Acute Urinary Tract Infection, Urinary Tract Infection
Conditions
Keywords
Renal scarring, Dexamethasone, Child, Corticosteroids, Pediatric, Urinary tract infection, Escherichia Coli Urinary Tract Infection
Brief summary
In this study the investigators will determine whether corticosteroids given at the time of urinary tract infection help prevent permanent damage to the kidneys.
Detailed description
Because host inflammatory response is the final and most important step in the formation of renal scars, the use of anti-inflammatory agents may be the best strategy to reduce renal scarring. In animal studies, the use of corticosteroids has been shown to be effective in preventing post-pyelonephritic scarring. We will conduct a randomized, double-blind, placebo-controlled trial to determine the efficacy of 3 days of daily adjuvant dexamethasone on the incidence of renal scarring 4 to 6 months after a first febrile urinary tract infection (UTI). We hypothesize that the proportion of children with UTI who develop renal scarring will be lower among children who are treated with both dexamethasone and antibiotics as compared with children treated with antibiotics alone.
Interventions
DRUGPlacebo
Twice daily for 3 days
DRUGDexamethasone
0.15 mg/kg/dose twice daily for 3 days
Sponsors
National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK)
Nader Shaikh
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
PREVENTION
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
2 Months to 6 Years
Healthy volunteers
No
Inclusion criteria
* Age: 2 months to 6 years * Pyuria: ≥10 white blood cells per cubic millimeter (WBC/mm3) in an uncentrifuged specimen or ≥5 white blood cells per high power field (WBC/hpf) in a centrifuged specimen or ≥1+ leukocyte esterase (LE) on dipstick * Fever: documented temperature of at least 101 °F or 38.3°C, measured anywhere on the body either at home or at doctor's office within 24 hours of diagnosis
Exclusion criteria
* Other concurrent systemic bacterial infection(s) such as meningitis or pneumonia; * Planned admission to intensive care unit; * Known bacteremia; * Previous protocol defined UTI; * Known major urinary tract anomalies (severe hydronephrosis, ureterocele, urethral valve, solitary or profoundly small kidney, multicystic dysplastic kidney, neurogenic bladder, pelvic or fused kidney); * Congenital/acquired immunodeficiency; * Bag urine collection * Chronic diseases that could potentially interfere with response to therapy, such as chronic gastrointestinal conditions (i.e. malabsorption, inflammatory bowel disease), liver/kidney failure; * Allergy to dexamethasone * Antibiotic use within 7 days of enrollment (except if given in the last 48 hours) * Systemic use of corticosteroids or other immunomodulating agents within 14 days of enrollment * History of Kawasaki disease * Sickle cell disease (not trait)
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| The Distribution of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | The outcome DMSA scan was 5-24 months from enrollment. The mean number of months was 6.1. | Renal scarring was defined as decreased uptake of tracer with or without loss of contours. Three radiologists independently reviewed for scarring all DMSA scans that were of adequate quality. For a given kidney, the presence or absence of scarring was the diagnosis endorsed by the majority of readers, i.e. 2 of 3. For a given child, if either kidney or both kidneys were diagnosed with scarring by the majority of readers, then the child was determined to have renal scarring. |
| The Distribution of Children With Severe Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | The outcome DMSA scan was 5-24 months from enrollment. The mean number of months was 6.1. | Renal scarring was defined as decreased uptake of tracer with or without loss of contours. Scarring was assessed semi-quantitatively by dividing the renal cortex into 12 equal segments. Severe scarring was defined as greater than 4 affected renal segments or global atrophy, i.e. diffuse scarring or shrunken kidney. Three radiologists independently reviewed for scarring all DMSA scans that were of adequate quality. For a given kidney, the presence or absence of severe scarring was the diagnosis endorsed by the majority of readers, i.e. 2 of 3. For a given child, if either kidney or both kidneys were diagnosed with severe scarring by the majority of readers, then the child was determined to have severe renal scarring. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| The Mean Proportion of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan Taken Across the 3 Radiologists | The outcome DMSA scan was 5-24 months from enrollment. The mean number of months was 6.1. | Renal scarring was defined as decreased uptake of tracer with or without loss of contours. Three radiologists independently reviewed for scarring all DMSA scans that were of adequate quality. For each radiologist, for each child, if either kidney or both kidneys were diagnosed with scarring, then the child was determined to have renal scarring. For each radiologist, the proportion of children with scarring in a given treatment group is the number of children diagnosed with scarring divided by the number of children in the treatment group. The mean proportion of children with scarring in a given treatment group is the average proportion taken across the 3 radiologists. |
Countries
United States
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Adjuvant Dexamethasone Dexamethasone: 0.15 mg/kg/dose twice daily for 3 days | 197 |
| Placebo Placebo: Twice daily for 3 days | 188 |
| Total | 385 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Ineligible | 3 | 0 |
| Overall Study | No DMSA | 73 | 57 |
| Overall Study | Urine Culture Negative or Indeterminate | 71 | 87 |
Baseline characteristics
| Characteristic | Total | Adjuvant Dexamethasone | Placebo |
|---|---|---|---|
| Age, Customized 1-23 months | 277 Participants | 145 Participants | 132 Participants |
| Age, Customized 24-47 months | 71 Participants | 39 Participants | 32 Participants |
| Age, Customized 48-71 months | 37 Participants | 13 Participants | 24 Participants |
| Duration of Fever < 48 hours | 206 Participants | 110 Participants | 96 Participants |
| Duration of Fever >= 48 hours | 179 Participants | 87 Participants | 92 Participants |
| Escherichia Coli Present in Urine Culture No | 22 Participants | 10 Participants | 12 Participants |
| Escherichia Coli Present in Urine Culture Yes | 363 Participants | 187 Participants | 176 Participants |
| Ethnicity (NIH/OMB) Hispanic or Latino | 29 Participants | 16 Participants | 13 Participants |
| Ethnicity (NIH/OMB) Not Hispanic or Latino | 356 Participants | 181 Participants | 175 Participants |
| Ethnicity (NIH/OMB) Unknown or Not Reported | 0 Participants | 0 Participants | 0 Participants |
| Ibuprofen Taken in the Past 24 hours No | 171 Participants | 88 Participants | 83 Participants |
| Ibuprofen Taken in the Past 24 hours Yes | 214 Participants | 109 Participants | 105 Participants |
| Maternal Education College graduate | 142 Participants | 66 Participants | 76 Participants |
| Maternal Education High school graduate or equivalent | 212 Participants | 116 Participants | 96 Participants |
| Maternal Education Less than high school | 17 Participants | 6 Participants | 11 Participants |
| Maternal Education Unknown | 14 Participants | 9 Participants | 5 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants | 0 Participants | 0 Participants |
| Race (NIH/OMB) Asian | 16 Participants | 10 Participants | 6 Participants |
| Race (NIH/OMB) Black or African American | 69 Participants | 41 Participants | 28 Participants |
| Race (NIH/OMB) More than one race | 44 Participants | 17 Participants | 27 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 1 Participants | 1 Participants | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 1 Participants | 0 Participants | 1 Participants |
| Race (NIH/OMB) White | 254 Participants | 128 Participants | 126 Participants |
| Sex: Female, Male Female | 354 Participants | 183 Participants | 171 Participants |
| Sex: Female, Male Male | 31 Participants | 14 Participants | 17 Participants |
| Study Site American Family Children's Hospital, Madison | 2 Participants | 1 Participants | 1 Participants |
| Study Site Children's Hospital of Pittsburgh, Pittsburgh | 360 Participants | 185 Participants | 175 Participants |
| Study Site Children's National Medical Center, D.C. | 3 Participants | 1 Participants | 2 Participants |
| Study Site Hasbro Children's Hospital, Providence | 2 Participants | 1 Participants | 1 Participants |
| Study Site Nationwide Children's Hospital, Columbus | 15 Participants | 7 Participants | 8 Participants |
| Study Site Primary Children's Hospital, Salt Lake City | 3 Participants | 2 Participants | 1 Participants |
| Type of Health Insurance None | 9 Participants | 6 Participants | 3 Participants |
| Type of Health Insurance Private | 178 Participants | 81 Participants | 97 Participants |
| Type of Health Insurance Public | 194 Participants | 108 Participants | 86 Participants |
| Type of Health Insurance Unknown | 4 Participants | 2 Participants | 2 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 0 / 271 | 0 / 275 |
| other Total, other adverse events | 68 / 271 | 52 / 275 |
| serious Total, serious adverse events | 9 / 271 | 9 / 275 |
Outcome results
Primary
The Distribution of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan
Renal scarring was defined as decreased uptake of tracer with or without loss of contours. Three radiologists independently reviewed for scarring all DMSA scans that were of adequate quality. For a given kidney, the presence or absence of scarring was the diagnosis endorsed by the majority of readers, i.e. 2 of 3. For a given child, if either kidney or both kidneys were diagnosed with scarring by the majority of readers, then the child was determined to have renal scarring.
Time frame: The outcome DMSA scan was 5-24 months from enrollment. The mean number of months was 6.1.
Population: The analysis was Intent-to-Treat (ITT). The number of participants is equal to the number of children randomized and eligible who had a positive urine culture at enrollment and a DMSA renal scan, of adequate quality, 5-24 months from the time of enrollment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adjuvant Dexamethasone | The Distribution of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | With scarring | 12 Participants |
| Adjuvant Dexamethasone | The Distribution of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | Without scarring | 111 Participants |
| Placebo | The Distribution of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | With scarring | 22 Participants |
| Placebo | The Distribution of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | Without scarring | 109 Participants |
Comparison: Null hypothesis: There is no difference between the two treatment arms regarding the proportion of children with renal scarring at the outcome DMSA renal scan.p-value: 0.16Regression, Logistic
Primary
The Distribution of Children With Severe Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan
Renal scarring was defined as decreased uptake of tracer with or without loss of contours. Scarring was assessed semi-quantitatively by dividing the renal cortex into 12 equal segments. Severe scarring was defined as greater than 4 affected renal segments or global atrophy, i.e. diffuse scarring or shrunken kidney. Three radiologists independently reviewed for scarring all DMSA scans that were of adequate quality. For a given kidney, the presence or absence of severe scarring was the diagnosis endorsed by the majority of readers, i.e. 2 of 3. For a given child, if either kidney or both kidneys were diagnosed with severe scarring by the majority of readers, then the child was determined to have severe renal scarring.
Time frame: The outcome DMSA scan was 5-24 months from enrollment. The mean number of months was 6.1.
Population: The analysis was ITT. The number of participants is equal to the number of children randomized and eligible who had a positive urine culture at enrollment and a DMSA renal scan, of adequate quality, 5-24 months from the time of enrollment.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Adjuvant Dexamethasone | The Distribution of Children With Severe Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | With severe scarring | 0 Participants |
| Adjuvant Dexamethasone | The Distribution of Children With Severe Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | Without severe scarring | 123 Participants |
| Placebo | The Distribution of Children With Severe Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | With severe scarring | 3 Participants |
| Placebo | The Distribution of Children With Severe Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan | Without severe scarring | 128 Participants |
Comparison: Null hypothesis: There is no difference between the two treatment arms regarding the proportion of children with severe renal scarring at the outcome DMSA renal scan.p-value: 0.25Test of equality - 2 Poisson parameters
Secondary
The Mean Proportion of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan Taken Across the 3 Radiologists
Renal scarring was defined as decreased uptake of tracer with or without loss of contours. Three radiologists independently reviewed for scarring all DMSA scans that were of adequate quality. For each radiologist, for each child, if either kidney or both kidneys were diagnosed with scarring, then the child was determined to have renal scarring. For each radiologist, the proportion of children with scarring in a given treatment group is the number of children diagnosed with scarring divided by the number of children in the treatment group. The mean proportion of children with scarring in a given treatment group is the average proportion taken across the 3 radiologists.
Time frame: The outcome DMSA scan was 5-24 months from enrollment. The mean number of months was 6.1.
Population: The analysis was ITT. The number of participants is equal to the number of children randomized and eligible who had a positive urine culture at enrollment and a DMSA renal scan, of adequate quality, 5-24 months from the time of enrollment.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Adjuvant Dexamethasone | The Mean Proportion of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan Taken Across the 3 Radiologists | 0.127 proportion of participants with scarring | Standard Deviation 0.05 |
| Placebo | The Mean Proportion of Children With Renal Scarring at the Outcome Dimercaptosuccinic Acid (DMSA) Renal Scan Taken Across the 3 Radiologists | 0.204 proportion of participants with scarring | Standard Deviation 0.046 |
Comparison: Null hypothesis: There is no difference between the two treatment arms regarding the mean proportion of children with renal scarring at the outcome DMSA scan taken across the 3 radiologists.p-value: 0.07Generalized estimating equations