Corticomedullary Shunting After Ischaemia and Reperfusion in The Porcine Kidney?

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Michael Rehling, Stine Gram Skjøth, Anna Krarup Keller, Lene Elsebeth Nielsen, and 3 more This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-70107/v1 This work is licensed under a CC BY 4.0 License Status: Published Journal Publication published 15 Apr, 2022 Read the published version in BMC Nephrology → Version 1 posted 4 You are reading this latest preprint version Abstract Background: An animal model offers the opportunity to study organs in vivo and the porcine model was chosen to simulate a renal transplantation with complications. Renal perfusion may redistribute from cortex to medulla during systemic hypovolaemia and after renal ischaemia for other reasons, but there is no consensus on this matter. We studied renal perfusion after renal ischaemia and reperfusion. Methods: Renal perfusion distribution was examined by use of 153 Gadolinium-labeled microspheres (MS) after 2 hours (hrs) and 4 hrs ischaemia of the pig kidney followed by 4 hrs of reperfusion. Intra-arterial injected MS are trapped in the glomeruli in renal cortex, which means that MS are not present in the medulla under normal physiological conditions. Results: Visual evaluation after reperfusion demonstrated that MS redistributed from the renal cortex to the medulla in 6 out of 16 pigs (38%) subjected to 4 hrs ischaemia and in one out of 18 pigs subjected to 2 hrs ischaemia. Central renal uptake of MS covering the medullary/total renal uptake was significantly higher in kidneys subjected to 4 hrs ischaemia compared with pigs subjected to 2 hrs ischaemia (69±5% vs. 63±1%, p<0.001), and also significantly higher than in the contralateral kidney (69±5% vs. 63±2, p<0.001). Analysis of blood and urine demonstrated no presence of radioactivity. Conclusion: The study demonstrated the presence of MS in the renal medulla in response to renal ischaemia and reperfusion suggesting that severe ischaemia and reperfusion of the pig kidney leads to opening of functional shunts bypassing glomeruli. Urology & Nephrology Microspheres Renal blood flow Renal ischaemia Renal perfusion Renal redistribution Renal shunts. Figures Figure 1 Figure 2 Background Blood perfusion of the kidney is higher than the perfusion of any other organ. In the human kidney, approximately 80% of the total perfusion distributes to the cortex providing only a minor fraction of the perfusion to the renal medulla [ 1 ], which also has a higher oxygen extraction during perfusion than the cortex. However, after severe systemic hypovolaemia, pale renal cortex with red highly perfused medulla is seen, and cortical necrosis with no regain of function is seen in some cases. In 1947, Trueta and coworkers reported that renal blood flow appeared to be shunted to the renal medulla during haemorrhage or shock [ 2 ]. This phenomenon was termed “Cortical ischaemia with maintained blood flow through the medulla” [ 3 , 4 ]. Redistribution of renal perfusion with relative cortical ischaemia is still an accepted outcome in response to haemorrhagic shock. Although more than 70 years have passed by since this original observation, there is still not a clear understanding on how this takes place [ 5 – 9 ]. Microspheres (MS) can be used to measure regional tissue blood flow [ 10 ]. Under normal physiological conditions intra-arterial injected microspheres are trapped in the glomeruli in the renal cortex. Thus, MS are not present in the renal medulla unless they have bypassed the glomeruli. We have developed a pig model where kidneys can be subjected to ischaemia and we hypothesise that the number of MS present in the renal medulla is proportional to the number of functional shunts in the glomeruli. Thus, we examined the renal distribution of intra-arterial injected MS with the assumption that the presence of radio labeled MS in the renal medulla is a result of MS that have entered the renal medulla via shunts. Methods The methods are described in detail elsewhere [ 11 ]. In brief, 34 female crossbred slaughter pigs (Danish Landrace-Yorkshire-Duroc) weighing 35–45 kg were used. The pigs were housed in the research stable facility in Trige, Aarhus. All pigs were bred on a conventional sow farm, and moved to a collaborating farm when weighing approximately 15 kg. The 34 pigs were randomized and went through the study. The pigs with a mean weight of 38 ± 2 kg were exposed to unilateral warm ischaemia by clamping the renal artery for 2 hrs (n = 18) or for 4 hrs (n = 16) followed by 4 hrs of reperfusion. Catheters were inserted in the left jugular vein, and the carotid artery for continuous monitoring of blood pressure, infusion of drugs and fluid. The aorta was catheterised through the femoral artery and the catheter tip for MS injection was placed in the aortic arch. After 4 hrs of reperfusion, renal perfusion was estimated by injection of 15–20 MBq of 153 Gadolinium-labeled MS with a diameter of 15 µm. At the end of the experiment, the animals were put to death with an overdose of pentobarbital while under anesthesia. After termination and nephrectomy, the renal distribution of MS was studied in absolute counts over each kidney using a gamma-camera. Total renal counts and counts over the central renal areas including medulla were estimated by computer drawing of the region of the entire kidney and over the central 75% of the kidney. All counts were corrected for background radiation and acquisition time, and normalised to the amount of injected tracer. Based on the visual perfusion redistribution of the scintigram, each kidney was graded from 0–3 in a blinded way by two observers: Grade 0: Homogeneous pattern similar to control kidneys. Grade 1: Weaker activity, but still homogeneous. Grade 2: Showing a pattern, identifying the medulla. Grade 3: Showing a pattern, clearly showing the medullary architecture and the anatomical outline of calyces. Statistics For statistical analysis an open-source statistical package from SciPy was used [12]. Data are expressed as mean ± standard deviation, geometric mean with 95% confidence interval (CI) or number with percentages, and with 95% CI when appropriate. Differences between groups were tested using Welsh T-test. A difference was considered significant when P < 0.05. Results The weight of the kidneys subjected to 4 hrs of ischaemia was significantly higher than the weight of the kidneys subjected to 2 hrs of ischaemia (p < 0.005) (Table 1 ). In both groups the renal weight was significantly higher than the weight of the contralateral non-ischaemic kidney (p < 0.001). Table 1. The table gives the weight of the two kidneys and the absolute and relative uptake of microspheres in the kidney after two and four hours of unilateral renal ischaemia followed by reperfusion for four hours. Ischaemia 2 hrs (n = 18) Ischaemia 4 hrs (n = 16) Ischaemic kidney Contralateralkidney Ischaemic kidney Contralateral kidney Kidney weight (gram) 109 ± 13 90 ± 13 136 ± 28 101 ± 17 Absolute uptake of microspheres (cps MBq − 1 ) 3.8 ± 1.5 4.1 ± 1.8 1.6 ± 1.5 4.0 ± 1.3 Relative uptake of microspheres (percent of total uptake) 48 ± 14 52 ± 14 29 ± 19 71 ± 19 Renal uptake in central 75% including renal medulla (percent of whole kidney uptake) 63 ± 1 62 ± 2 69 ± 5 63 ± 2 All numbers as means ± SD The total renal uptake of MS as an indicator of blood flow was significantly lower after 4 hrs ischaemia than after 2 hrs ischaemia (p < 0.001). After 4 hrs ischaemia the MS uptake was also significantly lower than the uptake of the contralateral kidney (p < 0.001). The renal MS uptake after 2 hrs ischaemia did not differ significantly from the uptake of the contralateral kidney (p = 0.5) (Table 1 ). Uptake of MS in the 75% central renal area including the medulla measured in per cent of uptake in the total kidney was significantly higher in kidneys subjected to 4 hrs compared to 2 hrs ischaemia (p < 0.001). In kidneys subjected to renal ischaemia for 4 hrs it was also significantly higher than in the contralateral kidney (p < 0.001) (Table 1 ). Redistribution of MS from cortex to medulla as assessed by blinded visual evaluation of the scintigrams showed redistribution in 6 out of 16 pigs (38%) subjected to ischaemia for 4 hrs, and in one out of 18 pigs (5%) with ischaemia for 2 hrs. Figure 1 shows an example of renal MS redistribution after 4 hrs ischaemia. The scintigram from the ischaemic side shows high activity in the medulla and faint activity in the renal cortex. Figure 2 shows that the higher the perfusion redistribution grade of the kidney, the higher uptake of MS in the central renal area including the medulla relative to uptake in total kidney. Analysis of blood and urine samples demonstrated that no detectable radioactivity was present in these samples. One pig died directly after tracer injection at the end of the reperfusion phase (t = 420) from unknown causes, and for this reason was excluded from the study Discussion The present study suggests that radioactive labeled microspheres (MS) can identify corticomedullary shunts after ischaemia and reperfusion of the human like polypapillary porcine kidney. We studied renal blood flow by use of uptake of MS after unilateral renal ischaemia for 2 and 4 hrs followed by 4 hrs of observation after reperfusion. After intra-arterial injection of MS the absolute renal uptake of MS was significantly reduced in the kidneys subjected to 4 hrs total ischaemia. The uptake of MS after 2 hrs of renal ischaemia did not differ significantly from the uptake in the contralateral non-ischaemic kidney. After 4 hrs ischaemia, there was a relatively high uptake of MS in the central area of the kidney including the renal medulla both on the scintigrams and calculated from the absolute values. These observations may be explained by the special anatomy of blood supply to the kidneys. Blood supply to the nephron is maintained by two vascular systems organised in a serial manner: the capillaries in the glomeruli and the tubular capillaries in the renal medulla [ 1 ]. Thus, intra-arterial injected MS reach the renal cortex with the arterial blood, and in the glomeruli they are trapped due to their diameter of 15 µm and thereby separated from the blood stream. Thus, measuring total renal blood flow may be done from the number of MS in the whole kidney, whereas regional distribution of MS is unreliable in calculation of the relative distribution of renal perfusion. However, this normal trapping of MS in the glomeruli explained by renal anatomy makes it possible to quantify functional active shunts from the number of MS present in the renal medulla. In contrast to the early anatomical studie by Trueta and others [ 2 ] we made a physiological study with MS as a tracer. We measured uptake of radiolabelled MS on planar images by use of a 2-dimensional technique. We did not have access to SPECT/CT images in these pig studies. Therefore, due to anatomical overlap of medulla and cortex the uptake in renal medulla will be overestimated, but the uptake in the central 75% includes the total medulla. Our results are consistent with the opening of corticomedullary shunts in the ischaemic kidney. However, we cannot exclude that vasodilation in cortical juxtamedullary afferent arterioles after long-term ischaemia could explain our findings, although we believe that our 15 µm MS would not be able to pass the capillaries in glomeruli. Our visualisation technique seems to indicate presence of MS in medulla and not in the juxtamedullary cortex. Conclusion In conclusion, the study showed the presence of radiolabeled MS in the renal medulla in response to severe renal ischaemia suggesting that this leads after reperfusion to opening of functional shunts bypassing the glomeruli. Radiolabeled MS have been used for decades for the measurement of organ blood flow and perfusion and the present results point to functional intrarenal shunts, which have been suggested for decades, but not verified so far. Abbreviations MS : 153 Gadolinium-labeled microspheres Hrs : hours Kg : kilogram MBq : Megabecquerel µm: Mikrometer CI : Confidence interval SPECT : Single-photon emission computed tomography CT : Computed tomography Declarations Ethics approval and consent to participate Animal experiments conform to internationally accepted standards and have been approved by the appropiate institutional review board. The study was approved by the Danish Inspectorate of Animal Experiments (2010/561-1837) Consent for publication Not applicable. Availability of data and materials The datasets generated and analysed during the current study are included in this published article, and are available from the corresponding author on reasonable request. Competing interests The authors declare that they have no competing interests. Funding The project was carried out with financial support from the Faculty of Health Sciences, Aarhus University, the Institute of Clinical Medicine, Aarhus University, Helen & Ejnar Bjørnows Foundation, Sophus Jacobsen & Hustru Astrid Jacobsens Foundation, the A.P. Moeller Foundation, the Danish Kidney Foundation, and C.C. Klestrup & Hustru Henriette Klestrups Foundation. The Funding did not have anything to do with the study design, data collection, analysis, interpretation or writing. Authors’ Contributions MR has made contributions to study conception, design, interpretation, drafting and critical revising the manuscript. SSP has made contributions to study conception, design, acquisition, analysis, interpretation, drafting and revising the manuscript. AKK has made contributions to conception, design, acquisition and interpretation. LEN has made contributions to design, acquisition, analysis and revising the manuscript. CF has made contributions to interpretation, specifically data analyses, drafting and critical revising the manuscript. BJ has made contributions to study conception, design, interpretation, drafting and critical revising the manuscript. JF has made contributions to study interpretation, drafting and revising the manuscript. All Authors have edited, read and approved the final manuscript. Acknowledgements We thank Alain Prigent, Paris and Birger Hesse, Copenhagen, for their advice and helpful suggestions and Ken Peter Kragsfeldt for help with the figures. References Munger K, Kost Jr C, Brenner B, Maddox D. The renal circulations and glomerular ultrafiltration. In: Taal M, Chertow G, Marsden P, Skorecki K, Yu Y, Brenner B, editors. Brenner and Rectors, The Kidney. Philadelphia: Elsevier Saunders; 2012. p. 94-137. Trueta J, Barclay A, Daniel P. Studies of the renal circulation. Oxford: Blackwell Scientific Publications Ltd, 1947. Daniel P, Peabody C, Prichard M. Cortical ischaemia of the kidney with maintained blood flow through the medulla. Q J Exp Physiol Cogn Med Sci. 1952;37:11-8. Daniel P, Peabody C, Prichard M. Observations on the circulation through the cortex and the medulla of the kidney. Q J Exp Physiol Cogn Med Sc. 1951;36:199-203. Lilienfields L, Maganzini H, Bauer M. Blood flow in the renal medulla. Circ Res. 1961;9:614-7. Spinelli FR, Wirz H, Brucher C, Pehling G. Non-existence of shunts between afferent and efferent arterioles of juxtamedullary glomeruli in dog and rat kidneys. Nephron. 1972;9:123-8. Stone AM, Stein T, LaFortune J, Wise L. Changes in intrarenal blood flow during sepsis. Surg Gynecol Obstet. 1979; 148:731-4. Greenfield SP, Lewis W III, Perry B, Wan J, Morin F III. Regional renal blood flow measurements using radioactive microspheres in a chronic porcine model with unilateral vesicoureteral reflux. J Urol. 1995;154:816-9. Langenberg C, Bellomo R, May C, Wan L, Egi M, Morgera S. Renal blood flow in sepsis. Crit Care. 2005;9:R363-74. Peters A, Myers M. Measurement of blood flow. In: Peters A, Myers M, editors. Physiological measurements with Radionuclides in Clinical Practice. Oxford: Oxford University Press; 2003. p. 63-67. Pedersen SS, Keller AK, Nielsen MK, Jespersen B, Falborg L, Rasmussen JT, et al. Cell injury after ischemia and reperfusion in the porcine kidney evaluated by radiolabelled microspheres, sestamibi, and lactadherin. EJNMMI Res. 2013;3:62. Virtanen P, Gommers R, Oliphant TE, et al. SciPy 1.0: Fundamental algorithms for scientific computing in Python. Nat Methods 2020;17:261–272. Available from: http://www.scipy.org/ . Accessed August 2020. Cite Share Download PDF Status: Published Journal Publication published 15 Apr, 2022 Read the published version in BMC Nephrology → Version 1 posted First submitted to journal 14 Sep, 2020 Editor assigned by journal 14 Sep, 2020 Submission checks completed at journal 13 Sep, 2020 Editor invited by journal 13 Sep, 2020 You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. 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Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-70107","acceptedTermsAndConditions":true,"allowDirectSubmit":false,"archivedVersions":[],"articleType":"Research article","associatedPublications":[],"authors":[{"id":3044872,"identity":"e01514e4-d0d4-4e5f-9b7c-f7dddfee0f1b","order_by":0,"name":"Michael Rehling","email":"","orcid":"","institution":"Aarhus Universitetshospital, department of Nuclear Medicine And PET","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Michael","middleName":"","lastName":"Rehling","suffix":""},{"id":3044873,"identity":"ae893218-4655-4d26-986c-f0f10bae795b","order_by":1,"name":"Stine Gram Skjøth","email":"","orcid":"","institution":"Aarhus Universitet Institut for Klinisk Medicin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Stine","middleName":"Gram","lastName":"Skjøth","suffix":""},{"id":3044874,"identity":"29c4cc3c-12c1-4b4f-b775-6e285ee83598","order_by":2,"name":"Anna Krarup Keller","email":"","orcid":"","institution":"Aarhus Universitetshospital","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Anna","middleName":"Krarup","lastName":"Keller","suffix":""},{"id":3044875,"identity":"50700ca1-6e75-4615-a2e1-ed003087f8f8","order_by":3,"name":"Lene Elsebeth Nielsen","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAABDElEQVRIie2PMWvCQBTH33FwWS7JelIlXyEhEJfQz5IgdJIuBXFwiAjPKXukYL9Gx0igU0g/gEvdHSJd6qB4UVoRPHHscL/ljj/vx/89AI3mH2L9fhjQRD4hWPQUkEyhsPOHNMoTsLsVOCnFX6JWjHTxBUN4tozxpN68fzrMMHPYInRmiULhVc+FEl4YX2BrVi49pFZEUgT/VdUi+oEgCDGKGKmJy4hR7oIpk7lKcdbdH7KXirOafO+wOipkd0sRPGgOly0keSCYHxXatCgX431fRB9yKx5jK8WevIW7RbsSvup82yi9uh6F8du0KOotPjq2XXqr9SDsZLmipiECcRnIYXF1UqPRaDT3cQACp0wQaj4OGgAAAABJRU5ErkJggg==","orcid":"https://orcid.org/0000-0002-8936-9976","institution":"Aarhus Universitetshospital","correspondingAuthor":true,"submittingAuthor":false,"prefix":"","firstName":"Lene","middleName":"Elsebeth","lastName":"Nielsen","suffix":""},{"id":3044876,"identity":"9f528c59-7d00-4f12-aef4-71fa92c77f6f","order_by":4,"name":"Christian Flø","email":"","orcid":"","institution":"Aarhus Universitetshospital dept. of Nuclear Medicine and PET","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Christian","middleName":"","lastName":"Flø","suffix":""},{"id":3044877,"identity":"0aa26d3c-990e-4aea-a9ec-c42b141d5633","order_by":5,"name":"Bente Jespersen","email":"","orcid":"","institution":"Aarhus Universitetshospital Nyremedicinsk Afdeling C","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Bente","middleName":"","lastName":"Jespersen","suffix":""},{"id":3044878,"identity":"3ba9c8db-de6e-4621-9ce2-9ca5ed629dc1","order_by":6,"name":"Jørgen Frøkiær","email":"","orcid":"","institution":"Aarhus Universitet Institut for Klinisk Medicin","correspondingAuthor":false,"submittingAuthor":false,"prefix":"","firstName":"Jørgen","middleName":"","lastName":"Frøkiær","suffix":""}],"badges":[],"createdAt":"2020-09-01 11:41:29","currentVersionCode":1,"declarations":"","doi":"10.21203/rs.3.rs-70107/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-70107/v1","draftVersion":[],"editorialEvents":[{"content":"https://doi.org/10.1186/s12882-022-02780-0","type":"published","date":"2022-04-15T12:54:03+00:00"}],"editorialNote":"","failedWorkflow":false,"files":[{"id":2781713,"identity":"50a84c9f-4a3f-41d3-9724-719bae5ac5bf","added_by":"auto","created_at":"2020-10-05 15:26:21","extension":"jpg","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":20369,"visible":true,"origin":"","legend":"Distribution of radio-labeled microspheres in a pig after renal ischaemia and reperfusion.\nIn comparison to the non-ischaemic right kidney, the left kidney shows an increased uptake of radio-labeled microspheres in renal medulla relative to the total kidney.","description":"","filename":"Fig1.JPG","url":"https://assets-eu.researchsquare.com/files/rs-70107/v1/Fig1.JPG"},{"id":2781714,"identity":"9b32d851-2451-4f14-b9df-0b243a1c1e50","added_by":"auto","created_at":"2020-10-05 15:26:21","extension":"jpg","order_by":2,"title":"Figure 2","display":"","copyAsset":false,"role":"figure","size":46220,"visible":true,"origin":"","legend":"Comparison of methods for the study of distribution of radio-labeled microspheres. The figure shows a positive correlation between visual distribution score grade 1-3 and the measured fraction of microspheres in the central kidney including medulla relative to the entire kidney (r2 =0.98).\nGrade 0 is a homogeneous pattern similar to control kidneys and Grade 3 is a pattern clearly showing the medullary architecture and the anatomical outline of calyces.","description":"","filename":"Fig2.JPG","url":"https://assets-eu.researchsquare.com/files/rs-70107/v1/Fig2.JPG"},{"id":20384888,"identity":"39bb9932-60e8-4b2a-bcf6-0264381713be","added_by":"auto","created_at":"2022-04-15 12:54:06","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":298854,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-70107/v1/c0e6ba0c-c9e7-468b-ab44-09d1b141fd8a.pdf"}],"financialInterests":"","formattedTitle":"\u003cp\u003eCorticomedullary Shunting After Ischaemia and Reperfusion in The Porcine Kidney?\u003c/p\u003e","fulltext":[{"header":"Background","content":" \u003cp\u003eBlood perfusion of the kidney is higher than the perfusion of any other organ. In the human kidney, approximately 80% of the total perfusion distributes to the cortex providing only a minor fraction of the perfusion to the renal medulla [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e], which also has a higher oxygen extraction during perfusion than the cortex. However, after severe systemic hypovolaemia, pale renal cortex with red highly perfused medulla is seen, and cortical necrosis with no regain of function is seen in some cases.\u003c/p\u003e \u003cp\u003eIn 1947, Trueta and coworkers reported that renal blood flow appeared to be shunted to the renal medulla during haemorrhage or shock [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e]. This phenomenon was termed \u0026ldquo;Cortical ischaemia with maintained blood flow through the medulla\u0026rdquo; [\u003cspan citationid=\"CR3\" class=\"CitationRef\"\u003e3\u003c/span\u003e, \u003cspan citationid=\"CR4\" class=\"CitationRef\"\u003e4\u003c/span\u003e]. Redistribution of renal perfusion with relative cortical ischaemia is still an accepted outcome in response to haemorrhagic shock. Although more than 70\u0026nbsp;years have passed by since this original observation, there is still not a clear understanding on how this takes place [\u003cspan additionalcitationids=\"CR6 CR7 CR8\" citationid=\"CR5\" class=\"CitationRef\"\u003e5\u003c/span\u003e\u0026ndash;\u003cspan citationid=\"CR9\" class=\"CitationRef\"\u003e9\u003c/span\u003e].\u003c/p\u003e \u003cp\u003eMicrospheres (MS) can be used to measure regional tissue blood flow [\u003cspan citationid=\"CR10\" class=\"CitationRef\"\u003e10\u003c/span\u003e]. Under normal physiological conditions intra-arterial injected microspheres are trapped in the glomeruli in the renal cortex. Thus, MS are not present in the renal medulla unless they have bypassed the glomeruli. We have developed a pig model where kidneys can be subjected to ischaemia and we hypothesise that the number of MS present in the renal medulla is proportional to the number of functional shunts in the glomeruli. Thus, we examined the renal distribution of intra-arterial injected MS with the assumption that the presence of radio labeled MS in the renal medulla is a result of MS that have entered the renal medulla via shunts.\u003c/p\u003e "},{"header":"Methods","content":" \u003cp\u003eThe methods are described in detail elsewhere [\u003cspan citationid=\"CR11\" class=\"CitationRef\"\u003e11\u003c/span\u003e]. In brief, 34 female crossbred slaughter pigs (Danish Landrace-Yorkshire-Duroc) weighing 35\u0026ndash;45\u0026nbsp;kg were used. The pigs were housed in the research stable facility in Trige, Aarhus. All pigs were bred on a conventional sow farm, and moved to a collaborating farm when weighing approximately 15\u0026nbsp;kg. The 34 pigs were randomized and went through the study. The pigs with a mean weight of 38\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u0026nbsp;kg were exposed to unilateral warm ischaemia by clamping the renal artery for 2 hrs (n\u0026thinsp;=\u0026thinsp;18) or for 4 hrs (n\u0026thinsp;=\u0026thinsp;16) followed by 4 hrs of reperfusion. Catheters were inserted in the left jugular vein, and the carotid artery for continuous monitoring of blood pressure, infusion of drugs and fluid. The aorta was catheterised through the femoral artery and the catheter tip for MS injection was placed in the aortic arch. After 4 hrs of reperfusion, renal perfusion was estimated by injection of 15\u0026ndash;20\u0026nbsp;MBq of \u003csup\u003e153\u003c/sup\u003eGadolinium-labeled MS with a diameter of 15\u0026nbsp;\u0026micro;m. At the end of the experiment, the animals were put to death with an overdose of pentobarbital while under anesthesia. After termination and nephrectomy, the renal distribution of MS was studied in absolute counts over each kidney using a gamma-camera. Total renal counts and counts over the central renal areas including medulla were estimated by computer drawing of the region of the entire kidney and over the central 75% of the kidney. All counts were corrected for background radiation and acquisition time, and normalised to the amount of injected tracer.\u003c/p\u003e \u003cp\u003eBased on the visual perfusion redistribution of the scintigram, each kidney was graded from 0\u0026ndash;3 in a blinded way by two observers: Grade 0: Homogeneous pattern similar to control kidneys. Grade 1: Weaker activity, but still homogeneous. Grade 2: Showing a pattern, identifying the medulla. Grade 3: Showing a pattern, clearly showing the medullary architecture and the anatomical outline of calyces.\u003c/p\u003e \n\u003cp\u003e\u003cstrong\u003eStatistics\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eFor statistical analysis an open-source statistical package from SciPy was used [12]. Data are expressed as mean \u0026plusmn; standard deviation, geometric mean with 95% confidence interval (CI) or number with percentages, and with 95% CI when appropriate. Differences between groups were tested using Welsh T-test. A difference was considered significant when P \u0026lt; 0.05.\u003c/p\u003e"},{"header":"Results","content":" \u003cp\u003eThe weight of the kidneys subjected to 4 hrs of ischaemia was significantly higher than the weight of the kidneys subjected to 2 hrs of ischaemia (p\u0026thinsp;\u0026lt;\u0026thinsp;0.005) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e). In both groups the renal weight was significantly higher than the weight of the contralateral non-ischaemic kidney (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001).\u003c/p\u003e \u003cp\u003e \u003cdiv class=\"gridtable\"\u003e\u003ctable float=\"Yes\" id=\"Tab1\" border=\"1\"\u003e \u003ccaption language=\"En\"\u003e \u003cdiv class=\"CaptionNumber\"\u003e\u003cstrong\u003eTable 1.\u003c/strong\u003e The table gives the weight of the two kidneys and the absolute and relative uptake of microspheres in the kidney after two and four hours of unilateral renal ischaemia followed by reperfusion for four hours.\u003c/div\u003e \u003cdiv class=\"CaptionContent\"\u003e\u003c/div\u003e \u003c/caption\u003e \u003ccolgroup cols=\"5\"\u003e \u003cthead\u003e \u003ctr\u003e \u003cth align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c3\" namest=\"c2\"\u003e \u003cp\u003eIschaemia 2 hrs \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;18)\u003c/p\u003e \u003c/th\u003e \u003cth align=\"left\" colspan=\"2\" nameend=\"c5\" namest=\"c4\"\u003e \u003cp\u003eIschaemia 4 hrs \u003c/p\u003e \u003cp\u003e(n\u0026thinsp;=\u0026thinsp;16)\u003c/p\u003e \u003c/th\u003e \u003c/tr\u003e \u003c/thead\u003e \u003ctbody\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e\u0026nbsp;\u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003eIschaemic\u003c/p\u003e \u003cp\u003ekidney\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003eContralateralkidney\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003eIschaemic\u003c/p\u003e \u003cp\u003ekidney\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003eContralateral\u003c/p\u003e \u003cp\u003ekidney\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eKidney weight\u003c/p\u003e \u003cp\u003e\u003cem\u003e(gram)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e109\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e90\u0026thinsp;\u0026plusmn;\u0026thinsp;13\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e136\u0026thinsp;\u0026plusmn;\u0026thinsp;28\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e101\u0026thinsp;\u0026plusmn;\u0026thinsp;17\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eAbsolute uptake of microspheres \u003cem\u003e(cps MBq\u003c/em\u003e\u003csup\u003e\u003cem\u003e\u0026minus;\u0026thinsp;1\u003c/em\u003e\u003c/sup\u003e\u003cem\u003e)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e3.8\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e4.1\u0026thinsp;\u0026plusmn;\u0026thinsp;1.8\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e1.6\u0026thinsp;\u0026plusmn;\u0026thinsp;1.5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e4.0\u0026thinsp;\u0026plusmn;\u0026thinsp;1.3\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRelative uptake of microspheres\u003c/p\u003e \u003cp\u003e\u003cem\u003e(percent of total uptake)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e48\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e52\u0026thinsp;\u0026plusmn;\u0026thinsp;14\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e29\u0026thinsp;\u0026plusmn;\u0026thinsp;19\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e71\u0026thinsp;\u0026plusmn;\u0026thinsp;19\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003ctr\u003e \u003ctd align=\"left\" colname=\"c1\"\u003e \u003cp\u003eRenal uptake in central 75% including renal medulla\u003c/p\u003e \u003cp\u003e\u003cem\u003e(percent of whole kidney uptake)\u003c/em\u003e\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c2\"\u003e \u003cp\u003e63\u0026thinsp;\u0026plusmn;\u0026thinsp;1\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c3\"\u003e \u003cp\u003e62\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c4\"\u003e \u003cp\u003e69\u0026thinsp;\u0026plusmn;\u0026thinsp;5\u003c/p\u003e \u003c/td\u003e \u003ctd align=\"left\" colname=\"c5\"\u003e \u003cp\u003e63\u0026thinsp;\u0026plusmn;\u0026thinsp;2\u003c/p\u003e \u003c/td\u003e \u003c/tr\u003e \u003c/tbody\u003e \u003c/colgroup\u003e \u003ctfoot\u003e \u003ctr\u003e\u003ctd colspan=\"5\"\u003eAll numbers as means\u0026thinsp;\u0026plusmn;\u0026thinsp;SD\u003c/td\u003e\u003c/tr\u003e \u003c/tfoot\u003e \u003c/table\u003e\u003c/div\u003e \u003c/p\u003e \u003cp\u003eThe total renal uptake of MS as an indicator of blood flow was significantly lower after 4 hrs ischaemia than after 2 hrs ischaemia (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). After 4 hrs ischaemia the MS uptake was also significantly lower than the uptake of the contralateral kidney (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). The renal MS uptake after 2 hrs ischaemia did not differ significantly from the uptake of the contralateral kidney (p\u0026thinsp;=\u0026thinsp;0.5) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eUptake of MS in the 75% central renal area including the medulla measured in per cent of uptake in the total kidney was significantly higher in kidneys subjected to 4 hrs compared to 2 hrs ischaemia (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001). In kidneys subjected to renal ischaemia for 4 hrs it was also significantly higher than in the contralateral kidney (p\u0026thinsp;\u0026lt;\u0026thinsp;0.001) (Table\u0026nbsp;\u003cspan refid=\"Tab1\" class=\"InternalRef\"\u003e1\u003c/span\u003e).\u003c/p\u003e \u003cp\u003eRedistribution of MS from cortex to medulla as assessed by blinded visual evaluation of the scintigrams showed redistribution in 6 out of 16 pigs (38%) subjected to ischaemia for 4 hrs, and in one out of 18 pigs (5%) with ischaemia for 2 hrs. Figure\u0026nbsp;\u003cspan refid=\"Fig1\" class=\"InternalRef\"\u003e1\u003c/span\u003e shows an example of renal MS redistribution after 4 hrs ischaemia. The scintigram from the ischaemic side shows high activity in the medulla and faint activity in the renal cortex. Figure\u0026nbsp;\u003cspan refid=\"Fig2\" class=\"InternalRef\"\u003e2\u003c/span\u003e shows that the higher the perfusion redistribution grade of the kidney, the higher uptake of MS in the central renal area including the medulla relative to uptake in total kidney.\u003c/p\u003e \u003cp\u003eAnalysis of blood and urine samples demonstrated that no detectable radioactivity was present in these samples.\u003c/p\u003e \u003cp\u003eOne pig died directly after tracer injection at the end of the reperfusion phase (t\u0026thinsp;=\u0026thinsp;420) from unknown causes, and for this reason was excluded from the study\u003c/p\u003e "},{"header":"Discussion","content":" \u003cp\u003eThe present study suggests that radioactive labeled microspheres (MS) can identify corticomedullary shunts after ischaemia and reperfusion of the human like polypapillary porcine kidney.\u003c/p\u003e \u003cp\u003eWe studied renal blood flow by use of uptake of MS after unilateral renal ischaemia for 2 and 4 hrs followed by 4 hrs of observation after reperfusion. After intra-arterial injection of MS the absolute renal uptake of MS was significantly reduced in the kidneys subjected to 4 hrs total ischaemia. The uptake of MS after 2 hrs of renal ischaemia did not differ significantly from the uptake in the contralateral non-ischaemic kidney. After 4 hrs ischaemia, there was a relatively high uptake of MS in the central area of the kidney including the renal medulla both on the scintigrams and calculated from the absolute values. These observations may be explained by the special anatomy of blood supply to the kidneys. Blood supply to the nephron is maintained by two vascular systems organised in a serial manner: the capillaries in the glomeruli and the tubular capillaries in the renal medulla [\u003cspan citationid=\"CR1\" class=\"CitationRef\"\u003e1\u003c/span\u003e]. Thus, intra-arterial injected MS reach the renal cortex with the arterial blood, and in the glomeruli they are trapped due to their diameter of 15\u0026nbsp;\u0026micro;m and thereby separated from the blood stream. Thus, measuring total renal blood flow may be done from the number of MS in the whole kidney, whereas regional distribution of MS is unreliable in calculation of the relative distribution of renal perfusion. However, this normal trapping of MS in the glomeruli explained by renal anatomy makes it possible to quantify functional active shunts from the number of MS present in the renal medulla. In contrast to the early anatomical studie by Trueta and others [\u003cspan citationid=\"CR2\" class=\"CitationRef\"\u003e2\u003c/span\u003e] we made a physiological study with MS as a tracer. We measured uptake of radiolabelled MS on planar images by use of a 2-dimensional technique. We did not have access to SPECT/CT images in these pig studies. Therefore, due to anatomical overlap of medulla and cortex the uptake in renal medulla will be overestimated, but the uptake in the central 75% includes the total medulla. Our results are consistent with the opening of corticomedullary shunts in the ischaemic kidney. However, we cannot exclude that vasodilation in cortical juxtamedullary afferent arterioles after long-term ischaemia could explain our findings, although we believe that our 15\u0026nbsp;\u0026micro;m MS would not be able to pass the capillaries in glomeruli. Our visualisation technique seems to indicate presence of MS in medulla and not in the juxtamedullary cortex.\u003c/p\u003e "},{"header":"Conclusion","content":" \u003cp\u003eIn conclusion, the study showed the presence of radiolabeled MS in the renal medulla in response to severe renal ischaemia suggesting that this leads after reperfusion to opening of functional shunts bypassing the glomeruli. Radiolabeled MS have been used for decades for the measurement of organ blood flow and perfusion and the present results point to functional intrarenal shunts, which have been suggested for decades, but not verified so far.\u003c/p\u003e "},{"header":"Abbreviations","content":"\u003cp\u003e\u003cstrong\u003eMS\u003c/strong\u003e:\u003csup\u003e 153\u003c/sup\u003eGadolinium-labeled microspheres\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eHrs\u003c/strong\u003e: hours\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eKg\u003c/strong\u003e: kilogram\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eMBq\u003c/strong\u003e: Megabecquerel\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003e\u0026micro;m: \u003c/strong\u003eMikrometer\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCI\u003c/strong\u003e: Confidence interval\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eSPECT\u003c/strong\u003e: Single-photon emission computed tomography\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCT\u003c/strong\u003e: Computed tomography\u003c/p\u003e"},{"header":"Declarations","content":"\u003cp\u003e\u003cstrong\u003eEthics approval and consent to participate\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eAnimal experiments conform to internationally accepted standards and have been approved by the appropiate institutional review board. The study was approved by the Danish Inspectorate of Animal Experiments (2010/561-1837)\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eConsent for publication\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eNot applicable.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAvailability of data and materials\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe datasets generated and analysed during the current study are included in this published article, and are available from the corresponding author on reasonable request.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eCompeting interests\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe authors declare that they have no competing interests.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eFunding\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eThe project was carried out with financial support from the Faculty of Health Sciences, Aarhus University, the Institute of Clinical Medicine, Aarhus University, Helen \u0026amp; Ejnar Bj\u0026oslash;rnows Foundation, Sophus Jacobsen \u0026amp; Hustru Astrid Jacobsens Foundation, the A.P. Moeller Foundation, the Danish Kidney Foundation, and C.C. Klestrup \u0026amp; Hustru Henriette Klestrups Foundation.\u003c/p\u003e\n\u003cp\u003eThe Funding did not have anything to do with the study design, data collection, analysis, interpretation or writing.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAuthors\u0026rsquo; Contributions\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eMR has made contributions to study conception, design, interpretation, drafting and critical revising the manuscript. SSP has made contributions to study conception, design, acquisition, analysis, interpretation, drafting and revising the manuscript. AKK has made contributions to conception, design, acquisition and interpretation. LEN has made contributions to design, acquisition, analysis and revising the manuscript. CF has made contributions to interpretation, specifically data analyses, drafting and critical revising the manuscript. BJ has made contributions to study conception, design, interpretation, drafting and critical revising the manuscript. JF has made contributions to study interpretation, drafting and revising the manuscript.\u003c/p\u003e\n\u003cp\u003eAll Authors have edited, read and approved the final manuscript.\u003c/p\u003e\n\u003cp\u003e\u003cstrong\u003eAcknowledgements\u003c/strong\u003e\u003c/p\u003e\n\u003cp\u003eWe thank Alain Prigent, Paris and Birger Hesse, Copenhagen, for their advice and helpful suggestions and Ken Peter Kragsfeldt for help with the figures.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n\u003cli\u003eMunger K, Kost Jr C, Brenner B, Maddox D. The renal circulations and glomerular ultrafiltration. In: Taal M, Chertow G, Marsden P, Skorecki K, Yu Y, Brenner B, editors. Brenner and Rectors, The Kidney. Philadelphia: Elsevier Saunders; 2012. p. 94-137.\u003c/li\u003e\n\u003cli\u003eTrueta J, Barclay A, Daniel P. Studies of the renal circulation. Oxford: Blackwell Scientific Publications Ltd, 1947.\u003c/li\u003e\n\u003cli\u003eDaniel P, Peabody C, Prichard M. Cortical ischaemia of the kidney with maintained blood flow through the medulla. Q J Exp Physiol Cogn Med Sci. 1952;37:11-8.\u003c/li\u003e\n\u003cli\u003eDaniel P, Peabody C, Prichard M. Observations on the circulation through the cortex and the medulla of the kidney. Q J Exp Physiol Cogn Med Sc. 1951;36:199-203.\u003c/li\u003e\n\u003cli\u003eLilienfields L, Maganzini H, Bauer M. Blood flow in the renal medulla. Circ Res. 1961;9:614-7.\u003c/li\u003e\n\u003cli\u003eSpinelli FR, Wirz H, Brucher C, Pehling G. Non-existence of shunts between afferent and efferent arterioles of juxtamedullary glomeruli in dog and rat kidneys. Nephron. 1972;9:123-8.\u003c/li\u003e\n\u003cli\u003eStone AM, Stein T, LaFortune J, Wise L. Changes in intrarenal blood flow during sepsis. Surg Gynecol Obstet. 1979; 148:731-4.\u003c/li\u003e\n\u003cli\u003eGreenfield SP, Lewis W III, Perry B, Wan J, Morin F III. Regional renal blood flow measurements using radioactive microspheres in a chronic porcine model with unilateral vesicoureteral reflux. J Urol. 1995;154:816-9.\u003c/li\u003e\n\u003cli\u003eLangenberg C, Bellomo R, May C, Wan L, Egi M, Morgera S. Renal blood flow in sepsis. Crit Care. 2005;9:R363-74.\u003c/li\u003e\n\u003cli\u003ePeters A, Myers M. Measurement of blood flow. In: Peters A, Myers M, editors. Physiological measurements with Radionuclides in Clinical Practice. Oxford: Oxford University Press; 2003. p. 63-67.\u003c/li\u003e\n\u003cli\u003ePedersen SS, Keller AK, Nielsen MK, Jespersen B, Falborg L, Rasmussen JT, et al. Cell injury after ischemia and reperfusion in the porcine kidney evaluated by radiolabelled microspheres, sestamibi, and lactadherin. EJNMMI Res. 2013;3:62.\u003c/li\u003e\n\u003cli\u003eVirtanen P, Gommers R, Oliphant TE, et al. SciPy 1.0: Fundamental algorithms for scientific computing in Python. Nat Methods 2020;17:261\u0026ndash;272. Available from:\u0026nbsp;\u003ca href=\"http://www.scipy.org/\"\u003ehttp://www.scipy.org/\u003c/a\u003e. Accessed August 2020.\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":false,"hideJournal":false,"highlight":"","institution":"","isAcceptedByJournal":true,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true},"keywords":"Microspheres, Renal blood flow, Renal ischaemia, Renal perfusion, Renal redistribution, Renal shunts.","lastPublishedDoi":"10.21203/rs.3.rs-70107/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-70107/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003e\u003cstrong\u003eBackground:\u003c/strong\u003e An animal model offers the opportunity to study organs in vivo and the porcine model was chosen to simulate a renal transplantation with complications. Renal perfusion may redistribute from cortex to medulla during systemic hypovolaemia and after renal ischaemia for other reasons, but there is no consensus on this matter. We studied renal perfusion after renal ischaemia and reperfusion.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eMethods:\u003c/strong\u003e Renal perfusion distribution was examined by use of \u003csup\u003e153\u003c/sup\u003eGadolinium-labeled microspheres (MS) after 2 hours (hrs) and 4 hrs ischaemia of the pig kidney followed by 4 hrs of reperfusion. Intra-arterial injected MS are trapped in the glomeruli in renal cortex, which means that MS are not present in the medulla under normal physiological conditions.\u003c/p\u003e\u003cp\u003e\u003cstrong\u003eResults:\u003c/strong\u003e Visual evaluation after reperfusion demonstrated that MS redistributed from the renal cortex to the medulla in 6 out of 16 pigs (38%) subjected to 4 hrs ischaemia and in one out of 18 pigs subjected to 2 hrs ischaemia. Central renal uptake of MS covering the medullary/total renal uptake was significantly higher in kidneys subjected to 4 hrs ischaemia compared with pigs subjected to 2 hrs ischaemia (69±5% vs. 63±1%, p\u0026lt;0.001), and also significantly higher than in the contralateral kidney (69±5% vs. 63±2, p\u0026lt;0.001). Analysis of blood and urine demonstrated no presence of radioactivity. \u003c/p\u003e\u003cp\u003e\u003cstrong\u003eConclusion:\u003c/strong\u003e The study demonstrated the presence of MS in the renal medulla in response to renal ischaemia and reperfusion suggesting that severe ischaemia and reperfusion of the pig kidney leads to opening of functional shunts bypassing glomeruli.\u003c/p\u003e","manuscriptTitle":"Corticomedullary Shunting After Ischaemia and Reperfusion in The Porcine Kidney?","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2020-10-05 15:26:17","doi":"10.21203/rs.3.rs-70107/v1","editorialEvents":[{"type":"communityComments","content":0},{"type":"submitted","content":"","date":"2020-09-14T12:00:00+00:00","index":"","fulltext":""},{"type":"editorAssigned","content":"","date":"2020-09-14T12:00:00+00:00","index":"","fulltext":""},{"type":"checksComplete","content":"","date":"2020-09-13T12:00:00+00:00","index":"","fulltext":""},{"type":"editorInvited","content":"","date":"2020-09-13T12:00:00+00:00","index":"","fulltext":""}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"bmc-nephrology","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":false,"externalIdentity":"bnep","sideBox":"Learn more about [BMC Nephrology](http://bmcnephrol.biomedcentral.com/)","snPcode":"","submissionUrl":"https://www.editorialmanager.com/bnep/default.aspx","title":"BMC Nephrology","twitterHandle":"BMC_series","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"em","reportingPortfolio":"BMC Series","inReviewEnabled":true,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"7e0ef32e-d062-4131-861f-4e8e8768f9b8","owner":[],"postedDate":"October 5th, 2020","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"published-in-journal","subjectAreas":[{"id":687305,"name":"Urology \u0026 Nephrology"}],"tags":[],"updatedAt":"2022-04-15T12:54:03+00:00","versionOfRecord":{"articleIdentity":"rs-70107","link":"https://doi.org/10.1186/s12882-022-02780-0","journal":{"identity":"bmc-nephrology","isVorOnly":false,"title":"BMC Nephrology"},"publishedOn":"2022-04-15 12:54:03","publishedOnDateReadable":"April 15th, 2022"},"versionCreatedAt":"2020-10-05 15:26:17","video":"","vorDoi":"10.1186/s12882-022-02780-0","vorDoiUrl":"https://doi.org/10.1186/s12882-022-02780-0","workflowStages":[]},"version":"v1","identity":"rs-70107","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-70107","identity":"rs-70107","version":["v1"]},"buildId":"WrCJVZZCHTDjtuVLN7oU0","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}