How to PREDICT utility of AB prophylaxis in

children with VUR?

Giovanni MontiniPediatric Nephrology and Dialysis Unit

University of Milan

giovanni.montini@unimi.it

The old conceptThe old concept

G. Montini, I. Hewitt and K Tullus

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

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

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

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

Gonzalez Celedon PN 2007176 CAKUT children

Progression of CKD

Current Understanding of Febrile Urinary Tract Infections and Renal Scarring.

Montini G et al. N Engl J Med 2011

PREDICTing utility of AB Prophylaxis

1. Recurrence of febrile UTIs

6.7%

5.7%

8%

27.5%

42.8%

J De Bessa, J Urol 2015

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

Hoberman, NEJM 2014

71/126

toilet-

trained

children

VUR GRADE II-III = 80%

PREDICTing utility of AB Prophylaxis

1. Recurrence of febrile UTIs

2. Risk of new renal scarring

Montini et al 2008

Hoberman, NEJM 2014

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

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

THE PREDICT TRIAL

Antibiotic Prophylaxis and REnal Damage In Congenital

abnormalities of the kidney and urinary Tract

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

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

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)

Gut

Microbiota

BIOINFORMATICS

Genomics

Proteomics

Metabolomics

EUROPEAN GUIDELINES

BIOMARKERS

PREDICT

RANDOMIZED

CLINICAL

TRIAL

BIOBANK

PROJECT MANAGMENT

MONITORING

Clinical Practise

Registry

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)

STATE OF THE ART:

COUNTRIES

14

EUROPEAN

COUNTRIES

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

RANDOMIZED127

(33.7%)

NOT ELEGIBLE 206

ENROLLABLE PATIENTS 43

TOTAL SCREENED 376

376 PATIENTS 40 CENTERS 8 COUNTRIES

STATE OF THE ART:

SCREENED PATIENTS

PREDICTing utility of AB Prophylaxis

1. Recurrence of febrile UTIs

2. Risk of new renal scarring

Current Understanding of Febrile Urinary Tract Infections and Renal Scarring.

Montini G et al. N Engl J Med 2011