Renal Scarring in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) Trial.

2016

54-61

2016 Jan 7

1555-905X

<p><strong>BACKGROUND AND OBJECTIVES: </strong>The main objectives of the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial were to evaluate the role of antimicrobial prophylaxis in the prevention of recurrent urinary tract infection (UTI) and renal scarring in children with vesicoureteral reflux (VUR). We present a comprehensive evaluation of renal scarring outcomes in RIVUR trial participants.</p>

<p><strong>DESIGN, SETTING, PARTICIPANTS, &amp; MEASUREMENTS: </strong>This multicenter, randomized, placebo-controlled trial enrolled 607 children aged 2-71 months with grade 1-4 VUR diagnosed after a first or second febrile or symptomatic UTI. Study participants received trimethoprim-sulfamethoxazole or placebo and were followed for 2 years. Renal scarring was evaluated by baseline and follow-up (99m)technetium dimercaptosuccinic acid (DMSA) renal scans that were reviewed independently by two blinded reference radiologists.</p>

<p><strong>RESULTS: </strong>At the end of the study, 58 (10%) of 599 children and 63 (5%) of 1197 renal units had renal scarring. New renal scarring did not differ between the prophylaxis and placebo groups (6% versus 7%, respectively). Children with renal scarring were significantly older (median age, 26 versus 11 months; P=0.01), had a second UTI before enrollment (odds ratio [OR], 2.85; 95% confidence interval [95% CI], 1.38 to 5.92), were more likely to be Hispanic (OR, 2.22; 95% CI, 1.13 to 4.34), and had higher grades of VUR (OR, 2.79; 95% CI, 1.56 to 5.0). The proportion of new scars in renal units with grade 4 VUR was significantly higher than in units with no VUR (OR, 24.2; 95% CI, 6.4 to 91.2).</p>

<p><strong>CONCLUSIONS: </strong>Significantly more renal scarring was seen in relatively older children and in those with a second episode of febrile or symptomatic UTI before randomization. Preexisting and new renal scars occurred significantly more in renal units with grade 4 VUR than in those with low-grade or no VUR. Antimicrobial prophylaxis did not decrease the risk of renal scarring.</p>

10.2215/CJN.05210515

Clin J Am Soc Nephrol

26555605

Recurrent Urinary Tract Infections in Children With Bladder and Bowel Dysfunction.

2016

1-7

2016 Jan

1098-4275

<p><strong>BACKGROUND: </strong>Little generalizable information is available on the outcomes of children diagnosed with bladder and bowel dysfunction (BBD) after a urinary tract infection (UTI). Our objectives were to describe the clinical characteristics of children with BBD and to examine the effects of BBD on patient outcomes in children with and without vesicoureteral reflux (VUR).</p>

<p><strong>METHODS: </strong>We combined data from 2 longitudinal studies (Randomized Intervention for Children With Vesicoureteral Reflux and Careful Urinary Tract Infection Evaluation) in which children &lt;6 years of age with a first or second UTI were followed for 2 years. We compared outcomes for children with and without BBD, children with and without VUR, and children with VUR randomly assigned to prophylaxis or placebo. The outcomes examined were incidence of recurrent UTIs, renal scarring, surgical intervention, resolution of VUR, and treatment failure.</p>

<p><strong>RESULTS: </strong>BBD was present at baseline in 54% of the 181 toilet-trained children included; 94% of children with BBD reported daytime wetting, withholding maneuvers, or constipation. In children not on antimicrobial prophylaxis, 51% of those with both BBD and VUR experienced recurrent UTIs, compared with 20% of those with VUR alone, 35% with BBD alone, and 32% with neither BBD nor VUR. BBD was not associated with any of the other outcomes investigated.</p>

<p><strong>CONCLUSIONS: </strong>Among toilet-trained children, those with both BBD and VUR are at higher risk of developing recurrent UTIs than children with isolated VUR or children with isolated BBD and, accordingly, exhibit the greatest benefit from antimicrobial prophylaxis.</p>

10.1542/peds.2015-2982

Pediatrics

26647376

Antimicrobial Resistance and Urinary Tract Infection Recurrence.

2016

2016 Mar 11

1098-4275

<p><strong>BACKGROUND: </strong>The Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial found that recurrent urinary tract infections (rUTI) with resistant organisms were more common in the trimethoprim-sulfamethoxazole prophylaxis (TSP) arm. We describe factors associated with trimethoprim-sulfamethoxazole (TMP-SMX) resistance of rUTIs in RIVUR.</p>

<p><strong>METHODS: </strong>Children aged 2 to 71 months with first or second UTI (index UTI) and grade I to IV vesicoureteral reflux (VUR) were randomized to TSP or placebo and followed for 2 years. Factors associated with TMP-SMX-resistant rUTI were evaluated.</p>

<p><strong>RESULTS: </strong>Among 571 included children, 48% were &lt;12 months old, 43% had grade II VUR, and 38% had grade III VUR. Recurrent UTI occurred in 34 of 278 children receiving TSP versus 67 of 293 children receiving placebo. Among those with rUTI, 76% (26/34) of subjects receiving TSP had TMP-SMX-resistant organisms versus 28% (19/67) of subjects receiving placebo (P &lt; .001). The proportion of TMP-SMX-resistant rUTI decreased over time: in the TSP arm, 96% were resistant during the initial 6 months versus 38% resistant during the final 6 months; corresponding proportions for the placebo arm were 32% and 11%. Among children receiving TSP, 7 (13%) of 55 with TMP-SMX-resistant index UTI had rUTI, whereas 27 (12%) of 223 with TMP-SMX-susceptible index UTI had rUTI (adjusted hazard ratio 1.38, 95% confidence interval 0.54-3.56). Corresponding proportions in placebo arm were 17 (26%) of 65 and 50 (22%) of 228 (adjusted hazard ratio 1.33, 95% confidence interval 0.74-2.38).</p>

<p><strong>CONCLUSIONS: </strong>Although TMP-SMX resistance is more common among children treated with TSP versus placebo, resistance decreased over time. Among children treated with TSP, there was no significant difference in UTI recurrence between those with TMP-SMX-resistant index UTI versus TMP-SMX-susceptible UTI.</p>

10.1542/peds.2015-2490

Pediatrics

26969273

Development and impact of an intervention to boost recruitment in a multicenter pediatric randomized clinical trial.

2014

151-7

2014 Feb

1938-2707

<p><strong>OBJECTIVES: </strong>Our primary objective was to develop and evaluate an intervention to increase recruitment in a multicenter pediatric randomized clinical trial (RCT). Our secondary objective was to assess the impact beyond 120 days.</p>

<p><strong>METHODS: </strong>The study was conducted at 17 academic centers participating in a pediatric RCT. The intervention consisted of utilizing a recruitment assessment tool at a site visit or teleconference with key site personnel.</p>

<p><strong>RESULTS: </strong>We found a significant increase in the number of individuals enrolled for all 17 sites at 120 days postintervention (mean = 1.12 per site; median = 1 per site; 95% confidence interval = 1-2; P = .04). No significant differences were apparent beyond the first 120 days postintervention.</p>

<p><strong>CONCLUSIONS: </strong>Successful recruitment in RCTs is essential to the quality, generalizability, and cost-effectiveness of clinical research. Implementation of this recruitment intervention may effectively increase recruitment in RCTs. Beyond the first 120 days postintervention, repeated interventions may be required. What is new? Despite general and pediatric-specific challenges to recruitment in RCTs, a paucity of evidence exists on effective recruitment strategies or assessment tools to reliably enhance recruitment. We developed a recruitment intervention for use in RCTs that enables clinical researchers to enhance recruitment.</p>

10.1177/0009922813506961

Clin Pediatr (Phila)

24151147

The RIVUR trial: profile and baseline clinical associations of children with vesicoureteral reflux.

2013

e34-45

2013 Jul

1098-4275

<p><strong>BACKGROUND AND OBJECTIVE: </strong>Vesicoureteral reflux (VUR) is diagnosed in ∼30% to 40% of children who have imaging studies after urinary tract infections (UTIs). Our goal is to characterize children enrolled in the Randomized Intervention for Children with Vesicoureteral Reflux (RIVUR) trial and to compare our study cohort with those from previously published studies.</p>

<p><strong>METHODS: </strong>RIVUR investigators from 19 pediatric sites in the United States recruited 607 children with grade I through IV VUR. Children were enrolled after a first or second UTI. This cross-sectional report of baseline data includes extensive clinical, parental report, and imaging study results.</p>

<p><strong>RESULTS: </strong>RIVUR recruited 607 children (558 girls, 49 boys) with grade I (11%), II (42%), III (38%), or IV (8%) reflux. The median age was 12 months, and most children (91%) were enrolled after their first UTI. The UTI leading to enrollment was both febrile and symptomatic for 323 children, febrile only in 197 children, and symptomatic only in 86. Renal involvement at baseline as documented by a (99m)Tc dimercaptosuccinic acid scan was uncommon with cortical defects identified in 89 (15%) children. Bladder and bowel dysfunction was identified in 71 (56%) of 126 toilet-trained subjects assessed.</p>

<p><strong>CONCLUSIONS: </strong>RIVUR is the largest prospective, randomized trial for children with primary VUR to date, comparing prophylaxis with placebo. The study sample comprises patients from 19 pediatric clinical sites in the United States, whose demographic and clinical characteristics may differ from those of children enrolled in previous trials from other countries.</p>

10.1542/peds.2012-2301

Pediatrics

23753091

Factors that influence parental decisions to participate in clinical research: consenters vs nonconsenters.

2013

561-6

2013 Jun

2168-6211

<p><strong>IMPORTANCE: </strong>A child's health, positive perceptions of the research team and consent process, and altruistic motives play significant roles in the decision-making process for parents who consent for their child to enroll in clinical research. This study identified that nonconsenting parents were better educated, had private insurance, showed lower levels of altruism, and less understanding of study design.</p>

<p><strong>OBJECTIVE: </strong>To determine the factors associated with parental consent for their child's participation in a randomized, placebo-controlled trial.</p>

<p><strong>DESIGN: </strong>Cross-sectional survey conducted from July 2008 to May 2011. The survey was an ancillary study to the Randomized Intervention for Children with VesicoUreteral Reflux Study.</p>

<p><strong>SETTING: </strong>Seven children's hospitals participating in a randomized trial evaluating management of children with vesicoureteral reflux.</p>

<p><strong>PARTICIPANTS: </strong>Parents asked to provide consent for their child's participation in the randomized trial were invited to complete an anonymous online survey about factors influencing their decision. A total of 120 of the 271 (44%) invited completed the survey; 58 of 125 (46%) who had provided consent and 62 of 144 (43%) who had declined consent completed the survey.</p>

<p><strong>MAIN OUTCOMES AND MEASURES: </strong>A 60-question survey examining child, parent, and study characteristics; parental perception of the study; understanding of the design; external influences; and decision-making process. RESULTS Having graduated from college and private health insurance were associated with a lower likelihood of providing consent. Parents who perceived the trial as having a low degree of risk, resulting in greater benefit to their child and other children, causing little interference with standard care, or exhibiting potential for enhanced care, or who perceived the researcher as professional were significantly more likely to consent to participate. Higher levels of understanding of the randomization process, blinding, and right to withdraw were significantly positively associated with consent to participate. CONCLUSIONS AND RELEVANCE Parents who declined consent had a relatively higher socioeconomic status, had more anxiety about their decision, and found it harder to make their decision compared with consenting parents, who had higher levels of trust and altruism, perceived the potential for enhanced care, reflected better understanding of randomization, and exhibited low decisional uncertainty. Consideration of the factors included in the conceptual model should enhance the quality of the informed consent process and improve participation in pediatric clinical trials.</p>

10.1001/jamapediatrics.2013.1050

JAMA Pediatr

23546617

Antimicrobial prophylaxis for children with vesicoureteral reflux.

2014

2367-76

2014 Jun

1533-4406

<p><strong>BACKGROUND: </strong>Children with febrile urinary tract infection commonly have vesicoureteral reflux. Because trial results have been limited and inconsistent, the use of antimicrobial prophylaxis to prevent recurrences in children with reflux remains controversial.</p>

<p><strong>METHODS: </strong>In this 2-year, multisite, randomized, placebo-controlled trial involving 607 children with vesicoureteral reflux that was diagnosed after a first or second febrile or symptomatic urinary tract infection, we evaluated the efficacy of trimethoprim-sulfamethoxazole prophylaxis in preventing recurrences (primary outcome). Secondary outcomes were renal scarring, treatment failure (a composite of recurrences and scarring), and antimicrobial resistance.</p>

<p><strong>RESULTS: </strong>Recurrent urinary tract infection developed in 39 of 302 children who received prophylaxis as compared with 72 of 305 children who received placebo (relative risk, 0.55; 95% confidence interval [CI], 0.38 to 0.78). Prophylaxis reduced the risk of recurrences by 50% (hazard ratio, 0.50; 95% CI, 0.34 to 0.74) and was particularly effective in children whose index infection was febrile (hazard ratio, 0.41; 95% CI, 0.26 to 0.64) and in those with baseline bladder and bowel dysfunction (hazard ratio, 0.21; 95% CI, 0.08 to 0.58). The occurrence of renal scarring did not differ significantly between the prophylaxis and placebo groups (11.9% and 10.2%, respectively). Among 87 children with a first recurrence caused by Escherichia coli, the proportion of isolates that were resistant to trimethoprim-sulfamethoxazole was 63% in the prophylaxis group and 19% in the placebo group.</p>

<p><strong>CONCLUSIONS: </strong>Among children with vesicoureteral reflux after urinary tract infection, antimicrobial prophylaxis was associated with a substantially reduced risk of recurrence but not of renal scarring. (Funded by the National Institute of Diabetes and Digestive and Kidney Diseases and others; RIVUR ClinicalTrials.gov number, NCT00405704.).</p>

10.1056/NEJMoa1401811

N. Engl. J. Med.

24795142