Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract (PREDICT)

September 26, 2023 updated by: Giovanni Montini, Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico

The exact role of urinary tract infection in the appearance of chronic kidney disease is unclear. Children with congenital malformations of kidney and urinary tract have the higher risk of impairment of renal function. To understand if the use of antibiotic prophylaxis can reduce the risk of urinary tract infection in children with these malformations, this study will randomize children in two groups. Group A will not take antibiotic prophylaxis, Group B will take antibiotic prophylaxis for 2 years. This study will assess if antibiotic prophylaxis reduce the risk of urinary tract infections in these children and if urinary tract infections influence the appearance of renal damage.

Our hypothesis is that prophylaxis reduce the risk of infection in severe vesicoureteral reflux and that urinary tract infections, in morphologically normal kidneys, will not result in chronic renal failure.

Study Overview

Status

Active, not recruiting

Conditions

Intervention / Treatment

Detailed Description

Bacterial urinary tract infections (UTI) are common in young children. The presence of fever is considered to be a marker of renal parenchymal involvement. Renal damage during the acute phase of infection may lead to scarring, yet the role that scarring plays in the appearance of chronic kidney failure is unknown. It is also unclear what influence scars have on the natural course of kidney function, especially in children with renal hypodysplasia, with or without vesicoureteral reflux (VUR). Renal hypodysplasia is the most common cause for dialysis and transplantation in the pediatric population.

Patients suffering from recurrent UTIs and VUR have often undergone corrective surgery. For many years, it was also thought necessary to prescribe long-term antibiotic prophylaxis to all children with VUR. These treatment strategies were based on the ideas and opinions of the experts, rather than on hard scientific evidence. As regards the prevention of recurrent UTIs and the subsequent development of renal scarring, a long-term international study on Reflux was not able to demonstrate that surgical correction is more effective than antibiotic prophylaxis. Very little data is available regarding the use of long-term antibiotic prophylaxis in children with high grade reflux with or without renal hypodysplasia.

The use of antibiotics during the first few months of life has been associated with a significant increase in body mass index (BMI). Even though this effect is probably limited, it could have a significant impact on public health given the widespread use of antibiotics and due to the considerable increase in cases of pediatric and adult obesity seen over the last few years.

In spite of the lack of evidence, the use of prophylaxis is largely routine practice in most centres. Therefore, a randomized study is necessary in order to evaluate whether prophylaxis reduces the risk of symptomatic infections and subsequent renal damage.

To assess the role of prophylaxis in patient with high grade vesicoureteral reflux we will perform a multicentre, prospective, randomized, controlled, open-label, study.

Patients enrolled will be randomized in two groups:

Group A: no antibiotic prophylaxis. Group B: antibiotic prophylaxis for 24 months. The choice of which antibiotic to prescribe from the list below is left to the discretion of each investigator, on the basis of local antibiotic resistance patterns.

nitrofurantoin 1.5-2 mg/kg per day
amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicillin)
cefixime 2 mg/kg per day
trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)

The study is comprised of:

Phase 1: Pre-randomization - screening tests to determine eligibility for the trial.
Phase 2: Active treatment - this phase follows randomization and foresees 24 months of antibiotic prophylaxis for Group B and clinical surveillance for Group A.
Phase 3: Follow-up - a further 36 months of clinical, laboratory and instrumental evaluation of renal function and the progression of renal damage for a total follow-up period of 5 years

Study Type

Interventional

Enrollment (Actual)

292

Phase

Phase 3

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

Italy
- - Milan, Italy, 20122
    - Pediatric Nephrology Dialysis and Transplant Unit IRCCS Ca'Granda

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

1 month to 4 months (Child)

Accepts Healthy Volunteers

Description

Inclusion Criteria:

Age between 1 and 4 months (> 4 weeks and <20 weeks of post-natal age)
Gestational age > 35 weeks
Glomerular filtration rate (calculated according to Schwartz) > 15 ml/min/1.73 m2
No previous symptomatic UTI
Imaging Diagnostic work-up completed and presence of grade III to V vesicoureteral reflux
Informed consent of parents

Exclusion Criteria:

Age <1 and >4 months
Gestational age < 35 weeks
Glomerular filtration rate (calculated according to Schwartz) < 15 ml/min/1.73 m2 at three months of age
Patients with neurogenic bladder, myelomeningocele, ureteropelvic junction and/or ureterovesical junction obstruction, or other malformations leading to potential voiding disturbances.
Presence of urethral valves
Patients with no or low grade reflux (grade I and II).
Hypersensitivity to the all the utilized antimicrobial agent
Children with serious clinical conditions which, according to the investigator, prevent them from being included in the study cohort.
Use of experimental drugs in the month previous to the beginning of the study
Children unable to follow the established protocol procedures or whose parents are unable to sign the informed consent.

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

Primary Purpose: Prevention
Allocation: Randomized
Interventional Model: Parallel Assignment
Masking: None (Open Label)

Number of Arms

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Active Comparator: ANTIBIOTIC PROPHYLAXIS Children in this arm will take antibiotic prophylaxis for 2 years. Patients in this arm will do clinical/instrumental follow-up for 5 years. The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day Amoxicillin-Potassium Clavulanate Combination 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)	Drug: nitrofurantoin antibiotic prophylaxis of urinary tract infections The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim) Other Names: Furadantin Drug: Amoxicillin-Potassium Clavulanate Combination antibiotic prophylaxis of urinary tract infections The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim) Other Names: amoxicilline/clavulanic acid, augmentin, clavulin Drug: Trimethoprim/sulfamethoxazole antibiotic prophylaxis of urinary tract infections The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim) Other Names: bactrim Drug: Cefixime antibiotic prophylaxis of urinary tract infections The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs Physicians can chose one the following schedules: nitrofurantoin 1.5-2 mg/kg per day amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicilline) cefixime 2 mg/kg per day trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim) Other Names: cefixoral
Experimental: NO PROPHYLAXIS Children in this arm will not take antibiotic prophylaxis. Patients in this arm will do clinical/instrumental follow-up for 5 years	Other: No prophylaxis children will be followed, but no antibiotic prophylaxis will be administered

Participant Group / Arm

Intervention / Treatment

Active Comparator: ANTIBIOTIC PROPHYLAXIS

Children in this arm will take antibiotic prophylaxis for 2 years. Patients in this arm will do clinical/instrumental follow-up for 5 years.

The antibiotic for prophylaxis will be chosen by Physicians according to the local resistance spectrum of bacteria responsible of UTIs