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

Study Overview
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Brief Summary
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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.

Detailed Description
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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

Official Title
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Antibiotic Prophylaxis and Renal Damage In Congenital Abnormalities of the Kidney and Urinary Tract

Conditions
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Vesicoureteral Reflux, Renal Hypodysplasia, Nonsyndromic, 1, Chronic Kidney Disease

Intervention / Treatment
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* Drug: nitrofurantoin
* Other: No prophylaxis
* Drug: Amoxicillin-Potassium Clavulanate Combination
* Drug: Trimethoprim/sulfamethoxazole
* Drug: Cefixime


Participation Criteria
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Eligibility Criteria
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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.

Ages Eligible for Study
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Minimum Age: 1 Month
Maximum Age: 4 Months

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

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


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: ANTIBIOTIC PROPHYLAXIS<br>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<br>* 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)<br>* Other names: Furadantin;Drug: Amoxicillin-Potassium Clavulanate Combination<br>* 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)<br>* Other names: amoxicilline/clavulanic acid, augmentin, clavulin;Drug: Trimethoprim/sulfamethoxazole<br>* 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)<br>* Other names: bactrim;Drug: Cefixime<br>* 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)<br>* Other names: cefixoral;|
| Experimental: NO PROPHYLAXIS<br>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<br>* children will be followed, but no antibiotic prophylaxis will be administered<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| urinary tract infections rate | 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 | during the first 24 months from enrolment | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| febrile urinary tract infections | 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 | during the first 24 months from enrolment | 
| renal scars | 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. | at 2 years and 5 years from enrolment | 
| serum creatinine (renal function) | The renal function (serum creatinine) will be monitored for all enrolled patients to explore the appearance and progression of renal damage | at the enrolment,1 year, 2 years, 3 years, 4 years, 5 years | 
| hypertension | the appearance of hypertension will be monitored at every visit in all enrolled children | at 4, 8, 12, 18, 24, 36, 48, 60 months from enrolment | 
| proteinuria | the appearance of proteinuria will be monitored at every visit in all enrolled children | at 4, 8, 12, 18, 24, 36, 48, 60 months from enrolment | 
| body mass index | 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 | at 2 and 5 years from enrolment | 
| serum cystatin C (renal function) | The renal function (serum cystatin-C) will be monitored for all enrolled patients to explore the appearance and progression of renal damage | at the enrolment,1 year, 2 years, 3 years, 4 years, 5 years | 
| modification in gut microbiota induced by continuous antibiotic exposure during the first months of life | A stool sample will be collected, frozen and stored for gut microbiota and resistome profile analysis | at the enrollment, 4 months, 8 months, 12 months, 2 years, 3 years, 4 years, 5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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renal hypodysplasia, vesicoureteral reflux, congenital abnormalities of kidney, chronic kidney disease, antibiotic prophylaxis