Cell injury after ischemia and reperfusion in the porcine kidney evaluated by radiolabelled microspheres, sestamibi, and lactadherin

Springer Science and Business Media LLC - Tập 3 Số 1 - 2013
Stine Søgaard Pedersen1,2, Anna Krarup Keller3,2, Marie Kaldahl Nielsen2, Bente Jespersen4,2, Lise Falborg1, Jan T. Rasmussen5, Christian W. Heegaard5, Michael Rehling1,2
1Department of Clinical Physiology and Nuclear Medicine, Aarhus University Hospital, Skejby, Denmark
2Institute of Clinical Medicine, Aarhus University, Aarhus, Denmark
3Department of Urology, Aarhus University Hospital, Skejby, Denmark
4Department of Nephrology, Aarhus University Hospital, Skejby, Denmark
5Protein Chemistry Laboratory, Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark

Tóm tắt

Abstract Background The purpose of the present study was to quantify renal cell injury after ischemia and reperfusion in a pig model using 99mTc-lactadherin as a marker of apoptosis and 99mTc-sestamibi as a marker of mitochondrial dysfunction. Methods Thirty-four pigs were randomized into unilateral renal warm ischemia of 120 (WI120) or 240 min (WI240). The glomerular filtration rate (GFR) was calculated by renal clearance of 51Cr-ethylenediaminetetraacetic acid, and apoptosis was quantified by immunohistochemical detection of caspase-3. After 240 min of reperfusion, intravenous 99mTc-lactadherin or 99mTc-sestamibi was injected simultaneously with 153Gd microspheres into the aorta. Ex-vivo static planar images of the kidneys were acquired for determination of the differential renal function of tracer distribution using a gamma camera. Results In WI120, there was no significant difference in the uptake of microspheres in the ischemic and contralateral normal kidney indicating adequate perfusion (uptake in ischemic kidney relative to the sum of uptake in both kidneys; 46% ± 12% and 51% ± 5%). In WI240, the uptake of microspheres was severely reduced in both groups (17% ± 11% and 27% ± 17%). GFR was severely reduced in the post ischemic kidney in both groups. In both groups, the uptake of lactadherin was reduced (41% ± 8%, 17% ± 13%) but not different from the uptake of 153Gd microspheres. Caspase-3-positive cell profiles were increased in the post-ischemic kidneys (p < 0.001) and increased as the length of ischemia increased (p = 0.003). In both WI120 and WI240, the amount of 99mTc-sestamibi in the ischemic kidney was significantly lower than the amount of 153Gd microspheres (40 ± 5 versus 51 ± 5 and 20 ± 11 versus 27 ± 17; p < 0.05). Conclusions In an established pig model with unilateral renal warm ischemia, we found significantly reduced 99mTc-sestamibi uptake relative to perfusion in the kidneys exposed to ischemia indicating a potential ability to detect renal ischemic and reperfusion injuries. However, apoptosis was not detected using 99mTc-lactadherin in the post-ischemic kidneys despite increased number of caspase-3-positive cell profiles. Trial registration This study is approved by the Danish Inspectorate of Animal Experiments (2010/561-1837).

Từ khóa


Tài liệu tham khảo

Halloran PF, Hunsicker LG: Delayed graft function: state of the art. Am J Transplant 2001, 1: 115–120.

Johnston O, O’kelly P, Spencer S, Donohoe J, Walshe JJ, Little DM, Hickey D, Conlon PJ: Reduced graft function (with or without dialysis) vs immediate graft function–a comparison of long-term renal allograft survival. Nephrol Dial Transplant 2006, 21: 2270–2274. 10.1093/ndt/gfl103

Perico N, Cattaneo D, Sayegh MH, Remuzzi G: Delayed graft function in kidney transplantation. Lancet 2004, 364: 1814–1827. 10.1016/S0140-6736(04)17406-0

Sharma AK, Tolani SL, Rathi GL, Sharma P, Gupta H, Gupta R: Evaluation of factors causing delayed graft function in live related donor renal transplantation. Saudi J Kidney Dis Transpl 2010, 21: 242–245.

Shah N, Langone A: Renal donation after cardiac death. J Am Soc Nephrol 2010, 21: 888–890. 10.1681/ASN.2010040415

Shoskes DA, Halloran PF: Delayed graft function in renal transplantation: etiology, management and long-term significance. J Urol 1996, 155: 1831–1840. 10.1016/S0022-5347(01)66023-3

Kaushal GP, Singh AB, Shah SV: Identification of gene family of caspases in rat kidney and altered expression in ischemia-reperfusion injury. Am J Physiol 1998, 274: F587-F595.

Shi Y, Melnikov VY, Schrier RW, Edelstein CL: Downregulation of the calpain inhibitor protein calpastatin by caspases during renal ischemia-reperfusion. Am J Physiol Renal Physiol 2000, 279: F509-F517.

Clarkson MR, Friedewald JJ, Joseph AE, Rabb H: Acute kidney injury. In Brenner & Rector’s The Kidney, 8th edition. Edited by: Brenner BM. Philadelphia: Saunders Elsevier; 2008:943–986.

Brown ED, Chen MY, Wolfman NT, Ott DJ, Watson NE Jr: Complications of renal transplantation: evaluation with US and radionuclide imaging. Radiographics 2000, 20: 607–622.

Cohen B, Smits JM, Haase B, Persijn G, Vanrenterghem Y, Frei U: Expanding the donor pool to increase renal transplantation. Nephrol Dial Transplant 2005, 20: 34–41. 10.1093/ndt/gfh506

Dasgupta SK, Abdel-Monem H, Guchhait P, Nagata S, Thiagarajan P: Role of lactadherin in the clearance of phosphatidylserine-expressing red blood cells. Transfusion 2008, 48: 2370–2376. 10.1111/j.1537-2995.2008.01841.x

Dasgupta SK, Guchhait P, Thiagarajan P: Lactadherin binding and phosphatidylserine expression on cell surface-comparison with annexin A5. Transl Res 2006, 148: 19–25. 10.1016/j.lab.2006.03.006

Huppertz B, Frank HG, Kaufmann P: The apoptosis cascade–morphological and immunohistochemical methods for its visualization. Anat Embryol (Berl) 1999, 200: 1–18. 10.1007/s004290050254

Waerens LN, Rasmussen JT, Heegaard CW: Preparation and in vitro evaluation of 99mTc-labelled bovine lactadherin as a novel radioligand for apoptosis detection. J Label Compd Radiopharm 2007, 50: 211–217. 10.1002/jlcr.1207

Piwnica-Worms D, Kronauge JF, Chiu ML: Uptake and retention of hexakis (2-methoxyisobutyl isonitrile) technetium(I) in cultured chick myocardial cells: mitochondrial and plasma membrane potential dependence. Circulation 1990, 82: 1826–1838. 10.1161/01.CIR.82.5.1826

Sand NP, Bottcher M, Madsen MM, Nielsen TT, Rehling M: Evaluation of regional myocardial perfusion in patients with severe left ventricular dysfunction: comparison of 13N-ammonia PET and 99mTc sestamibi SPECT. J Nucl Cardiol 1998, 5: 4–13. 10.1016/S1071-3581(98)80004-4

Crane P, Laliberte R, Heminway S, Thoolen M, Orlandi C: Effect of mitochondrial viability and metabolism on technetium-99m-sestamibi myocardial retention. Eur J Nucl Med 1993, 20: 20–25. 10.1007/BF02261241

Poulsen RH, Botker HE, Rehling M: Postreperfusion myocardial technetium-99m-sestamibi defect corresponds to area at risk. Experimental results from an ischemia-reperfusion porcine model. Nucl Med Biol 2011, 38: 819–825.

Grossini E, Molinari C, Pollesello P, Bellomo G, Valente G, Mary D, Vacca G, Caimmi P: Levosimendan protection against kidney ischemia/reperfusion injuries in anesthetized pigs. J Pharmacol Exp Ther 2012, 342: 376–388. 10.1124/jpet.112.193961

Rosen S, Heyman SN: Difficulties in understanding human “acute tubular necrosis”: limited data and flawed animal models. Kidney Int 2001, 60: 1220–1224. 10.1046/j.1523-1755.2001.00930.x

Heyman SN, Rosenberger C, Rosen S: Acute kidney injury: lessons from experimental models. Contrib Nephrol 2011, 169: 286–296.

Lameire N: The pathophysiology of acute renal failure. Crit Care Clin 2005, 21: 197–210. 10.1016/j.ccc.2005.01.001

Weld KJ, Montiglio C, Bush AC, Dixon PS, Schwertner HA, Hensley DM, Cowart JR, Cespedes RD: Predicting irreparable renal ischemic injury using a real-time marker in the porcine model. J Urol 2008, 180: 2218–2225. 10.1016/j.juro.2008.07.017

Rosen S, Stillman IE: Acute tubular necrosis is a syndrome of physiologic and pathologic dissociation. J Am Soc Nephrol 2008, 19: 871–875. 10.1681/ASN.2007080913

Chiu ML, Kronauge JF, Piwnica-Worms D: Effect of mitochondrial and plasma membrane potentials on accumulation of hexakis (2-methoxyisobutylisonitrile) technetium(I) in cultured mouse fibroblasts. J Nucl Med 1990, 31: 1646–1653.

Wackers FJ, Berman DS, Maddahi J, Watson DD, Beller GA, Strauss HW, Boucher CA, Picard M, Holman BL, Fridrich R: Technetium-99m hexakis 2-methoxyisobutyl isonitrile: human biodistribution, dosimetry, safety, and preliminary comparison to thallium-201 for myocardial perfusion imaging. J Nucl Med 1989, 30: 301–311.

Waring P, Lambert D, Sjaarda A, Hurne A, Beaver J: Increased cell surface exposure of phosphatidylserine on propidium iodide negative thymocytes undergoing death by necrosis. Cell Death Differ 1999, 6: 624–637. 10.1038/sj.cdd.4400540

Krysko O, De Ridder L, Cornelissen M: Phosphatidylserine exposure during early primary necrosis (oncosis) in JB6 cells as evidenced by immunogold labeling technique. Apoptosis 2004, 9: 495–500.

Fadok VA, Bratton DL, Frasch SC, Warner ML, Henson PM: The role of phosphatidylserine in recognition of apoptotic cells by phagocytes. Cell Death Differ 1998, 5: 551–562. 10.1038/sj.cdd.4400404

Koopman G, Reutelingsperger CP, Kuijten GA, Keehnen RM, Pals ST, van Oers MH: Annexin V for flow cytometric detection of phosphatidylserine expression on B cells undergoing apoptosis. Blood 1994, 84: 1415–1420.

Toda S, Hanayama R, Nagata S: Two-step engulfment of apoptotic cells. Mol Cell Biol 2012, 32: 118–125. 10.1128/MCB.05993-11

Hannon JP, Bossone CA, Wade CE: Normal physiological values for conscious pigs used in biomedical research. Lab Anim Sci 1990, 40: 293–298.

Swindle MM, Smith AC, Hepburn BJ: Swine as models in experimental surgery. J Invest Surg 1988, 1: 65–79. 10.3109/08941938809141077

Weld KJ, Montiglio C, Bush AC, Harroff HH, Cespedes RD: Real-time analysis of renal interstitial metabolites during induced renal ischemia. J Endourol 2008, 22: 571–574. 10.1089/end.2007.0256

Poulsen RH, Rasmussen JT, Ejlersen JA, Flo C, Falborg L, Heegaard CW, Rehling M: Pharmacokinetics of the phosphatidylserine tracers 99mTc-lactadherin and 99mTc-annexin V in pigs. EJNMMI Res 2013,3(1):15. 10.1186/2191-219X-3-15

Savi A, Gerundini P, Zoli P, Maffioli L, Compierchio A, Colombo F, Matarrese M, Deutsch E: Biodistribution of Tc-99m methoxy-isobutyl-isonitrile (MIBI) in humans. Eur J Nucl Med 1989, 15: 597–600.

Sand NP, Juelsgaard P, Rasmussen K, Flo C, Thuesen L, Bagger JP, Nielsen TT, Rehling M: Arterial concentration of 99mTc-sestamibi at rest, during peak exercise and after dipyridamole infusion. Clin Physiol Funct Imaging 2004, 24: 394–397. 10.1111/j.1475-097X.2004.00570.x

Falborg L, Waehrens LN, Alsner J, Bluhme H, Frokiaer J, Heegaard CW, Horsman MR, Rasmussen JT, Rehling M: Biodistribution of 99mTc-HYNIC-lactadherin in mice–a potential tracer for visualizing apoptosis in vivo. Scand J Clin Lab Invest 2010, 70: 209–216. 10.3109/00365511003663648

Shi J, Heegaard CW, Rasmussen JT, Gilbert GE: Lactadherin binds selectively to membranes containing phosphatidyl-L-serine and increased curvature. Biochim Biophys Acta 2004, 1667: 82–90. 10.1016/j.bbamem.2004.09.006

Hurwitz GA, Ghali SK, Mattar AG, Gravelle DR, Husni M: Dynamic renal imaging with technetium-99m-sestamibi in hypertension: potential for assessment of renovascular disorders. J Nucl Med 1994, 35: 1959–1964.

Thông tin
Thông tin xuất bản

Springer Science and Business Media LLC

Tập 3 Số 1

Thông tin tác giả