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Resource Article
Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis
Patrick D. Olson, Lisa K. McLellan, Alice Liu, Kelleigh L. Briden, Kristin M. Tiemann, Allyssa L. Daugherty, Keith A. Hruska, David A. Hunstad
Disease Models & Mechanisms 2017 : dmm.030130 doi: 10.1242/dmm.030130 Published 7 September 2017
Patrick D. Olson
Medical Scientist Training Program, Washington University School of Medicine, St. Louis, MO, USADepartment of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
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Lisa K. McLellan
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
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Alice Liu
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
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Kelleigh L. Briden
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
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Kristin M. Tiemann
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
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  • ORCID record for Kristin M. Tiemann
Allyssa L. Daugherty
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USA
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Keith A. Hruska
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USADepartment of Cell Biology and Physiology, Washington University School of Medicine, St. Louis, MO, USA
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David A. Hunstad
Department of Pediatrics, Washington University School of Medicine, St. Louis, MO, USADepartment of Molecular Microbiology, Washington University School of Medicine, St. Louis, MO, USA
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  • ORCID record for David A. Hunstad
  • For correspondence: dhunstad@wustl.edu
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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 histologic abscess at the end of treatment, despite microbiologic 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.

  • Received April 18, 2017.
  • Accepted September 4, 2017.
  • © 2017. Published by The Company of Biologists Ltd
http://creativecommons.org/licenses/by/3.0

This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution and reproduction in any medium provided that the original work is properly attributed.

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Keywords

  • Pyelonephritis
  • Renal scarring
  • Fibrosis
  • Urinary tract infection
  • Chronic kidney disease
  • Hydronephrosis

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Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis
Patrick D. Olson, Lisa K. McLellan, Alice Liu, Kelleigh L. Briden, Kristin M. Tiemann, Allyssa L. Daugherty, Keith A. Hruska, David A. Hunstad
Disease Models & Mechanisms 2017 : dmm.030130 doi: 10.1242/dmm.030130 Published 7 September 2017
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Renal scar formation and kidney function following antibiotic-treated murine pyelonephritis
Patrick D. Olson, Lisa K. McLellan, Alice Liu, Kelleigh L. Briden, Kristin M. Tiemann, Allyssa L. Daugherty, Keith A. Hruska, David A. Hunstad
Disease Models & Mechanisms 2017 : dmm.030130 doi: 10.1242/dmm.030130 Published 7 September 2017

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