Current kidney function parameters overestimate kidney tissue repair in reversible experimental kidney disease

Barbara Mara Klinkhammer, Simone Buchtler, Sonja Djudjaj, Nassim Bouteldja, Runolfur Palsson, Vidar Orn Edvardsson, Margret Thorsteinsdottir, Jürgen Floege, Matthias Mack, Peter Boor*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

1 Citation (Scopus)

Abstract

Although underlying mechanisms and the clinical course of kidney disease progression are well described, less is known about potential disease reversibility. Therefore, to analyze kidney recovery, we adapted a commonly used murine chronic kidney disease (CKD) model of 2,8- dihydroxyadenine (2,8-DHA) crystal-induced nephropathy to study disease recovery and efficacy of disease-modifying interventions. The recovery phase after CKD was characterized by improved kidney function after two weeks which remained stable thereafter. By contrast, even after eight weeks recovery, tubular injury and inflammation were only partially reduced, and fibrosis persisted. Deep-learning-based histologic analysis of 8,604 glomeruli and 596,614 tubular cross sections revealed numerous tubules had undergone either prominent dilation or complete atrophy, leading to atubular glomeruli and irreversible nephron loss. We confirmed these findings in a second CKD model, reversible unilateral ureteral obstruction, in which a rapid improvement of glomerular filtration rate during recovery also did not reflect the permanent histologic kidney injury. In 2,8-DHA nephropathy, increased drinking volume was highly effective in disease prevention. However, in therapeutic approaches, high fluid intake was only effective in moderate but not severe CKD and established tissue injury was again poorly reflective of kidney function parameters. The injury was particularly localized in the medulla, which is often not analyzed. Thus, recovery after crystal- or obstruction-induced CKD is characterized by ongoing tissue injury, fibrosis, and nephron loss, but not reflected by standard measures of kidney function. Hence, our data might aid in designing kidney recovery studies and suggest the need for biomarkers specifically monitoring intra-kidney tissue injury.

Original languageEnglish
Pages (from-to)307-320
Number of pages14
JournalKidney International
Volume102
Issue number2
DOIs
Publication statusPublished - 1 Aug 2022

Bibliographical note

Funding Information:
The authors thank Simon Wilhelm Otten, Marie Cherelle Timm, Christina Gianussis, Jana Baues, and Louisa Boettcher for excellent laboratory assistance, as well as David Laurin Hölscher and Tim Caspers for technical support. This study was funded by the German Research Foundation (DFG; Project-IDs 322900939, 432698239, 454024652 to PB, 432698239 to SD, 445703531 to BMK, SD, JF, and PB, and 387509280 to MM), the medical faculty of the RWTH Aachen University (109/20 to BMK), the German Federal Ministries of Education and Research (BMBF: STOPFSGS-01GM1901A to PB and SD), Health (DEEP LIVER, ZMVI1-2520DAT111 to PB), and Economic Affairs and Energy (EMPAIA to PB), and the European Research Council (ERC) under the European Union’s Horizon 2020 research and innovation program (grant agreement no. 101001791).

Funding Information:
The authors thank Simon Wilhelm Otten, Marie Cherelle Timm, Christina Gianussis, Jana Baues, and Louisa Boettcher for excellent laboratory assistance, as well as David Laurin Hölscher and Tim Caspers for technical support. This study was funded by the German Research Foundation (DFG; Project-IDs 322900939, 432698239, 454024652 to PB, 432698239 to SD, 445703531 to BMK, SD, JF, and PB, and 387509280 to MM), the medical faculty of the RWTH Aachen University (109/20 to BMK), the German Federal Ministries of Education and Research (BMBF: STOPFSGS-01GM1901A to PB and SD), Health (DEEP LIVER, ZMVI1-2520DAT111 to PB), and Economic Affairs and Energy (EMPAIA to PB), and the European Research Council (ERC) under the European Union's Horizon 2020 research and innovation program (grant agreement no. 101001791). BMK, SB, MM, and PB were responsible for the overall study design. BMK, SB, SD, NB, and MT performed the experiments. BMK analyzed the data. BMK and PB contributed to the writing of the manuscript. All authors discussed and refined the manuscript.

Publisher Copyright:
© 2022 International Society of Nephrology

Other keywords

  • adenine nephropathy
  • kidney fibrosis
  • regeneration
  • rUUO
  • tubular injury
  • Animals
  • Fibrosis
  • Ureteral Obstruction/pathology
  • Mice
  • Kidney/pathology
  • Kidney Glomerulus/pathology
  • Renal Insufficiency, Chronic/pathology

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