A novel rodent model of severe renal ischemia reperfusion injury that better mimics the renal transplant recipient
Ryan Ghita1,2, Rashida Lathan1, Robert Pearson1,2, Henry Whalen1,2, Patrick Mark1,2, Marc Clancy1.
1Institute of Cardiovascular and Renal Sciences, University of Glasgow, Glasgow, United Kingdom; 2Renal Transplant Unit, Queen Elizabeth University Hospital of Glasgow, NHS Greater Glasgow and Clyde, Glasgow, United Kingdom
Introduction: The increasing use of renal allografts from “extended criteria” donors has resulted in increased numbers of organs that are subjected to significant peri- transplantation injury. In order to develop therapies to ameliorate the ischaemia reperfusion injury (IR) an animal model that closely replicates the transplant patient is vital. Many rodent models do not produce a permanent reduction in renal function. In 2016 our published an animal model that produces a severe, consistent renal injury that closely replicates the pathological processes encountered in clinical IR. The model also incorporated the use of inulin clearance studies to assess glomerular filtration rate. However, one main issues with the rodent model, and other models of IR, is that the injured kidney is not recovering in an environment of chronic renal failure. In the clinical scenario a transplanted kidney is more often than not implanted and recovering in a patient with chronic renal failure (CRF). Furthermore, glomerular filtration assessment using inulin clearance was time consuming and a terminal event for the rodent. In an attempt to address these shortcomings a new rodent model was devised.
Methods: In 75 Fischer 344 rats, renal artery branches supplying 2/3rd of the right kidney were ligated. The rats were allowed to recover for a minimum of 2 weeks before undergoing 120 minutes of warm ischaemia of the left, previously untouched, kidney. Renal function was calculated using a transdermal transducer which measured the light emitted from the administered, and renal excreted, fluorescently labelled polysaccharide (MediBeacon, Mannheim Germany).
Results: One rat death was recorded in 75 rats that underwent 2/3rd nephrectomy of right kidney and subsequent 120 minutes warm ischaemia of the left kidney. Rat weights dipped after each surgery then increased back to pre-operative weights. Operating time to perform 2/3rd nephrectomy surgery from skin to skin varied between 15 and 30 minutes. Glomerular filtration rate of naïve rats (n=7) was 0.41ml/min/100gbw compared to 0.23ml/min/100gbw (p 0.09) in rats that underwent 2/3rd nephrectomy then subsequent 120min IR (n=4).
Discussion: The 5/6 nephrectomy model has been a commonly used model of CRF over the last 50 years. A rat with 1/6th renal function remaining develop features of CRF such as increased blood pressure, urea, creatinine, sodium and potassium.The 2/3rd nephrectomy of the right kidney creates an environment of reduced renal function in which the left kidney recovers. Therefore, better mimicking the conditions faced by a transplanted kidney in the clinical scenario. One reason this has not been tested before is the fear of an unacceptable increase in rat deaths. This animal model has pushed the boundaries in terms of optimising the rodent IR transplant model but still manages to follow the strict code of conduct of animal testing. The addition of the novel MediBeacon® transdermal GFR measurement system allows for quicker, easier, minimally invasive and non-terminal accurate measurement of renal function. Further improving the animal model.
 A novel rodent model of severe renal ischemia reperfusion injury Whalen, H., Shiels, P. , Littlejohn, M. and Clancy, M. (2016) A novel rodent model of severe renal ischemia reperfusion injury. Renal Failure, 38(10), pp. 1694-1701. (doi:10.3109/0886022x.2016.1144024) (PMID:26887330)
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