Danielle E Soranno1,2,3, Hyo-Wook Gil1,4, Lara Kirkbride-Romeo2, Christopher Altmann1, John R Montford1,5, Haichun Yang6, Ani Levine3, Jane Buchanan2, Sarah Faubel7,2. 1. Division of Renal Disease and Hypertension, Department of Medicine. 2. Section of Pediatric Nephrology, Department of Pediatrics, and. 3. Department of Bioengineering, University of Colorado, Aurora, Colorado. 4. Department of Internal Medicine, Soonchunhyang University Cheonan Hospital, Cheonan, Korea. 5. Department of Medicine, Rocky Mountain Regional Veterans Affairs Medical Center, Aurora, Colorado; and. 6. Department of Pathology, Microbiology and Immunology, Vanderbilt University Medical Center, Nashville, Tennessee. 7. Division of Renal Disease and Hypertension, Department of Medicine, sarah.faubel@ucdenver.edu.
Abstract
BACKGROUND: The duration of renal ischemia that is associated with (or leads to) renal injury in patients is uncertain, and a reverse translational research approach has been proposed to improve animal models of AKI to facilitate clinical translatability. We developed a two murine models of unilateral renal ischemia to match a recently published human study that investigated renal injury after unilateral renal ischemia during partial nephrectomy. METHODS: Eight 10-week-old C57BL/6 male mice underwent left UiAKI or sham procedure, with or without intra-operative ice packs. Functional, histological, and biomarker outcomes were followed at 2, 6 and 24 hours, or 14 or 28 days later. The 14 and 28 day cohorts were duplicated such that contralateral nephrectomy could be performed 3 days prior to sacrifice with functional measurements obtained to isolate the glomerular filtration rate of the injured kidney. RESULTS: The short-term outcomes correlated with the human study findings with urine and serum biomarkers of injury peaking around 24 hours and then normalizing, and reassuring immediate histological outcomes. Functional and histological outcomes at the later time-points (14 and 28 days) demonstrate an increase in fibrosis markers, and a reduction in glomerular filtration rate in the injured kidney, corresponding to the duration of ischemia, while serum and urine biomarkers remained reassuring. CONCLUSIONS: Our findings suggest that clinically available biomarkers of renal function are falsely reassuring against long-term injury following UiAKI, and that the duration of ischemia correlates with impaired function and increased fibrosis.
BACKGROUND: The duration of renal ischemia that is associated with (or leads to) renal injury in patients is uncertain, and a reverse translational research approach has been proposed to improve animal models of AKI to facilitate clinical translatability. We developed a two murine models of unilateral renal ischemia to match a recently published human study that investigated renal injury after unilateral renal ischemia during partial nephrectomy. METHODS: Eight 10-week-old C57BL/6 male mice underwent left UiAKI or sham procedure, with or without intra-operative ice packs. Functional, histological, and biomarker outcomes were followed at 2, 6 and 24 hours, or 14 or 28 days later. The 14 and 28 day cohorts were duplicated such that contralateral nephrectomy could be performed 3 days prior to sacrifice with functional measurements obtained to isolate the glomerular filtration rate of the injured kidney. RESULTS: The short-term outcomes correlated with the human study findings with urine and serum biomarkers of injury peaking around 24 hours and then normalizing, and reassuring immediate histological outcomes. Functional and histological outcomes at the later time-points (14 and 28 days) demonstrate an increase in fibrosis markers, and a reduction in glomerular filtration rate in the injured kidney, corresponding to the duration of ischemia, while serum and urine biomarkers remained reassuring. CONCLUSIONS: Our findings suggest that clinically available biomarkers of renal function are falsely reassuring against long-term injury following UiAKI, and that the duration of ischemia correlates with impaired function and increased fibrosis.
Authors: R Houston Thompson; Brian R Lane; Christine M Lohse; Bradley C Leibovich; Amr Fergany; Igor Frank; Inderbir S Gill; Michael L Blute; Steven C Campbell Journal: Urology Date: 2012-02 Impact factor: 2.649
Authors: Neil A Hukriede; Danielle E Soranno; Veronika Sander; Tayla Perreau; Michelle C Starr; Peter S T Yuen; Leah J Siskind; Michael P Hutchens; Alan J Davidson; David M Burmeister; Sarah Faubel; Mark P de Caestecker Journal: Nat Rev Nephrol Date: 2022-02-16 Impact factor: 42.439
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Authors: Danielle E Soranno; Lara Kirkbride-Romeo; Sara A Wennersten; Kathy Ding; Maria A Cavasin; Peter Baker; Christopher Altmann; Rushita A Bagchi; Korey R Haefner; Christian Steinkühler; John R Montford; Brysen Keith; Katja M Gist; Timothy A McKinsey; Sarah Faubel Journal: JACC Basic Transl Sci Date: 2021-02-22
Authors: Danielle E Soranno; Peter Baker; Lara Kirkbride-Romeo; Sara A Wennersten; Kathy Ding; Brysen Keith; Maria A Cavasin; Christopher Altmann; Rushita A Bagchi; Korey R Haefner; John Montford; Katja M Gist; Laurent Vergnes; Karen Reue; Zhibin He; Hanan Elajaili; Kayo Okamura; Eva Nozik; Timothy A McKinsey; Sarah Faubel Journal: Sci Rep Date: 2022-01-12 Impact factor: 4.996
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Authors: Jin Wei; Jie Zhang; Shan Jiang; Lan Xu; Larry Qu; Bo Pang; Kun Jiang; Lei Wang; Suttira Intapad; Jacentha Buggs; Feng Cheng; Shyam Mohapatra; Luis A Juncos; Jeffrey L Osborn; Joey P Granger; Ruisheng Liu Journal: J Am Soc Nephrol Date: 2021-06-14 Impact factor: 14.978