NEJM 2014
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Reflux grades of all RCTs of antibiotic prophylaxis
VUR grade n
0 549
I-II 777
III 577
IV 172
V 5
Total 2080
Previous studies
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TRIAL MALE (%) FEMALE (%)
Garin, 2006 40/178 (18%) 178/218 (82%)
Pennesi, 2008 48/100 (48%) 52/100 (52%)
Montini, 2008 104/338 (31%) 234/338 (69%)
Roussey-Kesler, 2008 69/225 (31%) 156/225 (69%)
Craig, 2009 207/576 (36%) 369/576 (64%)
Brandstrom, 2010 75/203 (37%) 128/203 (63%)
Hoberman, 2014 49/607 (8%) 558/607 (92%)
SEX DISTRIBUTION IN UTIs TRIALS
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THE PREDICT TRIAL
Antibiotic Prophylaxis and REnal Damage In Congenital
abnormalities of the kidney and urinary Tract
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PREDICT Trial: DESIGN
Prospectic, Controlled, Randomized, Open-label, Multicentric Trial
PURPOSE: To study the role of antibiotic prophylaxis in children with VUR grade III-
V
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PREDICT Trial:INCLUSION/EXCLUSION CRITERIA
INCLUSION CRITERIA
•Age 1 - 4 months (until the 20th week of post-natal age!)
•Gestational age > 35 weeks
•GFR (according to Schwartz) > 15 ml/min/1.73 m2
•Grade III to V vesico-ureteral reflux
•No previous symptomatic UTI
EXCLUSION CRITERIA
- Neurogenic bladder - Myelomeningocele- Uretero-pelvic junction and/or uretero-vescico junction obstruction- Malformations leading to potential voiding disturbances
- Urethral valves
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326 (���� 436 )PATIENTS with VUR III-V
36 months FOLLOW-UP
STRATIFICATION
Renal damage
CAKUT (prenatal or postnatal US screening)
PRE-RANDOMIZATION
renal function, US, VCUG and DMSA
GROUP B
Antibiotic
prophylaxis
GROUP A
Follow-up
RANDOMIZATION
24 months (renal function, US + DMSA +/- VCUG+ BMI)
60 months (renal function, US + DMSA + VCUG+ BMI)
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Gut
Microbiota
BIOINFORMATICS
Genomics
Proteomics
Metabolomics
EUROPEAN GUIDELINES
BIOMARKERS
PREDICT
RANDOMIZED
CLINICAL
TRIAL
BIOBANK
PROJECT MANAGMENT
MONITORING
Clinical Practise
Registry
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Aims:
- explore the modification in gut microbiota induced by antibiotic
exposure in early infancy
- Modifications in the pattern of resistance genes coded by gut
microbiota (gut resistome profile).
GUT MICROBIOTA
collect and freeze a
STOOL SAMPLE
from every patient
8 time points:
(0, 4, 8, 12, 24, 36, 48, 60 m)
New Partner: Dr MARCO CANDELA (Bologna, ITALY)
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STATE OF THE ART:
COUNTRIES
14
EUROPEAN
COUNTRIES
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STATE OF THE ART
STATE OF THE STUDY COUNTRIES
APPROVED
AND
ENROLLING
(8 COUNTRIES)
FRANCE, ITALY, LITHUANIA, POLAND,
PORTUGAL, SERBIA, TURKEY, AUSTRALIA
APPROVED
NOT ENROLLING
(6 COUNTRIES)
BELGIUM, CROATIA, CZECH REPUBLIC,
GERMANY, SPAIN, SWEDEN
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RANDOMIZED127
(33.7%)
NOT ELEGIBLE 206
ENROLLABLE PATIENTS 43
TOTAL SCREENED 376
376 PATIENTS 40 CENTERS 8 COUNTRIES
STATE OF THE ART:
SCREENED PATIENTS
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PREDICTing utility of AB Prophylaxis
1. Recurrence of febrile UTIs
2. Risk of new renal scarring
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Current Understanding of Febrile Urinary Tract Infections and Renal Scarring.
Montini G et al. N Engl J Med 2011