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Cited by 16Acute Kidney Injury ResearchChronic Kidney Disease and DiabetesRenal and Vascular Pathologies

Murine models of renal ischemia reperfusion injury: an opportunity for refinement using noninvasive monitoring methods

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Harwood, Rachel, Bridge, Joshua, Ressel, Lorenzo, Scarfe, Lauren, Sharkey, Jack, Czanner, Gabriela, Kalra, Philip A, Odudu, Aghogho +3 more·2022·Physiological Reports
DOI 10.14814/phy2.15211PMC PMC8907719
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Abstract

Background Renal Ischaemia Reperfusion Injury (R-IRI) can cause Acute Kidney Injury (AKI) and Chronic Kidney Disease (CKD), resulting in significant morbidity and mortality. To understand the underlying mechanisms, reproducible small-animal models of AKI and CKD are needed. We describe how innovative technologies for measuring kidney function non-invasively in small rodents allow successful refinement of the R-IRI models, and offer the unique opportunity to monitor longitudinally in individual animals the transition from AKI to CKD. Methods Male BALB/c mice underwent bilateral renal pedicle clamping (AKI) or unilateral renal pedicle clamping with delayed contralateral nephrectomy (CKD) under isoflurane anaesthetic. Transdermal GFR monitoring and multi-spectral optoacoustic tomography in combination with statistical analysis were used to identify and standardise variables within these models. Results Pre-clamping anaesthetic time was one of the most important predictors of AKI severity after R-IRI. Standardising pre-clamping time resulted in a more predictably severe AKI model. In the CKD model, initial improvement in renal function was followed by significant progressive reduction in function between weeks 2 and 4. Performing contralateral nephrectomy on day 14 enabled the development of CKD in a survivable way. Conclusions Non-invasive monitoring of global and individual renal function after R-IRI is feasible, reproducible and correlates well with classical markers of injury. This facilitates refinement of kidney injury models and enables the degree of injury seen in pre-clinical models to be translated to those seen in the clinical setting. Thus, future therapies can be tested in a clinically relevant, non-invasive manner. What is already known The severity of Renal Ischaemia Reperfusion injury (R-IRI) varies between animal strain, gender and age. Experimental variables including temperature and clamping time are usually tightly controlled but significant variability still exists. Classically, small rodent experiments depend on endpoint evaluation of serum and histological features of disease. However, new technologies including transdermal glomerular filtration rate (GFR) monitoring and Multispectral Optoacoustic Tomography (MSOT) may enable renal function to be accurately monitored longitudinally, enabling better refinement of these models. What this study adds This study shows that transdermal GFR measurements have reliably enabled refinement of the R-IRI model by standardisation of the duration of isoflurane prior to commencing surgery. Individual kidney function can be assessed in-vivo after unilateral R-IRI using MSOT imaging. The excretion t max of IRDye-800 reliably represents the relative function of the injured kidney, permitting longitudinal in-vivo assessment of differential kidney function. What impact this may have on practice This study demonstrates the utility of two minimally-invasive in-vivo methods of monitoring kidney function which have advantages over classical methods and potentially enable fewer animals to be used in future studies. The study demonstrates refinement of bilateral and unilateral R-IRI models which will also enable a reduction in the number of animals needed for experimentation.

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  • A physiologically valid renal I/R model has not yet been fully established.

    “a physiologically valid renal I/R model has not yet been fully established”

    From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Harwood et al., 2022

    The Introduction (page unavailable) describes renal I/R models as variable and in need of refinement, which supports the concern behind the claim. It does not say that a physiologically valid model has yet to be established; instead, it says the authors developed clinically relevant models of kidney injury. (LLM, conf=0.81)

    Experimental — accuracy not yet measured

  • It is difficult to strictly control the changes in the oxygen environment associated with ischemia and reperfusion.

    “it is difficult to strictly control the changes in the oxygen environment associated with ischemia and reperfusion”

    From Material-dependent oxygen transport governs ischemia-reperfusion injury and drug response in a kidney microphysiological system (2026) · cites this paper as Harwood et al., 2022

    The Results section describes variability in the murine renal ischemia–reperfusion model even when clamp time and temperature are standardized. The Methods and Discussion describe oxygenated anesthesia and the effects of anesthetic duration, but no passage addresses whether changes in the oxygen environment during ischemia and reperfusion are difficult to control (searched: oxygen environment, oxygenation, hypoxia). (LLM, conf=0.70)

    Experimental — accuracy not yet measured

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Cited by

Sorted by citations

Authors
Harwood, R., Bridge, J., Ressel, L., Scarfe, L., Sharkey, J., Czanner, G., Kalra, P. A., Odudu, A., Kenny, S., Wilm, B., & Murray, P.
Affiliations
  • University of Liverpool (GB)
  • Slovak University of Technology in Bratislava (SK)
  • Salford Royal NHS Foundation Trust (GB)
  • University of Manchester (GB)
Corresponding author
Harwood, Rachel
ORCID
Venue
Physiological Reports
Publisher
Wiley
Published
2022-03
Volume
10
Issue
5
Pages
e15211-e15211
ISSN
2051-817X (ISSN-L)
DOI
10.14814/phy2.15211
PMC
PMC8907719
OpenAlex
W4221094002
Cited by
16
References
0
Citations by year
2026: 3 · 2025: 5 · 2024: 4 · 2023: 2 · 2022: 2
FWCI
2.01
Type
journal article
Language
en
Open access
Licence
Locations
  • Physiological Reports (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • Liverpool John Moores University (acceptedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Kidney Research UK
  • Wellcome Trust
Topics
  • Health Sciences › Medicine › Nephrology › Acute Kidney Injury Research
  • Health Sciences › Medicine › Nephrology › Chronic Kidney Disease and Diabetes
  • Health Sciences › Medicine › Pulmonary and Respiratory Medicine › Renal and Vascular Pathologies
Keywords
renal ischemia-reperfusion injury, acute kidney injury, chronic kidney disease, mouse model, multispectral optoacoustic tomography, renal pedicle clamping, contralateral nephrectomy, model standardization
MeSH terms
Animals, Disease Models, Animal, Kidney, Male, Mice, Inbred BALB C, Reperfusion Injury, Mice, Renal Insufficiency, Chronic, Acute Kidney Injury

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