PREDICT: Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract
Study Details
Study Description
Brief Summary
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.
| Condition or Disease | Intervention/Treatment | Phase |
|---|---|---|
|
Phase 3 |
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.
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nitrofurantoin 1.5-2 mg/kg per day
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amoxicilline/clavulanic acid 15 mg/kg per day (dose expressed in units equivalent to amoxicillin)
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cefixime 2 mg/kg per day
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trimethoprim/sulfamethoxazole 2.5 mg/kg per day (dose expressed in units equivalent to trimethoprim)
The study is comprised of:
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Phase 1: Pre-randomization - screening tests to determine eligibility for the trial.
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Phase 2: Active treatment - this phase follows randomization and foresees 24 months of antibiotic prophylaxis for Group B and clinical surveillance for Group A.
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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 Design
Arms and Interventions
| 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:
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:
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:
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:
|
| 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
|
Outcome Measures
Primary Outcome Measures
- urinary tract infections rate [during the first 24 months from enrolment]
Urinary tract infections will be strictly monitored in all enrolled patients (both group A and group B). The rate of urinary tract infections in the first 24 months from the enrolment will be compared between 2 groups
Secondary Outcome Measures
- febrile urinary tract infections [during the first 24 months from enrolment]
Febrile urinary tract infections will be strictly monitored in all enrolled patients (both group A and group B). The rate of febrile urinary tract infections in the first 24 months from the enrolment will be compared between 2 groups
- renal scars [at 2 years and 5 years from enrolment]
the appearance of renal scars in a dimercaptosuccinic acid (DMSA) scan will be detected at 2 and 5 years from enrolment and compared between the 2 groups.
- serum creatinine (renal function) [at the enrolment,1 year, 2 years, 3 years, 4 years, 5 years]
The renal function (serum creatinine) will be monitored for all enrolled patients to explore the appearance and progression of renal damage
- hypertension [at 4, 8, 12, 18, 24, 36, 48, 60 months from enrolment]
the appearance of hypertension will be monitored at every visit in all enrolled children
- proteinuria [at 4, 8, 12, 18, 24, 36, 48, 60 months from enrolment]
the appearance of proteinuria will be monitored at every visit in all enrolled children
- body mass index [at 2 and 5 years from enrolment]
body mass index will be evaluated at 2 and 5 years of follow-up and it will be correlated to the use of antibiotic prophylaxis
- serum cystatin C (renal function) [at the enrolment,1 year, 2 years, 3 years, 4 years, 5 years]
The renal function (serum cystatin-C) will be monitored for all enrolled patients to explore the appearance and progression of renal damage
- modification in gut microbiota induced by continuous antibiotic exposure during the first months of life [at the enrollment, 4 months, 8 months, 12 months, 2 years, 3 years, 4 years, 5 years]
A stool sample will be collected, frozen and stored for gut microbiota and resistome profile analysis
Eligibility Criteria
Criteria
Inclusion Criteria:
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Age between 1 and 4 months (> 4 weeks and <20 weeks of post-natal age)
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Gestational age > 35 weeks
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Glomerular filtration rate (calculated according to Schwartz) > 15 ml/min/1.73 m2
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No previous symptomatic UTI
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Imaging Diagnostic work-up completed and presence of grade III to V vesicoureteral reflux
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Informed consent of parents
Exclusion Criteria:
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Age <1 and >4 months
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Gestational age < 35 weeks
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Glomerular filtration rate (calculated according to Schwartz) < 15 ml/min/1.73 m2 at three months of age
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Patients with neurogenic bladder, myelomeningocele, ureteropelvic junction and/or ureterovesical junction obstruction, or other malformations leading to potential voiding disturbances.
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Presence of urethral valves
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Patients with no or low grade reflux (grade I and II).
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Hypersensitivity to the all the utilized antimicrobial agent
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Children with serious clinical conditions which, according to the investigator, prevent them from being included in the study cohort.
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Use of experimental drugs in the month previous to the beginning of the study
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Children unable to follow the established protocol procedures or whose parents are unable to sign the informed consent.
Contacts and Locations
Locations
| Site | City | State | Country | Postal Code | |
|---|---|---|---|---|---|
| 1 | Pediatric Nephrology Dialysis and Transplant Unit IRCCS Ca'Granda | Milan | Italy | 20122 |
Sponsors and Collaborators
- Fondazione IRCCS Ca' Granda, Ospedale Maggiore Policlinico
- Ministero della Salute, Italy
- IL Sogno di Stefano
Investigators
- Study Chair: Giovanni Montini, MD, Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan
- Study Director: Franz Schaefer, Professor, Center for Pediatrics and Adolescent Medicine Division of Pediatric Nephrology, Heidelberg, Germany
- Principal Investigator: Otto Mehls, Professor, Center for Pediatrics and Adolescent Medicine Division of Pediatric Nephrology, Heidelberg, Germany
- Principal Investigator: Lutz T. Weber, Professor, Ärztlicher Leiter der Kindernephrologie Klinik und Poliklinik für Kinder- und Jugendmedizin Uniklinik Köln - Köln
- Principal Investigator: Aleksandra M Zurowska, Professor, Medical University of Gdansk, Department Paediatric & Adolescent Nephrology & Hypertension - Gdansk - Poland
- Principal Investigator: Fatos Yalcinkaya, Professor, Department of Pediatric Nephrology, School of Medicine, Ankara University, Ankara, Turkey
- Principal Investigator: Esra Baskin, Professor, Paediatric Nephrology Division, Department of Paediatrics, Faculty of Medicine, Baskent University, Ankara, Turkey
- Principal Investigator: Enrico Verrina, MD, UOC Nefrologia, Dialisi e Trapianto, IRCCS Giannina Gaslini, Genova, Italy
- Principal Investigator: William Morello, MD, Pediatric Nephrology, Dialysis and Transplant Unit, Fondazione IRCCS Ca' Granda Ospedale Maggiore Policlinico Milan
- Principal Investigator: Piotr Czarniak, MD, Department of Nephrology, Transplantology and Internal Medicine, Medical University of Gdansk, Gdansk - Poland
Study Documents (Full-Text)
None provided.More Information
Publications
None provided.- PREDICT trial