Urinary tract infection (UTI) is the most common serious bacterial infection in young febrile children. Between 70 000 and 180 000 of the ∼4 million children born in the United States each year will have a UTI by the age of 6 years.1,2 Infections of the urinary tract can progress to acute pyelonephritis (infection and inflammation of the kidneys and ureters), which in turn can lead to renal scarring,3–6 renal insufficiency, hypertension,7–10 or renal failure necessitating hemodialysis.
The current standard of care for young children diagnosed with a UTI is to perform a renal ultrasound to identify anatomic abnormalities of the kidneys and collecting system and a voiding cystourethrogram or a radionuclide cystogram to evaluate for the presence of vesicoureteral reflux (VUR),11 a condition in which urine flows retrograde during micturition from the bladder toward the kidneys. VUR is thought to be important in the evaluation and management of children with UTI because of the observed relationship between degree of VUR and subsequent renal scarring. In some studies, patients with high-grade VUR were 4 to 6 times more likely to have scarring than those with low-grade VUR and 8 to 10 times as likely as those with no VUR.12–14 On the basis of these associations, a conceptual model has been developed that postulates that the combination of recurrent UTI and VUR leads to renal scarring. The therapeutic implication of this model is that management strategies have focused on surgical correction of VUR and/or prevention of UTI with prophylactic antibiotics.15
However, these management strategies and the conceptual model from which they were derived have been called into question.16,17 Analyses of dialysis and transplant registries have shown that the diagnosis and treatment of children with VUR that started in the 1960s have not been associated with a reduction in the incidence of end-stage renal disease attributable to reflux nephropathy.18 In addition, neither observational studies19 nor small clinical trials20–22 have demonstrated any reduction in the incidence of recurrent UTIs in children who receive prophylactic antibiotics. Critics of continuous prophylaxis also worry about the development of antimicrobial resistance and the subsequent risk of inappropriate empiric therapy for children with recurrent UTIs.19,23
Given the unclear effectiveness and potential harms of the current model for the management of children with UTI and VUR, in 2004 the Division of Kidney, Urologic, and Hematologic Diseases of the National Institute of Diabetes and Digestive and Kidney Diseases (NIDDK) solicited cooperative agreement applications for pediatric clinical treatment centers (CTC) and a data coordinating center (DCC) for the design and conduct of a study to determine the effectiveness of prophylactic antibiotic use for prevention of recurrent UTIs and preservation of renal function.24 The 5 selected core CTCs and DCC formed a steering committee in October 2005 and met monthly to develop the research protocol. In July 2007, patient enrollment began for the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) study, a multicenter, double-blind, randomized, placebo-controlled trial designed to evaluate the effectiveness of antimicrobial prophylaxis in children who are found to have VUR after an initial UTI. RIVUR represents a collaboration of 5 core CTCs and multiple satellite recruitment sites throughout North America, a central DCC at the University of North Carolina at Chapel Hill, and the NIDDK.
This supplement to Pediatrics includes 2 articles related to the RIVUR trial. The first article25 is a comprehensive review of the subject of VUR and controversies regarding current management strategies. The second article26 provides a detailed description of the RIVUR trial methods along with the rationale for many of the decisions that were made in designing the study.
- Accepted June 6, 2008.
- Address correspondence to Ron Keren, MD, MPH, Children's Hospital of Philadelphia, Department of Pediatrics, 3535 Market St, Room 1524, Philadelphia, PA 19104. E-mail:
The author has indicated he has no financial relationships relevant to this article to disclose.
- ↵Uhari M, Nuutinen M. Epidemiology of symptomatic infections of the urinary tract in children. BMJ.1988;297 (6646):450– 452
- ↵Winberg J, Andersen HJ, Bergstrom T, Jacobsson B, Larson H, Lincoln K. Epidemiology of symptomatic urinary tract infection in childhood. Acta Paediatr Scand Suppl.1974;(252):1– 20
- Doganis D, Siafas K, Mavrikou M, et al. Does early treatment of urinary tract infection prevent renal damage? Pediatrics.2007;120 (4). Available at: www.pediatrics.org/cgi/content/full/120/4/e922
- Jakobsson B, Berg U, Svensson L. Renal scarring after acute pyelonephritis. Arch Dis Child.1994;70 (2):111– 115
- Jacobson SH, Eklöf O, Eriksson CG, Lins LE, Tidgren B, Winberg J. Development of hypertension and uraemia after pyelonephritis in childhood: 27 year follow up. BMJ.1989;299 (6701):703– 706
- ↵American Academy of Pediatrics, Committee on Quality Improvement, Subcommittee on Urinary Tract Infection. Practice parameter: the diagnosis, treatment, and evaluation of the initial urinary tract infection in febrile infants and young children [published corrections appear in Pediatrics. 1999;103(5 pt 1):1052; 1999;104(1 pt 1):118; and 2000;105(1 pt 1):141]. Pediatrics.1999;103 (4 pt 1):843– 852
- Gleeson FV, Gordon I. Imaging in urinary tract infection. Arch Dis Child.1991;66 (11):1282– 1283
- ↵Wheeler DM, Vimalachandra D, Hodson EM, Roy LP, Smith GH, Craig JC. Interventions for primary vesicoureteric reflux. Cochrane Database Syst Rev.2004;(3):CD001532
- ↵Craig JC, Irwig LM, Knight JF, Roy LP. Does treatment of vesicoureteric reflux in childhood prevent end-stage renal disease attributable to reflux nephropathy? Pediatrics.2000;105 (6):1236– 1241
- ↵Garin EH, Olavarria F, Garcia Nieto V, Valenciano B, Campos A, Young L. Clinical significance of primary vesicoureteral reflux and urinary antibiotic prophylaxis after acute pyelonephritis: a multicenter, randomized, controlled study. Pediatrics.2006;117 (3):626– 632
- ↵Department of Health and Human Services. Clinical study of vesicoureteral reflux in children: RFA-DK-04-019. Available at: http://grants.nih.gov/grants/guide/rfa-files/RFA-DK-04-019.html. Accessed October 1, 2008
- ↵Chesney RW, Carpenter MA, Moxey-Mims M, et al. Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR): background commentary of RIVUR investigators. Pediatrics.2008;122 (6):S233– S239
- ↵Keren R, Carpenter MA, Hoberman A, et al. Rationale and design issues of the Randomized Intervention for Children With Vesicoureteral Reflux (RIVUR) Study. Pediatrics.2008;122 (6):S240– S250
- Copyright © 2008 by the American Academy of Pediatrics