Editorial with respect to “Corticosteroids to prevent kidney scarring in children with a febrile urinary tract infection—a randomized trial”

Abstract

In their study published in a recent issue of Pediatric Nephrology, Shaikh et al. hypothesize that inflammation may be the critical factor that drives kidney scar formation after a urinary tract infection (UTI) [1]. To test this hypothesis, they performed a randomized double-blind control trial to evaluate whether treatment with dexamethasone is effective in preventing kidney scar formation in children with UTI. This is an important topic because kidney scarring post-UTI with and without vesico-ureteric reflux remains a relatively common cause of kidney failure in both pediatric and adult databases. Kidney scarring refers to the development of fibrosis in response to infection and/or inflammation. In children, kidney scarring is often seen in those who have UTIs that may occur with or without vesico-ureteric reflux. Although the majority of children are able to eliminate the bacteria during a UTI with antibiotic treatment and control the inflammatory response, approximately 10–25% will develop kidney scarring [2]. In the RIVUR trial, antibiotic treatment was shown to be effective in the prevention of recurrent UTIs; however, there was no difference in the rate of kidney scarring in children on antibiotic treatment compared to those in the placebo group. This suggests that there are other factors besides bacterial infection that predispose to kidney scarring. Additional risk factors were subsequently identified to be associated with kidney scarring in RIVUR participants. These included highgrade vesico-ureteric reflux, recurrent UTIs, older age (e.g., more than 2 years of age), and Hispanic ethnicity [3]. Taken together, there is a need to understand the mechanism by which kidney scars arise since this could reveal new therapeutic avenues to prevent scar formation. Kidney scarring may arise from inflammation which is how the host’s immune response responds to bacterial infection of the kidney. The inflammatory response in the kidney includes the recruitment of neutrophils and macrophages as well as the release of reactive oxygen species and lysosomal enzymes. Transforming growth factor β1 is also stimulated as part of the initiation and the resolution of inflammation and provokes deposition of extracellular matrix proteins including collagen. If these effectors are not well regulated, there is a risk for an excessive response that damages the kidney and resolves with the deposition of collagen in a scar. To target the inflammation of the host immune response, different treatments have been administered in clinical trials of childrenwith UTIs, with some success. Vitamin A, which is an antioxidant, has been shown to reduce kidney scarring in four trials (three from Iran and one from China) [4]. All of these trials were limited by a low number of participants, very few male subjects, and possible selection and performance bias. The efficacy of vitamin A to prevent kidney scar formation therefore requires further exploration. More recently, a group in Taiwan evaluated the effectiveness of oral methylprednisolone treatment (1.6 mg/kg once a day for 3 days) in patients with acute pyelonephritis and found a significant reduction in scarring in the treatment group [5]. This study was limited by small numbers, with 19 patients in the treatment group and 65 patients in the control group. Nonetheless, these promising findings set the stage for the current study by Shaikh et al., who performed a large-scale double-blind placebo-controlled randomized clinical trial to assess the use of dexamethasone to prevent kidney scarring in children with febrile UTIs [1]. Shaikh et al. used adjuvant oral dexamethasone (0.15 mg/kg/dose bid for 3 days) or placebo with antimicrobial therapy to treat children aged 2 months to 6 years who presented with their first UTI. Post-UTI, the children were assessed for kidney scarring using a DMSA scan which was performed anywhere from 5–24 months after the first UTI. Although rates of kidney scarring were 9.8% and 16.8% in the corticosteroid and placebo groups respectively, this was not a * Indra R. Gupta [email protected]