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Summary

Abstract

Introduction

Protocol

Representative Results

Discussion

Acknowledgements

Materials

References

Medicine

A Large Animal Model for Acute Kidney Injury by Temporary Bilateral Renal Artery Occlusion

Published: February 2nd, 2021

DOI:

10.3791/62230

1Department of Cardiac Surgery, Boston Children’s Hospital, Harvard Medical School

This study presents a highly reproducible large animal model of renal ischemia-reperfusion injury in swine using temporary percutaneous bilateral balloon-catheter occlusion of the renal arteries for 60 min and reperfusion for 24 h.

Acute kidney injury (AKI) is associated with higher risk for morbidity and mortality post-operatively. Ischemia-reperfusion injury (IRI) is the most common cause of AKI. To mimic this clinical scenario, this study presents a highly reproducible large animal model of renal IRI in swine using temporary percutaneous bilateral balloon-catheter occlusion of the renal arteries. The renal arteries are occluded for 60 min by introducing the balloon-catheters through the femoral and carotid artery and advancing them into the proximal portion of the arteries. Iodinated contrast is injected in the aorta to assess any opacification of the kidney vessels and confirm the success of the artery occlusion. This is furtherly confirmed by the flattening of the pulse waveform at the tip of the balloon catheters. The balloons are deflated and removed after 60 min of bilateral renal artery occlusion, and the animals are allowed to recover for 24 h. At the end of the study, plasma creatinine and blood urea nitrogen significantly increase, while eGFR and urine output significantly decrease. The need for iodinated contrast is minimal and does not affect renal function. Bilateral renal artery occlusion better mimics the clinical scenario of perioperative renal hypoperfusion, and the percutaneous approach minimizes the impact of the inflammatory response and the risk of infection seen with an open approach, such as a laparotomy. The ability to create and reproduce this clinically relevant swine model eases the clinical translation to humans.

Acute kidney injury (AKI) is a commonly diagnosed condition among surgical patients associated with significant morbidity and mortality1,2. Available data show that AKI can affect even half of all hospitalized patients worldwide and leads to 50% mortality rate in patients in the intensive care unit1,3. Despite its high prevalence, current AKI therapy remains limited to preventive strategies, such as fluid management and dialysis. Therefore, there is an ongoing interest in exploring alternative therapies for AKI4,

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All in vivo studies were conducted in accordance with the National Institutes of Health's guidelines on animal care and use and were approved by the Boston Children's Hospital's Animal Care and Use Committee (Protocol 18-06-3715). All animals received humane care in compliance with the Guide for the Care and Use of Laboratory Animals. Figure 1 shows the timeline including anesthesia, surgical preparation, and timepoints for primary outcome measurements of this study.

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Functional analysis
The representative results of this study arise from 6 animals and the data shown are mean ± standard error of the mean.Renal function is assessed by determining the urine output, estimated glomerular filtration rate (eGFR), plasma creatine, and blood urea nitrogen (BUN). The biomarkers of renal function are assessed using a portable chemistry analyzer. eGFR is calculated according to the following formula: eGFR =1.879 × BW1.092/PCr0.6 (.......

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AKI is a common clinical disorder affecting up to 50% of hospitalized adult patients worldwide6,12. A clinically relevant animal model is needed to further investigate the pathophysiology of the disease and potential therapeutic targets. Although there are several murine models replicating AKI, these do not completely mimic their respective clinical scenarios and the anatomy of the human kidney. This study proposes a clinically relevant swine model to allow for t.......

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We would like to thank Dr. Arthur Nedder for his help and guidance. This work was supported by the Richard A. and Susan F. Smith President's Innovation Award, Michael B. Klein and Family, The Sidman Family Foundation, The Michael B. Rukin Charitable Foundation, The Kenneth C. Griffin Charitable Research Fund, and The Boston Investment Council.

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Name Company Catalog Number Comments
0.9% sodium chloride injection, usp, 100 ml viaflex plastic container Baxter 2B1302 For animal hydration
Agent contrast 100.0ml injection media btl ioversal 74% CARDINAL HEALTH 133311 For visualizing the vasculature
Bard Bardia Closed System Urinary Drainage Bag BARD Inc 802001 For urine collection
BD Vacutainer K2 EDTA BD 367841 For blood sample storage
BD Vacutainer Lithium Heparin BD 366667 For blood sample storage
Betadine Henry Schein 6906950 For skin disinfection
Bookwalker retractor Codman For skin retraction
Bupivacaine 0.25% Hospira Administer at incision site for analgesia
Buprenorphine SR Zoo Pharm 10mg/ml bottle, Dose: 0.2mg/kg SC
Cath angio 5.0 Fr x100.0 cm 0.038 in JR4 MERIT MEDICAL SYSTEM INC 7523-21 For identification of the renal arteries
Cuffed endotracheal tube Emdamed To establish a secure airway for the duration of the operation
EKG Medtronics- Physiocontrol LifePak 20 Oxygen saturation monitor GE Healthcare Madison WI For oxygen saturation monitoring
Encore 26 inflator BOSTON SCIENTIFIC 710113 For inflating the balloon catheters
Ethanol 95% (Ethyl alcohol) Henry Schein For skin disinfection
Fentanyl patch Mylan Dose: 25-50mcg/hr, TD
Gold silicone coated Foley TELEFLEX MEDICAL INC 180730160 For urine collection
Heparin sodium LEO Pharma A/S Dose: 200 IU/kg IV
i33 ultrasound machine Phillips Use ultrasonographic guidance for femoral catherization if necessary
Inqwire diagnostic guide wire - 0.035" (0.89 mm) - 260 cm (102") - 1.5 mm j-tip MERIT MEDICAL SYSTEM INC 6609-33 For guiding the balloon catheters to the renal arteries
Intravenous catheter, size 20 gauge Santa Cruz Biotechnology Inc SC-360097 For fluid administration
Isoflurane Patterson Veterinary Supply, Inc. 21283620 Dose: 3%, INH
Metzenbaum blunt curved 14.5 cm - 5(3/4)" Rudolf Medical RU-1311-14M For tissue dissection and cutting
Neonatal disposable transducer kit with 30ml/hr flush device and double 4-way stopcocks for continuous monitoring Argon Medical 041588505A For pressure measurement
Powerflex pro PTA dilatation catheter 6 x 20 mm - shaft length (135cm) CARDINAL HEALTH 4400602X For occlusion of the renal arteries
Pressure monitoring lines mll/mll - 12" clear, mll/mll Smiths Medical B1571/MX571 For pressure measurement
Procedure pack Molnlycke Health Care 97027809 Surgical drape, gauze pads, syringes, beaker etc
Protamine Henry Schein 1044148 For heparin reversal
Scalpel blade - size #10 Cardinal Health (Allegiance) 32295-010 For the skin incisions
Stopcock iv 4 way lrg bore rotg male ll adptr strl Peoplesoft 1550 For connecting tubings
Straight lateral retractor Codman For skin retraction
Suture perma hnd 18in 2-0 braid silk blk CARDINAL HEALTH 1 A185H For suturing incision site and securing catheters
Syringe contrast injection 10ml fixed male luer red MERIT MEDICAL SYSTEM INC MSS111-R To administer the contrast agent
Syringe medical 60ml ll plst strl ltx free disp CARDINAL HEALTH 1 BF309653 For urine collection and flushing of the angiocath
Tilzolan (tiletamine/zolazepam) Patterson Veterinary Supply, Inc. 07-893-1467 Dose: 4-6 mg/kg, IM
Xylazine Putney, INC Dose: 1.1-2.2 mg/kg, IM

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