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Carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine kidney ischemia/reperfusion injury

Šárka Matějková| Angelika Scheuerle| Florian Wagner| Oscar McCook| José Matallo| Michael Gröger| Andrea Seifritz| Bettina Stahl| Brigitta Vcelar| Enrico Calzia| Michael Georgieff| Peter Möller| Hubert Schelzig| Peter Radermacher| Florian Simon
Experimental
Volume 39, Issue 3 / March , 2013

Pages 497 - 510

Abstract

Purpose

To test the hypothesis that a carbamylated EPO-FC fusion protein (cEPO-FC) or recombinant human erythropoietin (rhEPO) would protect against kidney ischemia/reperfusion (I/R) injury in pigs with atherosclerosis.

Methods

Anesthetized and mechanically ventilated animals received cEPO-FC (50 μg kg−1), rhEPO (5,000 IU kg−1), or vehicle (n = 9 per group) prior to 120 min of aortic occlusion and over 4 h of reperfusion. During aortic occlusion, mean arterial pressure (MAP) was maintained at 80–120 % of baseline values by esmolol, nitroglycerin, and ATP. During reperfusion, noradrenaline was titrated to keep MAP at pre-ischemic levels. Blood creatinine and neutrophil gelatinase-associated lipocalin (NGAL) levels, creatinine clearance, fractional Na+ excretion, and HE and PAS staining were used to assess kidney function and histological damage. Plasma interleukin-6, tumor necrosis factor-α, nitrate + nitrite and 8-isoprostane levels were measured to assess systemic inflammation, and nitrosative and oxidative stress.

Results

I/R caused acute kidney injury with reduced creatinine clearance, increased fractional Na+ excretion and NGAL levels, moderate to severe glomerular and tubular damage and apoptosis, systemic inflammation and oxidative and nitrosative stress, but there were no differences between the treatment groups. Pre-ischemia nitrate + nitrite and 8-isoprostanes levels were lower and higher, respectively, than in healthy animals of a previous study, and immune histochemistry showed higher endothelial nitric oxide synthase and lower EPO receptor expression in pre-ischemia kidney biopsies than in biopsies from healthy animals.

Conclusions

In swine with atherosclerosis, rhEPO and cEPO-FC failed to attenuate prolonged ischemia-induced kidney injury within an 8-h reperfusion period, possibly due to reduced EPO receptor expression resulting from pre-existing oxidative stress and/or reduced NO release.

Keywords

References

  1. Gelman S (1995) The pathophysiology of aortic cross-clamping and unclamping. Anesthesiology 82:1026–1057
    • View reference on PubMed
    • View reference on publisher's website
  2. Sharples EJ, Patel N, Brown P, Stewart K, Mota-Philipe H, Sheaff M, Kieswich J, Allen D, Harwood S, Raftery M, Thiemermann C, Yaqoob MM (2004) Erythropoietin protects the kidney against injury and dysfunction caused by ischemia-reperfusion. J Am Soc Nephrol 15:2115–2124
    • View reference on PubMed
    • View reference on publisher's website
  3. Patel NSA, Sharples EJ, Cuzzocrea S, Chatterjee PK, Britti D, Yaqoob MM, Thiemermann C (2004) Pretreatment with EPO reduces the injury and dysfunction caused by ischemia/reperfusion in the mouse kidney in vivo. Kidney Int 66:983–989
    • View reference on PubMed
    • View reference on publisher's website
  4. Vesey DA, Cheung C, Pat B, Endre Z, Gobé G, Johnson DW (2004) Erythropoietin protects against ischaemic acute renal injury. Nephrol Dial Transplant 19:348–355
    • View reference on PubMed
    • View reference on publisher's website
  5. Ates E, Yalcin AU, Yilmaz S, Koken T, Tokyol C (2005) Protective effect of erythropoietin on renal ischemia and reperfusion injury. ANZ J Surg 75:1100–1105
    • View reference on PubMed
    • View reference on publisher's website
  6. Spandou E, Tsouchnikas I, Karkavelas G, Dounousi E, Simeonidou C, Guiba-Tziampiri O, Tsakiris D (2006) Erythropoietin attenuates renal injury in experimental acute renal failure ischaemic/reperfusion model. Nephrol Dial Transplant 21:330–336
    • View reference on PubMed
    • View reference on publisher's website
  7. Johnson DW, Pat B, Vesey DA, Guan Z, Endre Z, Gobé GC (2006) Delayed administration of darbepoetin or erythropoietin protects against ischemic acute renal injury and failure. Kidney Int 69:1806–1813
    • View reference on PubMed
    • View reference on publisher's website
  8. Nijboer WN, Ottens PJ, van Dijk A, van Goor H, Ploeg RJ, Leuvenink HGD (2010) Donor pretreatment with carbamylated erythropoietin in a brain death model reduces inflammation more effectively than erythropoietin while preserving renal function. Crit Care Med 38:1155–1161
    • View reference on PubMed
    • View reference on publisher's website
  9. Forman CJ, Johnson DW, Nicol DL (2007) Erythropoietin administration protects against functional impairment and cell death after ischaemic renal injury in pigs. BJU Int 99:162–165
    • View reference on PubMed
    • View reference on publisher's website
  10. Simon F, Scheuerle A, Calzia E, Bassi G, Öter S, Nguyen Duy C, Kick J, Brückner UB, Radermacher P, Schelzig H (2008) Erythropoietin during porcine aortic balloon occlusion-induced ischemia/reperfusion injury. Crit Care Med 36:2143–2150
    • View reference on PubMed
    • View reference on publisher's website
  11. Maio R, Sepodes B, Patel NS, Thiemermann C, Mota-Filipe H, Costa P (2011) Erythropoietin preserves the integrity and quality of organs for transplantation after cardiac death. Shock 35:126–133
    • View reference on PubMed
    • View reference on publisher's website
  12. Sølling C, Christensen AT, Krag S, Frøklær J, Wogensen L, Krog J, Tønnesen EK (2011) Erythropoietin administration is associated with short-term improvement in glomerular filtration rate after ischemia-reperfusion injury. Acta Anaesthesiol Scand 55:185–195
    • View reference on PubMed
    • View reference on publisher's website
  13. Ishii Y, Sawada T, Murakami T, Sakuraoka Y, Shiraki T, Shimizu A, Kubota K, Fuchinoue S, Teraoka S (2011) Renoprotective effect of erythropoietin against ischaemia-reperfusion injury in a non-human primate model. Nephrol Dial Transplant 26:1157–1162
    • View reference on PubMed
    • View reference on publisher's website
  14. Song YR, Lee T, You SJ, Chin HJ, Chae DW, Lim C, Park KH, Han S, Kim JH, Na KY (2009) Prevention of acute kidney injury by erythropoietin in patients undergoing coronary artery bypass grafting. Am J Nephrol 30:253–260
    • View reference on PubMed
    • View reference on publisher's website
  15. Endre ZH, Walker RJ, Pickering JW, Shaw GM, Frampton CM, Henderson SJ, Hutchinson R, Mehrtens JE, Robinson JM, Schollum JBW, Westhuyzen J, Celi LA, McGinley RJ, Campbell IJ, George PM (2010) Early intervention with erythropoietin does not affect the outcome of acute kidney injury (the EARLYARF trial). Kidney Int 77:1020–1030
    • View reference on PubMed
    • View reference on publisher's website
  16. Brines M, Grasso G, Fiordaliso F, Sfaceteria A, Ghezzi P, Fratelli M, Latini R, Xie QW, Smart J, Su-Rick CJ, Pobre E, Diaz D, Gomez D, Hand C, Coleman T, Cerami A (2004) Erythropoietin mediates tissue protection through an erythropoietin and common beta-subunit heteroceptor. Proc Natl Acad Sci U S A 101:14907–14912
    • View reference on PubMed
    • View reference on publisher's website
  17. Coleman TR, Westenfelder C, Tögel FE, Yang Y, Hu Z, Swenson LA, Leuvenink HGD, Ploeg RJ, d’Uscio LV, Katusic ZS, Ghezzi P, Zanetti A, Kaushansky K, Fox NE, Cerami A, Brines M (2006) Cytoprotective doses of erythropoietin or carbamylated erythropoietin have markedly different procoagulant and vasoactive activities. Proc Natl Acad Sci U S A 103:5965–5970
    • View reference on PubMed
    • View reference on publisher's website
  18. Brines M, Cerami A (2008) Erythropoietin-mediated tissue protection: reducing collateral damage from the primary injury response. J Int Med 264:405–432
    • View reference on publisher's website
  19. Leist M, Ghezzi P, Grasso G, Bianchi R, Viia P, Fratelli M, Savino C, Bianchi M, Nielsen J, Gerwien J, Kallunki P, Larsen AK, Helboe L, Christensen S, Pedersen LO, Nielsen M, Torup L, Sager T, Sfacteria A, Erbayraktar S, Erbayraktar Z, Gokmen N, Yilmaz O, Cerami-Hand C, Xie QW, Coleman T, Cerami A, Brines M (2004) Derivatives of erythropoietin that are tissue protective but not erythropoietic. Science 305:239–242
    • View reference on PubMed
    • View reference on publisher's website
  20. Schriebl K, Trummer E, Lattenmayer C, Weik R, Kunert R, Müller D, Katiger H, Vorauer-Uhl K (2006) Biochemical characterization of rhEPO-Fc fusion protein expressed in CHO cells. Protein Expr Purif 49:265–275
    • View reference on PubMed
    • View reference on publisher's website
  21. Simon F, Scheuerle A, Gröger M, Vcelar B, Möller P, Georgieff M, Calzia E, Radermacher P, Schelzig H (2011) Comparison of carbamylated erythropoietin-FC fusion protein and recombinant human erythropoietin during porcine aortic balloon occlusion-induced spinal cord ischemia/reperfusion injury. Intensive Care Med 35:1525–1533
  22. Svensson LG, Crawford ES, Hess KR, Coselli JS, Safi HJ (1993) Experience with 1509 patients undergoing thoracoabdominal aortic operations. J Vasc Surg 17:357–370
    • View reference on PubMed
    • View reference on publisher's website
  23. Black SA, Brooks MJ, Naidoo MN, Wolfe JH; Joint Vascular Research Group (2006) Assessing the impact of renal impairment on outcome after arterial intervention: a prospective review of 1,559 patients. Eur J Vasc Endovasc Surg 32:300–304
    • View reference on PubMed
    • View reference on publisher's website
  24. Safi HJ, Harlin SA, Miller CC, Iliopoulos DC, Joshi A, Mohasci TG, Zippel R, Letsou GV (1996) Predictive factors for acute renal failure in thoracic and thoracoabdominal aortic aneurysm surgery. J Vasc Surg 24:338–345
    • View reference on PubMed
    • View reference on publisher's website
  25. Thim T, Hagensen MK, Drouet L, Bal Dit Sollier C, Bonneau M, Granada JF, Nielsen LB, Paaske WP, Bøtker HE, Falk E (2010) Familial hypercholesterolaemic downsized pig with human-like coronary atherosclerosis: a model for preclinical studies. EuroIntervention 6:261–268
    • View reference on PubMed
    • View reference on publisher's website
  26. Hasler-Rapacz J, Ellegren H, Fridolfsson AK, Kirkpatrick B, Kirk S, Andersson L, Rapacz J (1998) Identification of a mutation in the low density lipoprotein receptor gene associated with recessive familial hypercholesterolemia in swine. Am J Med Genet 76:379–386
    • View reference on PubMed
    • View reference on publisher's website
  27. Simon F, Scheuerle A, Gröger M, Stahl B, Wachter U, Vogt J, Speit G, Hauser B, Möller P, Calzia E, Szabó C, Schelzig H, Georgieff M, Radermacher P, Wagner F (2011) Effects of intravenous sulfide during porcine aortic occlusion-induced kidney ischemia/reperfusion injury. Shock 35:156–163
    • View reference on PubMed
    • View reference on publisher's website
  28. Jochmanns I, Lerut E, van Pelt J, Monbaliu D, Pirenne J (2011) Circulating AST, H-FABP, and NGAL are early and accurate biomarkers of graft injury and dysfunction in a preclinical model of kidney transplantation. Ann Surg 254:784–792
    • View reference on publisher's website
  29. Cruz DN, Ricci Z, Ronco C (2009) Clinical review: RIFLE and AKIN – time for reappraisal. Crit Care 13:211
    • View reference on PubMed
    • View reference on publisher's website
  30. Fiordaliso F, Chimenti S, Staszewsky L, Bai A, Carlo E, Cuccovillo I, Doni M, Mengozzi M, Tonelli R, Ghezzi P, Coleman T, Brines M, Cerami A, Latini R (2005) A nonerythropoietic derivative of erythropoietin protects the myocardium from ischemia–reperfusion injury. Proc Natl Acad Sci USA 102:2046–2051
    • View reference on PubMed
    • View reference on publisher's website
  31. Xu X, Cao Z, Cao B, Li J, Guo L, Que L, Ha T, Chen Q, Li C, Li X (2009) carbamylated erythropoietin protects the myocardium from acute ischemia/reperfusion injury through a PI3K/Akt-dependent mechanism. Surgery 146:506–514
    • View reference on PubMed
    • View reference on publisher's website
  32. Xu K, George I, Klotz S, Hay I, Xydas S, Zhang G, Cerami A, Wang J (2010) Erythropoietin derivate improves left ventricular systolic performance and attenuates left ventricular remodeling in rats with myocardial infarct-induced heart failure. J Cardiovasc Pharmacol 56:506–512
    • View reference on PubMed
    • View reference on publisher's website
  33. Grams ME, Rabb H (2012) The distant organ effects of acute kidney injury. Kidney Int 81:942–948
    • View reference on PubMed
    • View reference on publisher's website
  34. Kristensen J, Soegaard H, Maeng M, Rehling M, Nielsen TT (2006) Acute haemodynamic effects of erythropoietin alone and in combination with dopamine in a porcine model. Clin Physiol Funct Imaging 26:283–287
    • View reference on PubMed
    • View reference on publisher's website
  35. Jie KE, Verhaar MC, Cramer MJM, van der Putten K, Gaillard CAJM, Doevendans PA, Koomans HA, Joles JA, Braam B (2006) Erythropoietin and the cardiorenal syndrome: cellular mechanisms on the cardiorenal connectors. Am J Physiol Renal Physiol 291:F932–F944
    • View reference on PubMed
    • View reference on publisher's website
  36. van der Putten K, Braam B, Jie KE, Gaillard CAJM (2008) Mechanisms of disease: erythropoietin resistance in patients with both heart and kidney failure. Nat Clin Pract Nephrol 4:47–57
    • View reference on PubMed
    • View reference on publisher's website
  37. Stenvinkel P, Bárány P (2002) Anaemia, rHuEPO resistance, and cardiovascular disease in end-stage renal failure; links to inflammation and oxidative stress. Nephrol Dial Transplant 17(Suppl 5):32–37
    • View reference on PubMed
    • View reference on publisher's website
  38. Kawata T, Hashimotot S, Koike T (1998) Effects of chronic nitric oxide synthase inhibition on renal function and histology in polycythemic rats. Kidney Blood Press Res 21:22–28
    • View reference on PubMed
    • View reference on publisher's website
  39. d’Uscio LV, Smith LA, Santhanam AV, Richardson D, Nath KA, Katusic ZS (2007) Essential role of endothelial nitric oxide synthase in vascular effects of erythropoietin. Hypertension 49:1142–1148
    • View reference on PubMed
    • View reference on publisher's website
  40. Rodríguez JA, Grau A, Eguinoa E, Nespereira B, Pérez-Ilzarbe M, Arias R, Belzunce MS, Páramo JA, Martínez-Caro D (2002) Dietary supplementation with vitamins C and E prevents downregulation of endothelial NOS expression in hypercholesteremia in vivo and in vitro. Atherosclerosis 165:33–40
    • View reference on PubMed
    • View reference on publisher's website
  41. Chade AR, Rodriguez-Porcél M, Grande JP, Krier JD, Lerman A, Carlos Romero J, Napoli C, Lerman LO (2002) Distinct renal injury in early atherosclerosis and renovascular disease. Circulation 106:1165–1171
    • View reference on PubMed
    • View reference on publisher's website
  42. Chade AR, Rodriguez-Porcél M, Herrmann J, Zhu X, Grande JP, Napoli C, Lerman A, Lerman LO (2004) Antioxidant intervention blunts renal injury in experimental renovascular disease. J Am Soc Nephrol 15:958–966
    • View reference on PubMed
    • View reference on publisher's website
  43. Kawashima S, Yokoyama M (2004) Dysfunction of endothelial nitric oxide synthase and atherosclerosis. Arterioscler Thromb Vasc Biol 24:998–1005
    • View reference on PubMed
    • View reference on publisher's website
  44. Simmons MN, Schreiber MJ, Gill IS (2008) Surgical renal ischemia: a contemporary overview. J Urol 180:19–30
    • View reference on PubMed
    • View reference on publisher's website
  45. Laven BA, Orvieto MA, Chuang MS, Ritch CR, Murray P, Harland RC, Inman SR, Brendler CB, Shalhav AL (2004) Renal tolerance to prolonged warm ischemia time in a laparoscopic versus open surgery porcine model. J Urol 172:2471–2474
    • View reference on PubMed
    • View reference on publisher's website
  46. Baldwin DD, Maynes LN, Berger KA, Desai PJ, Zuppan CW, Zimmerman GJ, Winkielman AM, Sterling TH, Tsai CK, Ruckle HC (2004) Laparoscopic warm renal ischemia in the solitary porcine kidney model. Urology 64:592–597
    • View reference on PubMed
    • View reference on publisher's website
  47. Orvieto MA, Tolhurst SR, Chuang MS, Lyon MB, Ritch CR, Rapp DE, Shalhav AL (2005) Defining the maximal renal tolerance to warm ischemia in porcine laparoscopic and open surgery model. Urology 66:1111–1115
    • View reference on PubMed
    • View reference on publisher's website
  48. Humphreys MR, Castle EP, Lohse CM, Sebo TJ, Leslie KO, Andrews PE (2009) Renal ischemia time in laparoscopic surgery: an experimental study in a porcine model. Int J Urol 16:105–109
    • View reference on PubMed
    • View reference on publisher's website
  49. Sabbagh R, Chawla A, Tisdale B, Kwan K, Chatterjee S, Kwiecien JM, Kapoor A (2011) Renal histopathology features according to various warm ischemia times in porcine laparoscopic and open surgery model. Can Urol Assoc J 5:40–43
    • View reference on PubMed
    • View reference on publisher's website
  50. Orvieto MA, Zorn KC, Mendiola F, Lyon MB, Mikhail AA, Gofrit ON, Shalhav AL (2007) Recovery of renal function after complete renal hilar versus artery alone clamping during open and laparoscopic surgery. J Urol 177:2371–2374
    • View reference on PubMed
    • View reference on publisher's website
  51. Novick AC (1983) Renal hypothermia: in vivo and ex vivo. Urol Clin N Am 10:637–644
  52. Moyer JH, Heider C, Morris GC, Handley C (1957) Hypothermia: III. The effect of hypothermia on renal damage resulting from ischemia. Ann Surg 146:152–166
    • View reference on PubMed
    • View reference on publisher's website
  53. Ward JP (1975) Determination of the optimum temperature for regional renal hypothermia during temporary renal ischaemia. Br J Urol 47:17–24
    • View reference on PubMed
    • View reference on publisher's website
  54. Brasile L, Green E, Haisch C (1997) Ex vivo resuscitation of kidney after postmortem warm ischemia. ASAIO J 43:M427–M430
    • View reference on PubMed
    • View reference on publisher's website
  55. de Albuquerque Dos Santos Abreu A, Kawano PR, Yamamoto H, Damião R, Fugita OEH (2011) Comparative study between trimetazidine and ice slush hypothermia in protection against renal ischemia/reperfusion injury in a porcine model. Int Braz J Urol 37:649–656
    • View reference on publisher's website
  56. Zager RA, Altschuld R (1986) Body temperature: an important determinant of the severity of ischemic renal injury. Am J Physiol Renal Fluid Electrolyte Physiol 251:F87–F93
  57. Zager RA, Gmur DJ, Bredl CR, Eng MJ (1989) Degree and time sequence of hypothermic protection against experimental ischemic acute renal failure. Cric Res 65:1263–1269
    • View reference on publisher's website
  58. Pelkey TJ, Frank RS, Stanley JJ, Frank TS, Zelenock GB, D’Alecy LG (1992) Minimal physiologic temperature variations during renal ischemia alter functional and morphologic outcome. J Vasc Surg 15:619–625
    • View reference on PubMed
    • View reference on publisher's website
  59. Delbridge MS, Shrestha BM, Raftery AT, El Nahas AM, Haylor JL (2007) The effect of body temperature in a rat model of renal ischemia-reperfusion injury. Transplant Proc 39:2983–2985
    • View reference on PubMed
    • View reference on publisher's website
  60. Gröger M, Scheuerle A, wagner F, Simon F, Matallo J, McCook O, Seifritz A, Stahl B, Wachter U, Vogt JA, Asfar P, Matejovic M, Möller P, Lampl L, Bracht H, Calzia E, Georgieff M, Radermacher P, Stahl W (2013) Effects of prophylactic hypothermia during resuscitated porcine hemorrhagic shock. Crit Care Med (in press)
  61. Miller Q, Peyton BD, Cohn EJ, Holmes GF, Harlin SA, Bird ET, Harre JG, Miller ML, Riley KD, Hogan MB, Taylor A (2003) The effects of intraoperative fenoldopam on renal blood flow and tubular function following suprarenal aortic cross-clamping. Ann Vasc Surg 17:656–662
    • View reference on PubMed
    • View reference on publisher's website

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