Urinary tract infections in children with CAKUT and introduction of the PREDICT trial Giovanni Montini, Bologna, Italy.

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1 Urinary tract infections in children with CAKUT and introduction of the PREDICT trial Giovanni Montini, Bologna, Italy

2 Causes of CKD (n=1197) Heredithary nephropathies 15.4% Others 13.2% Hypodysplasia and VUR 24.7% PUV 10.2% HUS 3.6% Glomerulopathies 6.8% Other uropathies Hypodysplasia 12.2% 13.9% ItalKid 2003

3 Age at diagnosis of vesicoureteral reflux (as cumulative percent) by sex in children with CRF (n:187) Cumulat ive % mont hs 2 3 3, , ,5 9, Age at diagnosis of VUR years males f emales ItalKid 2002

4 176 CAKUT children Gonzalez Celedon PN 2007

5 Outcome renal function Recruited children 3479 Prevalence of patients with impaired renal function: 0-56% 1029 children included in 8 prospective studies; of the 55 children with CKD at the end of follow-up, only in 4 (0.4%) renal function was normal at start. Almost all children with a decreased renal function at the end of follow-up showed scars or hypodysplastic kidneys at start. Toffolo A, Acta Paediatrica 2012

6 The old concept G. Montini, I. Hewitt and K Tullus

7 RANDOMIZED STUDIES Surgery vs Prophylaxis The International Reflux Study in Children (1981) The Birmingham study (1983) The London study (2001) Overall favorable outcome. No difference in progression of existing scarring (9%) or new scarring (2%).

11 Outcome for GFR from the plasma clearance of 51Cr-EDTA at 4 and 10 years follow-up Medical Surgical t0 GFR 72.4 (24.1) 71.7 (22.6) n t4 years GFR 70.2 (26.3) 73.7 (24.9) n t10 years GFR 68.3 (29.8) 74.1 (35.6) n JM Smellie The Lancet, 2001

12 JM Smellie The Lancet, 2001

13 This study further supports earlier findings that most damage has already occurred at a very early stage and that severely damaged or dysplastic kidneys will either remain stable or progress to end-stage renal failure, despite all efforts to cure the reflux. Rien JM Nijman Lancet 2001

14 The old concept G. Montini, I. Hewitt and K Tullus

15 n = % 5.7% 8% 27.5% 42.8%

16 Antibiotic prophylaxis vs no antibiotic prophylaxis and VUR NNT 17 CI: 9 to 62 Journal of Paediatrics and Child Health 49 (2013)

17 BACKGROUND

18 BACKGROUND

19 BACKGROUND

20 May 4, 2014

21 VUR GRADE II-III = 80% Hoberman, NEJM 2014

22 RESULTS: PRIMARY ENDPOINT 111 children had 171 recurrences of UTI Of 111 first recurrences: 80 febrile (72,1%) P 0,002 P < 0,001 The risk of F/S UTI was reduced by half among children receiving prophilaxis vs placebo (hazard ratio 0,50; 95% CI 0,34 to 0,74) Hoberman, NEJM 2014

23 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

24 RESULTS p. NS p < 0,001 The treatment group had in excess of 600 years of prophylaxis without a demonstrable effect on scar formation but a much higher propensity to induce bacterial resistance

26 Current primary care management of children 1-36 months of age with urinary tract infections in Europe. Large scale survey. 1,129 paediatricians EAPRASnet: European Academy of Paediatrics Research in Ambulatory Setting Network in press

27 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

28 Previous studies Reflux grades of all RCTs of antibiotic prophylaxis VUR grade n I-II 777 III 577 IV 172 V 5 Total 2080

29 Previous studies Did not recruit children with hypo-dysplasia, at major risk for CRI and in whom post infectious scarring could have major adverse consequences Were not able to distinguish between primary renal damage and UTI-related scars as all children who entered the study had previous UTIs Prospective studies starting from the first months of life are missing In all previous studies long-term effects of recurrent UTIs on renal function have not been tested

30 THE PREDICT TRIAL Antibiotic Prophylaxis and REnal Damage In Congenital abnormalities of the kidney and urinary Tract Escape study group Nefrologia e Dialisi Pediatrica Policlinico Sant Orsola-Malpighi Bologna

31 STUDY DESIGN Prospectic, Controlled, Randomized, Open-label, Multicentric Trial PURPOSE: Evaluate the role of antibiotic prophilaxis in children with VUR grade III-V

32 OBJECTIVES PRIMARY: Effectiveness of antimicrobial prophylaxis in infants with VUR grade III- V, started before the first symptomatic infection. SECONDARY: 1. Role of symptomatic and febrile UTIs on the appearance and progression of kidney damage and development of renal function; 2. Natural history of renal function of paediatric patients with congenital kidney and high grade VUR during the first 5 years of life; 3. Natural evolution of VUR during the first 5 years of life and its correlation with UTIs, renal scars and impairment of renal function 4. Hypothetic role of antibiotic prophylaxis during the first months of life on BMI at 2 and 5 years of age.

33 INCLUSION CRITERIA Age >1 and <4 months(<20 wks) and gestational age > 35 weeks High Grade VUR (III-V) at the completed diagnostic work-up Glomerular Filtration Rate (Schwartz formula) > 15 ml/min/1.73 m 2 NO previous Urinary Tract Infections (UTIs) Informed Consenst EXCLUSION CRITERIA: Neurogenic bladder, myelomeningocele, uretero-pelvic junction and/or uretero-vescico junction obstruction, or other malformations leading to potential voiding disturbances, apart from urethral valves

34 Renal/urinary tract abnormalities (prenatal or postnatal US screening) PRE-RANDOMIZATION : US, cystography and DMSA 436 PATIENTS with VUR III-V GROUP A Follow-up RANDOMIZATION STRATIFICATION Renal damage; urethral valves GROUP B Antibiotic prophyplaxis 24 months (renal function, US + DMSA +/- cystography + BMI) 36 months FOLLOW-UP 60 months (renal function, US + DMSA + cystography + BMI)

35 PREDICT Trial: Procedures PROCEDURES Screening Enrollment 4 mo 8 mo 12 mo 18 mo 24 mo 36 mo 48 mo 60 mo Inclusion/exclusion criteria X Informed Consent X US X X X X X X X DMSA scan X X X Cystography X X c X d Randomization X Vital signs (clinical visit) X X X X X X X X X Blood Pressure X X X X X X X X X Urine analysis X X X X X X X X X Urine Culture X X X X X X X X X Antibiotic Prophylaxis a X X X X X X Compliance a X X X X X Adverse Events a X X X X X Renal function b X X X X X X CBC, ALT and AST X X X BMI X X X DNA Sample e Urine sample (frozen) X X X 24 hrs blood pressure X

36 ANTIBIOTIC PROPHYLAXIS Nitrofurantoin (1.5-2 mg/kg/day) Co-amoxiclav (15 mg/kg/day) Cefixime (2 mg/kg/day) Trimetropim/sulfametoxazole (2,5 mg/kg/die) ONCE DAILY AT EVENING According to the local antibiotic resistance pattern of E. coli Each single patient may switch from one antibiotic to another.

37 END POINTS Primary End point : symptomatic urinary tract infection rate during the first 24-month. Secondary End points: febrile UTIs, number of new renal scars at the 2 years follow-up DMSA scan, development of renal function, hypertension and/or proteinuria, anatomical growth of the kidneys at 2 and 5 years follow-up, evaluation of the natural course of renal function for hypo-dysplastic kidneys during the first 5 years of life and evaluation of BMI at 2 and 5 years of age.

38 F PARTICIPATING COUNTRIES

PREDICT: PARTICIPATING COUNTRIES COUNTRY (n centres) PROTOCOL ENROLMENT BELGIUM (2) SUBMITTED NO CZECH REPUBLIC (1) APPROVED In progress CROATIA (1) APPROVED In progress FRANCE (3) APPROVED In

39 PREDICT: PARTICIPATING COUNTRIES COUNTRY (n centres) PROTOCOL ENROLMENT BELGIUM (2) SUBMITTED NO CZECH REPUBLIC (1) APPROVED In progress CROATIA (1) APPROVED In progress FRANCE (3) APPROVED In Progress GERMANY (8) SUBMITTED NO HUNGARY (1) SUBMITTED NO ITALY (13) APPROVED YES LITHUANIA (2) APPROVED YES POLAND (11) APPROVED YES PORTUGAL (1) SUBMITTED NO SERBIA (2) APPROVED YES SPAIN (4) SUBMITTED NO SWEDEN (1) IN PROGRESS NO TURKEY (17) APPROVED YES AUSTRALIA (1) SUBMITTED NO

40 THE PREDICT TRIAL Antibiotic Prophylaxis and REnal Damage In Congenital abnormalities of the kidney and urinary Tract Giovanni Montini Nefrologia e Dialisi Pediatrica Policlinico Sant Orsola-Malpighi Bologna

Is antibiotic prophylaxis of any use in nephro-urology? Giovanni Montini Pediatric Nephrology and Dialysis Unit University of Milan Italy

Is antibiotic prophylaxis of any use in nephro-urology? Giovanni Montini Pediatric Nephrology and Dialysis Unit University of Milan Italy UTI_VUR Bacteria and Humans: diverse behaviours!! Bacteria Humans