Kidney Week

Abstract: TH-OR012

Chronic Inflammation Drives Renal Scarring in Mice and Humans with Pyelonephritis

Session Information

• CKD: Exploring Intertwined Mechanisms of Disease Progression
  November 06, 2025 | Location: Room 362A, Convention Center
  Abstract Time: 04:50 PM - 05:00 PM

Category: CKD (Non-Dialysis)

• 2303 CKD (Non-Dialysis): Mechanisms

Authors

• Kimbrough, Denise M., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Denise M. Kimbrough, MD, PhD

• Patel, Rishil H., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Rishil H. Patel

• Li, Birong, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Birong Li, MSc

• Cortado, Hanna H., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Hanna H. Cortado, MS, MSc

• Kercsmar, Macie M., Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Macie M. Kercsmar

• Wang, Xin, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Xin Wang, PhD

• Ruiz-Rosado, Juan de Dios, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Juan de Dios Ruiz-Rosado, PhD

• Becknell, Brian, Abigail Wexner Research Institute at Nationwide Children's Hospital, Columbus, Ohio, United States

Brian Becknell, MD, PhD

Group or Team Name

• Kidney and Urinary Tract Center.

Background

Acute pyelonephritis (PN) is a common bacterial infection that can lead to acute kidney injury as well as chronic PN with renal scarring (RS). Most cases of PN are due to uropathogenic Escherichia coli (UPEC). Herein, we used curated tissue from human subjects and an experimental model of PN to examine the histopathologic sequence linking acute PN with chronic PN and progression to RS. We hypothesized that chronic inflammation drives RS in PN.

Methods

Adult female C3H/HeOuJ mice were sham infected or transurethrally inoculated with 10⁸ CFU of UPEC strain CFT073 and euthanized at 1, 3, 7, and 28 days post infection (dpi) to measure UPEC burden, investigate kidney histopathology, and evaluate the renal spatial transcriptome. To eliminate UPEC in mice with established PN, we administered Ceftriaxone daily for ten days beginning 7 dpi and euthanized mice at 44 dpi, i.e., 28 days after the last dose. Nephrectomy specimens from human subjects with a history of chronic PN were obtained through an approved protocol.

Results

UPEC inoculation led to pyelitis 1 and 3 dpi, followed by features of acute PN by 7 dpi (tubulointerstitial nephritis, acute tubular necrosis, and neutrophil-laden casts). Features of chronic PN were also present by 7 dpi and subsequent time points, characterized by infiltrates composed of T cells, B cells, and macrophages, along with collagen deposition in a wedge-shaped distribution, reflecting RS. Spatial transcriptome analysis identified regional enrichment of macrophage- and lymphocyte-specific transcripts within chronic PN lesions, along with activation of TGF-β signaling and extracellular matrix deposition. Antibiotic therapy was associated with UPEC eradication and absence of acute PN, whereas chronic PN and RS histopathological changes persisted. Similar histopathologic features were evident in nephrectomy specimens from human subjects with a history of chronic PN.

Conclusion

Our mouse model recapitulates features of acute and chronic PN found in human patients. The persistence of chronic inflammation and RS in mice despite antibiotic treatment mirrors PN associated RS in humans and attests to the need for therapeutic measures to mitigate RS and chronic kidney disease in patients with PN.

Funding

• NIDDK Support

Digital Object Identifier (DOI)

• doi: 10.1681/ASN.2025wsmppb2c