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Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis.

ABSTRACT: We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic Escherichia coli (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively females, which (in most mouse strains) exhibit inherent resistance to severe ascending kidney infection; consequently, no existing preclinical model has assessed the consequences of recovery from pyelonephritis following antibiotic treatment. We recently published a novel mini-surgical bladder inoculation technique, with which male C3H/HeN mice develop robust ascending pyelonephritis, highly prevalent renal abscesses and evidence of fibrosis. Here, we devised and optimized an antibiotic treatment strategy within this male model to more closely reflect the clinical course of pyelonephritis. A 5-day ceftriaxone regimen initiated at the onset of abscess development achieved resolution of bladder and kidney infection. A minority of treated mice displayed persistent histological abscess at the end of treatment, despite microbiological cure of pyelonephritis; a matching fraction of mice 1?month later exhibited renal scars featuring fibrosis and ongoing inflammatory infiltrates. Successful antibiotic treatment preserved renal function in almost all infected mice, as assessed by biochemical markers 1 and 5?months post-treatment; hydronephrosis was observed as a late effect of treated pyelonephritis. An occasional mouse developed chronic kidney disease, generally reflecting the incidence of this late sequela in humans. In total, this model offers a platform to study the molecular pathogenesis of pyelonephritis, response to antibiotic therapy and emergence of sequelae, including fibrosis and renal scarring. Future studies in this system may inform adjunctive therapies that may reduce the long-term complications of this very common bacterial infection.

SUBMITTER: Olson PD

PROVIDER: S-EPMC5719254 | biostudies-literature | 2017 Nov

REPOSITORIES: biostudies-literature

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Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis.

Olson Patrick D PD McLellan Lisa K LK Liu Alice A Briden Kelleigh E KE Tiemann Kristin M KM Daugherty Allyssa L AL Hruska Keith A KA Hunstad David A DA

Disease models & mechanisms 20170907 11

We present a new preclinical model to study treatment, resolution and sequelae of severe ascending pyelonephritis. Urinary tract infection (UTI), primarily caused by uropathogenic <i>Escherichia coli</i> (UPEC), is a common disease in children. Severe pyelonephritis is the primary cause of acquired renal scarring in childhood, which may eventually lead to hypertension and chronic kidney disease in a small but important fraction of patients. Preclinical modeling of UTI utilizes almost exclusively ...[more]

PMID: 28882930

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Project description:Importance:National guidelines recommend treating children with pyelonephritis for 7 to 14 days of antibiotic therapy, yet data are lacking to suggest a more precise treatment duration. Objective:To compare the clinical outcomes of children receiving a short-course vs a prolonged-course of antibiotic treatment for pyelonephritis. Design, Setting, and Participants:Retrospective observational study using inverse probability of treatment weighted propensity score analysis of data from 5 hospitals in Maryland between July 1, 2016, and October 1, 2018. Participants were children aged 6 months to 18 years with a urine culture growing Escherichia coli, Klebsiella species, or Proteus mirabilis with laboratory and clinical criteria for pyelonephritis. Exposures:Treatment of pyelonephritis with a short-course (6 to 9 days) vs a prolonged-course (10 or more days) of antibiotics. Main Outcomes and Measures:Composite outcome of treatment failure within 30 days of completing antibiotic therapy: (a) unanticipated emergency department or outpatient visits related to urinary tract infection symptoms, (b) hospital readmission related to UTI symptoms, (c) prolongation of the planned, initial antibiotic treatment course, or (d) death. A subsequent urinary tract infection caused by a drug-resistant bacteria within 30 days was a secondary outcome. Results:Of 791 children who met study eligibility criteria (mean [SD] age 9.2 [6.3] years; 672 [85.0%]) were girls, 297 patients (37.5%) were prescribed a short-course and 494 patients (62.5%) were prescribed a prolonged-course of antibiotics. The median duration of short-course therapy was 8 days (interquartile range, 7-8 days), and the median duration of prolonged-course therapy was 11 days (interquartile range, 11-12 days). Baseline characteristics were similar between the groups in the inverse probability of treatment weighted cohort. There were 79 children (10.1%) who experienced treatment failure. The odds of treatment failure were similar for patients prescribed a short-course vs a prolonged-course of antibiotics (11.2% vs 9.4%; odds ratio, 1.22; 95% CI, 0.75-1.98). There was no significant difference in the odds of a drug-resistant uropathogen for patients with a subsequent urinary tract infection within 30 days when prescribed a short-courses vs prolonged-course of antibiotics (40% vs 64%; odds ratio, 0.36; 95% CI, 0.09-1.43). Conclusions and Relevance:The study findings suggest that short-course antibiotic therapy may be as effective as prolonged-courses for children with pyelonephritis, and may mitigate the risk of future drug-resistant urinary tract infections. Additional studies are needed to confirm these findings.

Dataset Information

Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis.

Publications

Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis.

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